Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol

Department of Internal Medicine, University of Pisa, Pisa, Italy.
British Journal of Pharmacology (Impact Factor: 4.84). 07/2009; 157(4):527-36. DOI: 10.1111/j.1476-5381.2009.00240.x
Source: PubMed


The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent antiatherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide (NO) as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions, such as hypertension, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium-derived contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension. However, cyclooxygenase-dependent EDCFs production is characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.


Available from: Lorenzo Ghiadoni
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    • "However, in the presence of pathological conditions (such as hypertension) endothelial cells, in response to a number of agents and physical stimuli, become also a source of ET-1, Angiotensin II (Ang II) and particularly, cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension (Versari et al., 2009). "
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    ABSTRACT: Aging impairs blood vessel function and leads to cardiovascular disease. The mechanisms underlying the age-related endothelial, smooth muscle and extracellular matrix vascular dysfunction are discussed. Vascular dysfunction is caused by: 1) Oxidative stress enhancement. 2) Reduction of nitric oxide (NO) bioavailability, by diminished NO synthesis and/or augmented NO scavenging. 3) Production of vasoconstrictor/vasodilator factor imbalances. 4) Low-grade pro-inflammatory environment. 5) Impaired angiogenesis. 5) Endothelial cell senescence. The aging process in vascular smooth muscle is characterized by: 1) Altered replicating potential. 2) Change in cellular phenotype. 3) Changes in responsiveness to contracting and relaxing mediators. 4) Changes in intracellular signaling functions. Systemic arterial hypertension is an age-dependent disorder, and almost half of the elderly human population is hypertensive. The influence of hypertension on the aging cardiovascular system has been studied in models of hypertensive rats. Treatment for hypertension is recommended in the elderly. Lifestyle modifications, natural compounds and hormone therapies are useful for initial stages and as supporting treatment with medication but evidence from clinical trials in this population is needed. Since all antihypertensive agents can lower blood pressure in the elderly, therapy should be based on its potential side effects and drug interactions.
    Ageing research reviews 10/2014; 18. DOI:10.1016/j.arr.2014.10.001 · 4.94 Impact Factor
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    • "The relationship between the attenuation of skin microvascular, vasodilatory responses and ageing alone is well documented (Gates et al., 2009; Tew et al., 2010), being largely the result of a depleted endothelial function (Gates et al., 2009). A number of studies (i.e., Dod et al., 2010; Versari et al., 2009) have exemplified the importance of maintaining endothelial function unaltered, as endothelium appears to be an early and important promoter for atherosclerosis and thrombosis, playing a decisive role in the occurrence of cardiovascular events. With the occurrence of cardiovascular disease being on the rise (OECD, 2013) and subsequently the disease management cost adding a huge burden to healthcare systems around the globe (i.e., more than £28 billion in the UK alone; Luengo-Fernández et al., 2006), it is important to find appropriate strategies to stimulate disease reduction. "
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    ABSTRACT: Background: Preserving endothelial function and microvascular integrity is suggested to reduce cardiovascular disease risk. It was recently shown that the age-dependent decline in endothelial and microvascular integrity may be reversed when combining exercise with Mediterranean diet (MD) in an 8-week intervention. The present study investigates whether the risk-reduction improvement in microcirculatory and cardiorespiratory functions are sustained in this age-group after a 1-year follow-up. Design and methods: Twenty sedentary healthy participants (age, 55±4years) from the original study underwent cardiopulmonary exercise tolerance test and were assessed for their upper- and lower-limb vascular endothelial cutaneous vascular conductance (CVC) using laser Doppler fluximetry (LDF) with endothelium-dependent [ACh (acetylcholine chloride)] and endothelium-independent [SNP (sodium nitroprusside)] vasodilation, 1year after completing the intervention. Results: Both MD and exercise groups appeared to have an improved microvascular responses, in comparison to baseline as far as ACh is concerned. Exploring the interactions between the time point and the original group, however, revealed a stronger improvement in the MD group in comparison to the exercise group, for ACh (p=0.04, d=0.41). In the upper body, the time point and group interaction for ACh, indicated a better improvement for MD, without however statistical significance (p=0.07, d=0.24). Additionally, cardiorespiratory improvement in ventilatory threshold was maintained, 1year after (12.2±3.0 vs. 13.2±3.2ml∙kg(-1)∙min(-1), p<0.05). Conclusions: The original improvements from an 8-week exercise and MD intervention were still evident, particularly in the microcirculatory and cardiorespiratory assessments, 1year after the initial study. This suggests that a brief intervention combining MD with exercise in this high-risk group promises long-term health benefits.
    Microvascular Research 08/2014; 95(1). DOI:10.1016/j.mvr.2014.07.015 · 2.13 Impact Factor
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    • "Finally, such an endothelial dysfunction, due to hypertension or hyperglycemia, is implied in atherosclerosis and cardiovascular events [16]. Therefore anti-AGE agents would prevent the endothelial dysfunction and could slow down the cardiovascular alteration then avoiding clinical events [17]. Earlier phytochemical studies on Mammea species have shown that this genus is rich in prenylated 4-phenyl and 4-propylcoumarins, xanthones and benzophenones whereas pentacyclic triterpenes and steroids as well as flavan-3-ols and procyanidins were also reported [18] [19] [20] [21] [22] [23] [24]. "
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    ABSTRACT: Advanced Glycation End-products (AGEs) are associated with many pathogenic disorders such as pathogenesis of diabetes or endothelial dysfunction leading to cardiovascular events. Therefore identification of new anti-AGE molecules or extracts aims at preventing such pathologies. Many Clusiaceae and Calophyllaceae species are used in traditional medicines to treat arterial hypertension as well as diabetes. Focusing on these plant families, an anti-AGE plant screening allowed us to select Mammea neurophylla for further phytochemical and biological studies. Indeed, both DCM and MeOH stem bark extracts demonstrated in vitro their ability to prevent inflammation in endothelial cells and to reduce vasoconstriction. A bioguided fractionation of these extracts allowed us to point out 4-phenyl- and 4-(1-acetoxypropyl)coumarins and procyanidins as potent inhibitors of AGE formation, potentially preventing endothelial dysfunction. The fractionation steps also led to the isolation of two new compounds, namely neurophyllols A and B from the DCM bark extract together with thirteen known mammea A and E coumarins (mammea A/AA, mammea A/AB, mammea A/BA, mammea A/BB, mammea A/AA cycloD, mammea A/AB cycloD, disparinol B, mammea A/AB cyclo E, ochrocarpin A, mammea A/AA cycloF, mammea A/AB cyclo F, mammea E/BA, mammea E/BB) as well as δ-tocotrienol, xanthones (1-hydroxy-7-methoxyxanthone, 2-hydroxyxanthone) and triterpenes (friedelin and betulinic acid). During this study, R,S-asperphenamate, previously described from fungal origin was also purified.
    Fitoterapia 04/2014; 96. DOI:10.1016/j.fitote.2014.04.005 · 2.35 Impact Factor
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