1,721,015 research outputs found
Phosphodiesterase 5 inhibition in essential hypertension.
No full textPhosphodiesterase (PDE) 5 inhibitors reduce cyclic guanylate monophosphate breakdown, promoting vascular relaxation in the corpora cavernosa and penile erection during sexual stimulation. Sildenafil, vardenafil, and tadalafil were approved as effective treatments for male erectile dysfunction. Because PDE5 is present in artery and vein smooth muscle cells throughout the body, PDE5 inhibitors have mild systemic vasodilatory effects and thus the potential to impact the vascular system. The US Food and Drug Administration has approved PDE5 inhibitors for treating pulmonary hypertension. Moreover, their systemic vasodilating properties theoretically make these drugs suitable for treating hypertension. Studies indicate that PDE5 inhibition may be an option for reducing blood pressure in hypertensive patients. Additional benefits may be related to improved arterial stiffness and endothelial dysfunction, two early vascular abnormalities characterizing essential hypertension. More investigation is needed on PDE5 inhibitors as antihypertensive drugs, especially with slow-release formulations or compounds with long half-life. Studies on safety during long-term administration, interactions with antihypertensive and nonantihypertensive drugs, and effect on target organ damage are needed
Endothelium-dependent contractions and endothelial dysfunction in human hypertension
No full textThe 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
Which endothelium-derived factors are really important in humans?
No full textThe endothelium plays a primary role in the local control of vascular function and structure, mainly by the production and release of NO, a potent vasodilator that also inhibits all the mechanisms involved in the pathogenesis of atherosclerosis, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. Cardiovascular risk factors are associated with endothelial dysfunction, which involves enhanced production of oxygen free radicals that reduce NO availability and the release of contracting factors, including prostanoids and endothelin-1. In humans, endothelium-dependent relaxation can be assessed by tests that explore vascular reactivity. Besides the degree of vasodilation, which represents a crude estimate of endothelial function, the utilization of a complex experimental design, requiring the administration of specific agonists and antagonists, allows detailed exploration of the mediators and mechanisms involved in endothelium-dependent vasodilation. At present, the degree of endothelium-dependent vasodilation (evoked by receptor-operated agonists or the application of mechanical forces) is considered an independent predictor of cardiovascular events. In contrast, scant information is available concerning the clinical relevance of different mediators involved in endothelial function. Further studies are needed in the future to assess the specific impact of different endothelial responses on the clinical outcome in patients with cardiovascular risk factors and disease
Non-Invasive Diagnostic Tools for Investigating Endothelial Dysfunction
No full textThe endothelium is not merely a barrier but it plays a key role in the maintenance of vascular homeostasis. A dysfunctional endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function and in the last two decades, several methodologies were developed to study it non invasively in the peripheral macrocirculation (conduit arteries) and microcirculation (resistance arteries and arterioles). This review will centre on the most relevant available non-invasive techniques in the research on endothelial function, their advantages and limitations. Flow mediated dilation (FMD) of the brachial artery by ultrasounds is the most widely used vascular test to assess endothelium-dependent vasodilation. Other approaches include measurement of microcirculatory reactive hyperaemia by forearm venous pletysmography or digital pulse amplitude tonometry, response to β2 agonist by applanation tonometry or digital photoplethysmography and several test by skin laser doppler. It appears that FMD is the most reproducible test when an appropriate and accurate methodology is applied. Recently, post-ischemic vasodilation in the cavernous arteries was also suggested to study endothelial function in patients with erectile dysfunction. Systemic markers proposed as measures of NO biology, inflammatory cytokines, adhesion molecules, or markers of endothelial damage and repair have only a very limited role as a result of biological and assay availability and variability, these factors currently have a limited role in the assessment of individual patients. The optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Therefore, no available test to assess endothelial function has sufficient sensitivity and specificity to be used yet in clinical practice. Only the growing concordant results from different reproducible and reliable non-invasive methods exploring endothelial function with different stimuli will support and strengthen experimental findings, thus providing conclusive answers in this area of research
Mechanisms of endothelial dysfunction: clinical significance and preventive non-pharmacological therapeutic strategies
No full textEndothelium-derived NO is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis. Cardiovascular risk factors are associated with an imbalance of the redox equilibrium towards oxidative stress and, therefore, impair the integrity of the endothelium, leading to endothelial activation which involves blunted endothelium-dependent vasodilation (vasodilator dysfunction) as well as inflammatory processes extending to the milieu within the whole vasculature, making plaques prone to rupture. In prospective studies endothelial dysfunction is associated with increased incidence of cardiovascular events. Thus, the prevention of endothelial dysfunction can determine a strong advantage in the clinical outcome of patients with cardiovascular risk factors. Several non-pharmacological interventions can prevent endothelial dysfunction or improve impaired endothelium-dependent vasodilation. Probably the most effective non-pharmacological measure is represented by aerobic physical activity, which can reduce production of oxidative stress associated to increasing age. Moreover, physical activity can improve endothelial dysfunction even in patients with cardiovascular risk factors such as essential hypertension. In addition several other approaches, including vitamin and fish oil supplementation, or tea and red wine consumption, can lead to an improvement of endothelium-dependent vasodilation, possibly by a restoration of NO availability. It is worth noting that most of non-pharmacological measures act by preventing or reducing oxidative stress
Clinical significance of the assessment of endothelial function.
No full textEndothelium-derived nitric oxide is not only a potent vasodilator but also inhibits platelet aggregation, vascular smooth muscle cell migration and proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall from the development of atherosclerosis and thrombosis. Major cardiovascular risk factors are associated with endothelial dysfunction, which involves enhanced production of oxygen free radicals, that can destroy nitric oxide and reduce its availability, and release of endothelium-derived contracting factors including prostanoids and endothelin-1. Endothelial dysfunction is a promoter of atherosclerotic and thrombotic damage and in prospective studies on patients with high cardiovascular risk impaired endothelium-dependent vasodilation is associated with an increased incidence of cardiovascular events. However, endothelial function cannot yet be included among the surrogate endpoints which need to be measured for cardiovascular risk stratification. This limitation springs from the fact that available tests to assess endothelium-dependent vasodilation are invasive or, if noninvasive, they have no sufficient sensitivity and specificity to be proposed for clinical practice. Moreover, no study is available demonstrating that reversal of endothelial dysfunction, which can be obtained by appropriate treatment, is independently associated with a better clinical outcome. However it is conceivable that in the future, by the utilization of a noninvasive method such as the determination of brachial artery flow-mediated dilation, large-scale multicenter trials might provide a definitive answer to the real prognostic value of endothelial dysfunction, in terms of cardiovascular risk and therapeutic approach
Endothelium, aging, and hypertension
No full textEndothelium plays a primary role in modulating vascular tone and structure through production of the relaxing factor nitric oxide (NO), which also protects the vessel wall against the pathogenesis of atherosclerosis and thrombosis. A dysfunctioning endothelium due to reduced NO availability and increased production of oxidative stress is considered an early indicator of atherothrombotic damage and of cardiovascular events. Aging is associated with the development of cardiovascular structural and functional alterations, which can explain the age-related increase in cardiovascular risk. Advancing age is associated with endothelial dysfunction in both normotensive subjects and essential hypertensive patients, an alteration caused by a progressive impairment of the NO pathway and production of oxidative stress. Once oxidative stress production becomes detectable, NO availability is totally compromised. Essential hypertension represents a mere acceleration of the changes induced by aging on endothelial function. Currently, dynamic physical activity represents the only effective intervention in preventing age-related impaired endothelium-dependent vasodilation in aged healthy individuals
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