Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The vascular pharmacology, physiological relevance and pathophysiological roles of the endothelium-derived vasoconstrictor peptide endothelin-1 have been unclear. These issues were investigated, in vivo in man, using infusion of drugs into the brachial artery or dorsal hand vein, with responses measured by forearm plethysmography and the hand vein displacement technique respectively. 2. Endothelin-1 is a potent and sustained constrictor of resistance and capacitance vessels in vivo in man, acting through both subtypes (ETA and ETB) of endothelin receptors. Endothelin-1 stimulates generation of vasodilator prostaglandins, but not of nitric oxide, that act to oppose its direct constrictor actions. Venoconstriction to endothelin-1 is blocked more effectively by K(+)-channel openers than by Ca(2+)-channel antagonists, suggesting a novel cellular mechanism of action for this peptide. 3. The forearm vasculature is able to convert the precursor big endothelin-1 to the mature peptide, endothelin-1, thus demonstrating the local presence of 'endothelin-converting enzyme' in man. Local inhibition of this enzyme, or blockade of ETA receptors, causes slow-onset forearm vasodilatation, suggesting that endogenously generated endothelin-1 contributes to basal resistance vessel tone in man. 4. Venoconstriction to endothelin-1 is selectively enhanced in patients with untreated essential hypertension. Endothelin-1 also potentiates sympathetically mediated vasoconstriction, but only in hypertensive subjects. 5. Endogenous generation of endothelin-1 plays a fundamental physiological role in the maintenance of basal vascular tone. Endothlin-converting enzyme inhibitors and endothelin receptor antagonists possess novel vasodilator properties and should represent a major therapeutic advance in cardiovascular disease.
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PMID:Endothelins as regulators of vascular tone in man. 761 9

ENDOTHELIUM-DERIVED NITRIC OXIDE: The endothelium is a source of vasoactive factors among which the most relevant are nitric oxide and endothelin. Nitric oxide is synthesized from L-arginine by a family of nitric oxide synthases and is a widespread biological mediator. It is implicated in many physiological and pathophysiological processes, including a variety of cardiovascular diseases like hypertension. NITRIC OXIDE AND HYPERTENSION: The release of nitric oxide seems to be modulated by changes in blood pressure. However, the role of nitric oxide in hypertension is still controversial and seems to vary depending on the stage of the disease and the model studied. In spontaneous hypertension, the production of nitric oxide is increased but inefficacious, probably because of increased inactivation or scavenging. In the heart the production of nitric oxide seems to be increased, probably as a compensatory mechanism against hypertension. In salt-induced hypertension, nitric oxide production may be impaired. In human hypertension, pharmacological experiments reveal an impaired nitric oxide dilator mechanism. In pulmonary hypertension, the use of nitric oxide gas inhalation has been proposed as a future therapy for this condition. ENDOTHELIN: Endothelin-1 is a potent vasoconstrictor peptide produced and released from endothelial cells. In isolated blood vessels, endothelin causes profound contraction. The hemodynamic effects of endothelin can be explained by the activation of two endothelin receptors, ETA and ETB. The relationship between endothelin and hypertension is not clear. Although plasma endothelin levels are normal in most patients with essential hypertension, the hypertensive blood vessel wall may contract more profoundly in response to the peptide; hence, endothelin antagonists may have antihypertensive effects in patients with hypertension.
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PMID:Endothelium-derived vasoactive factors in hypertension: nitric oxide and endothelin. 857 87

Endothelins (ETs) are peptides of 21 amino acids synthesized and released by variety of cells. Endothelin (now this peptide is called endothelin-1 (ET-1)) was isolated and identified in 1988 by Yanagisawa et al. Following studies revealed two other isoforms of endothelin': Endothelin-2 (ET-2) and endothelin-3 (ET-3). All of them bind to two types of receptors (A and B (ET-A r, ET-Br). ET-A r are responsible for concentration mediating. Two subtypes of ET-B r are known. ET-B1 r mediates vasorelaxation; ET-B2 vasoconstriction. ETs (especially ET-1) have variety of biological actions but the most important are vasoconstrictor and mitogenic action. Through these two mechanism ETs may participate in the pathogenesis and/or in the maintenance of hypertension in both experimental animal models and human essential hypertension. The intravenous infusion of synthetic ET induces a long-lasting elevation of blood pressure in experimental animals and in healthy humans. Number of studies have shown enhanced responses to ET in hypertensive subjects but decreased responses have also been reported. Similarly, plasma levels of ET-1 are either normal or elevated in experimental and human essential hypertension. Numerous investigators have suggested an interaction between ET and angiotensin-converting enzyme inhibitors through the renin-angiotensin system or through the accumulation of endogenous bradykinin. Also calcium antagonists of different classes prevent endothelin-induced contractions. Endothelin- converting enzyme inhibitor (phosphoramidon) and ET-A/B r antagonists (bosentan, BQ-123, FR139317) may have potential role as vasodilators in the treatment of hypertension.
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PMID:[Endothelin and arterial hypertension]. 955 99

