[Show abstract][Hide abstract]ABSTRACT: Ceruloplasmin (Cp) antioxidant function is mainly related to its Ferroxidase I (FeOxI) activity, which influences iron-dependent oxidative and nitrosative radical species generation. Peroxynitrite (ONOO-), whose production is increased in heart failure (HF), can affect Cp antioxidant function through aminoacid modification.
We investigated the relationship between FeOxI and Cp tyrosine and cysteine modification and explored in a cohort of HF patients the potential clinical relevance of serum FeOxI.
In chronic HF patients (n=96, 76+9 years, NYHA class2.9+0.8), and age-matched controls (n=35,CTR) serum FeOxI, FeOxII, Cp, nitrotyrosine-bound Cp, BNP, norepinephrine, and hsCRP were measured and the patients were followed-up for 24 months. Cp, BNP, norepinephrine and hsCRP were increased in HF vs CTR. FeOxI was decreased in HF (-20%) and inversely related to nitrotyrosine-bound Cp (r= - 0.305,P=0.003). In HF, FeOxI lower tertile had a mortality rate doubled compared to middle-higher tertiles. FeOxI emerged as a mortality predictor (HR 2.95, CI 1.29-6.75, P=0.011) after adjustment for age, sex, hypertension, smoking, sodium level, eGFR and hsCRP. In experimental settings, ONOO- incubation of serum samples and isolated purified Cp reduced FeOxI activity while increasing Cp tyrosine nitration and cysteine thiol oxidation. Reduced glutathione prevented ONOO-induced FeOxI drop, tyrosine nitration and cysteine oxidation; flavonoid(-)-epicatechin, which prevented Cp tyrosine nitration but not cysteine oxidation, partially impeded ONOO-induced FeOxI drop.
Reduced activity of serum FeOxI is associated with Cp nitration and reduced survival in HF patients. Both Cp tyrosine nitration and cysteine thiol oxidation may be operant in vivo in ONOO-induced FeOxI activity inhibition.
Full-text · Article · Mar 2014 · Circulation Research
[Show abstract][Hide abstract]ABSTRACT: Background:
An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM.
Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75±8years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition.
Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31-0.76) p=0.002) and cTnI (HR 2.03 CI: (1.20-3.45) p=0.009). In fact, with respect to BNP-added SHFM (Harrell's C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+0.021, p=0.033) and only a trend was observed for cTn I (+0.023, p=0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement-IDI) at 1-year (IDI: cTnI, p=0.002; prealbumin, p=0.020), 2-years (IDI: cTnI, p=0.018; prealbumin: p=0.006) and 3-years of follow-up (IDI: cTnI p=0.024; prealbumin: p=0.012).
Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance.
No preview · Article · Apr 2013 · International journal of cardiology
[Show abstract][Hide abstract]ABSTRACT: Objective: To detect the sexual differentiation associated with oxidative stress, hypertension and insulin resistance on an accelerated experimental model of type II diabetes in rat. Methods and Results: Male and female Sprague-Dawley rats (225-250 g) chronically fed 10% of glucose were treated orally either with L-NAME (50 mg/kg/day) alone or with a combination of aspirin (100 mg/kg/day) for 4 weeks. L-NAME treatment in glucose-fed rats progressively increased the systolic blood pressure (with a telemetry device) by 59.3 mmHg (55.9%) in male and by 43.1 mmHg (40.2%) in female compare to control levels, enhanced the aortic and cardiac tissue superoxide production (with the lucigenin-enhanced chemiluminescence method) by 38.2% and 21.9% in male, 26.7% and 10.5% in female, and rose HOMA index by 4.6 times in male and by 2.5 time in female after 4 weeks treatment. The above differences between the male and the females were significant (P < 0.05). Simultaneous oral ASA treatment significantly attenuated the L-NAME plus glucose-induced increases in blood pressure by -34.4 mmHg (-20.8%) in male and by -17.1 mmHg (-11.5%) in female, in the aortic and the cardiac superoxide production (-24.9% and -16.9 % in male, -9.7 % and -8.1 % in female), in HOMA index by -66.0% in male and by -41.9% in female. Conclusions: Male rats are more susceptible to glucose-L-NAME-induced oxidative stress, hypertension, and insulin resistance than females. In addition, the male rats are also more sensitive than female rats to the antioxidant and preventive effects of aspirin against hypertension and diabetes.
No preview · Article · Sep 2012 · Journal of Hypertension
[Show abstract][Hide abstract]ABSTRACT: To evaluate the capacity of chronic ASA therapy to prevent cardiac alterations and increased oxidative stress in cardiomyopathic hamsters.
