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Mechanism of the Endothelium-Dependent Vasodilation and the Antihypertensive Effect of Brazilian Red wine
Abstract
The mechanisms involved in the cardioprotector effect of red wine have not yet been completely elucidated but probably an endothelium-dependent vasodilator action may play a significant role in this effect. Experiments were undertaken to determine whether a Brazilian red wine (BRW) induces vasodilation in the mesenteric vascular bed (MVB) and an antihypertensive effect was also assessed in rats with NO-deficient hypertension. In MVB precontracted with norepinephrine, BRW (alcohol-free lyophilized) induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of BRW. In vessels precontracted with norepinephrine and depolarized with KCl (25 Mm) or treated with Ca-dependent K channel blockers charybdotoxin (ChTx) plus apamin, the effect of BRW was significantly reduced. However, this effect is not affected by ATP-dependent K (KATP) channel blocker (glibenclamide). The residual vasodilator effect of BRW observed in vessels pretreated with ChTx plus apamin is completely abolished by ChTx plus apamin plus L-NAME. Concentrations of atropine, pyrilamine, yohimbine, and HOE 140 that significantly reduced the vasodilator effect of acetylcholine, histamine, clonidine, and bradykinin, respectively did not change the vasodilator effect of BRW. Chronic oral administration of BRW induced a significant reduction in systolic, mean and diastolic arterial pressure in rats with L-NAME hypertension. The present results demonstrated that vasodilator effect of BRW is dependent on endothelium-derived hyperpolarizing factor (EDHF) in combination with nitric oxide (NO). The antihypertensive effect of red wine demonstrated in the present study may play a significant role on the cardioprotective action of chronic red wine consumption.
... In spite of these studies, the cardioprotective effect of wine has not been fully disclosed yet. However, it has been proposed that this effect could the result of platelet aggregation inhibition, decrease in LDL-C oxidation, reduction of endothelin synthesis, and increase in endothelial-type NO-synthase expression and activity (de Moura et al., 2004). ...
... The effect of red wine consumption on the vasodilatation process has also been studied. de Moura et al. (2004), studied the vasodilatory effect of dealcoholized red wine using an ex vivo model, using isolated mesenteric vascular bed from rats. Red wine produced an endothelialdependent dilatation. ...
... EDHF is a major endothelium-derived relaxing factor in the coronary artery and the coronary microcirculation (Ndiaye et al., 2003). de Moura et al. (2004) observed that vasorelaxation produced by red wine decreased when NG-nitro-L-arginine methyl ester (L-NAME) and oxodiazoloquinoxlin-1-one (ODQ) were used. L-NAME is a NO synthase inhibitor, while ODQ is a guanylyl cyclase (GC) inhibitor. ...
Several studies have related moderate consumption of red wine with prevention of cardiovascular diseases (CVD). According to epidemiological studies, those regions with high consumption of red wine and a Mediterranean diet show a low prevalence of CVD. Such an effect has been attributed to phenolic compounds present in red wines. On the other hand, by-products obtained during winemaking are also a significant source of phenolic compounds but have been otherwise overlooked. The cardioprotective effect of red wine and its byproducts is related to their ability to prevent platelet aggregation, modify the lipid profile, and promote vasorelaxation. Phenolic content and profile seem to play an important role in these beneficial effects. Inhibition of platelet aggregation is dose-dependent and more efficient against ADP. The antioxidant capacity of phenolic compounds from red wine and its by-products, is involved in preventing the generation of ROS and the modification of the lipid profile, to prevent LDL oxidation. Phenolic compounds can also, modulate the activity of specific enzymes to promote NO production and vasorelaxation. Specific phenolic compounds like resveratrol are related to promote NO, and quercetin to inhibit platelet aggregation. Nevertheless, concentration that causes those effects is far from that in red wines. Synergic and additive effects of a mix of phenolic compounds could explain the cardioprotective effects of red wine and its byproducts.
... 12,13 A previous study showed that Brazilian red wine (Cabernet Sauvignon, 1999) presents endothelium-dependent vasodilator effect, probably dependent on the NO-GMPc pathway. 14 Therefore, this study combined different in vitro approaches such as assessment of the amount of quercetin, cisand trans-resveratrol, using a set of high-performance liquid chromatography with UV-visible detector, pharmacological studies in isolated rat superior mesenteric arteries, and determination of NO formation from endothelial cell culture to unravel the underlying mechanisms by which alcohol-free lyophilized red wine from Vale do São Francisco exerts its cardiovascular effects. ...
... The liquid residue was lyophilized and frozen at 220°C until the day of use. 14 ...
... The endotheliumdependent vasodilatation induced by GASH in the mesenteric artery rings of rats demonstrated in this study is in accordance with previous findings showing that French wine, Brazilian red wine, polyphenols, grape juice, and an extract obtained from the skin of vinifera grape also induce an endotheliumdependent vasorelaxant effect. 12,14,33,35,36 In blood vessels, endothelial cells play a critical role in maintaining local homeostasis, via the release of various autacoids on vascular and circulating cells. Among these factors, the NO, which is synthesized by endothelial NOS after activation of the enzyme by calcium-calmodulin or phosporylation/desphosporylation, has attracted much attention because of its multiple vasoprotective properties. ...
The aim of this study was to investigate the mechanisms underlying the vasorelaxant effect induced by the polyphenolic compounds found in red wine from Vale do São Francisco. In phenylephrine (10 μM) precontracted mesenteric artery rings, the red wine caused a concentration-dependent relaxation (maximum response to phenylephrine 10 μM = 87.5% ± 6.5%, n = 10). After endothelium removal, the vasorelaxant effect elicited by red wine was attenuated (28.4% ± 4.9%, n = 10). In addition, the vasorelaxant effect induced by red wine in rings pretreated with 100 μM of N(w)-nitro-l-arginine methyl ester and 10 μM of 1H-[1,2,4] oxadiazolo-[4,3-a]-quinoxalin-1-one was attenuated (23.4% ± 5.1%, n = 7 and 11.8% ± 2.7%, n = 6, respectively). Pretreatment with atropine did not affect the vasorelaxant effect induced by red wine (81% ± 3.9%, n = 6). Furthermore, in rabbit aortic endothelial cell line, red wine 100 and 300 μg/mL caused concentration-dependent increases in nitric oxide levels (58 ± 1; 82 ± 7.9; Δ% of fluorescence, n = 5, respectively). In conclusion, we suggest that the alcohol free-lyophilized red wine induces an endothelium-dependent vasorelaxant effect due, at least in part, to a secondary increase in the concentration of nitric oxide and that this effect might be associated with phenolic compounds found in the red wine.
... Recently, we have shown that chronic intake of the polyphenols contained in an alcohol-free lyophilized Brazilian red wine or in an alcohol-free grape skin extract (GSE) from Vitis labrusca reduced systolic, mean and diastolic arterial pressure in several experimental models of hypertension [16,17] . Both types of extracts also caused endothelium-dependent vasodilation in the perfused rat mesenteric vascular bed by increasing the endothelial formation of both NO and EDHF [16][17][18] . ...
... Recently, we have shown that chronic intake of the polyphenols contained in an alcohol-free lyophilized Brazilian red wine or in an alcohol-free grape skin extract (GSE) from Vitis labrusca reduced systolic, mean and diastolic arterial pressure in several experimental models of hypertension [16,17] . Both types of extracts also caused endothelium-dependent vasodilation in the perfused rat mesenteric vascular bed by increasing the endothelial formation of both NO and EDHF [16][17][18] . The aim of the present study was to characterize the signaling pathway leading to the enhanced endothelial formation of NO in response to GSE using isolated coronary arteries and cultured coronary artery endothelial cells. ...
... However, since the addition of charybdotoxin plus apamin to L -NA further reduced relaxations to GSE, EDHF is also involved to some extent. The present findings are in agreement with previous ones indicating that GSE caused vasodilatation in the perfused rat mesenteric arterial bed by increasing the formation of NO and EDHF [17,18] . Be-sides grape skin extracts, other grape-derived products, including red wine, red wine extracts, grape juices and grape seed extracts, have also been shown to cause endothelium-dependent relaxations involving NO and EDHF [9,10,13,28,29] . ...
Drinking red wine is associated with a decreased mortality from coronary heart diseases. This study examined whether polyphenols contained in a grape skin extract (GSE) triggered the endothelial formation of nitric oxide (NO) and investigated the underlying mechanism.
Vascular reactivity was assessed in organ chambers using porcine coronary artery rings in the presence of indomethacin (a cyclooxygenase inhibitor) and charybdotoxin plus apamin (inhibitors of endothelium-derived hyperpolarizing factor-mediated responses). The phosphorylation level of Src, Akt and endothelial NO synthase (eNOS) were assessed by Western blot analysis, and the formation of reactive oxygen species (ROS) was investigated using dihydroethidine and dichlorodihydrofluorescein.
GSE-induced endothelium-dependent relaxations were abolished by N(G)-nitro-L-arginine (an eNOS inhibitor) and ODQ (a soluble guanylyl cyclase inhibitor), and they were reduced by MnTMPyP, polyethyleneglycol catalase, PP2 (an inhibitor of Src kinase) and wortmannin (an inhibitor of phosphoinositide 3-kinase). GSE caused phosphorylation of Src, which was prevented by MnTMPyP. It also caused phosphorylation of Akt and eNOS, which were prevented by MnTMPyP, polyethyleneglycol catalase, PP2, wortmannin and LY294002. GSE elicited the formation of ROS in native and cultured endothelial cells, which was prevented by MnTMPyP.
GSE causes endothelium-dependent NO-mediated relaxations of coronary arteries. This effect involves the intracellular formation of ROS in endothelial cells leading to the Src kinase/phosphoinositide 3-kinase/Akt-dependent phosphorylation of eNOS.
... Red wine contains a range of polyphenols derived from the skin of the grape and these include flavonols (quercetin and myricetin), gallic acid, condensed tannins (catechin and epicatechin polymers) and polymeric anthocyanins (Frankel et al., 1995). Variations in the concentration of these constituents among red wines may be responsible for the range of biological effects and this suggests that not all red wines might have the same pharmacological properties (Ritchey and Waterhouse, 1999;Leighton et al., 1999;Howard et al., 2002;Soares de Moura et al., 2004). ...
... Since it has been hypothesized that other mediators than NO may be involved in vasodilator responses in small vessels (such as coronary and mesenteric arteries), and because the mechanisms of these mediators may involve K + channels (Soares de Moura et al., 2004;Dabisch et al., 2004;Ndiaye et al., 2004), the current study was undertaken to investigate the role of NO, as well as K + channels in mediating the vasodilator responses to an ethyl acetate fraction (EAF) obtained from a Southern Brazilian red wine, in vitro. ...
... The present study suggests that the vasodilator effect of the EAF partially depends on the release of NO from the endothelial cells, since the perfusion of the MAB with L-NOARG, an inhibitor of NO-synthase and ODQ, an inhibitor of guanylate cyclase, significantly reduced the effect of EAF (Fig. 2, Table 1). Similar results were found in a recent study which showed that another inhibitor of NOsynthase, NG-nitro-l-arginine methyl ester (L-NAME), significantly reduced the vasodilator effect of a Brazilian red wine, in the rat MAB (Soares de Moura et al., 2004). ...
A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CAD). In this study, we investigated the effect of a crude extract (CE), as well as an ethyl acetate fraction (EAF) obtained from a Brazilian red wine in the mesenteric arterial bed (MAB) from rats. Our results showed that after the tonus of MAB was increased with phenylephrine (PE), increasing concentrations of CE induced a concentration-dependent relaxation; moreover, EAF was more potent in relaxing the MAB when compared with CE. In vessels depolarized with KCl (80 mM) or treated with the Na(+)/K(+)-ATPase pump inhibitor, ouabain (OUA; 100 microM), or with the K(+) channel blockers: barium (BaCl(2), 100 microM) and tetraethylammonium (TEA; 500 microM), the effect of EAF was significantly reduced. However, this effect was not altered by the ATP-dependent K(+) (K(ATP)) channel blocker, glibenclamide (GLI; 100 microM) as well as Charybdotoxin (ChTx 10 nM), a nonselective inhibitor of K(Ca) channels of large and intermediate conductance plus Apamin (Apamin 100 nM), a specific inhibitor of K(Ca) channels of small conductance. The residual vasodilator effect of EAF observed in vessels pretreated with L-NOARG (100 microM), 1H-[1,2,4,] oxadiazolo[4,3-alfa]quinoxalin, ODQ (10 microM) or KCl (80 mM), given separately, was reduced by the administration of KCl (40 mM) plus L-NOARG (100 microM). The present study demonstrates that the vasodilator effect of EAF is partially dependent upon membrane hyperpolarization in combination with nitric oxide (NO) release.
... Polyphenol-rich diets, food, and beverages, especially red wine, grape juice, tea, and extracts rich in polyphenols, have been shown to have a protective effect against cardiovascular diseases (Idris Khodja, Chataigneau, Stoclet et al., 2004). Chronic intake of red wine, a particularly rich source of phenolic compounds, caused antihypertensive effects and vasodilatation in normal and hypertensive rats (Soares de Moura et al., 2004). Red wine has also been shown to decrease lipid peroxidation, induce endotheliumderived nitric oxide (NO)-mediated relaxations, enhance NO bioavailability, and to improve the endothelial function (Andriantsitohaina et al., 2012;Auger et al., 2010;Diebol, Bucher, & Adriantsitohaina, 2001). ...
