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

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.
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PMID:Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. 1046 Jun 93

The cardiac abnormalities associated with hypertension include left ventricular hypertrophy and vascular changes. The latter may affect the cardiac microvasculature and predispose to myocardial ischemia. To test the hypothesis that endothelin-1 contributes to changes in the microcirculation of the heart, we studied cardiac microvessels of the deoxycorticosterone acetate-salt (DOCA-salt) model of hypertension in the rat, in which the endothelin system is activated, and the effect of the endothelin-A (ET(A)) subtype-selective endothelin receptor antagonist A-127722. A-127722 (30 mg x kg(-1) x d(-1)) was administered for 4 weeks. Arterioles (</=20 microm in lumen diameter) were identified in the myocardium by use of immunolabeling with an anti-smooth muscle alpha-actin antibody, and capillaries with an anti-laminin antibody with nuclear counterstaining by nuclear fast red. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (UniNx), 202+/-3.2 mm Hg in DOCA-salt (P<0.01 versus UniNx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt (P<0.01 versus DOCA-salt or UniNx). Arteriolar and capillary densities were altered significantly in the subendocardial myocardium but not in the subepicardial myocardium of the left ventricle. Arteriolar density per square millimeter was 18.1+/-1.48 in UniNx, 31.9+/-3.26 in DOCA-salt (P<0.01 versus UniNx), and 24.2+/-1.36 in ET(A) antagonist-treated DOCA-salt (P<0.05 versus DOCA-salt or UniNx). Capillary density per square millimeter was 2395+/-148 in UniNx, 1576+/-107 in DOCA-salt (P<0.01 versus UniNx), and 1982+/-31 in ET(A) antagonist-treated DOCA-salt (P<0.01 versus DOCA-salt or UniNx). In conclusion, in DOCA-salt hypertensive rats, subendocardial arteriolar growth and capillary rarefaction were observed in the left ventricular myocardium, and both were partially corrected by ET(A) receptor antagonism. This suggests a role for endothelin-1 in cardiac arteriolar growth and capillary rarefaction, which may have pathophysiological implications by contributing to myocardial ischemia in hypertension.
Hypertension 1999 Oct
PMID:Cardiac microvasculature in DOCA-salt hypertensive rats : effect of endothelin ET(A) receptor antagonism. 1052 63

Endothelin has been implicated in the pathogenesis and/or maintenance of hypertension. Endothelin receptor antagonists lower blood pressure in the spontaneously hypertensive rat (SHR), but the regional haemodynamic effects of such drugs in the SHR remain unknown. The aim of this study was to examine the regional haemodynamic effects of the endothelin receptor antagonist, (+/-)-(1S,2R,3S)-3-(2-carboxymethoxy-4-methoxyphenyl)-1-(3, 4-methylenedioxyphenyl)-5-(prop-1-yloxy)-indane-2-carboxylic acid (SB 209670), in SHR and Wistar-Kyoto (WKY) rats. Rats underwent a two-stage operation for implantation of Doppler flow probes and intravascular catheters. Recordings were made of mean arterial pressure (MAP), heart rate (HR) and renal (Ren), mesenteric (Mes) and hindquarters (HQ) blood flows and conductances (Cond). SHR and WKY received 4.5 h infusions of saline or SB 209670 (5 mg/kg priming dose+1 or 5 mg/kg/h, i.v.). SB 209670 lowered blood pressure in both SHR (-23+/-2 mm Hg) and WKY rats (-13+/-1 mm Hg). In addition, a lower dose infusion of SB 209670 also had an antihypertensive effect in SHR (-15+/-5 mm Hg). In SHRs which received the higher dose of antagonist, Ren, Mes and HQ Cond were significantly increased as was the HQ Cond in a low-dose group. In WKY rats, SB 209670 decreased Ren blood flow whilst increasing Mes and HQ blood flows and Cond. SB 209670 also attenuated the regional vasoconstrictor effects of endothelin-1, except in the Mes circulation in SHR. This study illustrates that SB 209670 causes differential haemodynamic effects in SHR and WKY rats. In SHR, the antihypertensive effect of SB 209670 was accompanied by a generalised vasodilatation in the Ren, Mes and HQ vascular beds. In WKY rats, the hypotensive effect of SB 209670 was accompanied by Mes and HQ vasodilatation, but with Ren vasoconstriction. Thus, endothelin is involved in the maintenance of blood pressure and vascular tone in both SHR and WKY rats, but the haemodynamic profiles of these effects differ between the two strains.
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PMID:Differential haemodynamic effects of endothelin receptor antagonist, SB 209670, in conscious hypertensive and normotensive rats. 1052 29

