Physiological role of endothelin in cardiovascular and renal hemodynamics: studies in animals
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Even though the pharmacology of the endothelin receptor subtypes ETB and ETB is well characterized, their physiological role in the control of basal vascular tone is poorly uindertood. It has been proposed that a tonic vasoconstriction mediated by endothelin counterbalances a vasodilator tone mediated by nitric oxide, the major endothelium-derived relaxing factor. Recent evidence suggest that the endogenous endothelin-1, released from the endothelial cells, mediates both vasodilation and vasoconstriction and indicates the existence of a negative feedback system involving endothelin-1, the endothelial ETB receptor and nitric oxideKeywords:
Vascular tone
Endothelial Dysfunction
Endothelins (ETs) mediate paracrine control of vascular tone and secretion of steroids and catecholamines in the adrenal gland through two ET receptor subtypes, ETA and ETB. The differential distribution and function of these subtypes are responsible for the multiplicity of endothelin actions in this tissue. This study examines the regulatory effects of experimental diabetes on the gene expression, subtype specificity and localization of ET receptor subtypes, ET isopeptides, and endothelin-converting enzyme-1 (ECE-1) in the rat adrenal gland. The densities, pharmacological properties and distribution of ET receptor subtypes ETA and ETB in adrenal glands from streptozotocin-induced diabetic, insulin-treated diabetic and age-matched control rats were investigated, using radioligand receptor binding and autoradiographic techniques. The gene expression of ETA and ETB receptors ET-1, ET-3 and ECE-1 was evaluated using relative multiplex reverse transcription/PCR. The induction of diabetes caused a marked reduction in body weight but no significant change in adrenal gland size. The density of ET receptors was significantly increased in the diabetic rat adrenal gland, mainly because of an increase in the expression of ETB receptors. Insulin treatment normalized the diabetes-induced changes in the expression levels of ET receptor subtypes to control levels. The expression level of ET-1 mRNA was up-regulated, whereas ET-3 mRNA was down-regulated in the diabetic adrenal gland compared with the controls. The ECE-1 mRNA level in the adrenal gland was not altered by the induction of diabetes. Autoradiographic studies showed that ETA and ETB are the predominant receptor subtypes in the adrenal medulla and cortex respectively. These results suggest that ETA and ETB receptors are differentially distributed and regulated in the diabetic rat adrenal gland.
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Endothelial Dysfunction
Vasoactive
Pathogenesis
Vascular tone
Coronary atherosclerosis
Coronary disease
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Purpose: Endothelin-1 contributes to endothelial dysfunction in patients with atherosclerosis and type 2 diabetes. In healthy arteries the endothelin a (ETA) receptor mediates the main part of the vasoconstriction induced by endothelin-1 while the endothelin b (ETB) receptor mediates vasodilatation. The ETB receptor expression is upregulated in atherosclerosis and may thereby contribute to the vasoconstrictor tone and development of endothelial dysfunction. The aim was to compare the effects of selective ETA and dual ETA/ETB blockade on endothelial function in patients with type 2 diabetes and coronary artery disease. Methods: Twelve patients were included in this cross-over study with blinded evaluation. Forearm blood endothelium-dependent and endothelium-independent vasodilatation was assessed by venous occlusion plethysmography during intra-arterial infusions of serotonin and nitroprusside, respectively, before and after 60 minutes of intra-arterial infusion of either the selective ETA antagonist BQ123 or the combination of BQ123 and the ETB antagonist BQ788. Changes between the two treatments were compared using 2-way analysis of variance. Results: Dual ETA/ETB receptor blockade increased baseline forearm blood flow by 30+14% (P<0.01) whereas selective ETA blockade did not (14+8%). Both selective ETA blockade and dual ETA/ETB blockade significantly improved endothelium-dependent vasodilatation. This improvement did not differ between the two treatments (Figure). There was no change in endothelium-independent vasodilatation. Conclusions: Both selective ETA and dual ETA/ETB improve endothelial function in patients with type 2 diabetes and coronary artery disease. ETB blockade increases basal blood flow but does not additionally improve endothelial function.
Endothelial Dysfunction
Brachial artery
Endothelin receptor antagonist
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Endothelin-1 and nitric oxide are the most potent factors of the endothelium-derived substances. The factors play opposite roles in regulation of cardiovascular system, and their interaction underlies the balance of vasoconstrictor and vasodilator influences on vascular tone under normal conditions. In our experiments, changes in endothelin-1 blood concentration were associated with affected production of endogenous nitric oxide. The altered interrelationships between the endothelium-derived vasoactive substances may precede pathological shifts in the cardiovascular system.