Male Syrian cardiomyopathic and age-matched inbred control hamsters received ASA orally from the age of 60 days. Animals were sacrificed at the age of 150, 250, and 350 days to evaluate the time course of cardiac hypertrophy and cardiovascular tissue superoxide anion (O(2)(-)) production. At the age of 150 days, the ventricular weight over body weight ratio, resting heart rate, and cardiovascular O(2)(-) production were much higher in cardiomyopathic hamsters than those in control. At the age of 250 days, in addition to the continual deterioration of these parameters with age, the blood pressure started to fall and the signs of heart failure appeared. In these cardiomyopathic hamsters, chronic ASA treatment (a) completely prevented elevated O(2)(-) production and the NAD(P)H oxidase activity, (b) significantly slowed down the development of the cardiac hypertrophy and fibrosis.
Chronic ASA treatment significantly prevents the deterioration of cardiac function and structure as well as the increased oxidative stress in the cardiomyopathic hamster. Our findings suggest that ASA presents a therapeutic potential to prevent cardiac dysfunction.
Full-text · Article · Jul 2012 · Oxidative Medicine and Cellular Longevity
[Show abstract][Hide abstract]ABSTRACT: The objective of the study was to evaluate the efficacy of an interdisciplinary intervention known as Educoeur in reducing cardiovascular risk and improving health behaviors in people without evidence of cardiovascular disease and to compare the Educoeur program to interventions in a specialized clinic and in usual care family practice. In a parallel, randomized, controlled trial of 185 adults with at least two modifiable cardiovascular risk factors, patients were randomly assigned to either Educoeur, specialized clinic or usual care. Cardiovascular risk, biological and lifestyle measures were assessed at baseline and at 2 years. In Educoeur, measurements were also taken before and after the lifestyle group treatment program. In 12 weeks, patients in Educoeur significantly lowered their cardiovascular risk, weight, body mass index, waist circumference, systolic blood pressure, kilocalories intake and improved their VO(2) Max and mental health. Changes remained significant at 2 years. Between group comparisons at 2 years demonstrated that Educoeur was significantly better in reducing cardiovascular risk than interventions in usual care. Together, these results highlight the importance of providing interdisciplinary programs that optimize cardiovascular risk reduction and promote active lifestyles in patients at risk of cardiovascular disease.
No preview · Article · Mar 2012 · Journal of Behavioral Medicine
[Show abstract][Hide abstract]ABSTRACT: Inflammation and oxidative stress have been identified as integral parts in the pathogenesis of hypertension. Cyclo-oxygenase-2 which could elicit inflammation and free radicals generation appears to be a key enzyme in hypertension. Cyclo-oxygenase-2 expression and oxidative stress in cardiovascular tissues are increased in the angiotensin II model.
Cyclo-oxygenase-1 and cyclo-oxygenase-2 deficient mice and their cultured aortic smooth muscle cells were used to investigate the role of these enzymes in angiotensin II induced superoxide production and hypertension.
At resting state, the superoxide production in aortic and cardiac tissues was lower in cyclo-oxygenase-2 deficient than in the wild type or in cyclo-oxygenase-1 deficient mice. Chronic angiotensin II infusion increased the superoxide production in these tissues from both cyclo-oxygenase-deficient and wild-type mice whereas the level in cyclo-oxygenase-2 deficient mice was equivalent to the basal level in wild-type mice. The hypertensive effect of angiotensin II was attenuated in cyclo-oxygenase-2 deficient mice. Aspirin treatment reduced the basal superoxide production and blunted the oxidative and hypertensive effect of angiotensin II in wild type and cyclo-oxygenase-1 deficient mice whereas it lost completely its antioxidative property in angiotensin II-treated aortic smooth muscle cells isolated from cyclo-oxygenase-2 deficient mice.
Cyclo-oxygenase-2 pathway plays a major role in the superoxide generation as well as in the angiotensin II-induced oxidative stress and blood pressure. Cyclo-oxygenase-1 activity didn't show any influence on these parameters. These results suggest that cyclo-oxygenase-2 is involved in the pathogenesis of hypertension.
No preview · Article · Aug 2011 · American Journal of Hypertension
[Show abstract][Hide abstract]ABSTRACT: The combined effect of a β2-antagonist and an α2-agonist on the release of adrenal catecholamines was studied in the anaesthetized and vagotomized dog. The electrical stimulation of the splanchnic nerve (5-V pulses of 2 ms duration for 3 min at a frequency of 3 Hz) produced a significant rise in adrenal catecholamine release in the adrenal vein. Intravenous injection of a β2-antagonist significantly reduced this response and a subsequent injection of an α2-agonist further reduced the release of catecholamines. However, if the α2-agonist is injected first, the release is not different compared with the control stimulation, and the subsequent injection of the β2-antagonist also did not modify the release in response to electrical stimulation. These results suggest that the blockade of presynaptic β2-receptors reduces the release of adrenal catecholamines without interfering with the activation of the α2-adrenoceptors. In contrast, the pretreatment with the α2-agonist, which does not modify the release of catecholamine at 3 Hz, seems to interfere with the inhibitory effect of the β2-antagonist.