... The present findings indicate that such a low dose of the RSCS treatment was able to significantly reduce the L-NAME-induced high level of blood pressure without affecting heart rate. Previous studies by Soares de Moura et al. (2004) have also indicated that oral administration of a lyophilized southern Brazilian red wine induced an antihypertensive effect in L-NAME-treated rats. In addition, the polyphenol quercetin decreased blood pressure in several models of hypertension in rats including the spontaneously hypertensive rat, the L-NAME hypertensive rat, and the DOCA-salt hypertensive rat (Larson, Symons, & Jalili, 2010). ...
Red wines have been shown to protect the vascular system by increasing the endothelial formation of nitric oxide (NO). This study investigated the vasoactive properties of an alcohol-free Cabernet-Sauvignon northeastern Brazilian red wine – RIOSOL (RSCS) extract. The polyphenolic-rich RSCS contained 4.2 mg GAE/L of polyphenols, and its major compounds included quercetin, myricetin and kaempferol. In normotensive conscious rats, RSCS produced hypotension and tachycardia, which were attenuated by the endothelial NO synthase inhibitor (eNOS), L-NAME. In addition, after 2 weeks of oral treatment, RSCS reduced arterial pressure in L-NAME-treated hypertensive rats. RSCS caused NO-mediated relaxations in phenylephrine contracted mesenteric artery rings, and induced the formation of NO and superoxide anions and a redox-sensitive phosphorylation of Akt and eNOS in cultured endothelial cells. In conclusion, the findings indicate that an alcohol-free lyophilized RSCS induced hypotension and endothelium-dependent vasorelaxation as a consequence of the activation of the Akt-eNOS-NO pathway in a redox-sensitive manner.
... We speculate that a high and simultaneous concentration of EA and E2 could potentially trigger additional mechanisms. For example, in both estrogen deficiency and stimulation with polyphenols, vasodilation endothelium-dependent resistant to NOs inhibitors could also be attributed to endothelium-derived hyperpolarizing factor (EDHF) and gap junctions intracellular communication [56][57][58][59][60] . However, EDHF was not the focus of this study, and therefore, not further explored. ...
Cardiovascular diseases (CVD) rank the top causes of death worldwide, with a substantial increase in women compared to men. Such increase can beexplained by the drastic decrease in 17-β-estradiol hormone during menopause and associated with endothelium-dependent vascular dysfunction. The current treatments for CVDs (e.g hypertension), are only palliative and therefore, feasible, non-invasive options for preventing further vascular damage are needed. The polyphenol ellagic acid (EA) has risen as a candidate with possible vascular protection properties. This study evaluated the effects of EA in small mesenteric arteries of ovariectomized spontaneously hypertensive rats (SHR). Our findings showed that EA oral treatment for four weeks preserved vasodilation endothelial-dependent in acetylcholine pre-constricted arteries of SHR to the same extent as 17-β-estradiol treatment, an effect that was abolished in the presence of the NOS inhibitor L-NAME. Moreover, EA induced vascular NO release, by increasing both the activitation site phosphorylation and total levels of the endothelial NO synthase (eNOS). Finally, EA decreased superoxide anion while increased total levels of the antioxidant enzymes SOD2 and catalase. We concluded that EA has vasodilation properties acting via eNOS activation and a potential antioxidant effect by stimulating the SOD2-catalase pathway.
... Although the dose of Captopril exceeds the recommended maximal prescription dose of 450 mg/day, the dose of 3.40 g of cocoa polyphenols are within the range of Human consumption. Similar reductions in blood pressure after intake of grape-derived products have also been reported in other experimental models of hypertension including the N G -nitro L-arginine-induced hypertension [86][87][88], the DOCA-saltinduced hypertension [89,90], and the Ang II-induced hypertension in rats [61]. Moreover, the antihypertensive effect of red wine and red wine extracts is associated with an improved endothelial function in the DOCA-salt rat [89,90], the spontaneously hypertensive rat [77,79,91], and the Ang II-induced hypertensive rat [61]. ...
Since last few decades, considerable data have been suggested that the protective effect of anthocyanin on cardiovascular system is likely to involve an improvement of endothelial function by increase nitric oxide (NO) formation. However, comprehensive studies on the subsequent mechanisms of protective effect by anthocyanin intracellular transportation in vascular endothelial cell is poorly understood. The aim of this thesis is to evaluate the possibility that SGLT1 and 2, the two major sodium-glucose cotransporters (SGLT), contribute to blackcurrant anthocyanins and its major glucoside- and rutinoside-conjugated anthocyanins uptake into endothelial cells that promoting the subsequent activation of endothelial nitric oxide synthase (eNOS) pathway using isolated blood vessels and cultured endothelial cells. An anthocyanin rich blackcurrant extract (BCE) induced NO-mediated endothelium dependent relaxation in porcine coronary artery rings and activated Akt-eNOS signaling pathway in cultured endothelial cell. Furthermore, additional experiments suggested that such a protective effect of anthocyanin is based on the type of glucoside in anthocyanin structure and contribution of SGLTs for the intracellular transportation of anthocyanins. An ability of anthocyanin against endothelial dysfunction is highly potentiated in the endothelial cell replicative senescence model by the increase anthocyanin efflux according to the high expression of SGLTs. Altogether, the present findings indicate that blackcurrant anthocyanins are potent activator of the endothelial NO pathway in native and cultured endothelial cells. Among blackcurrant anthocyanins, glucose derivatives such as cyanidin and delphinidin -3-O-glucoside are the most potent anthocyanins for activation of NO pathway. In conclusion, anthocyanin can be more prominent by preferentially targeting an early stage of atherosclerotic site by their increase expression of SGLT1 and 2.
... Although the dose of Captopril exceeds the recommended maximal prescription dose of 450 mg/day, the dose of 3.40 g of cocoa polyphenols are within the range of Human consumption. Similar reductions in blood pressure after intake of grape-derived products have also been reported in other experimental models of hypertension including the N G -nitro L-arginine-induced hypertension [86][87][88], the DOCA-salt-induced hypertension [89,90], and the Ang IIinduced hypertension in rats [61]. Moreover, the antihypertensive effect of red wine and red wine extracts is associated with an improved endothelial function in the DOCA-salt rat [89,90], the spontaneously hypertensive rat [77,79,91], and the Ang II-induced hypertensive rat [61]. ...
Epidemiological studies have indicated that regular intake of polyphenol-rich diets such as red wine and tea, are associated with a reduced risk of cardiovascular diseases. The beneficial effect of polyphenol-rich products has been attributable, at least in part, to their direct action on the endothelial function. Indeed, polyphenols from tea, grapes, cacao, berries, and plants have been shown to activate endothelial cells to increase the formation of potent vasoprotective factors including nitric oxide (NO) and to delay endothelial ageing. Moreover, intake of such polyphenol-rich products has been associated with the prevention and/or the improvement of an established endothelial dysfunction in several experimental models of cardiovascular diseases and in Humans with cardiovascular diseases. This review will discuss both experimental and clinical evidences indicating that polyphenols are able to promote endothelial and vascular health, as well as the underlying mechanisms.
... One of the hallmarks of the hypertensive pathophysiological process is endothelium dysfunction provoked by excessive reactive oxygen species production and vascular inflammation [54]. Although numerous studies indicate that red wine and polyphenols present in wine induce an endothelium-dependent vasorelaxant effects [55][56][57], our results have shown that Fr 2 SySFV at concentrations of 0.01-1000 µg/mL induced concentration-dependent relaxation of isolated rat superior mesenteric rings pre-contracted with phenylephrine, an effect which was not attenuated by removal of ring endothelium. In a previous study with a lyophilized red wine from SFV, Luciano et al. (2011) [25] demonstrated the vasorelaxant activity of the wine was significantly attenuated by endothelium removal. ...
A particularly phenolic-rich fraction extracted from red wine from the São Francisco valley (Northeastern Brazil) was chemically characterized and its hypotensive and antioxidant effects on spontaneously hypertensive rats were studied both in vitro and in vivo. The liquid-liquid pH dependent fractionation scheme afforded a fraction with high content of bioactive phenolics such as flavonols, flavonol glycosides, phenolic acids and anthocyanins, whose identities were confirmed by liquid chromatography coupled to mass spectrometry analysis. Pretreatment of spontaneously hypertensive rats with this wine fraction at doses of 50 and 100 mg/kg by gavage. for 15 days was able to decrease mean arterial pressure and heart rate as well as decrease serum lipid peroxidation. The fraction at concentrations of 0.01-1000 µg/mL induced concentration-dependent relaxation of isolated rat superior mesenteric artery rings pre-contracted with phenylephrine and this effect was not attenuated by endothelium removal. Our results demonstrate it is possible for phenolic constituents of red wine that are orally bioavailable to exert in vivo hypotensive and antioxidant effects on intact endothelial function.
... SBP value at third and fourth weeks. Awwadi et al. (2004), de Moura et al. (2004and Pechnova et al. (2004) reported that polyphenols are able to prevent cardiac hypertrophy and the production of reactive oxygen species, as well as improving vascular function. The vasodilator and antioxidant actions exerted by guava extract have been reported (Jim et al., 2001). ...
The objective of this study was to determine the physicochemical properties of pink guava (Psidium guajava) puree and its anti-hypertensive effect on Spontaneous Hypertensive Rats (SHR). Antioxidant activities of pink guava puree in water and ethanol extracts, based on 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, were 1.43±0.04 mg/gfm and 0.28±0.01 mg/gfm, respectively. A total of 24 male SHRs were divided into a control group, CG, and 3 treatment dosage groups [low dose group, LDG (0.5 g/kg body weight/day), medium dose group, MDG (1.0 g/kg body weight/day), and high dose group, HDG (2.0 g/kg body weight/day)]. Final body weights for treatment dosage groups were lower [MDG (313.01±31.25 g), HDG (318.56±17.96 g), LDG (320.01±22.70 g)] compared to CG (331.08±41.29 g). Final systolic blood pressure values from the beginning and the end of the experiment in MDG and HDG were 231-179 mmHg and 246-169mm Hg, respectively. These results were significantly lower when compared with CG (241-223 mmHg) from the beginning until the end of the experiment. As a conclusion, these results showed that pink guava puree has anti-hypertensive properties.
... Moreover, the low-protein diet + ACH09 group differed significantly from the low-protein diet group when the number of glomeruli was correlated with birth weight. We suggest that the beneficial effect on the offspring growth observed in the groups treated with ACH09 is due to its vasodilatory effect [11,13,36]. Possibly, ACH09 induced a placental vasodilatation via polyphenolinduced increased NO production and availability [12,37], encouraging a greater supply of nutrients to the treated groups. ...
Protein-restricted diet during pregnancy is related to oxidative stress and, as a consequence, damage to nephrogenesis. We investigated the effects of vinifera grape skin extract (ACH09)-derived polyphenols on preserving renal morphology of maternal protein-restricted 1-day-old offspring.
Female C57/Bl-6 mice were fed two different isocaloric diets: control diet (19.3 % protein) and low-protein diet (6 % protein) with access to water or to the extract dissolved in drinking water (19.3 % protein plus ACH09 200 mg kg(-1) day(-1) and 6 % protein plus ACH09 200 mg kg(-1) day(-1)) throughout gestation. Renal morphology-glomerular number N[glom]; renal maturity-vascular glomeruli and avascular glomeruli ratio (v-N[glom]/a-N[glom]); medullar and cortical volumes, as well as mean glomerular volume, were analyzed in male offspring. Hepatic superoxide dismutase and catalase (CAT) activities were evaluated, and renal lipid peroxidation levels were measured.
Maternal protein restriction affected birth weight and naso-anal length in low-protein offspring compared to control and ACH09 restored both parameters. Protein restriction increased lipid peroxidation in kidney and liver and reduced CAT activity in low-protein group compared to control. Supplementation with ACH09 reduced the kidney oxidative damage and restored the antioxidant activity of CAT. ACH09 prevented glomerular loss and renal immaturity in the offspring.
The treatment of low-protein-fed dams during pregnancy with ACH09 provides protection from early-life deleterious renal morphological changes. The protective effect of ACH09 may involve antioxidant action and vasodilator effect of the extract.
... We identified the presence of polyphenols and flavonoids in EEAP. Studies have reported the involvement of polyphenols in endothelium-dependent relaxant effects mediated by the liberation of · NO and EDHF (Andriambeloson et al., 1997;De Moura et al., 2002;Ndiaye et al., 2003;De Moura et al., 2004). Senejoux et al. (2012) demonstrated the possibility that polyphenolic compounds found in the extract of Nitraria sibirica Pall fruit are involved in its hypotensive properties and endothelium-dependent relaxation effects; these mainly involve · NO liberation, EDHF, and stimulation of the muscarinic receptors. ...
The aims of this study were to evaluate the chemical profile, vascular reactivity, and acute hypotensive effect (AHE) of the ethanolic extract of leaves of Alpinia purpurata (Vieill) K. Schum (EEAP). Its chemical profile was evaluated using HPLC-UV, ICP-OES, and colorimetric quantification of total flavonoids and polyphenols. The vascular reactivity of the extract was determined using the mesenteric bed isolated from WKY. AHE dose-response curves were obtained for both EEAP and inorganic material isolated from AP (IAP) in WKY and SHR animals. Cytotoxic and mutagenic safety levels were determined by the micronucleus test. Rutin-like flavonoids were quantified in the EEAP (1.8 +/- 0.03%), and the total flavonoid and polyphenol ratios were 4.1 +/- 1.8% and 5.1 +/- 0.3%, respectively. We observed that the vasodilation action of EEAP was partially mediated by nitric oxide ((NO)-N-center dot). The IAP showed the presence of calcium (137.76 +/- 4.08 mu g mg(-1)). The EEAP and IAP showed an AHE in WKY and SHR animals. EEAP did not have cytotoxic effects or cause chromosomic alterations. The AHE shown by EEAP could result from its endothelium-dependent vascular action. Rutin-like flavonoids, among other polyphenols, could contribute to these biological activities, and the calcium present in EEAP could act in a synergistic way.
