Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With recognition of the significant role of the endothelin system in cardiovascular and pulmonary vascular diseases, attention has turned to the therapeutic application of agents that antagonize this system. Three strategies can be employed: dual endothelin receptor (ETA and ETB) antagonism, selective ETA antagonism and inhibition of endothelin-converting enzymes. The first two strategies have been evaluated in late-phase clinical trials, with mixed results. The use of the dual endothelin receptor antagonist bosentan in pulmonary arterial hypertension has been successful. Available data are less compelling, but nonetheless promising, for the use of bosentan in digital ulceration secondary to systemic sclerosis, and tezosentan (another dual receptor blocker) in acute heart failure. Both types of receptor antagonists, however, have been evaluated in systemic hypertension and chronic systolic heart failure and are unlikely to be further developed in these areas. For the treatment of hypertension, their (moderate) efficacy and safety/tolerability profiles appear no more favorable than existing antihypertensive agents. In terms of treatment for chronic heart failure, these agents appear to offer no further benefit over standard therapy for the treatment of chronic heart failure, and in fact, may be associated with poorer outcomes. The complexity of the endothelin system and its diverse roles in multiple disease states will ensure its position as a target for drug development.
 ...
PMID:Current status of endothelin blockade for the treatment of cardiovascular and pulmonary vascular disease. 1274 22

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.
 ...
PMID:Role of endothelin in human hypertension. 1283 65

Pulmonary hypertension (PH) may result from numerous clinical entities affecting the pulmonary circulation primarily or secondarily. It is recognized that vascular endothelial dysfunction contributes to the development and perpetuation of PH by creating an imbalance between vasodilating and antiproliferative forces and between vasoconstrictive and proliferative forces. In that context, endothelin-1 (ET-1) overproduction was rapidly targeted as a plausible contributor to the pathogenesis of PH. The lung is recognized as the major site for ET production and clearance. In all animal models of PH studied, circulating plasma ET-1 levels are elevated, accompanied by an increase in lung tissue expression of the peptide. The use of selective ETA and dual ETA-ETB receptor antagonists in these models both in prevention and in therapeutic studies have confirmed the contribution of ET-1 to the rise in pulmonary vascular tone, pulmonary medial hypertrophy, and right ventricular hypertrophy. This is found consistently in models affecting the pulmonary circulation primarily or producing PH secondarily. Recent clinical trials in patients with pulmonary arterial hypertension have confirmed the therapeutic effectiveness of ET-receptor antagonists in humans. We offer a systematic review of the pathogenic role of the ET system in the development of PH as well as the rationale behind the preclinical and ongoing clinical trials with this new class of agents.
 ...
PMID:The endothelin system in pulmonary hypertension. 1283 66

The present study evaluated the potential mechanism involved in the hypotensive effect induced by ET-1 in rats treated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in the drinking water during 7 days. Hypertension developed in the L-NAME-treated rats (164+/-3 versus 112+/-1 mm Hg in untreated control rats), and the hypotensive effect of ET-1 (100 pmol/kg IV) was significantly enhanced compared with control rats (32+/-2% versus 20+/-1% fall in mean arterial pressure). The enhanced ET-1 hypotensive effect in L-NAME-treated rats was abolished by the ETB receptor antagonist BQ-788 but was unaltered by the cyclooxygenase inhibitor diclofenac, the cytochrome P450 inhibitor fluconazole, or the potassium channel blockers apamin, glibenclamide, tetraethylammonium, and 4-aminopyridine. Pretreatment with the cannabinoid CB1 receptor antagonist SR141716A significantly reduced the hypotensive response to ET-1 in L-NAME-treated rats (20+/-1%), although it did not modify the response in untreated control rats (17+/-1%). These findings indicate that in rats under chronic NOS inhibition, the hypotensive effect of ET-1 is unexpectedly enhanced and appears to be mediated by a non-NO/non-prostanoid mechanism and involves an SR141716A-sensitive mechanism triggered by ETB receptor activation.
Hypertension 2003 Oct
PMID:SR141716A-sensitive enhancement of ET-1 hypotensive effect by chronic NOS inhibition. 1291 62