No preview · Article · Feb 2011 · Canadian Journal of Physiology and Pharmacology
[Show abstract][Hide abstract]ABSTRACT: It has been reported that HMG-CoA reductase inhibitors such as atorvastatin induce vascular smooth muscle cell (SMC) apoptosis in vitro. However, this effect remains to be demonstrated in vivo. The present studies were designed to test the ability of atorvastatin to induce SMC apoptosis in vivo, using the spontaneously hypertensive rat (SHR) as a well-known reference model of SMC apoptosis induction in vivo by cardiovascular drugs including the calcium channel blocker amlodipine. Atorvastatin was administered to SHR for 3 or 6 weeks either alone or together with amlodipine, a drug combination clinically available to patients. Primary endpoints included aortic medial hypertrophy and aortic SMC hyperplasia, internucleosomal DNA fragmentation and expression of the apoptosis regulatory proteins Bax and Bcl-2. The SHR aorta showed no evidence of SMC apoptosis induction by atorvastatin, even at the high dose of 50 mg kg(-1) day(-1), although the statin significantly reduced oxidative stress after 3 weeks and blood pressure after 6 weeks of administration. Amlodipine-induced regression of aortic hypertophy and aortic SMC hyperplasia were dose- and time-dependent, but there was no interaction between atorvastatin and amlodipine in modulating the primary endpoints. These results do not support the notion that atorvastatin induces SMC apoptosis in the aortic media in vivo.
No preview · Article · Oct 2010 · Vascular Pharmacology
[Show abstract][Hide abstract]ABSTRACT: To determine the contribution of nitric oxide (NO) in cardiovascular remodeling associated to hypertension and insulin resistance, male Sprague-Dawley rats received tap water supplemented or not (control), with 10% D-glucose (G) and/or 50 mg x kg(-1) x d(-1) L-NAME to inhibit NO synthase (G-LN or LN) for 4 weeks. Systolic blood pressure increased by 12%, 26%, and 39% with G, LN, and G-LN treatments, respectively. Hyperinsulinemia and insulin resistance (homeostasis model assessment index) occurred in G-treated rats (P < 0.05) and were further increased in G-LN (P < 0.01). Plasma adrenaline concentrations were markedly increased in all treated groups, especially in G-LN (P < 0.01), whereas noradrenaline was increased in G-treated rats only. Whereas no cardiac hypertrophy or fibrosis was detected, aortic hypertrophy occurred in LN and G-LN rats (P < 0.001) without smooth muscle hyperplasia. Superoxide anion formation was increased in the aorta of all treated groups (P < 0.01) and in the heart of LN (P < 0.05), but reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase activity was not affected. In conclusion, the loss of the wide-range protective effects of NO, the increased vascular oxidative stress, and the sympathoadrenal hyperactivity are among the contributing factors leading to the exacerbation of hypertension and insulin resistance in G-LN. These factors were sufficient to cause vascular but not cardiac hypertrophy.
[Show abstract][Hide abstract]ABSTRACT: Objective
To study the role of the serotoninergic 5-HT2B receptor in the development of cardiac hypertrophy and its link with left ventricular superoxide anion generation in a mouse model of angiotensin II-induced hypertension.
Wild-type and 5-HT2B receptor knock-out (KO) mice were perfused with angiotensin II (0.2 mg.kg-1.d-1) for 14 days with or without SB215505 (1 mg.kg-1.d-1), an antagonist of the 5-HT2B receptor. Heart rate and blood pressure were measured by tail-cuff plethysmography. Cardiac hypertrophy was evaluated by echocardiography and direct measurement of heart weight. Superoxide anion production and maximal NAD(P)H oxidase activity were measured by a chemiluminescence method using lucigenin. Superoxide anion production was also measured in primary left ventricular fibroblasts cell cultures.
Angiotensin II increased superoxide anion production (+32 %), the maximal activity of NAD(P)H oxidase (+84 %) in left ventricle of wild-type mice concomitantly with the arterial blood pressure (+37mmHg) and the heart/body weight ratio (+17 %). A pharmacological blockade (SB215505) or a genetic suppression of the 5-HT2B receptor prevented the increased superoxide anion production and cardiac hypertrophy but had no effect on cardiac hemodynamics or blood pressure. Angiotensin II also increased NAD(P)H oxidase activity in cultured cardiac fibroblasts and this increase was prevented by SB215505.
