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 1, 2, and 3 did not affect basal renin secretion, but selectively inhibited to a similar extent both cAMP-stimulated renin secretion and renin gene expression in isolated renal juxtaglomerular cells. In isolated perfused rat kidneys and after cAMP-stimulated renin secretion using isoproterenol, endothelins inhibited basal renin secretion at a perfusion pressure of 80 mm Hg. Endothelin's main action is mediated via the endothelin ETB receptor. It involves activation of phospholipase C, intracellular calcium mobilization in juxtaglomerular cells that is dependent on extracellular calcium and associated with prominent calcium-activated chloride currents, and subsequent processes. In normal rats and in rats with unilateral renal artery clips, a nonselective inhibitor of endothelin receptors, Ro 47-0203, did not significantly change renin secretion and renal renin gene expression, despite complete abolition of the vasoconstrictive and renin inhibitory action of exogenous endothelins by this drug in isolated perfused rat kidneys. In spite of a marked renin inhibitory efficacy of exogenous endothelins in vitro (isolated renal juxtaglomerular cells, isolated perfused rat kidney), endogenous endothelins play no relevant regulatory role in renin secretion and renin gene expression in normal and hypoperfused rat kidneys in vivo. However, endothelins may be of physiological relevance for the development of hypertension upon renal artery stenosis.
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PMID:Role of endothelins for renin regulation. 874 30

While there is evidence to suggest that endothelin-1 is involved in regulation of kidney function and blood pressure, the importance of endothelin ETA receptors in this area has not been clearly defined. The novel, non-peptide endothelin ETA receptor antagonist, BMS-182874, (5-(dimethylamino)-N-(3,4- dimethyl-5-isoxazolyl)-1-naphthalene sulfonamide) was used to examine effects of endothelin ETA receptor blockade on renal function in spontaneously hypertensive rats. Preliminary studies were conducted to determine an effective dose of BMS-182874. Infusion of BMS-182874 (10 mumol/kg/min, i.v.) inhibited effects of exogenous endothelin-1 on glomerular filtration rate, renal blood flow, and mean arterial pressure in Sprague-Dawley rats. Administration of BMS-182874 (10 mumol/kg/min, i.v.) to anesthetized, male, spontaneously hypertensive rats decreased renal blood flow by approximately 50% (1.2 +/- 0.11 ml/min/100 g body weight) compared to vehicle (2.7 +/- 0.23). There was no effect of BMS-182874 on glomerular filtration rate (0.5 +/- 0.05 ml/min/100 g body weight; vehicle: 0.7 +/- 0.06). Mean arterial pressure decreased significantly after BMS-182874 (123 +/- 3.8 mm Hg; vehicle: 162 +/- 4.8). Urine flow and renal vascular resistance were unchanged by BMS-182874. Endothelin ETA receptor density was increased approximately 50% in spontaneously hypertensive rat kidneys compared to normotensive kidneys, with no change in equilibrium dissociation constant. Endothelin ETB receptor density and equilibrium dissociation constant were similar in the two rat strains. Plasma immunoreactive endothelin was higher in hypertensive (5.9 +/- 0.31 fmol/ml) than normotensive rats (2.8 +/- 0.15). The results suggest endothelin ETA receptors may play a role in the regulation of renal function in this model of hypertension.
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PMID:A role for endothelin ETA receptors in regulation of renal function in spontaneously hypertensive rats. 878 30

The levels of endothelin-1-like immunoreactivity (ET-1-LI) and characteristics of endothelin receptors in the chorionic villous tissue of human placenta were determined. The ET-1-LI level in chorionic villous tissue obtained from normal term placenta was 2,450 +/- 940 pg/g wet weight (mean +/- SD, n = 4). Further analysis using gel permeation chromatography and reverse-phase high performance liquid chromatography showed that the main ET-1-LI constituent of ET-1-LI in this tissue was ET-1. Scatchard analysis of [125I]ET-1 binding to the membrane fraction of chorionic villous tissue obtained from term placenta showed high affinity receptor sites with an apparent dissociation constant (Kd) of 23.6 +/- 11.1 pM and a Bmax value of 388 +/- 238 fmol/mg protein (n = 5). The same binding study with [125I]ET 3 showed a Kd of 13.9 +/- 3.8 pM and a Bmax value of 176 +/- 78 fmol/mg protein (n = 5). These results suggest that both ET-A and ET-B receptors (ET-AR and ET-BR) are expressed in chorionic villous tissue. This finding was further confirmed by Northern blot analysis showing the expression of both ET-AR and ET-BR mRNAs in this tissue. ET-1-LI in the umbilical venous plasma of the newborns from women with pregnancy-induced hypertension (PIH) (38.3 +/- 10.4 pg/mL, n = 5) was significantly (P < 0.05) higher than that in the normal newborns from normotensive pregnant women (26.3 +/- 5.2 pg/mL, n = 12). However, in placental chorionic villous tissue obtained from PIH women, both ET-1-LI level and ET binding profile were not different from those in chorionic villous tissue from normotensive pregnant women. These results suggest that the abundant ET-ET receptor system is present in the placental chorionic villous tissue and that this system is not the major factor of the pathogenesis of placental dysfunction occurring in PIH because these systems are similar in normotensive and hypertensive pregnancies.
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PMID:Endothelin-1-like immunoreactivity and endothelin receptors in the human placenta from normotensive and hypertensive pregnancies. 895 Jul 25

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

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

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

This fifth international conference on ET serves to underline the rapid pace of development of our understanding of the very versatile ET system. On the one hand, the body uses ETs at several stages in embryonic development, in normal postnatal growth, and in cardiovascular homeostasis under healthy conditions. On the other hand, overwhelming evidence now exists that ET-1 plays important pathophysiological roles in conditions of decompensated vascular homeostasis. Indeed, in CHF this evidence is sufficient to justify the large-scale studies of morbidity and mortality needed to market ET antagonists as medicines. Other potentially important cardiovascular indications for ET antagonists are still emerging--including hypertension, stroke, subarachnoid haemorrhage and renal failure--and all are likely to be the subject of clinical trials over the next few years. As yet, there has been little work outside the cardiovascular and renal fields, but other areas, such as cancer treatment, may also prove promising. New molecules with increasing selectivity (ETA and ETB) continue to emerge and may be valuable. Inhibition of ECE-1 remains as an alternative approach and nonpeptide ECE inhibitors now exist. There appears to be a consensus that ETA blockade is beneficial in cardiovascular and renal disease. However, several strands of work presented at the meeting--the hypertensive salt-sensitive phenotype of rescued ETB knockout mice, the sustained and progressive hypertensive effects of ETB-selective antagonism in rats, ETB-mediated vasodilatation and natriuresis in dogs, and nitric oxide-dependent ETB-mediated vasodilatation in humans--all suggest that ETB-mediated vascular and renal responses may be protective. The development of selective ETA antagonists, therefore, now seems fully justified. In the future, direct comparisons in animal models, and patients, of ETA and ETA/B antagonists will be important in determining the value of additional ETB receptor blockade in individual diseases.
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PMID:Endothelin: new discoveries and rapid progress in the clinic. 950 92


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