... Recently, many experimental data have suggested that polyphenols that occur in many vegetables may participate in the mechanism of beneficial effect of some medicinal plants. It is also demonstrated that in alcohol-free red wine and products obtained from the skin of vinifera grapes, both rich in polyphenols, have vasodilator and antihypertensive effects in experimental animals 87 . ...
Hypertension is a common problem facing many peoples today. Although billions of dollars are spent annually for the treatment and detection of cardiovascular disease, current conventional treatments have done little to reduce the number of patients with hypertension . Alternative medicine offers an effective way to decrease the rising number of people with high blood pressure. Research has found a variety of alternative therapies to be successful in reducing high blood pressure including diet, exercise, stress, management, supplements and herbs. Every year, more and more studies are being performed on herbal remedies for high blood pressure. There are many herbal drugs like Punarnava, Barberry, Rouwolfia, Garlic, Ginger, Ginseng and Arjuna which can safely use for the treatment of hypertension. This review highlight the herbs proved scientifically for the treatment of hypertension.
... Upregulation of eNOS is probably based on synergistic mechanisms between the different polyphenolic components [60]. RWP has been shown to improve endothelial function in various animal models of hypertension61626364656667. Furthermore, 240 ml of red wine per day effectively counteracted endothelial dysfunction induced by a high-fat diet in otherwise healthy individuals [68]. ...
Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), is recognised as a central anti-inflammatory and anti-atherogenic principle in the vasculature. Decreased availability of NO in the vasculature promotes the progression of cardiovascular diseases. Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, may improve vascular function by enhancing NO bioavailability. In this article we first outline common pathways modulating endothelial NO production or bioavailability to provide a basis for subsequent mechanistic discussions. Then we comprehensively review natural products and plant extracts known to positively influence eNOS activity and/or endothelial function in vitro or in vivo. We will discuss red wine, highlighting polyphenols, oligomeric procyanidins (OPC) and resveratrol as modulators of endothelial NO production. Other dietary products and their active components known to activate eNOS include cocoa (OPC and its monomer (-)-epicatechin), pomegranates (polyphenols), black and green tea (flavanoids, especially epigallocatechin gallate), olive oil (oleic acid and polyphenols), soy (genistein), and quercetin, one of the most abundant flavonoids in plants. In addition, phytomedical preparations made from ginkgo, hawthorn and ginseng, as well as formulations used in traditional Chinese Medicine, have been shown to affect endothelial NO production. Recurring phytochemical patterns among active fractions and purified compounds are discussed. In summary, there is increasing evidence that several single natural products and plant extracts influence endothelial NO production. Identification of such compounds and characterisation of their cellular actions may increase our knowledge of the regulation of endothelial NO production and could provide valuable clues for the prevention or treatment of cardiovascular diseases.
... However, the intake of red wine polyphenols was reported to prevent angiotensin II-induced hypertension and endothelial dysfunction [27]. Some investigators have reported that the vasodilator effect of red wine is dependent on nitric oxide in the cardio-and renovascular systems [28,29]. Mozaffrieh et al [30] reported that red wine polyphenols exert vasoprotection by inhibiting the synthesis of endothelin-1. ...
The aim of the present study was to determine whether red or white wine affects urinary protein, 8-hydroxydeoxyguanosine (8-OHdG), and liver-type fatty acid-binding protein (L-FABP) excretion in type 2 diabetic nephropathy patients. Twenty-four type 2 diabetes mellitus patients with nephropathy were randomly allocated to drink a 118-mL (4-oz) glass of red wine (n = 12, group A) or white wine (n = 12, group B) daily for 6 months. Twelve type 2 diabetes mellitus patients with nephropathy who did not drink any wines served as control subjects (group C). Serum creatinine, 24-hour creatinine clearance, hemoglobin A(1c), urinary protein, urinary 8-OHdG, and urinary L-FABP were measured before and 3 and 6 months after the start of the study. In groups A, B, and C, serum creatinine, 24-hour creatinine clearance, and hemoglobin A(1c) changed little during the experimental period. However, urinary protein, 8-OHdG, and L-FABP excretions were significantly decreased at 3 (P < .05) and 6 months (P < .01) compared with the baseline values in group A. In contrast, these markers changed little during the experimental period in groups B and C. Thus, these urinary markers were significantly lower in group A than in groups B and C at 3 and 6 months. These results suggest that red wine is renoprotective whereas white wine has no such effect in type 2 diabetes mellitus patients with nephropathy. The renoprotective effect of red wine may be due in part to its ability to reduce oxidative stress.
... Studies by Duarte et al. (2001) and Ajay et al. (2006), suggest that the effects of quercetin are more pronounced when bioavailability of endothelium-derived nitric oxide (EDNO) is impaired. Flavonoids have recently been reported to elicit endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular reactivity in vascular preparations (De Moura et al., 2004;Woodman and Boujaoude, 2004). However, Xu et al., (2007) reported in their study that it is unlikely that flavonoids induce vascular muscle relaxation through hyperpolarization via activation of potassium channels. ...
In this study, we examined the effects of Psidium guajava Linn. leaf aqueous extract (PGE) on isolated, spontaneously-contracting portal veins, as well as on endothelium-intact and endothelium-denuded descending thoracic aortic ring preparations of healthy, normotensive rats. Graded concentrations of PGE (0.25-4.0 mg/ml) caused concentration-dependent, initial brief but significant (P<0.05) rises of the basal tones and amplitudes of pendular, rhythmic contractions, followed by secondary pronounced, longer-lasting and significant (P<0.05-0.001) inhibitions of contractile amplitudes of the isolated portal veins. Relatively low concentrations of PGE (<1.0 mg/ml) always contracted freshly-mounted, naïve, endothelium-intact aortic ring preparations. However, relatively high concentrations of PGE (1.0-4.0 mg/ml) always produced initial brief contractions/augmentations of noradrenaline (NA, 10(-7)M)-induced contractions of endothelium-intact and endothelium-denuded aortic ring preparations, followed by secondary, pronounced relaxations of the aortic ring muscles. Moreover, relatively high concentrations of PGE (1.0-4.0 mg/kg) always relaxed NA-induced contractions of the aortic ring preparations in a concentration-related manner. The arterial-relaxing effects of PGE were more pronounced in endothelium-intact aortic rings than in endothelium-denuded aortic ring preparations. The relaxant effects of PGE on endothelium-intact aortic rings were only partially inhibited by N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a nitric oxide synthase inhibitor, suggesting that the vasorelaxant effect of PGE on aortic rings is probably mediated via both endothelium-derived relaxing factor (EDRF)-dependent and EDRF-independent mechanisms. Taken together, the findings of this study indicate that PGE possesses a biphasic effect on rat isolated vascular smooth muscles.
... The chronic intake of x 3 -unsaturated fatty acids potentiates the endothelium-dependent relaxations of coronary arteries to aggregating platelets and other stimuli and have antiatherogenic properties (Shimokawa et al. 1987,b, Shimokawa & Vanhoutte 1989a, Shepherd & Vanhoutte 1991, von Schacky & Harris 2007, Sekikawa et al. 2008, Sena et al. 2008. The same holds true for the intake of flavonoids (Machha & Mustafa 2005, Machha et al. 2007, Xu et al. 2007) and other polyphenols, whether present in red wine (in particular resveratrol) (Stockley 1998, Leikert et al. 2002, Wallerath et al. 2002, da Luz & Coimbra 2004, Dell'Agli et al. 2004, Soares de Moura et al. 2004, Coimbra et al. 2005, Boban et al. 2006, Sarr et al. 2006, Das et al. 2007, Lefèvre et al. 2007, Aubin et al. 2008, Chan et al. 2008a,b, Csiszar et al. 2008, Lopez-Sepulveda et al. 2008, in green tea (Kuriyama et al. 2006, Alexopoulos et al. 2008, grape juice (Anselm et al. 2007), in pomegranate juice (Nigris et al. 2006(Nigris et al. , 2007a or in dark chocolate (Fisher et al. 2003, Engler et al. 2004, Grassi et al. 2005, Schroeter et al. 2006, Flammer et al. 2007, Taubert et al. 2007. ...
The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDHF-mediated responses). Endothelium-dependent relaxations involve both pertussis toxin-sensitive G(i) (e.g. responses to serotonin and thrombin) and pertussis toxin-insensitive G(q) (e.g. adenosine diphosphate and bradykinin) coupling proteins. The release of NO by the endothelial cell can be up-regulated (e.g. by oestrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and causing endothelium-dependent hyperpolarizations), endothelial cells also can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factor (EDCF). Most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells. EDCF-mediated responses are exacerbated when the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive patients.
... Incubation of the GP aortic rings with indomethacin caused an insignificant decrease of the vasorelaxation relative to the control RW-induced vasorelaxation (Fig. 3). In the rabbit aortic rings 4 and rat mesenteric vascular bed, 18 indomethacin also did not significantly interfere with the RW-induced vasodilation. Prostacyclin vasodilator activity is determined by the expression of specific receptors in vascular smooth muscle. ...
We examined and compared mechanisms of the red wine (RW)-induced vasorelaxation in guinea pig (GP) and rat aorta. Acetylcholine-induced relaxation of norepinephrine-precontracted aortic rings was stronger in rat aorta than in GP aorta, whereas RW-induced vasorelaxation was stronger in GP aorta. L-nitro-arginine methyl ester (L-NAME) abolished RW-induced vasorelaxation in rat aorta, whereas in GP aorta, it was only reduced by 50%. To examine mechanisms of the L-NAME-resistant relaxation, GP aortic rings were additionally exposed to indomethacin, clotrimazole, and their combination. Indomethacin insignificantly reduced RW-induced relaxation, but in combination with L-NAME, the relaxation was synergistically decreased (80%). After clotrimazole exposure, the relaxation was reduced by 25%, and addition of indomethacin caused no further reduction. Only the combination of L-NAME, indomethacin, and clotrimazole prevented RW-induced vasorelaxation. RW-induced vasorelaxation in KCl-precontracted GP rings was significantly smaller (Emax 78.31% +/- 6.09%) than the RW-induced relaxation in norepinephrine-precontracted rings (Emax 126.01% +/- 2.11%). L-NAME in KCl-precontracted GP rings prevented RW-induced vasorelaxation. In conclusion, different pathways are involved in the RW-induced vasorelaxation in GP aorta, in contrast to rat aorta, in which NO plays main role. Therefore, the uncritical extrapolation of the results from one species to another could be misleading.
... Many compounds from medicinal plants have been known as vasodilator (Fitzpatrick et al., 1995;Wazlawik et al., 1997;de Moura et al., 2004;Ernst, 2005). The plants showing NO production can be promising candidates for the vasodilation, which may have potential for the prevention and treatment of cardiovascular diseases such as hypertension and atherosclerosis. ...
Schisandra chinensis (SC) is a known medical herb for the treatment of cardiovascular symptoms associated with menopausal symptoms in Korea. However, the pharmacological action mechanisms involved have not been well studied. This study was aimed to investigate the vascular effects of SC in rat thoracic aorta.
We isolated the hexane, chloroform, and methanol extracts from SC and evaluated their vasodilatory effects in the rat thoracic aorta.
Hexane extracts of SC (SCHE, 5 x 10(-5) to 10(-3) g/L) caused a concentration-dependent relaxation in both endothelium-intact and -denuded aortas. The relaxant effect of SCHE on the endothelium-intact aorta was more prominent than on the endothelium-denuded aorta. The former was significantly attenuated by L-NAME, a nitric oxide synthase inhibitor, and ODQ, a soluble guanyl cyclase inhibitor, but not by tetraethylammonium, a nonselective blocker of K(+) channels, and indomethacin, a cyclooxygenase inhibitor. Furthermore, SCHE caused nitrite production as well as eNOS activation in aortic segments, suggesting implication of NO signal pathway in SCHE-induced relaxation. In endothelium-denuded aorta, SCHE-induced vasorelaxation was also attenuated by calyculin A, an inhibitor of myosin light chain (MLC) phosphatase, but not by ML-9, a MLC kinase inhibitor, suggestive of implication of MLC phosphatase activation. Phenylephrine-enhanced MLC phosphorylation ratio was significantly attenuated by SCHE, which was recovered to the control level by pretreatment with calyculin A.
Taken collectively, these findings suggest that the vascular relaxation evoked by SCHE was mediated by not only endothelium dependent NO pathway but also direct effect on vascular smooth muscle cell via dephosphorylation of MLC.
... These findings that quercetin can act in the partial or complete absence of EDNO bioavailability suggest quercetin can exert its vasodepressor effects via mechanisms other than, or in addition to, those involving free radical scavenging and antioxidant protective effects on EDNO. Flavonoids have been recently reported to elicit endothelium-derived hyperpolarizing factor (EDHF)mediated vascular reactivity in vascular preparations [27,28]. The present experimental conditions inhibiting endothelial nitric oxide-and prostacyclin-mediated vasodilatation suggest the observed vasodepressor effect of quercetin may have involved EDHF. ...