The 5-HT2B receptor is a new potential target for the prevention of cardiac hypertrophy and its associated superoxide anion production. Cells of the extracellular matrix could possibly be involved in this mechanism.
Preview · Article · Mar 2009 · Archives of Cardiovascular Diseases
[Show abstract][Hide abstract]ABSTRACT: Beneficial effects of an antioxidant (N-acetyl-L-cysteine, NAC) and an angiotensin I-converting enzyme (ACE) inhibitor (ramipril) were assessed in a rat model of insulin resistance induced by 10% glucose feeding for 20 weeks. Treatments with NAC (2 g/kg per day) and ramipril (1 mg/kg per day) were initiated at 16 weeks in the drinking fluid. Systolic blood pressure, plasma levels of insulin and glucose, and insulin resistance were significantly higher in rats treated with glucose for 20 weeks. This was associated with a higher production of superoxide anion and NADPH oxidase activity in aorta and liver and with a marked reduction in protein expression of skeletal muscle insulin receptor substrate-1 (IRS-1) in the gastrocnemius muscle. NAC prevented all these alterations. Although ramipril also reversed high blood pressure, it had a lesser effect on insulin resistance (including IRS-1) and blocked superoxide anion production only in aorta. Ramipril, in contrast to NAC, did not reduce NADPH oxidase activity in aorta and liver or plasma levels of 4-hydroxynonenal and malondialdehyde. Results suggest that the inhibition of the oxidative stress in hypertensive and insulin-resistant states contributes to the therapeutic effects of NAC and ramipril. Whereas NAC exerts effective antioxidant activity in multiple tissues, ramipril appears to preferentially target the vasculature.
Full-text · Article · Nov 2008 · Canadian Journal of Physiology and Pharmacology
[Show abstract][Hide abstract]ABSTRACT: Midodrine is an alpha-agonist prodrug of desglymidodrine (DGM) that has been reported to be of clinical benefit in patients with neurocardiogenic syncope. Its effects may be mediated not only by its hypertensive properties but also by its neurohumoral influences independent of blood pressure (BP).
The present study aimed to simultaneously characterize the effects of midodrine on BP, plasma catecholamines, plasma atrial natriuretic peptide (ANP), and power spectral analysis of heart rate (HR) in healthy volunteers.
This was a prospective, randomized, single-blind, 2-period, crossover study in which a single, oral, 5-mg dose of midodrine was compared with placebo. The washout period between midodrine and placebo was 1 week. The study parameters included plasma DGM (as measured by high-performance liquid chromatography [HPLC]); systolic and diastolic BP (as measured with an oscillometric monitor); HR; plasma catecholamines (measured by HPLC); plasma ANP, also known as venous return (measured by a radio-immunoassay); and low- and high-frequency HR variation (calculated from computerized 5-minute electrocardiographic recordings). All study parameters were measured simultaneously 12 times just before and over a period of 8 hours after drug administration.
Fifteen healthy nonsmoking male subjects (14 white, 1 black; mean [SD] age, 28.6 [4.7] years; weight, 74.5 [16.4] kg; seated BP, 109.9 [9.0]/73.6 [9.5] mm Hg; seated HR, 63.8 [8.4] bpm) were randomized. No significant effects of midodrine on BP were observed. At Cmax, midodrine decreased norepinephrine from 188.4 (30.6) to 162.5 (29.8) pg/mL (P = 0.011) and HR from 57.2 (7.3) to 54.9 (6.6) bpm (P = 0.022). A significant correlation was found between DGM concentration and HR ( varphi -0.61; P = 0.014). A DGM-related increase in plasma ANP (+29.6 [90.0] fmoL/mL) was observed.
This study in healthy male volunteers found that midodrine has sympatholytic influences that are independent of BP but related to augmented venous return.