The endothelin family consists of three structurally similar isopeptides: ET-1, ET-2, and ET-3. The two receptor subtypes, ETA and ETB, have different receptor affinities for the isopeptides. Stimulation of ETA and ETB receptors results in vasoconstriction, and ETB stimulation also causes vasodilation. These receptors may have profound impact on the etiologies of various diseases, including heart failure and hypertension. Studies with endothelin-receptor antagonists in animals and humans with heart failure show promising short- and long-term results. The place of the agents in the treatment of essential hypertension remains controversial, but they may have a greater role in hypertensive blacks and transplant recipients.
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PMID:The role of endothelin in heart failure and hypertension. 969 45

The endothelium can greatly influence vascular tone and structure. The main endothelium-derived factor is nitric oxide (NO), which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. The mechanism responsible for endothelial alteration in essential hypertensive patients appears to be the activation of an alternative pathway involving cyclooxygenase, which reduces NO availability through production of oxidative stress. In the presence of impaired NO availability a hyperpolarizing factor seems to act as a compensatory pathway to sustain endothelium-dependent relaxation. This compensatory pathway can be further depressed by the simultaneous presence of essential hypertension and hyperhomocysteinaemia, another cardiovascular risk factor causing endothelial dysfunction. Finally, reduced NO availability can increase the biological activity of endothelin-1 because, while in healthy conditions the vasoconstrictor effect of endothelin-1 is partially blunted by endothelial ETB-receptor mediated NO production, in essential hypertensive patients this protective mechanism is lacking on account of impaired NO availability. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis and therefore lead to cardiovascular events in essential hypertensive patients.
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PMID:Endothelial dysfunction in hypertension. 1181 68

Endothelin-1 (ET-1) is a pleiotropic hormone produced primarily by the endothelium. Synthesis of ET-1 is stimulated by the major signals of cardiovascular stress, such as vasoactive agents (angiotensin II, norepinephrine, vasopressin, and bradykinin), cytokines (e.g., tumor necrosis factor alpha and transforming growth factor beta), and other factors, including thrombin and mechanical stress. ET-1 induces vasoconstriction, is proinflammatory, promotes fibrosis, and has mitogenic potential, important factors in the regulation of vascular tone, arterial remodeling, and vascular injury. These effects are mediated via two receptor types, ETA and ETB. The role ET-1 plays in normal cardiovascular homeostasis and in mild essential hypertension in humans is unclear. However, certain groups of essential hypertensive patients may have ET-1-dependent hypertension, including blacks (subjects of African descent), salt-sensitive hypertensives, patients with low renin hypertension, and those with obesity and insulin resistance. ET-1 has also been implicated in severe hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all of these conditions, plasma immunoreactive ET levels are elevated and tissue ET-1 expression is increased. Accordingly, it is becoming increasingly apparent that ET-1 plays an important role in cardiovascular disease and in some forms of hypertension in humans. Data from clinical trials using combined ETA-ETB receptor blockers have already demonstrated significant blood-pressure-lowering effects. Thus, targeting the endothelin system may have important therapeutic potential in the treatment of hypertension, particularly by contributing to the prevention of target organ damage and the management of cardiovascular disease.
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PMID:Role of endothelin in human hypertension. 1283 65

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.
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PMID:Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. 1585 28

This article describes the pharmacological properties and the overall preclinical and clinical profiling of bosentan (Ro 47-0203), a non-peptide endothelin receptor antagonist with oral activity. Bosentan is a combined and competitive antagonist of both ETA and ETB receptors that is selective for the endothelin system. In vitro and in vivo, bosentan potently antagonises the vascular response elicited by the endothelins. Preclinical efficacy is demonstrated in a variety of pathological models including pulmonary and essential hypertension, renal failure of ischaemic and nephrotic origin and cerebral vasospasm following subarachnoid haemorrhage. Effects are particularly marked in experimental models of heart failure (HF) where bosentan acts as a potent vasodilator that improves overall left ventricular performance. After chronic treatment, bosentan also improves survival in rats with HF. As a result of the first encouraging clinical results that show pulmonary and systemic vasodilation, long-term studies are ongoing in the treatment of congestive heart failure (CHF).
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PMID:The pharmacology of bosentan. 1599 23