The renin-angiotensin-aldosterone (RAA) system and the endothelin (ET) system entail the most potent vasopressor mechanisms identified to date. Although they were studied in depth in relation to arterial hypertension and cardiovascular diseases, limited information on their interrelationships in causing hypertension and related target organ damage exists. The identification of consensus sequences for jun in the regulatory region of the preproendothelin-1 (ppET-1) gene raised the possibility of its transcriptional regulation by angiotensin II (Ang II). This was confirmed by the finding that stimulation with Ang II of cultured vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) induced expression of the ppET-1 gene and synthesis of ET-1. Endogenously produced ET-1 was found to contribute to the hypertrophic response of cardiomyocytes to Ang II and thereby to cardiac hypertrophy. Furthermore, ET-1 exerts multifaceted effects on the RAA system, such as dose-dependent inhibition of renin synthesis, and stimulation of aldosterone secretion. The finding of abundant specific ET-1 receptors in the adrenocortical zona glomerulosa (ZG) suggested a direct secretagogue effect of ET-1. In rats, ETB receptors mediate such an effect, whilst in humans, both ETA and ETB receptor subtypes intervene in regulating the transcription of the aldosterone synthase gene. In addition, ET-1 stimulates DNA synthesis and proliferation of ZG cells via ETA receptors and, therefore, might play a role in cell turnover of the normal adrenal cortex and in the onset of adrenal tumours. Studies on the in vivo interactions between ETs and the RAA system have given conflicting results, insofar as some suggested a participation of ET-1 in the pressor and cellular effects of exogenously administered Ang II, whereas others did not in the transgenic TGR(Ren 2m)27 rats and in the two-kidney, one clip.
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PMID:Interactions between endothelin-1 and the renin-angiotensin-aldosterone system. 1069 Mar 21

A rapidly growing body of data support the concept of endothelin as a paracrine acting endothelial regulators. The system of endothelin peptides--their chemical structure, physiological activity and role in cardiovascular pathological processes are reviewed. Molecular specificity, isoforms, and physicochemical parameters of the endothelin-converting enzyme (ECE) characterize this novel metalloproteinase as important regulator, that catalyses final step in the biosynthesis of endothelins. The role of the general endothelial system for various cardiovascular pathological states, including congestive heart failure and myocardial infarction, arterial hypertension, atherosclerotic vascular diseases is discussed. Therapeutic approaches with some endothelin receptor antagonists and ECE inhibitors are discussed, and endothelin system therefore represents a likely target for the development for the novel pharmaceutical agents.
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PMID:[The endothelin peptide system: mechanisms of cardiovascular pathology]. 1054 78

The endothelium is an important regulator of coronary vascular tone due to its ability to release potent vasoactive substances such as the vasodilators nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin (PGI2) and the potent vasoconstrictor endothelin. Endothelial dysfunction has been associated with a number of pathological states such as atherosclerosis, hypertension, diabetes and congestive heart failure. A disturbance of endothelial function may also contribute to the adverse effects that ischaemia and reperfusion exerts on the coronary vasculature. After ischaemia and reperfusion there is usually a selective impairment of endothelium-dependent relaxation in isolated coronary arteries. However, in the intact coronary circulation, there is a general loss of vasodilator reserve as responses to both endothelium-dependent and endothelium-independent agonists are attenuated. The release of vasoconstrictor(s) and plugging of capillaries with leukocytes may contribute to that impairment of the capacity of the coronary circulation to dilate together with the reduction in basal blood flow (no-reflow phenomenon). Ischaemic preconditioning is able to prevent ischaemic damage to the myocardium but the vasculature is less well protected as reperfusion is enhanced but the vasodilator reserve continues to be limited. Pharmacological preservation of vascular function has proved more successful with inhibitors of leukocyte adhesion, calcium channel blockers, endothelin receptor antagonists and inhibitors of oxygen radical generation all offering protection. Further refinement of protocols to preserve endothelial and vascular function after ischaemia will aid reperfusion, enhance vasodilator reserve and maximise recovery of myocardial function.
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PMID:Approaches to the prevention of coronary vascular dysfunction caused by myocardial ischaemia and reperfusion. 1060 62

