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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin (EPO) has been reported to induce hypertension in hemodialysis patients with family history of hypertension. In this study, to reveal the mechanism of EPO-induced hypertension, we examined the acute effect of EPO on blood pressure (BP) and renal hemodynamics in genetically hypertensive rats, and we also tested the effect of BQ-123, an endothelin ETA-receptor blocker, on EPO-induced changes in hemodynamics. Male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), aged 9-12 wk, were anesthetized, and BP was monitored through the carotid artery. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after an intravenous injection of EPO (1,000 U/kg body wt). In another group of SHR, BQ-123 was continuously infused (1.2 mg.kg body wt-1.h-1) during the experiments. The acute injections of EPO increased BP significantly in SHR in a dose-dependent manner, whereas WKY did not show a significant increase in BP after EPO injections. The effect of EPO on BP in SHR was blocked by BQ-123. In SHR, an acute injection of EPO decreased RPF significantly (from 1.78 +/- 0.16 to 1.49 +/- 0.18 ml.min-1.100 g body wt-1, P < 0.05) without a change in GFR, whereas WKY did not show significant changes in either RPF or GFR. The effect of EPO on RPF in SHR was completely blocked by BQ-123 (from 1.92 +/- 0.26 to 1.88 +/- 0.28 ml.min-1.100 g wt-1, NS). EPO caused a significant increase in plasma endothelin ET-1 in SHR (from 2.3 +/- 0.6 to 6.3 +/- 1.6 pg/ml, P < 0.05), but not in WKY. In conclusion, acute administration of EPO raised blood pressure and reduced RPF in SHR, and these vasoconstrictive effects of EPO are mediated via ETA receptors by an enhanced ET-1 release.
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PMID:Endothelin-mediated effect of erythropoietin on blood pressure and renal hemodynamics in hypertensive rats. 896 2

Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelin converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may provide an exciting prospect for the development of novel therapeutic drugs.
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PMID:Molecular pharmacology and pathophysiological significance of endothelin. 901 36

1. Enhanced endothelin-1 gene expression has been found in blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. In this study, the effects of salt, DOCA and the development of hypertension in DOCA-salt hypertensive rats on the expression of the endothelin-1 gene in blood vessels and on vascular hypertrophy were compared in Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR). 2. Increased endothelin-1 mRNA was found by northern blot analysis in the mesenteric arterial bed of DOCA-salt hypertensive rats and DOCA-salt SHR, but not in DOCA or salt-treated SD rats or in SHR, even when blood pressure reached a mean of 211 mmHg in DOCA-treated SHR. 3. Vascular structure was studied in small mesenteric arteries mounted on a wire myograph. The media width to lumen diameter ratio showed a close correlation with systolic blood pressure except in DOCA-salt hypertensive rats and DOCA-salt SHR, in which it was greater than accounted for by the level of blood pressure. Treatment of DOCA-salt hypertensive rats with the combined ETA/ETB endothelin antagonist bosentan lowered blood pressure slightly, but vascular hypertrophy regressed almost completely and any hypertrophy remaining could be explained by the residual elevated blood pressure. 4. In conclusion, SHR do not exhibit enhanced expression of endothelin-1 in blood vessels. DOCA, salt and elevated blood pressure interact to induce increased arterial expression of endothelin-1. Vascular overexpression of the endothelin-1 gene may produce vascular hypertrophy independently of blood pressure elevation.
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PMID:Endothelin-1 gene expression and vascular hypertrophy in DOCA-salt hypertension compared to spontaneously hypertensive rats. 907 49

1. Depressor and pressor effects of endothelin-1, -2 and -3 in relation to hypertension were investigated in conscious WKY and SHRSP. 2. Changes of systolic arterial pressure to both depressor and pressor responses caused by three doses of endothelin-1, -2 or -3 (0.1, 0.3 and 1 nmol/kg) occurred to a similar extent between WKY and SHRSP. These data showed that endothelins may not exert an important role on the pathogenesis of hypertension. 3. Endothelin-1 decreased the cardiac index more in SHRSP than in WKY, indicating the dominance of ETA receptors in SHRSP compared with WKY. 4. ET-1 was the most potent vasodepressor and vasodilator of three endothelin peptides in rats. 5. During the pressor responses to endothelin-1 and -3, cardiac arrhythmia was observed with high frequency in the animals of both groups, indicating the arrhythmogenic effect of ET.
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PMID:Comparative haemodynamic studies of endothelin-1, -2 and -3 on conscious SHRSP and WKY. 907 54