Endothelin-1 is an endothelium-derived compound that exerts a variety of hemodynamic and structural alterations in the cardiovascular and pulmonary circuits. The endothelin system is activated in an assortment of disorders and disease states, such as systemic hypertension, pulmonary hypertension, atherosclerosis, acute coronary syndromes, and congestive heart failure. The actions of endothelin are mediated by two types of receptors: ETA and ETB, which are widely distributed in the cardiovascular system. The complexity of biophysical effects mediated by these two types of receptors dictates the therapeutic implications, that is, selective (ETA) versus dual (ETA/ ETB) receptor antagonism. Preliminary experimental and clinical studies reveal a role played by endothelin as a pathogenetic substance and, conversely, a possible role for endothelin antagonism in clinical medicine.
 ...
PMID:Possible therapeutic role of endothelin antagonists in cardiovascular disease. 1462 76

Pulmonary arterial hypertension is a rapidly progressing disease characterized by an over- expression of endothelin. In addition to its potent pulmonary vasoconstrictor effects, endothelin has been shown to produce many of the aberrant changes, such as hypertrophy, fibrosis, inflammation, and neurohormonal activation that underlie the shortened life span in pulmonary arterial hypertensive patients. The fact that endothelin expression correlates significantly with disease severity and outcome in these patients suggests that endothelin, through binding to both ETA and ETB receptor subtypes, is a key causative agent in the pathophysiology of pulmonary arterial hypertension. The orally active dual endothelin receptor antagonist bosentan competitively antagonizes the binding of endothelin to both endothelin receptor subtypes with high affinity and specificity. In animal models relevant for the pathophysiology of pulmonary hypertension, bosentan not only causes selective pulmonary vasodilation, but also prevents vascular hypertrophy and cardiac remodeling, attenuates pulmonary fibrosis, decreases vascular inflammation, and blunts neurohormonal activation. These experimental data may explain the effects on disease progression and the long-term benefit observed with bosentan in pulmonary arterial hypertension.
 ...
PMID:Effects of bosentan on cellular processes involved in pulmonary arterial hypertension: do they explain the long-term benefit? 1470 70

Hypertension is accompanied by increased arterial endothelin-1 (ET-1) and decreased arterial contraction to ET-1. By contrast, veins remain responsive to ET-1 in hypertension. Isometric contraction was used to test the hypothesis that veins do not desensitize to ET-1 to the extent of arteries, possibly because of the presence of functional ETA and ETB receptors on veins and only functional ETA receptors on arteries. Contraction to ET-1 after exposure to ET-1 (100 nmol/L) was abolished in aortae, while in veins 36.3 +/- 0.2% of maximal contraction to ET-1 remained. Aortae were unresponsive to the ETA receptor agonist ET-1(1-31) (100 nmol/L) after ET-1 exposure, while 21.9 +/- 0.6% of maximum venous contraction to ET-1 (1-31) remained. In a similar manner, the venous ETB receptor did not lose responsiveness to the ETB receptor agonist sarafotoxin 6c (S6c, 100 nmol/L); aortae did not contract to S6c. In ET-1-desensitized veins, the ETB receptor antagonist BQ-788 (100 nmol/L) decreased maximum contraction to ET-1, but did not alter potency (-log EC50 control = 8.14 +/- 0.01 mol/L; BQ-788 = 8.13 +/- 0.04 mol/L). The ETA receptor antagonist atrasentan (100 nmol/L) blocked remaining venous contraction to ET-1 (control = 8.05 +/- 0.05 mol/L; atrasentan = unmeasurable). Maintained responsiveness to ET-1 in veins occurs primarily via the ETA receptor, while in arteries the ETA receptor is responsible for desensitization to ET-1.
 ...
PMID:Arteries and veins desensitize differently to endothelin. 1507 22