The present work examined ex vivo the acute effect of quercetin on diabetic rat aortic ring reactivity in response to endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) relaxants, and to the alpha(1)-adrenergic agonist phenylephrine (PE). Responses were compared to those of aortic rings from age- and sex-matched euglycemic rats. Compared to euglycemic rat aortic rings, diabetic rings showed less relaxation in response to ACh and SNP, and greater contraction in response to PE. Pretreatment with quercetin (10microM, 20min) increased ACh-induced relaxation and decreased PE-induced contraction in diabetic, but did not affect euglycemic rat aortic ring responses. Following pretreatment with the nitric oxide synthase inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME, 10microM), quercetin reduced PE-induced contractions in both aortic ring types, although l-NAME attenuated the reduction in the diabetic rings. Quercetin did not alter SNP vasodilatory effects in either ring type compared to their respective controls. These findings indicate that quercetin acutely improved vascular responsiveness in blood vessels from diabetic rats, and that these effects were mediated, at least in part, by enhanced endothelial nitric oxide bioavailability. These effects of quercetin suggest the possible beneficial effects of quercetin in vivo in experimental diabetes and possibly in other cardiovascular diseases.
... protective effect in vivo and ex vivo models in rats (Li et al., 1996) and schizandrin, one of the lignans isolated from Schizandra, is known to decrease heart rate (Xiao and Fu, 1991). Similar studies have implicated various plant extracts (Fitzpatrick et al., 1995;Wazlawik et al., 1997;Soares de Moura et al., 2004) and polyphenolic compounds (Andriambeloson et al., 1997;Orallo et al., 2002). Further work is necessary to isolate and identify the endothelium-dependent vasorelaxing components(s) of ScEx and those acting on smooth muscle directly. ...
An aqueous extract of Schizandra chinensis fruit (ScEx) has long been used to promote the vascular health of postmenopausal women in Korea. This study investigated the ability of ScEx to relax rat aorta constricted with norepinephrine (NE) and the mechanism(s) of such relaxation. ScEx induced partial, endothelium-dependent relaxation. In particular, the relaxation induced by lower concentrations of ScEx (0.1 and 0.3 mg/ml) was largely endothelium-dependent, and was essentially abolished by NG-nitro-L-arginine, methylene blue, 1H-[1,2,3] oxadiazole [4,4-a] quinoxalin-1-one, indomethacin, or ICI 182,780. The results indicate that the response to ScEx involves enhancement of the nitric oxide (NO)-cGMP system, and that it occurs via estrogen receptors. The magnitude of the inhibition with these treatments decreased with increasing ScEx concentration, however, indicating that other vasorelaxation mechanisms are involved, which depend on the ScEx concentration. Calcium concentration-dependent contraction curves in high potassium depolarization medium were shifted significantly to the right and downward after incubation with ScEx (0.3 and 1.0 mg/ml), implying that ScEx is also involved in inhibition of the extracellular calcium influx to vascular smooth muscle. These data demonstrate that ScEx caused both endothelium-dependent and -independent vasorelaxation, which may contribute to understanding the cardiovascular protective effect of ScEx.
Maintaining good vascular health is a major component in healthy ageing as it reduces the risk of cardiovascular diseases. Endothelial dysfunction, in particular, is a key mechanism in the development of major cardiovascular diseases including hypertension, atherosclerosis and diabetes. Recently, endothelial senescence has emerged as a pivotal early event in age-related endothelial dysfunction. Endothelial function is characterized by an imbalance between the endothelial formation of vasoprotective mechanisms, including the formation of nitric oxide (NO) and endothelium-dependent hyperpolarization responses, and an increased level of oxidative stress involving several pro-oxidant enzymes such as NADPH oxidases and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Pre-clinical studies have indicated that natural products, in particular several polyphenol-rich foods, can trigger activating pathways in endothelial cells promoting an increased formation of NO and endothelium-dependent hyperpolarization. In addition, some can even exert beneficial effects on endothelial senescence. Moreover, some of these products have been associated with the prevention and/or improvement of established endothelial dysfunction in several experimental models of cardiovascular diseases and in humans with cardiovascular diseases. Therefore, intake of certain natural products, such as dietary and plant-derived polyphenol-rich products, appears to be an attractive approach for a healthy vascular system in ageing.
Moderate consumption of wine has a protective effect on the cardiovascular system. This study proposes to investigate the cardiovascular protective effect of the lyophilized red wine RIO SOL Cabernet-Sauvignon (LRW-RSCS), produced in Northeastern Brazil, in SHR. Sixteen different phenolic compounds, such as gentisic acid, catechin, and resveratrol were identified in LRW-RSCS using high-performance liquid chromatography. LRW-RSCS presented anti-radical activity. Six-week treatment of SHR with LRW-RSCS (100 or 300 mg/Kg/day intra-gastrically) reduced blood pressure and hypercontractility, and improved mesenteric resistance artery endothelial function. The protective effect of LRW-RSCS on endothelial function, mediated relaxation involving both higher endothelial-NO and -EDHF. LRW-RSCS intake reduced vessel wall thickness, media-to-lumen ratio, collagen vascular deposition, and vessel oxidative stress. LRW-RSCS also attenuated platelet hyper aggregation and ROS generation. The results demonstrate that LRW-RSCS from Northeastern Brazil presents cardiovascular protective effect in SHR, at least in part by decreasing oxidative stress.
Background
Previous studies have shown that intake of polyphenols through the consumption of vegetables and fruits reduces the risk of cardiovascular disease (CVD) by potentially influencing endothelial cell function.
Objectives
In this review, the effects and molecular mechanisms of plant polyphenols, particularly resveratrol, epigallocatechin gallate (EGCG), and quercetin, on endothelial functions, and their putative protective effects against CVD are described.
Methods
Epidemiologic studies examined the effect of the CVD risk of vegetables and the fruit. Furthermore, studies with in vitro models investigated the underlying molecular mechanisms of the action of the flavonoid class of polyphenols. These findings help elucidate the effect of polyphenols on endothelial function and CVD risk reduction.
Results
Epidemiologic and in vitro studies have demonstrated that the consumption of vegetables and fruits decreases the incidence of CVDs. Furthermore, it has also been indicated that the dietary polyphenols are inversely related to the risk of CVD. Resveratrol, EGCG, and quercetin prevent oxidative stress by regulating the expression of oxidase and the antioxidant enzyme genes, contributing to the prevention of stroke, hypertension, heart failure, and ischemic heart disease.
Conclusion
High intake of dietary polyphenols may help prevent CVD. Polyphenols inhibit endothelial dysfunction and induce vascular endothelium-dependent vascular relaxation viz. redox regulation and nitric oxide production. The polyphenol-induced healthy endothelial cell function may be related to CVD prevention.
Winemaking by-products account for more than 30% of the grape production, but this inexpensive feedstock has not yet been fully exploited. Accordingly, we evaluated the potential biological activity of winemaking by-products produced with Syrah grapes in comparison with those of the wine produced using the same grape cultivar. Winemaking by-products showed higher contents of total anthocyanins, flavonols, stilbenes, and flavanols than red wine as evaluated by HPLC-DAD-FD (on a dry weight basis). In contrast, red wine was a better source of phenolic acids. However, the contribution of phenolic acids was minor for both samples. Furthermore, equivalent concentration of winemaking by-products (100 mg/kg/d) showed greater biological activity by than that of red wine by decreasing the levels of VLDL-cholesterol and triacylglycerols in Wistar rats. Therefore, this study supports the use of winemaking by-products as an economical source of bioactive phenolics with potential use in the food and nutraceutical industries.
Background:
The devastating effects of heavy alcohol drinking have been long time recognized. In the last decades, potential benefits of modest red wine drinking were suggested. In European countries in which red wide intake is not negligible (such as France), the association between cholesterol and cardiovascular (CV) risk was less evident, suggesting the action of some protective molecules in red wine or other foods and drinks.
Methods:
This narrative review is based on the material searched for and obtained via PubMed up to May 2016. The search terms we used were: "red wine, cardiovascular, alcohol" in combination with "polyphenols, heart failure, infarction".
Results:
Epidemiological and mechanistic evidence of a J-shaped relationship between red wine intake and CV risk further supported the "French paradox". Specific components of red wine both in vitro and in animal models were discovered. Polyphenols and especially resveratrol largely contribute to CV prevention mainly through antioxidant properties. They exert beneficial effects on endothelial dysfunction and hypertension, dyslipidemia, metabolic diseases, thus reducing the risk of adverse CV events such as myocardial infarction ischemic stroke and heart failure. Of interest, recent studies pointed out the role of ethanol itself as a potential cardioprotective agent, but a clear epidemiological evidence is still missing. The aim of this narrative review is to update current knowledge on the intracellular mechanism underlying the cardioprotective effects of polyphenols and ethanol. Furthermore, we summarized the results of epidemiological studies, emphasizing their methodological criticisms and the need for randomized clinical trials able to clarify the potential role of red wine consumption in reducing CV risk.
Conclusion:
Caution in avowing underestimation of the global burden of alcohol-related diseases was particularly used.
A large body of evidence has demonstrated beneficial effects of polyphenol-rich diets and herbal medicines on the vascular system. However, polyphenols encompass diverse compounds, and conclusions are limited by poor extract compositional data and lack of bioassay-guided fractionation aimed at identifying the active constituents. Research on the vasorelaxant potential of chemically defined proanthocyanidins is hitherto confined. A few studies focused only on purified fractions or well-characterized compounds, supporting unambiguously the beneficial effects of proanthocyanidins on endothelial dysfunction. The proanthocyanidin-containing samples evoked endothelium-dependent relaxation in arteries through multiple mechanisms, including the NO-cGMP pathway and, to a lesser extent, activation of the endothelium-derived hyperpolarizing factors (EDHF)-signaling cascade in a redox-sensitive manner. EDHF events are primarily associated with the modulation of Ca2+-dependent and -independent K+ channel functions. In addition, the vascular tone appears to be regulated to various extents by the intracellular Ca2+ concentration. This chapter presents a brief overview of the signaling events in relaxation, summarizes the literature on the vasorelaxant effects of proanthocyanidins in isolated arteries, and provides a critical assessment of plant-based test materials.
Endothelial dysfunction is now well established as a pivotal early event in the development of major cardiovascular diseases including hypertension, atherosclerosis and diabetes. The alteration of the endothelial function is often triggered by an imbalance between the endothelial formation of vasoprotective factors including nitric oxide (NO) and endothelium-dependent hyperpolarization, and an increased level of oxidative stress involving several pro-oxidant enzymes such as NADPH oxidase and, often also, the appearance of cyclooxygenase-derived vasoconstrictors. Pre-clinical studies have indicated that polyphenol-rich food and food-derived products such as grape-derived products, black and red berries, green and black teas and cocoa, and omega-3 fatty acids can trigger activating pathways in endothelial cells promoting an increased formation of NO and endothelium-dependent hyperpolarization. Moreover, intake of such food-derived products has been associated with the prevention and/or the improvement of an established endothelial dysfunction in several experimental models of cardiovascular diseases and in Humans with cardiovascular diseases. This review will discuss both experimental and clinical evidences indicating that different types of food and natural products are able to promote endothelial and vascular health, as well as the underlying mechanisms.
The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic huanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H2O2) now appears to play a dominat role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive Gi (e.g. responses to α2-adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive Gq (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated confirming that the release of NO by the endothelial cell can chronically be up- (e.g. by estrogens, exercise and dietary factors) and down-regulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with aging and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively loose the pertussis-toxin sensitive pathway for NO release which favors vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H2O2), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors (EDCF). Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, aging, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia) can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle. This article is protected by copyright. All rights reserved.
Hypertension is a major public health problem, and a leading cause of premature death and disability in both developed and developing countries, affecting one-quarter of the world's adult population. It is also one of the main cardiovascular risk factors in the elderly. The first steps for the management of hypertension involve following a healthy diet, and modifying lifestyle, including smoking cessation, moderate alcohol consumption, sodium intake restriction, weight reduction, and regular physical activity. Several observational and intervention studies have found an inverse association between the risk of cardiovascular disease and the consumption of polyphenol-rich foods and beverages such as cocoa, fruit and vegetables, tea, virgin olive oil, and wine. This paper reviews the recent clinical and epidemiological studies on the relationship between polyphenol intake and blood pressure, as well as the plausible mechanisms of action for a cardioprotective role of polyphenols. We describe how the vasoprotective effect of dietary polyphenols has been related to their ability to increase endothelial synthesis of nitric oxide and endothelium-derived hyperpolarizing factor-mediated responses.
Numerous studies indicate that regular intake of polyphenol-rich food and beverages such as red wine is associated with a protective effect on the cardiovascular system. In addition to the antioxidant property, polyphenols may also induce a beneficial effect on the cardiovascular system by several other mechanisms including the improvement of the vascular function. Indeed, experimental and clinical studies indicate that polyphenols are potent inducers of two major endothelial vasoprotective mechanisms, the formation of nitric oxide (NO) and the induction of endothelium-derived hyperpolarization (EDH).
Epidemiological studies have revealed an inverse relationship between the risk of cardiovascular mortality and morbidity and the consumption of polyphenol-rich products such as fruits, vegetables, red wine, cocoa and tea. The beneficial effect of polyphenols on the cardiovascular system has been attributable at least in part to their direct effect on blood vessels, and in particular on the endothelium. Indeed, experimental and clinical studies have indicated that polyphenols can increase the formation of endothelial vasoprotective factors and in particular nitric oxide (NO), a potent vasodilator and inhibitor of pro-inflammatory and pro-thrombotic responses, and improve endothelial dysfunction and vascular oxidative stress associated with cardiovascular diseases. The present review will provide both experimental and clinical evidences indicating that polyphenols and polyphenol-rich sources are able to improve the endothelial function and characterize the underlying mechanisms.
