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)

The existence of vasoconstrictive factors originating from the endothelium was confirmed by the description of endothelin, a 21-amino-acid peptide derived from a series of precursors, preproendothelin and a 38-amino-acid big endothelin. Three isoforms of endothelin, endothelin-1, -2 and -3, and 3 receptors (ETA, ETB and ETC) have been described and cloned. The cellular mode of action of endothelin seems to involve the modulation of intracellular calcium (through inositol trisphosphate, diacylglycerol and phospholipase C) and activation of calcium channels. The effects of endothelin are predominantly on the cardiovascular system. Its major effect is vasoconstriction, both systemic and pulmonary, with additional positive chronotropic and inotropic effects on the heart. It has also been implicated in homeostatic regulation of kidney microcirculation, and has powerful mitogenic effects on fibroblasts and smooth muscle cells. Many additional effects have been described on the endocrine system and on other systems. However, the clinical relevance of such effects is uncertain. Increased plasma endothelin levels have been reported in many diseases, but as yet it is not certain whether they are a cause or a consequence of the pathology. Pathologies most probably related to endothelin dysfunction are the vasospastic diseases, especially vasospasm after subarachnoid haemorrhage. Endothelin could be implicated to a lesser measure in diseases typical of the elderly population, such as hypertension or atherosclerosis. Drugs are being developed which act on endothelin metabolism, the most promising of which appear to be the inhibitors of endothelin converting enzyme and endothelin receptor antagonists. Some already existing drugs, such as calcium channel blockers or angiotensin converting enzyme inhibitors, probably act at least in part by interfering with endothelin metabolism or effects.
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PMID:Endothelins. A potential target for pharmacological intervention in diseases of the elderly. 819 96

Cultured rat vascular smooth muscle cells (VSMCs) possess receptors for potent vasoconstrictor endothelin-1 (ET-1) as well as potent vasodilator natriuretic peptides (atrial, brain, and C-type natriuretic peptides [ANP, BNP, and CNP, respectively]). However, little is known about molecular interactions between endothelin receptors and natriuretic peptides in VSMCs. To elucidate whether natriuretic peptides regulate vascular endothelin receptors, we studied the effects of three natriuretic peptides on the capacity of 125I-ET-1 binding and expression of endothelin type A (ETA) and type B (ETB) receptor mRNAs in cultured rat VSMCs. CNP (10(-6) mol/L) increased 125I-ET-1 binding capacity in a time-dependent manner (6 to 48 hours) and stimulated cyclic GMP (cGMP) generation in a dose-dependent manner (10(-8)) to 10(-6) mol/L). Pretreatment with CNP (10(-8) to 10(-6) mol/L) and 8-bromo-cGMP (10(-5) to 10(-3) mol/L) for 24 hours resulted in dose-dependent increases in 125I-ET-1 binding in VSMCs. The three natriuretic peptides at the highest concentration (10(-6) mol/L) increased 125I-ET-1 binding and stimulated cGMP generation with almost the same rank order of efficacy (CNP > BNP > ANP). Scatchard analysis of binding studies revealed that CNP (10(-6) mol/L) and 8-bromo-cGMP (10(-3) mol/L) increased vascular endothelin receptor number by 28% and 88%, respectively, without changing its affinity. Pretreatment with both CNP and 8-bromo-cGMP increased ET-1-stimulated inositol 1,4,5-trisphosphate formation.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Jun
PMID:C-type natriuretic peptide upregulates vascular endothelin type B receptors. 820 31

The cardiovascular consequences of endothelin (ET) blockade with the ETA-receptor antagonist FR 139317 were evaluated by determining the long-term effects of the drug on hemodynamic, hormonal, renal and structural parameters in stroke-prone spontaneously hypertensive rats (SHR-SP). Young SHR-SP on a high-sodium diet develop malignant hypertension accompanied by renovascular and cerebrovascular lesions. In control SHR-SP the systolic blood pressure increased from 196 +/- 3 to 260 +/- 4 mm Hg, whereas in animals treated with FR 139317 (20 mg/kg intraperitoneally, twice daily) it increased only from 196 +/- 4 to 212 +/- 3 mm Hg during a treatment period of 6 weeks. There was also an increase in heart weight. At the end of the experiment the plasma levels of atrial natriuretic peptide and brain natriuretic peptide were significantly lower in the group treated with FR 139317 than in the controls. The endothelin plasma levels were significantly higher and the plasma renin activity was lower in the group treated with the endothelin receptor antagonist. These data indicate that endothelin is involved in the maintenance of high blood pressure and cardiac hypertrophy in malignant hypertension, as exemplified by SHR-SP.
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PMID:Prolonged endothelin blockade prevents hypertension and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats. 855 37