The endothelins (ET-1, 2, and 3) constitute a family of 21 amino-acid peptides with potent biological activities. They are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. The production and release of endothelin is stimulated by many factors, hormonal and metabolic, and by growth factors, hypoxia, and shear stress. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release. The ETA receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) causes vasoconstriction and stimulation of vascular smooth muscle cell growth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angiotensin II, alpha-adrenergic agonists, Ca2+, and other growth factors. In animal models of hypertension, endothelin causes vascular hypertrophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat than in the spontaneously hypertensive rate. In humans there is an increase in the plasma concentration of endothelin in severe atherosclerotic disease, but not consistently in hypertension. Evidence for the role of endothelin in the vascular hypertrophy of human hypertension is scanty, but the development of nonpeptide and receptor subtype-selective antagonists will permit meaningful studies, including clinical trials of a new class of antihypertensive agents.
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PMID:Endothelin, vascular hypertrophy, and hypertension. 911 Jan 24

The purpose of this study was to determine the effect of chronic ETA receptor blockade, using the orally active antagonist A-127722 in rats with reduced renal mass. The initial series of experiments was designed to characterize the effects of the ETA-selective antagonist A-127722 on arterial pressure and renal function when administered via drinking water over a 4-wk period. Male Sprague-Dawley rats were acclimated to metabolism cages, and baseline 24-h urine collections were obtained. A-127722 was placed in the drinking water at concentrations that delivered doses of 1 to 10 mg/kg per d. The compound had no effect on any of the variables measured, including arterial pressure, food and water intake, urine volume, and sodium and potassium excretion. In a separate group of rats, ETA receptor blockade was verified after 3 d of drinking water containing A-127722. Rats were anesthetized, a jugular vein catheter was inserted for infusions, and a femoral artery catheter was used for monitoring arterial pressure. The pressor response to intravenous injection of Big endothelin-1 (1 nmol/kg, intravenously) was inhibited by > 50% in rats given A-127722 at 10 mg/kg per d, which confirms the efficacy of A-127722 in blocking ETA-mediated responses when placed in drinking water. In an additional series of experiments, rats were anesthetized, the right kidney was removed, and two of three major branches of the left renal artery were ligated. After recovery, rats were returned to their cages and given A-127722 in the drinking water to deliver 1 or 10 mg/kg per d. Control rats underwent the same surgical procedures but were given tap water to drink. After 4 wk, rats that were treated with A-127722 developed similar increases in arterial pressure and urinary protein excretion as rats that received tap water. Therefore, although the ETA receptor antagonist A-127722 can inhibit ETA-mediated hypertension, it has no effect on hypertension produced by a reduction in renal mass. It is concluded that ETA receptor activation does not play a significant role in the functional derangements associated with renal mass reduction in the rat.
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PMID:ETA receptor blockade prevents hypertension associated with exogenous endothelin-1 but not renal mass reduction in the rat. 921 54

Endothelin (ET-1) caused dose-related contraction of isolated superfused bronchus and pulmonary artery and bronchoconstriction and pulmonary vascular hypertension of the heart lung preparation (HLP) of guinea pig. The specific ETA receptor antagonist BQ 123 completely blocked the responses of the pulmonary artery, but failed to affect those of bronchus and of HLPs. The specific ETB receptor agonist Sarafotoxin S6c caused contractions of bronchus, but not of pulmonary artery, and bronchoconstriction and pulmonary hypertension in HLPs. It is concluded that non-ETA subtype receptors, perhaps ETB, appear to be the main responsible for the potent pulmonary hypertensive effects of ET-1.
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PMID:ETB receptor mediating pulmonary hypertension and bronchoconstriction induced by endothelin-1 in the guinea pig. 921 96

1. Chronic treatment with a combined ETA/ETB endothelin receptor antagonist has been shown to reduce blood pressure in experimental rat models of hypertension in which endothelin-1 gene overexpression occurs in the walls of blood vessels, particularly small, resistance-sized arteries, but not in those genetic or experimental models of hypertension in which there is no overexpression of vascular endothelin-1. Failure of some experimental models of hypertension to respond to treatment with the combined ETA/ETB endothelin antagonist may be due in part to blockade of vasorelaxant endothelial ETB receptors which could in theory reduce the efficacy of endothelin antagonism. 2. In this study the orally active ETA-selective endothelin antagonists A-127722.5 and LU 135252 were used in chronic experiments on deoxycorticosterone acetate (DOCA)-salt hypertensive rats (which overexpress vascular endothelin-1 and respond with blood pressure lowering to combined ETA/ETB endothelin receptor antagonism), on spontaneously hypertensive rats (SHR) (which do not overexpress vascular endothelin-1 and do not respond with blood pressure lowering to the combined ETA/ETB receptor antagonist), and in 1-kidney 1 clip Goldblatt (1-K IC) hypertensive rats (which present mild overexpression of vascular endothelin-1 but do not respond with blood pressure lowering to the combined ETA/ETB receptor antagonist). Additionally, it has been suggested that interruption of the renin-angiotensin system may sensitize responses to endothelin antagonism. Accordingly, SHR were treated with an angiotensin converting enzyme inhibitor, cilazapril, in addition to the ETA receptor antagonist. 3. Blood pressure of DOCA-salt hypertensive rats was lowered by a mean of 24 and of 27 mmHg (P < 0.01) by A-127722.5 after 4 weeks of treatment, when given orally at two different doses (10 and 30 mg kg-1 day-1), and by 18 mmHg by LU 135252 50 mg kg-1 day-1. 4. SHR treated with A-127722.5 for 8 weeks starting at 12 weeks of age exhibited the same progressive rise in blood pressure as untreated SHR. Addition of cilazapril resulted in similar reduction of blood pressure in A-127722.5-treated and untreated SHR. 5. Treatment of 1-K IC hypertensive rats with the dose of LU 135252 which lowered blood pressure in DOCA-salt hypertensive rats did not cause any reduction in blood pressure relative to untreated rats. 6. These results demonstrate that treatment with either dose of the selective ETA receptor antagonists A-127722.5 or LU 135252 caused reductions in blood pressure similar to those obtained for a combined ETA/ETB endothelin antagonist. Blood pressure was lowered only in hypertensive rats known to overexpress vascular endothelin-1 (DOCA-salt hypertensive rats) but not in those which do not (SHR) or only have mild vascular overexpression of endothelin-1 gene (1-K 1C hypertensive rats). Reduction in activity of the renin-angiotensin system in SHR did not sensitize blood pressure to potential hypotensive effects of an ETA-selective receptor antagonist.
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PMID:Effect of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats. 922 50