The study attempts to determine the involvement of oxidative stress in cardiovascular manifestations during Leiurus quinquestriatus quinquestriatus (LQQ) scorpion envenomation and to examine the possible protective role of red grape seed proanthocyanidins (GSP) against such effects. Lethality studies conducted in mice demonstrated a significant (p<0.01) protection of GSP against venom lethality. Pretreatment with GSP (200 mg kg(-1), p.o., 10 days) prior to venom injection (350 microg kg(-1), s.c.) resulted in a significant decrease in percent mortality as well as in significant prolongation of the animal's survival time (p<0.01). Monitoring the cardiovascular effects elicited by venom injection in anesthetized rats revealed a marked protection of GSP against the increase in mean arterial blood pressure evoked by LQQ venom. Moreover, pretreatment with GSP reduced the characteristic signs of conduction defects, myocardial ischemia, and infarction observed by venom injection. Biochemical analyses showed that scorpion envenomation caused significant (p<0.001) elevation in serum lactate dehydrogenase as well as creatine kinase-MB activities. Such elevation was ameliorated by GSP (p<0.001). Oxidative stress parameters revealed that scorpion venom significantly increased (p<0.001) the level of lipid peroxidative damage in cardiac tissues and reduced the activity of both glutathione reductase and glutathione peroxidase enzymes in cardiac tissues (p<0.05). In the meantime, GSP offered significant protection against lipid peroxidative damage (p<0.05) and enhanced cardiac glutathione reductase activity (p<0.001). In summary, the current study demonstrates that pretreatment with GSP offers significant protection against LQQ envenomation possibly via enhancement of the antioxidant defense systems.
In contrast to the intact wine, cardiovascular effects of the thermally treated wine have not been studied, despite widespread habits of cooking with wine and consumption of mulled wine. Vasodilatory effects of the red wine heated at 75 and 125°C were examined in the isolated rat and guinea pig aorta and compared with the intact and wine dealcoholized without thermal stress. Samples were analyzed for their phenolic content, antioxidant capacity, resveratrol and ethanol contents. Heating-induced degradation of individual phenolic fraction was observed only in the samples treated at 125°C, although total phenolic concentration and related antioxidant activity increased in the thermally treated samples due to the reduction in their volume. All wine samples regardless of treatment caused similar maximal relaxation in both species, but the response was stronger in aortas from guinea pigs. At the lowest concentrations up to 1‰, dealcoholized wine produced vasodilation greater than that produced by intact wine and wines treated at 75 and 125°C, which showed similar vasodilating activity at all concentrations. Our results indicate that wine thermally treated under heating conditions applicable to the preparation of a mulled wine and cooking with wine largely retains vasodilatory activity in vitro despite significant heat-induced changes in its composition.
Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances.
The endothelium maintains vascular homeostasis through the release of active vasodilators. Although nitric oxide (NO) is recognized as the primary factor at level of conduit arteries, increased evidence for the role of another endothelium-derived vasodilator known as endothelium-derived hyperpolarizing factor (EDHF) has accumulated in the last years. Despite the ongoing debate of its intriguingly variable nature and mechanisms of action, the contribution of EDHF to the endothelium-dependent relaxation is currently appreciated as an important feature of "healthy" endothelium. Since EDHF's contribution is greatest at level of small arteries, the changes in the EDHF action are of critical importance for the regulation of organ blood flow, peripheral vascular resistance and blood pressure, and particularly when production of NO is compromised. Moreover, depending on the type of cardiovascular disorders altered EDHF responses may contribute to, or compensate for endothelial abnormalities associated with pathogenesis of certain disease. Consequently, an identification of vessel-specific nature of EDHF, its modulation of biological activity by selective activators or inhibitors might have a significant impact to our understanding of vascular maintenance in health and disease, and provide basis for novel therapeutic strategies. In this review, the contemporary knowledge about mechanism, function and dysfunction of EDHF-typed responses is systemized. The relevance of this part of endothelium-dependent relaxation for main cardiovascular complications is under discussion. Several issues, like gender differences and role of estrogen for EDHF contribution are summarized for the first time. Authors based on their own experience and data of literature propose several guidelines for future research in the field of EDHF.
This study examined the effect of Vitis vinifera grape skin ACH09 extract (ACH09) on metabolic disorders and oxidative stress in adult offspring of rats fed a high-fat diet (HF) during lactation. Four groups of female rats were fed: control diet (7% fat); ACH09 (7% fat + 200 mg·kg·d ACH09 orally); HF (24% fat); HF+ ACH09 (24% fat + 200 mg·kg·d ACH09 orally) during lactation. From weaning onward, all female offspring were fed a control diet and killed when they were 90 or 180 days old. Systolic blood pressure was increased in adult offspring of HF-fed dams, and ACH09 prevented hypertension. Increased adiposity, plasma triglyceride, glucose levels, and insulin resistance were observed in offspring from both ages, and these changes were reversed by ACH09. The plasma oxidative damage assessed by malondialdehyde levels was increased, and nitrite levels decreased in the HF group of both ages, which were reversed by ACH09. In addition, ACH09 restored the decreased plasma and mesenteric artery antioxidant activities of superoxide dismutase, catalase, and glutathione peroxidase in the HF group. In conclusion, ACH09 protected normally fed offspring of HF-fed dams during lactation from phenotypic and metabolic characteristics of metabolic syndrome providing an alternative nutritional resource for the prevention of metabolic syndrome.
Lindera obtusiloba is a medical herb traditionally used in Asia for the improvement of blood circulation, treatment of inflammation, and prevention of liver damage. The possibility that L. obtusiloba affects vascular reactivity remains to be examined. Therefore, the aim of the present study was to evaluate both the in vitro and in vivo vascular effects of an ethanolic extract of L. obtusiloba stems (LOE). Vascular reactivity was assessed in organ chambers using rat aortic rings and the activation of endothelial NO synthase (eNOS) in cultured bovine aortic endothelial cells. LOE induced endothelium-dependent relaxations, which were abolished by inhibitors of nitric oxide synthase (N
ω-nitro-l-arginine) and guanylyl cyclase (1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-L-one), significantly reduced by inhibitors of PI3 kinase (wortmannin and LY294002), and not affected by inhibitors of cyclooxygenase (indomethacin) and endothelium-derived hyperpolarizing factor-mediated responses (charybdotoxin plus apamin). LOE prevented contractile responses to phenylephrine and angiotensin II in rings with endothelium, but not in those without endothelium. LOE caused a concentration-dependent phosphorylation of Akt at Serine473 and eNOS at Serine1177 in endothelial cells. Thereafter, the vasoprotective effect of LOE was investigated in an experimental model of hypertension in rats. Intake of LOE prevented the angiotensin II-induced increase in systolic blood pressure, and endothelial dysfunction to acetylcholine and oxidative stress as assessed using dihydroethidine in aortic rings. The present findings indicate that LOE has vasoprotective and antihypertensive properties most likely by stimulating the endothelial formation of NO and inhibiting oxidative stress.
Muscadine grape seeds have high concentrations of polyphenolic compounds with antioxidant and other properties that would be expected to have favorable effects on endothelial function.
To evaluate the effect of muscadine grape seed supplementation on endothelial function and cardiovascular risk factors in subjects with increased cardiovascular risk.
In a randomized, double-blind, placebo-controlled crossover trial, 50 adults with coronary disease or ≥1 cardiac risk factor received muscadine grape seed supplementation (1300 mg daily) and placebo for 4 weeks each, with a 4-week washout. Resting brachial diameter and brachial flow-mediated dilation (FMD) and biomarkers of inflammation, lipid peroxidation, and antioxidant capacity were determined at the beginning and end of each period and compared in mixed linear models.
There was no evidence of improved FMD (% change) with muscadine grape seed (muscadine grape seed: pre 5.2% ± 0.3%, post 4.6% ± 0.3%, p = 0.06; placebo: pre 5.3% ± 0.4%, post 5.2% ± 0.4%, p = 0.82; p for muscadine grape seed vs. placebo = 0.25). However, there was a significant increase in baseline diameter (mm) with muscadine grape seed supplementation (muscadine grape seed: pre 4.05 ± 0.09, post 4.23 ± 0.10, p = 0.002; placebo: pre 4.12 ± 0.11, post 4.12 ± 0.10, p = 0.93; p for muscadine grape seed vs. placebo = 0.026). All other biomarkers were not significantly altered by muscadine grape seed supplementation.
Four weeks of muscadine grape seed supplementation in subjects with increased cardiovascular risk did not produce a statistically significant increase in brachial flow-mediated vasodilation or a significant change in other biomarkers of inflammation, lipid peroxidation, or antioxidant capacity. However, the muscadine grape seed supplement did result in a significant increase in resting brachial diameter. The clinical significance of the effect on resting diameter is not yet established. More research is warranted to fully characterize the vascular effects of this and other grape-derived nutritional supplements and to determine whether these vascular effects translate into important clinical benefits.
Epidemiological studies have indicated that regular intake of fruit and vegetables and beverages such as red wine and tea, which contain high levels of polyphenols, is associated with a reduced risk of cardiovascular diseases. The beneficial effect of polyphenol-rich natural products has been attributable, at least in part, to their direct effect on blood vessels, and in particular on endothelial cells. Indeed, polyphenols from tea, grapes, berries, and plants have been shown to activate endothelial cells to increase the formation of potent vasoprotective factors including nitric oxide (NO) and endothelium-derived hyperpolarizing factor. Experimental and clinical studies have also indicated that chronic intake of several polyphenol-rich natural products is able to improve endothelial dysfunction and to decrease vascular oxidative stress associated with major cardiovascular diseases such as hypertension. Altogether, these observations suggest that polyphenol-rich sources of natural products have the potential to improve the function of blood vessels and, hence, to protect the vascular system.
The Mediterranean diet has been associated with greater longevity and quality of life in epidemiological studies. Indeed, because of the abundance of fruits and vegetables and a moderate consumption of wine, the Mediterranean diet provides high amounts of polyphenols thought to be essential bioactive compounds that might provide health benefits in terms of cardiovascular diseases and mortality. Several polyphenol-rich sources, such as grape-derived products, cocoa, and tea, have been shown to decrease mean blood pressure in patients with hypertension. The improvement of the endothelial function is likely to be one of the mechanisms by which polyphenols may confer cardiovascular protection. Indeed, polyphenols are able to induce nitric oxide (NO)-mediated endothelium-dependent relaxations in a large number of arteries including the coronary artery; they can also induce endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations in some of these arteries. Altogether, these mechanisms might contribute to explain the antihypertensive and cardio-protective effects of polyphenols in vivo. The aim of this review was to provide a nonexhaustive analysis of the effect of several polyphenol-rich sources and isolated compounds on the endothelium in in vitro, ex vivo, and in vivo models as well as in humans.
Previously, we have demonstrated that the seed of Euterpe oleracea Mart. (açaí) from the Amazon region exerts vasodilator and antihypertensive actions. The aim of our study was to assess the effects of oral chronic treatment with açaí seed extract (ASE, 300 mg · kg(-1) · d(-1)) on high-fat (HF) diet–induced metabolic syndrome (MS) in C57BL/6J mice. Four groups of C57BL/6 mice were fed with control diet (10% fat), ASE (10% fat), HF (60% fat), and HF + ASE (60% fat plus ASE) for 12 weeks. The vasodilator effects of acetylcholine (ACh) and nitroglycerine (NG) were studied in perfused mesenteric arterial bed. Body weight, plasma total cholesterol, triglyceride, glucose and insulin levels, oral glucose tolerance test, and oxidative damage were determined, and the insulin resistance measured by Homeostatic Model Assessment (HOMA) index. Vasodilator response to ACh but not to NG was reduced in HF mice, and ASE restored the response. Increased plasma malondialdehyde levels, body weight, plasma triglyceride, total cholesterol, glucose levels, and insulin resistance were observed in HF mice and reduced by ASE. Treatment with ASE also reduced glucose intolerance observed by oral glucose tolerance test in HF mice. In conclusion, ASE protected C57BL/6J mice fed HF diet from phenotypic and metabolic characteristics of MS, providing an alternative nutritional resource for prevention of MS.
Numerous studies indicate that regular intake of polyphenol-rich beverages (red wine and tea) and foods (chocolate, fruit, and vegetables) is associated with a protective effect on the cardiovascular system in humans and animals. Beyond the well-known antioxidant properties of polyphenols, several other mechanisms have been shown to contribute to their beneficial cardiovascular effects. Indeed, both experimental and clinical studies indicate that polyphenols improve the ability of endothelial cells to control vascular tone. Experiments with isolated arteries have shown that polyphenols cause nitric oxide (NO)-mediated endothelium-dependent relaxations and increase the endothelial formation of NO. The polyphenol-induced NO formation is due to the redox-sensitive activation of the phosphatidylinositol3-kinase/Akt pathway leading to endothelial NO synthase (eNOS) activation subsequent to its phosphorylation on Ser 1177. Besides the phosphatidylinositol3-kinase/Akt pathway, polyphenols have also been shown to activate eNOS by increasing the intracellular free calcium concentration and by activating estrogen receptors in endothelial cells. In addition to causing a rapid and sustained activation of eNOS by phosphorylation, polyphenols can increase the expression level of eNOS in endothelial cells leading to an increased formation of NO. Moreover, the polyphenol-induced endothelium-dependent relaxation also involves endothelium-derived hyperpolarizing factor, besides NO, in several types of arteries. Altogether, polyphenols have the capacity to improve the endothelial control of vascular tone not only in several experimental models of cardiovascular diseases such as hypertension but also in healthy and diseased humans. Thus, these experimental and clinical studies highlight the potential of polyphenol-rich sources to provide vascular protection in health and disease.