The predominant isoform of the endothelin peptide family. endothelin-1 (ET-1) exerts various biological effects. These include effects on arterial smooth muscle cells causing intense vasoconstriction and stimulation of cardiac cells. ET-1 promotes changes in cardiomyocytes that are consistent with electrical remodelling such as changes in ionic current density and inhomogeneous prolongation of action potential duration resulting in increased dispersion. As for the underlying mechanisms, ET-1 was shown to suppress several cAMP-dependent ionic currents, such as ICa, IK and ICl in various mammalian cardiac preparations including human myocytes; however, the degree of suppression of these currents is different and highly dependent on experimental conditions. The proposed arrhythmogenic effects of ET-1 may also involve enhancement of Ca2+ release from intracellular stores, generation of IP3, and acidosis due to stimulation of the Na+/H+ exchange. Furthermore, ET-1 acts as the natural counterpart to endothelium-derived nitric oxide, which exerts vasodilator, antithrombotic and antiproliferative effects, and inhibits leukocyte adhesion to the vascular wall. Effects of ET-1 are mediated through interaction with two major types of cell surface receptors. ETA receptors have been associated with electrical remodelling, vasoconstriction and cell growth, while ETB receptors are involved in the clearance of ET-1, inhibition of endothelial apoptosis, release of NO and prostacyclins, and inhibition of the expression of ET-1 converting enzyme. The derangement of endothelial function in various cardiovascular diseases, such as cardiomyopathies, hypertension or arteriosclerosis, is a crucial element of the pathomechanism, thus ET receptors are considered as important therapeutic targets. Indeed, ET receptor antagonists may be able to preserve or restore endothelial integrity and may have antiarrhythmic properties; therefore, they are promising tools in cardiovascular medicine.
 ...
PMID:Effects of endothelins on cardiac and vascular cells: new therapeutic target for the future? 1532 Aug 33

Vascular capacitance is reduced by endothelin-1 (ET-1) in deoxycorticosterone (DOCA)-salt hypertensive rats. This may contribute to hypertension development. Because the splanchnic blood vessels (especially veins) are important in determining vascular capacitance, we tested the hypothesis that ET-1 levels in the splanchnic vasculature are elevated in hypertensive DOCA-salt compared with normotensive rats. Tissue ET-1 content was measured by ELISA in aorta, vena cava, superior mesenteric artery and vein, and small mesenteric arteries and veins from normotensive sham-operated (sham) and 4-wk DOCA-salt rats. We also determined ET-1 concentration in aortic and portal venous blood (draining the nonhepatic splanchnic organs) in anesthetized and conscious sham and DOCA-salt rats before and after acute blockade of ETB receptor-mediated plasma clearance of ET-1. Results showed a higher ET-1 content in veins than in arteries of similar size. However, ET-1 content was similar in vessels from sham and DOCA-salt rats, except in aorta and superior mesenteric artery, where ET-1 content was greater in DOCA-salt rats. ET-1 concentration was significantly higher in portal venous than in aortic blood, indicating net nonhepatic splanchnic release (nNHSR) of ET-1. However, nNHSR of ET-1 was similar in sham and DOCA-salt rats. Although nNHSR of ET-1 increased significantly after ETB receptor blockade in sham rats, it was completely unchanged in DOCA-salt rats. These data suggest that, despite the absence of ETB receptor-mediated plasma clearance of ET-1, neither the venous peptide content nor the net release of ET-1 is increased in the splanchnic vasculature of DOCA-salt rats. These results argue against the hypothesis that increased venomotor tone in DOCA-salt hypertension is caused by increased ET-1 concentration around splanchnic venous smooth muscle cells.
 ...
PMID:Endothelin in the splanchnic vascular bed of DOCA-salt hypertensive rats. 1547 83

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.
 ...
PMID:Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. 1585 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>