Hypertension after renal transplantation continues to affect 50% or more of patients, despite use of modern immunosuppressive regimens. Relationships between poor control of blood pressure and reduced chronic allograft survival have been clearly demonstrated, and are analogous to the well-known acceleration of progressive renal disease by coexisting hypertension. It is likely, although to date it has not been formally proven by prospective study, that effective blood pressure control has a beneficial effect on chronic allograft outcome, as in progressive dysfunction of native kidneys. A further key question is whether differing classes of antihypertensive therapy may have differing effects on long-term graft outcome. It has been proposed that glomerular hypertension, hyperfiltration and hypertrophy, secondary both to inadequate nephron mass and to loss of functioning nephrons, may contribute to chronic allograft failure. If this is true, then use of converting enzyme inhibitors may particularly benefit long-term graft outcome. However, post-transplant hypertension in cyclosporine-treated patients is associated with sodium retention and renin system suppression, and a relative lack of renoprotective action of ACE inhibitors might be predicted in this context. An alternative hemodynamic factor underlying chronic allograft failure is glomerular ischemia, secondary to the vascular changes associated with chronic rejection and to cyclosporine-related afferent arteriolar vasoconstriction. In this setting, calcium channel blockers which lower systemic blood pressure in combination with afferent arteriolar vasodilatation may improve long-term allograft outcome. New strategies with a similar rationale include endothelin receptor antagonists and neutral endopeptidase inhibitors such as candoxatril, which in acute experimental and clinical studies reverse cyclosporine-induced reductions in renal blood flow and glomerular filtration rate. Long-term prospective controlled comparative studies are needed to assess the effect of all these differing therapeutic approaches on chronic allograft outcome.
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PMID:Does antihypertensive therapy modify chronic allograft failure? 858 70

Endothelin-1 (ET-1) has hypertrophic and mitogenic properties. Enhanced ET-1 gene expression in blood vessels of deoxycorticosterone acetate (DOCA)/salt hypertensive rats and DOCA/salt spontaneously hypertensive rats (SHRs) was previously demonstrated. In this study, the effect on ET-1 gene expression in blood vessels and on vascular hypertrophy of the development of hypertension of DOCA/salt hypertensive rats, and that of salt and DOCA, were investigated in Sprague-Dawley rats and in SHRs. Increased abundance of ET-1 mRNA and a greater content of immunoreactive ET-1 were found with progression of hypertension in the aorta and the mesenteric arterial bed only in DOCA/salt hypertensive rats and in DOCA/salt SHRs. Vascular expression of ET-1 was not enhanced in DOCA- or salt-treated rats, even when blood pressure rose to a mean systolic pressure of 210 mm Hg. The media thickness and the media cross-sectional area of mesenteric resistance arteries of all groups of rats, including SHRs and Wistar-Kyoto (WKY) rats, exhibited a close correlation with systolic blood pressure. In DOCA/salt hypertensive rats after 5 weeks and in DOCA/salt SHRs in which significant over-expression of ET-1 was present in blood vessels, vascular morphometric parameters were excessive for the level of systolic blood pressure. In DOCA/salt hypertensive rats and DOCA/salt SHRs treated with the combined ETA/ETB endothelin receptor antagonist bosentan, vascular morphometry correlated more closely with blood pressure, even though the blood pressure was only slightly lower than that of untreated rats. Lumen diameter correlated with blood pressure in all groups, including those overexpressing ET-1. These data support the hypothesis that ET-1 gene overexpression in blood vessels may accentuate vascular hypertrophy, but not remodeling, in DOCA/salt hypertensive rats and DOCA/salt SHRs in excess of that caused by blood pressure elevation per se.
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PMID:Enhanced expression of endothelin-1 gene may cause blood pressure-independent vascular hypertrophy. 858 58

The purpose of this study was to examine the effects of endothelin receptor inhibition on cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP). Structure and mechanics of cerebral arterioles were examined in untreated Wistar-Kyoto rats (WKY) and SHRSP that were either untreated or treated for 3 months with bosentan, an inhibitor of endothelin receptors (100 mg/kg per day). We measured pressure, external diameter, and cross-sectional area of the vessel wall (histologically) in maximally dilated (EDTA) arterioles on the cerebrum. Bosentan reduced but did not normalize arteriolar mean pressure (103 +/- 3 and 81 +/- 5 mm Hg in untreated and treated SHRSP versus 51 +/- 4 mm Hg in WKY, P < .05; mean +/- SEM) and pulse pressure (40 +/- 2 and 33 +/- 2 mm Hg in untreated and treated SHRSP versus 25 +/- 3 mm Hg in WKY, P < .05) in SHRSP. Cross-sectional area of the vessel wall (CSA) was increased in untreated SHRSP (1627 +/- 173 microm2), and CSA in treated SHRSP (1287 +/- 78 microm2) was similar to that in WKY (1299 +/- 65 microm2). Bosentan had no effect on reductions in external diameter (remodeling) of cerebral arterioles (104 +/- 7 and 96 +/- 4 microm in untreated and treated SHRSP compared with 126 +/- 7 microm in WKY, P < .05). Stress-strain curves indicate that bosentan had no significant effect on distensibility of arterioles on the cerebrum in SHRSP. The results suggest that endothelin-1 may contribute to the development of hypertrophy, but not remodeling or changes in distensibility, of cerebral arterioles in SHRSP.
Hypertension 1996 Mar
PMID:Effects of endothelin receptor inhibition on cerebral arterioles in hypertensive rats. 861 42

Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given daily to the rats by gavage during the last 5 days of cyclosporine treatment and to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff systolic pressure was measured daily during bosentan treatment. Bosentan but not gum alone significantly lowered blood pressure in the cyclosporine-hypertensive rats from 134 +/- l to 122 +/- 3 mm Hg (P<.Ol) and in the cyclosporine-hypertensive marmosets from 156 +/- 2 to 139+/- 4 mm Hg (P<.Ol). There were no differential effects on plasma creatinine concentration, endothelin concentration, or end-organ weights. Bosentan had no effect in the vehicle-treated rats. These data provide further evidence to support a role for endothelin in cyclosporine-induced hypertension and demonstrate the effectiveness of endothelin receptor antagonism as a novel treatment in cyclosporine-induced hypertension.
Hypertension 1996 Jun
PMID:Bosentan ameliorates cyclosporin A-induced hypertension in rats and primates. 864 46

Inhibition of nitric oxide synthase by L-arginine analogues such as N omega-nitro-L-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR) is associated with malignant hypertension and enhanced expression of the endothelin-1 gene in some blood vessels. In this study, SHR treated chronically with L-NAME (SHR-L-NAME) were given the angiotensin I-converting enzyme inhibitor cilazapril or the endothelin-A/endothelin-B receptor antagonist bosentan for 3 weeks. Systolic pressure was lowered slightly by cilazapril (213 +/- 2 versus 229 +/- 2 mm Hg in untreated SHR-L-NAME, P < .01) but was not significantly lowered by bosentan (223 +/- 2 mm Hg). Hypertrophy of aorta and small arteries (coronary, renal, mesenteric, and femoral) was decreased by cilazapril treatment and unaffected by bosentan. Expression of the endothelin-1 gene was evaluated in SHR-L-NAME by in situ hybridization histochemistry, which showed that endothelin-1 expression was enhanced in the endothelium of aorta but not in small mesenteric arteries in these rats. The absence of enhancement of endothelin-1 gene expression in small arteries may account for the absence of increased severity of hypertrophy of small vessels in SHR-L-NAME and may be a mechanism whereby L-NAME inhibits cardiovascular growth. These results suggest that in the absence of enhanced small-artery endothelin-1 expression, endothelin antagonism does not lower blood pressure. The blood pressure-lowering effect of angiotensin I-converting enzyme inhibition suggests a role for the renin-angiotensin system in the malignant form of hypertension that develops in SHR treated with L-NAME.
Hypertension 1996 Aug
PMID:Comparison of effect of endothelin antagonism and angiotensin-converting enzyme inhibition on blood pressure and vascular structure in spontaneously hypertensive rats treated with N omega-nitro-L-arginine methyl ester. Correlation with topography of vascular endothelin-1 gene expression. 870 80

The effects of the endothelin receptor antagonist TAK-044 (cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-1-yl)carbonyl]-L-ala nyl-L-alpha-aspartyl-D-2-(2-thienyl)glycyl-L-leucyl-D-tryptophyl]+ ++disodiu m salt) and BQ-123 (cyclo[D-Asp-Pro-D-Val-Leu-D-Trp]) were studied in the rat heart to characterize the receptor subtypes responsible for the cardiovascular actions of endothelin-1. Endothelin-1 induced a transient decrease and subsequent increase in perfusion pressure in perfused rat hearts, and increased left ventricular developed pressure. TAK-044 diminished these endothelin-1-induced responses (100 pmol/heart) with IC50 values of 140, 57 and 1.3 nM, respectively. BQ-123 (1-30 mu M) partially inhibited the endothelin-1-induced hypertension (30-40%) in the rat heart, and failed to inhibit the hypotension. The positive inotropic effect of endothelin-1 was abolished by BQ-123. Neither indomethacin (10 mu M) nor Nomega-nitro-L-arginine methyl ester (100 mu M) attenuated the endothelin-1-induced hypotension. TAK-044 and BQ-123 attenuated the positive inotropic effect of endothelin-1 in rat papillary muscles. In rat cardiac membrane fractions, TAK-044 and BQ-123 inhibited [125I]endothelin-1 binding to endothelin ET(A) receptors with IC50 values of 0.39 +/- 0.6 and 36 +/- 9 nM, respectively, whereas only TAK-044 potently blocked the endothelin ET(B) receptor subtype (IC50 value: 370 +/- 180 nM). These results suggest that endothelin-1 modulates cardiovascular functions in the rat heart by activating both endothelin ET(A) and endothelin ET(B) receptors, all of which are sensitive to TAK-044.
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PMID:Pharmacological characterization of cardiovascular responses induced by endothelin-1 in the perfused rat heart. 872 Apr 78

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.
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PMID:The clinical potential of endothelin receptor antagonists in cardiovascular medicine. 874 Dec 30


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