There are several epidemiological studies suggesting that moderate daily consumption of red wine may reduce cardiovascular risk. Additionally, results from a great number of in vitro studies indicate that constituents found in red wine are responsible for quite a few beneficial effects on endothelial cells. However, comparison of postprandial studies and clinical trials concerning red wine consumption leads to controversial results about its effect on endothelial function and especially flow-mediated dilatation (FMD). Endothelial function is an early indicator of atherosclerosis and vessel damage and at the same time, it is an independent prognostic factor for cardiovascular risk. Therefore, it is very important to investigate the known acute postprandial effects of red wine consumption, which is highly advised by dieticians and doctors, especially in high-risk populations, such as patients with coronary artery disease (CAD).
This is a review of studies investigating acute and short-term effects of red wine on endothelial function, as well as relevant in vitro studies.
Analysis of all data about the acute effects of red wine constituents on endothelial function, is inconclusive and it is obvious that new studies are necessary in order to elucidate this matter. Undoubtedly, one should be very careful in suggesting red wine consumption in high-risk populations, as its acute postprandial effect is not yet clear.
An alcohol-free grape-skin extract (GSE) obtained from skins of Vitis labrusca has significant anti-hypertensive, antioxidant and vasodilator effects. According to our previous results, the vasodilator effect of GSE in the isolated mesenteric vascular bed (MVB) of the rat is dependent on endothelium and partially dependent on nitric oxide (NO). In the MVB of the rat pre-contracted with norepinephrine (NE), bolus injections of GSE induced a long-lasting dose-dependent vasodilation that is significantly reduced after the treatment with 1H-[1,2,3] oxadiazolo [4,4-a] quinoxalin-1-one (ODQ). Additionally, in vessels pre-contracted with norepinephrine and depolarized with KCl (25 mM) or treated with Ca(2+)-dependent K(+)-channel blockers charybdotoxin (ChTx) plus apamin, the vasodilator effect of GSE was significantly reduced and almost abolished by ChTx plus apamin plus L-NAME. However, the vasodilator effect of GSE was unaffected by D-Arg[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykinin (HOE-140), atropine, yohimbine, pyrilamine and 4-aminopyridine (4-AP). The vasoconstriction response elicited by bolus injection of KCl was not affected by GSE, whereas the vasoconstrictor response induced by NE was dose-dependently and completed inhibited by GSE in the presence but not in the absence of endothelium. However, NE-induced vasoconstriction in calcium-free condition or without endothelium was not reduced by GSE. The present results demonstrate that GSE induces a vasodilator effect in the rat MVB, which is dependent on NO in combination with endothelium-derived hyperpolarizing factor (EDHF). Additionally, our results indicated that extracellular Ca(2+) has an important role on the endothelium-dependent vasodilator effect induced by GSE.
Alpinia zerumbet (K. Schum), a medicinal plant originated from West Asia, is used in the northeast and southeast of Brazil as infusions or decoctions as a diuretic, antihypertensive, and antiulcerogenic. Experiments were undertaken to determine whether a hydroalcoholic extract obtained from leaves of Alpinia zerumbet (AZE) induces vasodilation in the mesenteric vascular bed (MVB), and an antihypertensive effect was also assessed in rats with DOCA-salt hypertension. In MVB precontracted with norepinephrine, AZE induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3]oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of AZE. In vessels precontracted with norepinephrine, the vasodilator effect of AZE was not changed by 4-aminopyridine, glibenclamide, or by charybdotoxin plus apamin. Concentrations of atropine, pyrilamine, and yohimbine that significantly reduced the vasodilator effect of acetylcholine, histamine, and clonidine, respectively, did not change the vasodilator effect of AZE. HOE 140, which significantly reduced the vasodilator effect of bradykinin, induced a slight but significant reduction on the vasodilator effect of AZE. Chronic oral administration of AZE induced a significant reduction in systolic, mean, and diastolic arterial pressure in rats with DOCA-salt hypertension. Probably the vasodilator effect of AZE is dependent on the activation of the NO-cGMP pathway and independent of activation of ATP-dependent, voltage-dependent, and calcium-dependent K+ channels. Bradykinin receptors may also participate in the vasodilator effect of AZE. Finally, the vasodilator and antihypertensive effects of AZE demonstrated in the present study provide experimental support for the indication of Alpinia zerumbet as an antihypertensive medicinal plant.
There is a growing interest in the anti‐oxidant characteristics and use of flavonoids in the management of cardiovascular diseases. The cardiovascular mechanism of action of these plant derivatives remains controversial. This study compared the effects of the flavonoid quercetin with those of the anti‐oxidant vitamin ascorbic acid (vitamin C) on the reactivity of aortic rings from spontaneously hypertensive rats (SHR).
The phenylephrine (PE)‐induced contractile and the endothelium‐dependent and independent relaxant responses of aortic rings from 21 to 22 week old SHR and age‐matched normotensive Wistar (WKY) rats were observed in the presence of quercetin or ascorbic acid. All the experiments were performed in the presence of the cyclooxygenase inhibitor, indomethacin (10 mmol/L).
The endothelium‐dependent and independent relaxations to acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were significantly lesser in the SHR compared to the WKY tissues whereas the contractile responses to PE were similar in both tissues. Pretreatment of WKY rings with quercetin or ascorbic acid had no effect on the responses to ACh or PE. In the SHR tissues, however, quercetin or ascorbic acid significantly improved the relaxation responses to ACh and reduced the contractions to PE with greater potency for quercetin. Both compounds lacked any effects on the responses to SNP in either aortic ring types. Nw‐nitro‐L‐arginine methyl ester ( l ‐NAME, 10 mmol/L) significantly attenuated the vasodepressor effects of quercetin and ascorbic acid, raising the responses to PE to a level similar to that observed in the control SHR tissues. In l ‐NAME pretreated aortic rings, quercetin and ascorbic acid inhibited the contractile responses to PE with the same magnitude in WKY and SHR tissues.
The present results suggest that acute exposure to quercetin improves endothelium‐dependent relaxation and reduces the contractile responses of hypertensive aortae with a greater potency than ascorbic acid. This suggests a better vascular protection with this flavonoid than ascorbic acid in the SHR model of hypertension and possibly in human cardiovascular diseases.
The "French paradox" (apparent compatibility of a high fat diet with a low incidence of coronary atherosclerosis) has been attributed to the regular drinking of red wine. However, the alcohol content of wine may not be the sole explanation for this protection. Red wine also contains phenolic compounds, and the antioxidant properties of these may have an important role. In in-vitro studies with phenolic substances in red wine and normal human low-density lipoprotein (LDL) we found that red wine inhibits the copper-catalysed oxidation of LDL. Wine diluted 1000-fold containing 10 mumol/L total phenolics inhibited LDL oxidation significantly more than alpha-tocopherol. Our findings show that the non-alcoholic components of red wine have potent antioxidant properties toward oxidation of human LDL.
Deaths from ischaemic heart-disease in 18 developed countries are not strongly associated with health-service factors such as doctor and nurse density. There is a negative association with gross national product per capita and a positive but inconsistent association with saturated and monounsaturated fat intake. The principal finding is a strong and specific negative association between ischaemic heart-disease deaths and alcohol consumption. This is shown to be wholly attributable to wine consumption.
Although cyclic GMP was first described as a biological product more than 2 decades ago, the anticipated role of this cyclic nucleotide as another second messenger has been slow to develop. Many explanations could be offered for these delays, including its relatively low concentration in tissues. However, the presence of multiple isoenzyme forms of guanylate cyclase and their complex and unique mechanisms of regulation have no doubt been major contributors to the difficulties in this field. A detailed understanding of guanylate cyclase regulation has led to several proposed functions for cyclic GMP as summarized in this review. In recent years this isoenzyme forms have been purified and characterized from several tissues. The discoveries that these enzyme forms could be activated with nitrovasodilators, nitric oxide, other free radicals, endothelium-derived relaxant factor (EDRF), Escherichia coli heat-stable enterotoxin (ST), and atrial natriuretic factor (ANF) have markedly stimulated the interests in cyclic GMP and have led to several proposed functions of the guanylate cyclase-cyclic GMP system. This review will not consider some other major developments with cyclic nucleotide phosphodiesterases, cyclic GMP-dependent protein kinase, and identification of some of the latter enzyme's substrates. Clearly, cyclic GMP has emerged as one of the few fundamental second messengers. It has also become apparent that perturbation of one of these second messengers may alter the production, release, degradation, or action of the others. Complex interactions between cyclic GMP, cyclic AMP, calcium, and inositol phosphates have been described. This review will summarize many of the data available regarding the synthesis of cyclic GMP by guanylate cyclase and several of its functions.
The "French paradox" (apparent compatibility of a high fat diet with a low incidence of coronary atherosclerosis) has been attributed to the regular drinking of red wine. However, the alcohol content of wine may not be the sole explanation for this protection. Red wine also contains phenolic compounds, and the antioxidant properties of these may have an important role. In in-vitro studies with phenolic substances in red wine and normal human low-density lipoprotein (LDL) we found that red wine inhibits the copper-catalysed oxidation of LDL. Wine diluted 1000-fold containing 10 mumol/L total phenolics inhibited LDL oxidation significantly more than alpha-tocopherol. Our findings show that the non-alcoholic components of red wine have potent antioxidant properties toward oxidation of human LDL.
Statistical evidence of reduced coronary heart disease in areas of high wine consumption has led to the widespread belief that wine affords a protective effect. Although moderate drinking of any alcohol helps to reduce the incidence of coronary heart disease, there is no clear evidence that red wine confers an additional benefit. Here we show that red wines strongly inhibit the synthesis of endothelin-1, a vasoactive peptide that is crucial in the development of coronary atherosclerosis. Our findings indicate that components specific to red wine may help to prevent coronary heart disease.
The effects of the red wine polyphenolic compounds (Provinol) on hypertension, left ventricular hypertrophy, myocardial fibrosis, and vascular remodeling were investigated after chronic inhibition of nitric oxide (NO) synthase by administration of N(G)-nitro-L-arginine methyl ester (L-NAME) to rats. Rats were divided into four groups: a control group, a group treated for 4 wk with L-NAME (40 mg x kg(-1) x day(-1)), and two groups treated with L-NAME followed by 3 wk of either spontaneous recovery or recovery with Provinol treatment (40 mg x kg(-1) x day(-1)). Administration of Provinol produced a greater readiness of the decrease in blood pressure than that in the spontaneous recovery group. Provinol significantly depressed myocardial fibrosis and expedited the decrease in aortic cross-sectional area, the increase in endothelium-dependent relaxation, and the decrease in contraction of the aorta. These effects of Provinol were associated with a greater increase of NO synthase activity in the left ventricle and the aorta. The present study provides evidence that Provinol accelerates the regression of blood pressure and improves structural and functional cardiovascular changes produced by chronic inhibition of NO synthesis.
Epidemiological studies have suggested that moderate consumption of red wine may decrease the incidence of coronary artery disease. It was hypothesized that polyphenols may be involved in this cardioprotective effect because of their antioxidant and free radical scavenging properties, resulting in decreased generation of oxidized lipids. Recently the authors reported that red wine extracts (cabernet-sauvignon grape variety) enriched in polyphenolic compounds (RWPC) elicited enhanced NO generation, cyclic GMP accumulation and endothelium-dependent relaxation in rat aortic rings. To determine which group(s) of polyphenols are able to produce these effects, endothelium-dependent relaxation caused by chromatographically resolved fractions of RWPC was studied further in rat aortic rings. Both anthocyanins and oligomeric condensed tannins exhibited a pharmacological profile comparable with that of the original RWPC. Among the anthocyanins, delphinidin, but not malvidin or cyanidin, produced endothelial NO-dependent vasorelaxation, indicating that only some specific structures are able to cause endothelium-dependent vasorelaxation, independently of their antioxidant properties. The mechanism of RWPC-induced NO release was studied further in rat aortic rings. Extracellular Ca2+ was needed, suggesting that increased Ca2+ level accounted for endothelial NO synthase activation. These findings suggest that one of the mechanisms of the cardioprotective effects of red wine and other plants containing polyphenols may be the increase in endothelial NO production induced by oligomeric condensed tannins and anthocyanins.
The endothelium plays an obligatory role in a number of relaxations of isolated arteries. These endothelium-dependent relaxations are due to the release by the endothelial cells of potent vasodilator substances [endothelium-derived relaxing factors (EDRF)]. The best characterized EDRF is nitric oxide (NO). Nitric oxide is formed by the metabolism of L-arginine by the constitutive NO synthase of endothelial cells. In arterial smooth muscle, the relaxations evoked by EDRF are explained best by the stimulation by NO of soluble guanylate cyclase that leads to the accumulation of cyclic GMP. The endothelial cells also release an unidentified substance that causes hyperpolarization of the cell membrane (endothelium-derived hyperpolarizing factor, EDHF). The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive (alpha2-adrenergic activation, serotonin, thrombin, aggregating platelets) and insensitive (adenosine diphosphate, bradykinin) G-proteins. In blood vessels from animals with regenerated endothelium, and/or atherosclerosis, there is a selective loss of the pertussis-toxin sensitive mechanism of EDRF-release which favors the occurrence of vasospasm, thrombosis and cellular growth.
Objectives
The study tested the effect of red wine on endothelial-type nitric oxide synthase (eNOS) expression and eNOS activity in human endothelial cells.
Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Continuous production of endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. NO is also formed in the brain upon activation of glutamate receptors, which are thought to mediate central autonomic reflexes. In the present study we assessed whether NO plays a role in central autonomic regulation. For this, we have investigated the effects of NG-methyl-L-arginine (NMA), a selective inhibitor of NO synthesis from L-arginine, on sympathetic renal nerve activity (RNA), blood pressure, and heart rate in the anesthetized rat. NMA elicited a dose-dependent sustained increase in blood pressure (approximately 20 and 30 mm Hg, 5 minutes after 10 and 50 mumol/kg i.v., respectively). Heart rate and RNA decreased transiently (15 beats per minute and 40%, respectively); RNA subsequently increased (100%) while blood pressure remained elevated. Baroreceptor deafferentation markedly altered these responses to NMA; the transient decreases in heart rate and RNA were abolished, whereas the increases in RNA and blood pressure were significantly potentiated. After spinal C-1-C-2 transection, there was no increase in RNA, and blood pressure increased to a smaller extent. L-Arginine blocked the NMA-induced increases in blood pressure and RNA. Thus, in addition to modulating vascular resistance by a peripheral action, NO may also play a role in the central regulation of sympathetic tone.
The regional hemodynamic consequences of inhibiting vascular endothelial nitric oxide generation with NG-monomethyl-L-arginine (L-NMMA) were studied in conscious Long-Evans rats. Experiments were carried out in groups of chronically instrumented rats with intravascular catheters and pulsed Doppler probes to monitor regional blood flow. L-NMMA (0.3-300 mg/kg) caused a dose-dependent, long-lasting (5-90 minutes), and enantiomerically specific increase in mean blood pressure and also caused bradycardia. The increase in blood pressure was accompanied by a dose-dependent and long-lasting vasoconstriction in the internal carotid, mesenteric, renal, and hindquarters vascular beds that could be attenuated, in a concentration-dependent manner, by L-arginine but not by D-arginine. In contrast, L-arginine did not affect the pressor or vasoconstrictor effects of vasopressin. These results indicate that nitric oxide production by vascular endothelial cells contributes to the maintenance of blood pressure and to the control of the resting tone of different vascular beds in the conscious rat.
Stimulation of the endothelial lining of arteries with acetylcholine results in the release of a diffusible substance that relaxes and hyperpolarizes the underlying smooth muscle. Nitric oxide (NO) has been a candidate for this substance, termed endothelium-derived relaxing factor. But there are several observations that argue against the involvement of NO in acetylcholine-induced hyperpolarization. First, exogenous NO has no effect on the membrane potential of canine mesenteric arteries. Second, although haemoglobin (believed to bind and inactivate NO (refs 11-15)) and methylene blue (which prevents the stimulation of guanylate cyclase) inhibit relaxation, neither has an effect on hyperpolarization. Finally, nitroprusside, thought to generate NO in vascular smooth muscle, relaxes rat aorta without increasing rubidium efflux. Nevertheless, nitrovasodilators, nitroprusside and nitroglycerin cause hyperpolarization in some arteries. NO might therefore be responsible for at least part of the hyperpolarization induced by acetylcholine. We now report that hyperpolarization and relaxation evoked by acetylcholine are reduced by NG-monomethyl-L-arginine, an inhibitor of NO biosynthesis from L-arginine. Thus NO derived from the endothelium can cause hyperpolarization of vascular smooth muscle, which might also contribute to relaxation by closing voltage-dependent calcium channels. Our findings raise the possibility that hyperpolarization might be a component of NO signal transduction in neurons or inflammatory cells.
The response to endothelin, a novel 21-amino acid peptide, is investigated in isolated aortas with and without endothelium and in mesenteric microvessels in vivo-in situ, in Goldblatt II (GII) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Median effective concentrations and maximal responses to endothelin did not differ in aortas with endothelium isolated from GII, DOCA-salt hypertensive, and control rats. After removal of the endothelium, the potentiation of the aorta responses to endothelin was of the same magnitude in hypertensive and control rats. A closed-circuit television system was used to observe the microvascular bed of the exteriorized mesentery of anesthetized GII, DOCA-salt hypertensive, and control rats. The time necessary to induce a vasoconstrictor response was determined after the topical application of endothelin. Vessel diameters at rest and after endothelin application were also estimated. At the microcirculatory level, a greater reactivity to endothelin was observed in both hypertensive rat groups, whereas higher sensitivity to endothelin was recorded in the GII hypertensive microvessel preparations alone. It is suggested that the increased response to endothelin observed in hypertensive rats might be due to abnormal sensitivity or reactivity of the microvessels of these rats reflecting an alteration of the contractile sequence possibly at the plasma membrane level, or due to both. Endothelial dysfunction at the microcirculatory level, however, cannot be dismissed.
The evolution of renal excretory function and circulating vasoactive systems was studied during progressive increases in blood pressure (BP) induced in rats by oral administration of NG-nitro-L-arginine methyl ester (L-NAME; 5-30 mg/100 ml) for 5 wk. L-NAME induced a stepped elevation (P < 0.05) in BP levels without changing creatinine clearance, urine flow, or sodium excretion rate along the study. Reductions (P < 0.05) in plasma renin activity and plasma aldosterone concentration were found only during treatment with 30 mg/100 ml of L-NAME. Plasma norepinephrine and epinephrine concentrations were elevated (P < 0.05) in the last week of the study. Plasma concentrations of endothelin-1 and urinary excretion of prostaglandin E2, 6-ketoprostaglandin F1 alpha, and thromboxane B2 were not significantly affected by L-NAME. Similarly, no changes in plasma concentrations of glucose, insulin, total cholesterol, or triglycerides were observed. In summary, during long-term administration of L-NAME, progressive increases in BP levels were observed without changes in either sodium excretion or enhanced circulating vasoconstrictor activity. Thus, it is likely that inhibition of synthesis of nitric oxide (NO) in the vasculature leads to an imbalance between the tonic relaxing action of NO and the influences of vasoconstrictor agents even when the latter remain at normal levels.
Background Continuous production of nitric oxide (NO) from endothelial cells permanently inhibits the synthesis and the vasoconstrictor effects of endothelin. Thus, inhibition of NO synthesis might unmask a vasopressor response to endothelin. To assess whether endothelin contributes to the pressor response induced by inhibition of NO synthesis, we tested whether bosentan, a nonpeptide antagonist of ET A and ET B endothelin receptors, affected the hypertensive response induced by the NO synthase inhibitor N G -nitro l -arginine methyl ester (L-NAME).
Methods and Results Anesthetized rats received increasing doses of L-NAME (0.1 to 3 mg · kg ⁻¹ ) in the absence or the presence of bosentan (3 mg · kg ⁻¹ IV 15 minutes before L-NAME). Bosentan itself did not affect blood pressure. L-NAME induced a dose-dependent increase in mean arterial pressure (percent increase from baseline after 3 mg · kg ⁻¹ , 25±5%), and this was reduced by bosentan (13±3%; P <.05) or by the selective ET A antagonist BQ-123 (3 mg · kg ⁻¹ : controls, 25±4%; BQ-123, 14±5%; P <.01). In contrast, bosentan did not affect the pressor response to phenylephrine (1 to 100 μg · kg ⁻¹ ). The response to L-NAME (3 mg · kg ⁻¹ ) was also reduced by bosentan in ganglion-blocked (chlorisondamine 2.5 mg · kg ⁻¹ : controls, 89±10%; bosentan, 45±7%) or pithed rats (controls, 165±9%; bosentan, 85±12%; P <.01). Bosentan also inhibited the pressor response to another inhibitor of NO synthesis, N G -nitro l -arginine (3 mg · kg ⁻¹ ) in normal (controls, 24±5%; bosentan, 10±3%; P <.01) or ganglion-blocked (controls, 86±13%; bosentan, 25±8%; P <.01) rats. Finally, L-NAME induced a modest increase in plasma levels of endothelin-1 (controls, 26.8±4.1 pg · mL ⁻¹ ; L-NAME, 38.5±3.3 pg · mL ⁻¹ ; P <.05).
Conclusions These experiments demonstrate that inhibition of NO synthesis unmasks a tonic pressor influence of endothelin, suggesting that this peptide could play a major role in pathophysiological situations associated with an impaired formation of NO.
Moderate daily consumption of alcoholic beverages is a negative risk factor for the development of atherosclerosis and coronary artery disease (CAD), especially in France and other Mediterranean areas where red wine is regularly consumed with meals. Platelets contribute to the development of atherosclerosis, CAD, and acute arterial thrombus formation.
Anesthetized dogs were prepared with the Folts model of mechanically stenosed coronary arteries and intimal damage. Periodic acute platelet-mediated thrombus formation occurred, causing cyclic flow reductions (CFRs) in coronary blood flow. The CFRs were eliminated by the administration of 1.62 +/- 1.12 mL/kg red wine intravenously (IV) and 4.0 mL/kg intragastrically (IG). The CFRs were abolished by 2.04 +/- 1.42 mL/kg of grape juice IV and 10 mL/kg IG. White wine did not have significant results in eliminating the CFRs, either IV (2.0 mL/kg) or IG (4.0 mL/kg), decreasing the slopes of the CFRs only slightly.
Pure ethanol has been shown to inhibit platelet aggregation in vitro, ex vivo, and in vivo, although a blood alcohol content (BAC) of > or = 0.2 g/dL is usually required. The BAC of dogs administered the red wine-saline solution intravenously was 0.028 g/dL, much less than is usually necessary for platelet inhibition with pure ethanol. Because red wine and grape juice, but not white wine, abolished the CFRs, this suggests there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine. Wine and grape juice contain a wide variety of naturally occurring compounds, including fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones). These compounds have shown platelet inhibition in vitro by a variety of proposed mechanisms. Perhaps the biological activity of these compounds can explain the platelet-inhibitory properties of red wine and grape juice that are observed without high levels of ethanol.
The present study was designed to investigate the role of the autonomic nervous system in experimental hypertension induced by chronic administration of N-nitro-L-arginine methyl ester (L-NAME) in the drinking water (1 mg/mL) over 6 days. L-NAME ingestion caused a large rise in resting mean arterial pressure (MAP) (175 +/- 5 mm Hg) and heart rate (HR) (440 +/- 17 beats per minute) compared to nontreated control rats (resting MAP: 112 +/- 2 mm Hg and HR: 345 +/- 8 beats per minute). Ganglionic blockade induced by trimethaphan (5 mg/kg, intravenously) caused a significantly (P < .01) greater decrease in MAP (delta -86 +/- 7 mm Hg) compared to control rats MAP (delta -44 +/- 4 mm Hg). This strongly suggests that the level of central sympathetic tone in L-NAME-treated rats is much greater than in nontreated rats. Using atenolol and atropine alone and combined, the level of resting sympathetic drive to the heart was found to be significantly increased in L-NAME-treated rats compared to control rats. However, vagal tone to the heart was found to be virtually abolished in L-NAME-treated rats compared to control rats. These results indicate that an increase in central sympathetic drive plays an important role in the hypertension induced by chronic inhibition of nitric oxide synthesis with L-NAME.
Current interest in the presumed benefits of wine in protecting against coronary heart disease prompted us to investigate possible effects of various grape products on vascular function in vitro. Certain wines, grape juices, and grape skin extracts relaxed precontracted smooth muscle of intact rat aortic rings but had no effect on aortas in which the endothelium had been removed. Quercitin and tannic acid, compounds known to be present in grape skins, also produced endothelium-dependent relaxation; two other grape skin compounds, resveratrol and malvidin, did not relax the rings. Phenylephrine-induced contractions were attenuated by prior exposure of aortic rings to grape skin extracts. The extracts also increased guanosine 3',5'-cyclic monophosphate (cGMP) levels in intact vascular tissue, and both relaxation and the increase in cGMP were reversed by NG-monomethyl-L-arginine and NG-nitro-L-arginine, competitive inhibitors of the synthesis of the endothelium-derived relaxing factor, nitric oxide (NO). The vasorelaxation induced by grape products therefore appears to be mediated by the NO-cGMP pathway. If such responses occur in vivo, they could conceivably help to maintain a patent coronary artery and thereby possibly contribute to a reduced incidence of coronary heart disease.
1. Transmembrane potentials were recorded from isolated carotid arteries of the guinea-pig superfused with modified Krebs-Ringer bicarbonate solution. Smooth muscle cells were impaled from the adventitial side with intracellular glass microelectrodes filled with KCl (30-80 M omega). 2. Acetylcholine (1 microM) in the presence of inhibitors of nitric oxide synthase, (N omega-nitro-L-arginine (L-NOARG) 100 microM) and cyclo-oxygenase, (indomethacin 5 microM) induced an endothelium-dependent hyperpolarization (-18.9 +/- 1.6 mV, n = 15). 3. In the presence of these two inhibitors, S-nitroso-L-glutathione (10 microM), sodium nitroprusside (10 microM), 3-morpholinosydnonimine (SIN-1, 10 microM) and iloprost (0.1 microM) induced endothelium-independent hyperpolarizations of the smooth muscle cells (respectively: -16.0 +/- 2.3, -16.3 +/- 3.4, -12.8 +/- 2.0 and -14.5 +/- 1.5 mV, n = 4-6). 4. The addition of glibenclamide (1 microM) did not influence the acetylcholine-induced L-NOARG/ indomethacin-resistant hyperpolarization (-18.0 +/- 1.8 mV, n = 10). In contrast, the responses induced by S-nitroso-L-glutathione, sodium nitroprusside, SIN-1 and iloprost were abolished (changes in membrane potential: -0.8 +/- 1.1, 1.3 +/- 3.9, 4.5 +/- 4.6 and 0.3 +/- 0.8 mV respectively, n = 4-5). 5. In the presence of NO synthase and cyclo-oxygenase inhibitors, charybdotoxin (0.1 microM) or apamin (0.5 microM) did not influence the hyperpolarization produced by acetylcholine. However, in the presence of the combination of charybdotoxin and apamin, the acetylcholine-induced L-NOARG/indomethacin-resistant hyperpolarization was converted to a depolarization (4.4 +/- 1.2 mV, n = 20) while the endothelium-independent hyperpolarizations induced by S-nitroso-L-glutathione, sodium nitroprusside, SIN-1 and iloprost were not affected significantly (respectively: -20.4 +/- 3.4, -22.5 +/- 4.9, -14.5 +/- 4.7 and -14.5 +/- 0.5 mV, n = 4-5). 6. In the presence of the combination of charybdotoxin and apamin and in the absence of L-NOARG and indomethacin, acetylcholine induced a hyperpolarization (-19.5 +/- 3.7 mV, n = 4). This hyperpolarization induced by acetylcholine was not affected by the addition of indomethacin (-18.3 +/- 4.6 mV, n = 3). In the presence of the combination of charybdotoxin, apamin and L-NOARG (in the absence of indomethacin), acetylcholine, in 5 out of 7 vessels, still produced hyperpolarization which was not significantly smaller (-9.1 +/- 5.6 mV, n = 7) than the one observed in the absence of L-NOARG. 7. These findings suggest that, in the guinea-pig isolated carotid artery, the endothelium-independent hyperpolarizations induced by NO donors and iloprost involve the opening of KATP channels while the acetylcholine-induced endothelium-dependent hyperpolarization (resistant to the inhibition of NO-synthase and cyclo-oxygenase) involves the opening of Ca(2+)-activated potassium channel(s). Furthermore, in this tissue, acetylcholine induces the simultaneous release of various factors from endothelial origin: hyperpolarizing factors (NO, endothelium derived hyperpolarizing factor (EDHF) and prostaglandins) and possibly a depolarizing factor.