Vasoactive
Endothelium-derived relaxing factor
Vascular tone
Vasoconstrictor Agents
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Vasoconstrictor Agents
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Endothelial cells produce both vasodilatating compounds as nitric oxide, prostacycline, endothelial derived hyperpolarising factor and counteracting substances known as endothelial derived contracting factors: endothelin, tromboxan A2, prostaglandin H2, free oxygen radicals. Natural balance between both groups affects blood perfusion of various tissues and constitutes important element in blood pressure control. More and more attention is paid to endothelial dysfunction in patogenesis of hypertension. In a number of studies endothelial dysfunction in hypertensive patients was found out as decreased release of nitric oxide or increased production of endothelin. Principle mechanism of impaired function of endothelium in hypertension seems to be decreased production and increased degradation of nitric oxide mainly due to free oxygen radicals. Favorable effects in improvement of endothelial function were achieved by using ACE inhibitors, AT1 receptor blockers and calcium channel antagonists.
Endothelial Dysfunction
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Endothelium plays a primary role in the local modulation of vascular function and structure by the production and release of several substances including nitric oxide and endothelins (ET). Nitric oxide is a labile substance produced from the catabolism of L-arginine and not only causes vessel relaxation, but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion, adhesion molecules expression and endothelin-1 (ET-1) production. Endothelium-derived ET-1 is a potent vasoconstrictor and has inotropic and mitogenic properties. ET-1 acts through smooth muscle ETA and ETB receptors, which mainly mediate vasoconstriction, and endothelial ETB receptors, which oppose ETA- and ETB-mediated vasoconstriction by stimulating nitric oxide formation. Both nitric oxide and ET-1 play a crucial role in the cardiovascular physiology and an alteration of these systems can be a promoter of or be associated with most cardiovascular diseases. Essential hypertension is a pathological condition characterized by endothelial dysfunction. In hypertensive patients nitric oxide availability is impaired because of the production of cyclooxygenase-derived vasoconstrictor substances. The latter may also mediate the vasoconstrictor response to exogenous ET-1 because in forearm circulation of essential hypertensives, but not of normotensive controls, the ET-1-induced vasoconstriction is significantly blunted by intrabrachial indomethacin. Therefore, in normotensive subjects and essential hypertensives the vasoconstrictor effect of ET-1 seems to be dependent on different mechanisms. Moreover, in the peripheral circulation of normotensive subjects, where tonic nitric oxide production is preserved, unselective ETA/B receptor blockade by TAK-044 causes a very modest degree of vasodilation. In contrast in essential hypertensives, where the tonic nitric oxide production is reduced, the vasodilating effect of TAK-044 is more evident, indicating that the predominant vascular effect of endogenous ET-1 is the vasoconstriction. A possible explanation for this finding, in addition to an increased production of the peptide, could be related to a reduced ETB receptor-mediated nitric oxide activation. These peculiar aspects of the role of ET-1 in essential hypertension could have physiopathological relevance.
Endothelial Dysfunction
Omega-N-Methylarginine
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Vasoconstrictor Agents
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This review summarises the role of the endothelium in the regulation of the vascular tone, emphasizes the importance of nitric oxide and endothelin at the vasodilator and vasoconstrictor physiological processes. Mainly, the nitric oxide is responsible for the basal tone of the vasculature, but plenty of modifying factors (endothelin, angiotensin-II, prostacyclin) have also important effects. Endothelial dysfunction observable in hypertension, which characterised by disorder of the endothelium-dependent relaxation, and predominance of the vasoconstrictor processes. Disorder of synthesis, decreased biological activity and increased degradation of the nitric oxide could play a role in the fall of the basal vasodilator tone, as well as other factors influencing the production of nitric oxide. Due to a relaxation disorder, the vasoconstrictor endothelin come to the front, following morphological changes of the vessels, afterwards. Endothelial dysfunction of the medium size arteries lead to thickening of the intima, what can follow by non-invasive measurements at the common carotid arteries. It is unambiguous in hypertensive patients that augmenting the tone of the resistance vessels, the peripheral vascular tone increases. It is proved in hypertensive adults that damaged function of the cerebral arterioles results in decrease of the vasoreactivity following a hypo- or hypercapnic stimuli. The imbalance of the nitric oxide-endothelin system is not only a process what helps to partly explain the pathophysiology of hypertension, but also a therapeutic aim preventing the process of atherosclerosis.
Endothelial Dysfunction
Pathophysiology of hypertension
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Vasoconstrictor Agents
Cerebral circulation
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