The present review focuses on recent data regarding the role of endothelin as a mediator of renal vascular fibrosis. Following a brief description of the endothelin system, the question of whether endothelin is involved in hypertensive mechanisms is examined in experimental, genetic and transgenic animal models. Evidence is provided that implicates endothelin as an important factor of the development of tissue fibrosis and end-organ damage associated with hypertension, with particular emphasis on renal vascular fibrosis. Data indicating that endothelin interacts with other vasoconstrictor systems, such as angiotensin II, are also considered. Finally, results from preliminary clinical studies using endothelin receptor antagonists to treat cardiac and renal pathologies are briefly discussed.
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PMID:Endothelin and renal vascular fibrosis: of mice and men. 1065 22

The mutant mouse strain Mpv17-/-, carries a retroviral germline integration that inactivates the Mpv17 gene. Mpv17-deficient mice develop progressive glomerulosclerosis and sensineural deafness at early age. Characteristic basement membrane alterations are found in both sites of pathology. Mpv17 is a peroxisomal protein involved in the metabolism of reactive oxygen species, yet its molecular function is unknown. Dysregulation of antioxidant enzymes and basal membrane components has been established in this model and successful therapeutic intervention with antioxidants prove the causal role of reactive oxygen species in the development of the disease phenotype. We here investigated if the Mpv17-/- mice might be hypertensive. Indeed, our study revealed that Mpv17-/- mice developed significant systemic hypertension and tachycardia between 4 weeks and 5 months of age, accompanied by polyuria and elevated natriuresis. Judging from serum and urine parameters, the hypertensive condition develops concomitantly with the renal disease. Biochemical and pharmacological studies that used the endothelin receptor antagonist bosentan and the angiotensin converting enzyme inhibitor cilazapril indicated no involvement of the endothelin and renin-angiotensin systems in this hypertension, suggesting a potential novel mechanism of blood pressure regulation in this new murine hypertension model. Thus, Mpv17-/- mice unravel an intriguing new association between a defect in reactive oxygen metabolism and the age-dependent development of hypertension.
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PMID:Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease. 1067 53

The role of the endothelin-B receptor (ET(B)) in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal (sl) rats carry a naturally occurring deletion in the ET(B) gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of ET(B)(sl/sl) rats from this developmental defect using a dopamine--hydroxylase (DBH)-ET(B) transgene results in ET(B)-deficient adult rats. On a sodium-deficient diet, DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats both exhibit a normal arterial blood pressure, but on a high-sodium diet, the former are severely hypertensive. We find no difference in plasma renin activity or plasma aldosterone concentration between salt-fed wild-type, DBH-ET(B);ET(B)(+/+) or DBH-ET(B);ET(B)(sl/sl) rats, and acute responses to intravenous L-NAME and indomethacin are similar between DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats. Irrespective of diet, DBH-ET(B);ET(B)(sl/sl) rats exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ET(A)-antagonist. Normal pressure is restored in salt-fed DBH-ET(B);ET(B)(sl/sl) rats when the epithelial sodium channel is blocked with amiloride. We conclude that DBH-ET(B);ET(B)(sl/sl) rats are a novel single-locus genetic model of severe salt-sensitive hypertension. Our results suggest that DBH-ET(B);ET(B)(sl/sl) rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.
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PMID:Salt-sensitive hypertension in endothelin-B receptor-deficient rats. 1074 72

Endothelin-1 has vasoconstrictor and mitogenic properties and may contribute to the pathogenesis of hypertension by enhancing vasoconstrictor mechanisms. In this study, we investigated the ability of endothelin-1 decrease the hypotensive effects of the vasodilator bradykinin in anesthetized rats. We also studied the effects a two-week oral pre-treatment with losartan (10 mg/kg/day) or enalapril (25 mg/kg/day) on endothelin-1-induced changes in the hypotensive responses to bradykinin. Bradykinin (0.4, 1.6, 6.4, and 25 mcg/kg, i.v.) induced dose-dependent hypotensive responses which were attenuated (P<0.05) by endothelin-1 (2 mcg/kg, i.v.). This effect of endothelin-1 was abolished by the mixed endothelin receptor antagonist N-Acetyl-alpha-[10,11-Dihydro-5H-dibenzo[a, d]cycloheptadien-5-yl]-D-Gly-Leu-Asp-Ile-Ile-Trp (PD145065, 1 mg/kg, i.v.). Endothelin-1 also decreased (P<0.05) the responses to bradykinin in rats pre-treated with losartan, but had no effect in rats pre-treated with enalapril. These results suggest that endothelin-1 may contribute to the development of hypertension by decreasing the responses to bradykinin through a mechanism not involving angiotensin AT(1) receptors, although the inhibition of angiotensin converting enzyme blunted the effect of endothelin-1.
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PMID:Endothelin-1 attenuates bradykinin-induced hypotension in rats. 1084 36


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