In most blood vessels, the endothelium generates both vasodilator and growth-stabilizing mediators under normal physiological circumstances. The vasodilator influence of the endothelium modulates the vasoconstriction induced by adrenergic nerves, bloodborne substances, and local autacoids. Nitric oxide (NO) is a major endothelium-derived vasodilator, along with prostacyclin. A third substance called endothelium-derived hyperpolarizing factors (EDHF) mediates vasodilatation in certain conduit arteries and in most resistance vessels. EDHF may be a cytochrome P-450 metabolite of arachidonic acid. NO acts mostly through an elevation of cyclic guanosine monophosphate in vascular smooth muscle, whereas prostacyclin stimulates adenylate cyclase. The mode of action of EDHF involves the activation of K+ channels. The multiplicity of the factors released by the endothelium, as well as the complexity of the interactions among these factors and those with other nonendothelial mediators, determine the extent of vasomotor control exerted locally by the endothelium.
The contribution of the endothelium-derived hyperpolarizing factor (EDHF), proposed to be a cytochrome P450-derived metabolite of arachidonic acid, to endothelium-dependent dilatation under physiological conditions has yet to be established, because its effect can be detected only after inhibition of NO synthase and cyclooxygenase. The possibility that NO exerts a feedback inhibition on EDHF formation was studied in isolated perfused arterial segments.
Under combined blockade of NO synthase and cyclooxygenase, the EDHF-mediated vasodilatation elicited by receptor-dependent agonists in rabbit carotid and porcine coronary arteries was significantly attenuated by the NO donors C87-3786 and CAS 1609. The endothelium-independent dilatation elicited by isoproterenol was not altered by either NO donor. In NG-nitro-L-arginine-treated carotid artery segments, C87-3786 significantly attenuated the acetylcholine-induced increase in 6-keto-prostaglandin F1 alpha release, which was taken as an index of arachidonic acid liberation. In parallel experiments using cultured human endothelial cells, C87-3786 attenuated the Ca2+ response to bradykinin. The release of EDHF from a luminally perfused porcine coronary artery was detected by recording the membrane potential of downstream-situated cultured rat aortic smooth muscle cells. The NO donor C87-3786 had no effect on the hyperpolarization elicited by preformed EDHF but markedly inhibited its release from bradykinin-stimulated donor segments.
These findings indicate that under physiological conditions, the production of EDHF is damped by NO. Therefore, it follows that when NO synthesis is impaired, alleviation of this intrinsic inhibition may, at least in part, maintain endothelial vasodilator function.
Beneficial effects of wine on myocardial infarction mortality may be because of its vasodilatory properties. This study investigated whether the vasodilatory activity involves the endothelium and is specific for certain wines. Effects of different red and white wines and phenolic grape ingredients on vascular tension and cGMP content were studied in human coronary arteries and rat aortic rings in vitro. Only French and Italian red wines produced "en barrique" (Bordeaux, Châteauneuf du Pape, Barolo) (1:1,000, vol/vol), quercetin (1-100 microM), and tannic acid (1-100 microgram/ml) decreased tension of precontracted vascular rings and increased vascular cGMP content (both P < 0.001). The effects were abolished after endothelial denudation and reversible by nitric oxide synthase inhibition. Red wines not produced en barrique (Valpolicella, Ahr Spätburgunder), white wines (en barrique-produced Rioja, Chardonnay, Mosel-Riesling), and ethanol did not affect vascular tension or cGMP content. Thus endothelium-dependent vasodilatory effects appear to be specific for red barrique wines, possibly because of their high content of phenolic substances. Divergent effects of wines indicate that a general view on the effects of wine and alcoholic beverages is not warranted.
The mechanisms by which red wine polyphenolic compounds (RWPCs) induced endothelium-dependent relaxation were investigated in rat thoracic aorta rings with endothelium. RWPCs produced relaxation that was prevented by the nitric oxide (NO) synthase inhibitor, N(omega)-nitro-L-arginine-methyl-ester. This relaxation was abolished in the absence of extracellular calcium in the medium or in the presence of the Ca2+ entry blocker, La3+, but it was not affected by the nonselective K+ channels blocker, tetrabutylammonium. N-Ethyl-maleimide (NEM), a sulfhydryl alkylating agent, abolished vasorelaxation produced by RWPCs and acetylcholine but not that produced either by the sarcoendoplasmic reticulum Ca2+-adenosine triphosphatase (ATPase) pump inhibitor, cyclopyazonic acid (CPA) or the calcium ionophore, ionomycin. Neither pertussis toxin (PTX) nor cholera toxin (CTX) inhibited the vasorelaxant effect of RWPC. The effect of RWPC was not affected by the phospholipase C (PLC) blocker, L-alpha-glycerophospho-D-myo-inositol 4-monophosphate (Gro-pip), and the phospholipase A2 pathway blockers, quinacrine and ONO-RS-082. Finally, the protein kinase C (PKC) inhibitor, GF 109203X, and tyrosine kinase inhibitors, tyrphostin A-23 and genistein, did not impair the response to RWPCs. These results suggest that RWPCs produce endothelium-NO-derived vasorelaxation through an extracellular Ca2+-dependent mechanism via an NEM-sensitive pathway. They also show that PTX- or CTX-sensitive G proteins, activation of PLC or PLA2 pathways, PKC, or tyrosine kinase may not be involved.
Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine methyl ester (L-NAME) activates vascular angiotensin-converting enzyme (ACE) and causes oxidative stress. We investigated the role of oxidative stress in the pathogenesis of ACE activation in rats. Studies involved aortas of rats receiving no treatment, L-NAME, L-NAME plus L-arginine, or L-NAME plus an antioxidant drug (N-acetylcysteine, allopurinol, or ebselen) for 7 days. L-NAME significantly increased oxidative stress (O(2)(-)) and ACE activity. The increased O(2)(-) production was normalized by removal of endothelium. Immunohistochemistry showed the increased ACE activity in the endothelial layer. Treatment with antioxidant drugs did not affect the L-NAME-induced increase in systolic arterial pressure but did prevent increases in vascular O(2)(-) production and ACE activity. These results implicate oxidative stress in the pathogenesis of vascular ACE activation in rats with long-term inhibition of NO synthesis. The observed effects of antioxidant drugs on ACE activation do not appear to involve the hypertension induced by L-NAME.
Epidemiological studies have suggested that moderate consumption of red wine might reduce the risk of cardiovascular disease. Red Wine Polyphenolic Compounds (RWPC), a complex extract obtained from red wine, causes endothelium-dependent vasorelaxation in rat aortic rings pre-contracted with noradrenaline. This effect is associated with marked formation of NO in the vessel (directly shown by electron paramagnetic resonance spectroscopy) and it is abolished by the NO synthase inhibitor N(G)-nitro-L-arginine methylester (300 microM). It is mimicked by some defined polyphenols (like the anthocyanin delphinidin) but not by others (malvidin, cyanidin, quercetin, catechin, epicatechin), despite close structures. In addition, RWPC causes an extracellular Ca(2+)-dependent increase in [Ca2+]i in endothelial but not in smooth muscle cells. The efficiency of RWPC in inducing NO production in the aorta and increase in [Ca2+]i, in endothelial cells is comparable to those of carbachol and bradykinine, respectively. These findings provide evidence that RWPC and polyphenols with selective structures can activate an undefined target in endothelial cells. The resulting increase in [Ca2+]i activation of NO-synthase and enhanced formation of NO may be involved in cardiovascular protection.
Recent studies revealed important roles for endothelin-1 (ET-1) in the pathogenesis of hypertension. Whether ET-1 could be a primary cause of hypertension or a secondary factor associated with hypertension, however, remains unknown. In this study, we determined plasma ET-1 levels and the expression of ET-1 mRNA in tissues of rats rendered hypertensive using distinct mechanisms: deoxycorticosterone acetate (DOCA)-salt hypertension: N(G)-nitro-L-arginine-methyl ester- (L-NAME) induced hypertension; and spontaneously hypertensive rats (SHR-SP). ET-1 mRNA expression level was determined by reverse transcriptase polymerase chain reaction (RT-PCR) followed by Southern blotting. There was no significant difference in plasma ET-1 levels between the hypertensive rats and normotensive rats. By contrast, ET-1 mRNA level was significantly increased in various tissues including the adrenal, lung, kidney and brain of these hypertensive rats compared with control rats. Thus, ET-1 gene expression was ubiquitously augmented in tissues of hypertensive rats irrespective of the cause of the hypertension. The results suggest that the increase in ET-1 expression is not the primary cause of hypertension but a secondary outcome which may further exacerbate the hypertension.
Moderate consumption of alcoholic beverages is associated with a reduced risk of coronary heart disease (CHD). Some evidence suggests that red wine is particularly beneficial in this regard and may account in part for the French paradox, although the mechanism of this effect is unknown. We assessed the effects of red wine, ethanol, and quercetin, a major flavonoid constituent of red wine, in coronary resistance vessels (80-150 microm, i.d.) and conductance vessels (300-525 microm, i.d.) of the rabbit. Vessel wall tension was measured in isolated segments maintained in a wire-type myograph (37 degrees C) and preconstricted with 30 mM K+. At an alcohol concentration (14 mM) equivalent to moderate consumption, red wine evoked a small, transient constrictor effect in resistance and conductance vessels (9+/-4%, n = 5; 8+/-1%, n = 7, respectively; p < 0.05). Ethanol alone at this concentration was without effect. Quercetin (5.6, 8, and 30 microM) significantly relaxed resistance (-32+/-4%, n = 10; -47+/-2%, n = 7; -82+/-6%, n = 8, respectively) and conductance (-20+/-3%, n = 8; -32+/-4%, n = 8; -72+/-7%, n = 8, respectively) coronary arteries. Vasorelaxation by quercetin was endothelium-independent and was significantly greater in resistance than in conductance vessels. These data suggest that red wine and ethanol do not evoke relaxation in small coronary arteries at concentrations associated with moderate consumption. Quercetin elicits marked coronary vasorelaxation that is endothelium-independent. However, the concentrations of quercetin necessary to achieve this action are not attained with moderate red wine consumption.
The effects of short-term oral administration of red wine polyphenolic compounds on hemodynamic parameters and on vascular reactivity were investigated in rats. Endothelial function and vascular smooth muscle contractility were studied in association with the induction of gene expression in the vascular wall. Rats were treated daily for 7 days by intragastric administration of either 5% glucose or red wine polyphenolic compounds (20 mg/kg). Administration of these compounds produced a progressive decrease in systolic blood pressure, which became significantly different on day 4. Aortas from rats treated with red wine polyphenolic compounds displayed increased endothelium-dependent relaxation to acetylcholine that was related to increased endothelial NO activity and involved a mechanism sensitive to superoxide anion scavengers. However, no increase in whole-body oxidative stress has been observed in rats treated with red wine polyphenolic compounds, as shown by plasma glutathione assay. Also, in the aorta, red wine polyphenolic compounds increased the expression of cyclooxygenase-2 and increased the release of endothelial thromboxane A(2), which compensated for the extraendothelial NO-induced hyporeactivity in response to norepinephrine, resulting from enhanced inducible NO synthase expression. The present study provides evidence that short-term oral administration of red wine polyphenolic compounds produces a decrease in blood pressure in normotensive rats. This hemodynamic effect was associated with an enhanced endothelium-dependent relaxation and an induction of gene expression (of inducible NO synthase and cyclooxygenase-2) within the arterial wall, which together maintain unchanged agonist-induced contractility. These effects of red wine polyphenolic compounds may be a potential mechanism for preventing cardiovascular diseases.
The risks of excessive alcohol intake are well known, and heavy drinkers should decrease their intake or stop drinking. On the other hand, in comparison with non-drinkers, moderate drinkers are at much lower risk of cardiovascular disease and certain other diseases and have lower total mortality. Thus, middle-aged or older men and post-menopausal women with no contraindications to alcohol use should be informed that they have, on average, net health benefits from the regular consumption of small-to-moderate amounts of alcohol.