No preview · Article · Oct 2008 · Clinical Therapeutics
[Show abstract][Hide abstract]ABSTRACT: We established previously that 5-HT(2B) receptors are involved in cardiac hypertrophy through the regulation of hypertrophic cytokines in cardiac fibroblasts. Moreover, the generation of reactive oxygen species and tumor necrosis factor-alpha through the activation of reduced nicotinamide-adenine dinucleotide phosphate [NAD(P)H] oxidase has been implicated in cardiac hypertrophy. In this study, we investigated whether 5-HT(2B) receptors could be involved in the development of cardiac hypertrophy associated with superoxide anion production. Therefore, we measured the effects of serotonergic 5-HT(2B) receptor blockade on left-ventricular superoxide anion generation in 2 established pharmacological models of cardiac hypertrophy, ie, angiotensin II and isoproterenol infusions in mice. Angiotensin II infusion for 14 days increased superoxide anion concentration (+32%), NAD(P)H oxidase maximal activity (+84%), and p47(phox) NAD(P)H oxidase subunit expression in the left ventricle together with hypertension (+37 mm Hg) and cardiac hypertrophy (+17% for heart weight:body weight). The 5-HT(2B) receptor blockade by a selective antagonist (SB215505) prevented the increase in cardiac superoxide generation and hypertrophy. Similarly, infusion for 5 days of isoproterenol increased left-ventricular NAD(P)H oxidase activity (+48%) and cardiac hypertrophy (+31%) that were prevented by the 5-HT(2B) receptor blockade. Finally, in the primary culture of left-ventricular cardiac fibroblasts, angiotensin II and isoproterenol stimulated NAD(P)H oxidase activity. This activation was prevented by SB215505. These findings suggest that the 5-HT(2B) receptor may represent a new target to reduce cardiac hypertrophy and oxidative stress. Its blockade affects both angiotensin II and beta-adrenergic trophic responses without significant hemodynamic alteration.
[Show abstract][Hide abstract]ABSTRACT: The effect of age on autonomic nervous system was assessed at rest and while standing using systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate, and power spectral analysis of the time duration between 2 consecutive R waves of an electrocardiogram (RR) interval variability, as well as on plasma norepinephrine and epinephrine levels in mild to moderate hypertensive patients (DBP, 90-110 mm Hg). Patients younger than 60 years (n=57) and older than 60 years (n=32), were evaluated after a 3- to 4-week placebo period. Plasma catecholamines were measured in the supine position at rest and after 10 minutes of standing. Power spectral analysis of the RR interval variability was performed in each condition using the high-frequency (HF) band (0.15-0.4 Hz) as an index of parasympathetic activity and the low-frequency (LF) band (0.05-0.15 Hz) and LF-HF ratio to estimate sympathetic activity. The total power was calculated as the sum of LF and HF power. supine SBP was significantly higher in older patients (P<.05). SBP and DBP increased significantly only in younger patients during standing (P<.05), while the changes were smaller and nonsignificantly lower in older patients. HR was similar in both groups at rest and increased similarly during standing. Norepinephrine and epinephrine levels were similar at rest and increased similarly in both groups of patients during standing. At rest, lower LF and HF components were observed in older patients. The LF component increased less and the HF component decreased less in older patients during standing. A lower sympathetic and parasympathetic basal cardiac tone was observed at rest in older hypertensive patients. Moreover, reduced hemodynamic and sympathetic responses to standing as assessed by SBP, DBP, and the LF component of HR variability were observed in older hypertensives in the presence of a normal catecholamine response. These observations could reflect a decreased sensitivity of cardiac beta-adrenoceptors with aging.
Preview · Article · Feb 2008 · Journal of Clinical Hypertension
[Show abstract][Hide abstract]ABSTRACT: Diabetes causes sensory polyneuropathy with associated pain in the form of tactile allodynia and thermal hyperalgesia which are often intractable and resistant to current therapy. This study tested the beneficial effects of the non-peptide and orally active kinin B(1) receptor antagonist SSR240612 against tactile and cold allodynia in a rat model of insulin resistance.
Rats were fed with 10% D-glucose for 12 weeks and effects of orally administered SSR240612 (0.3-30 mg kg(-1)) were determined on the development of tactile and cold allodynia. Possible interference of SSR240612 with vascular oxidative stress and pancreatic function was also addressed.
Glucose-fed rats exhibited tactile and cold allodynia, increases in systolic blood pressure and higher plasma levels of insulin and glucose, at 12 weeks. SSR240612 blocked tactile and cold allodynia at 3 h (ID(50)=5.5 and 7.1 mg kg(-1), respectively) in glucose-fed rats but had no effect in control rats. The antagonist (10 mg kg(-1)) had no effect on plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rats.
We provide the first evidence that the B(1) receptors are involved in allodynia in an experimental rat model of insulin resistance. Allodynia was alleviated by SSR240612 most likely through a direct inhibition of B(1) receptors affecting spinal cord and/or sensory nerve excitation. Thus, orally active non-peptide B(1) receptor antagonists should have clinical therapeutic potential in the treatment of sensory polyneuropathy.
Full-text · Article · Oct 2007 · British Journal of Pharmacology