We previously showed that plasma endothelin-1 (ET-1) concentration was increased in deoxycorticosterone acetate (DOCA)-salt-induced malignant hypertension in spontaneously hypertensive rats (SHR). In contrast, in normal SHR, this value is similar to that seen in Wistar-Kyoto (WKY) rats. The purpose of this study was to examine the effects of the new combined ET type A/type B (ETA/B) receptor antagonist, TAK-044, on the development of hypertension in this model of malignant hypertension. TAK-044 10 mg/kg, which effectively blocks both ETA and ETB receptors, was administered intraperitoneally once per day for 4 weeks in DOCA-salt SHR, and the effects on ET-1 and other parameters were compared with the same values in untreated WKY rats, untreated DOCA-salt SHR, and hydralazine-treated DOCA-salt SHR. DOCA-salt caused marked increases in blood pressure, blood urea nitrogen (BUN), serum creatinine, and plasma ET-1 concentrations in SHR. Both TAK-044 and hydralazine significantly suppressed the increase in blood pressure in DOCA-salt SHR to the same extent. Both treatments also suppressed the increase in BUN and serum creatinine, but this attenuation was less marked with hydralazine than with TAK-044. Neither TAK-044 nor hydralazine affected plasma ET-1 concentration in this model. TAK-044 significantly reduced kidney weight in DOCA-salt SHR, whereas the decrease seen with hydralazine was less marked. Prevention of DOCA-salt-induced renal structural injury (mesangial hypercellularity, glomerular sclerotic changes, and tubulointerstitial damage) in this model was clearly greater with TAK-044 treatment than with hydralazine treatment. These results suggest that endogenous ET-1 may, at least in part, contribute to renal functional and structural damage in malignant DOCA-salt SHR. Our results raise the possibility of renoprotective effects of ETA/B receptor blockers in certain forms of malignant hypertension.
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PMID:Renoprotective effects of a combined endothelin type A/type B receptor antagonist in experimental malignant hypertension. 928 92

Immunosuppressive therapy with cyclosporine A (CsA) may be associated with severe side-effects such as nephrotoxicity and arterial hypertension. The partial reversability of these effects suggests that they are at least in part functional. We examined the effects of CsA on cellular signaling in cultured vascular smooth muscle cells from rat aorta. Intracellular free calcium concentrations ([Ca2+]i) were measured using fura-2. Total cell calcium was measured by atomic absorption and cellular endothelin production was estimated by radioimmunoassay. In the presence of CsA the calcium mobilizing effect of angiotensin (Ang) II was significantly enhanced. While the ETA receptor antagonist BQ 123 did not affect Ang II-induced calcium mobilization, the potentiating effect of CsA on [Ca2+]i was blocked by BQ 123. Preincubation of the cells with cyclosporine (10 micrograms/ml) for 30 minutes increased total cell calcium from 2.6 +/- 0.5 to 6.9 +/- 0.3 nmol/mg protein (P < 0.01). Within 24 hours endothelin production was significantly enhanced in the presence of cyclosporine (52.2 +/- 2.5 vs. 65.9 +/- 2.7 fmol/mg protein, P < 0.05). Therefore, the cyclosporine-induced rise of total cell calcium in smooth muscle cells is associated with an enhanced production of endothelin. We speculate that cyclosporine induced changes of Ca(2+)-kinetics may be mediated by endothelin. These results indicate that endothelin may play a major role in cyclosporine-associated side-effects.
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PMID:Cellular mechanisms of cyclosporine A-associated side-effects: role of endothelin. 932 59


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