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)

Endothelin-1 (ET-1) is the most potent vasoconstrictor known. Disturbances in the renal release and/or actions of ET-1 are involved in the pathogenesis and maintenance of essential and renal parenchymal hypertension. In animal models of disease evidence is presented for ET playing a role in the pathogenesis of some renal diseases: acute renal failure, ciclosporine nephrotoxicity, radiocontrast nephrotoxicity, glomerulonephritis, diabetic nephropathy and renal glomerulosclerosis. The studies in humans have been restricted to measurements of ET levels in blood and urine, and therefore determination of its true role in the pathogenesis of arterial hypertension and kidney diseases must await the development of safe, potent and highly selective ETA and ETB receptor antagonists as well as selective ETB receptor agonists. These compounds could become therapeutic agents in the future. The use of ET converting enzyme inhibitors may also become an important modality for treatment of diseases linked with increased ET production.
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PMID:Endothelins in hypertension and kidney diseases. 988 30

The endothelins (ET) are potent 21-amino-acid vasoconstrictor peptides produced in many different tissues, particularly in the endothelium of blood vessels. ET-1 is the main endothelin secreted by the endothelium, and acts in a paracrine or autocrine fashion on blood vessels by interacting with ETA or ETB receptors on smooth muscle to stimulate contraction or on ETB receptors on endothelial cells to induce the release of vasorelaxants (nitric oxide and prostacyclin). Production of ET-1 is enhanced in several experimental models of hypertension in the rat, such as sodium-sensitive forms, e.g. deoxycorticosterone acetate (DOCA)-salt hypertensive, DOCA-salt-treated spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats, as well as other models such as stroke-prone SHR, angiotensin II-infused rats and fructose-fed rats, and possibly 1-K 1C Goldblatt hypertensive rats. In contrast, SHR, 2-K 1C Goldblatt hypertensive rats and nitric oxide-deficient (L-NAME-treated) hypertensive rats do not exhibit an ET-1 component. Endothelin dependency is manifested by excessive vascular growth, particularly in small arteries, and blood pressure lowering and regression of vascular growth after treatment with endothelin antagonists. The latter may be combined ETA/ETB or selective ETA antagonists, of which several are orally active and already in clinical development. In humans, endothelin-dependent vascular tone has been shown in studies of forearm blood flow. Enhanced expression of ET-1 mRNA has been demonstrated in the endothelium of small arteries of patients with moderate to severe hypertension. In a 4-week trial the combined ETA/ETB antagonist bosentan reduced the blood pressure of essential hypertensive patients equally to enalapril. Bosentan improved hemodynamics in patients with heart failure in acute and 2-week-long studies. Endothelin antagonists also offer promise in a rapidly fatal condition, primary pulmonary hypertension. Thus, the endothelin system appears to be involved in different forms of cardiovascular disease in experimental animals and humans, and its interruption offers great promise as a new therapeutic intervention in hypertension, heart failure and other diseases.
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PMID:Endothelin and endothelin antagonists in hypertension. 988 74

-In vivo studies could not detect a positive inotropy of endothelin (ET)-1 as described in in vitro experiments. ET-induced direct positive inotropy, which seems to be mediated by ETB receptors, may be antagonized in vivo by an indirect cardiodepressive effect owing to an ET-induced coronary vasoconstriction via ETA receptors. This study compares the effects of a dose of 1 nmol/kg ET-1 alone on myocardial contractility and myocardial energy metabolism with the effects of 1 nmol/kg ET-1 after pretreatment with 5 mg/kg molsidomine or with 100 microg/kg of the ETA receptor antagonist BQ 610. We investigated the effects of ET-1 versus saline controls in open-chest rats. In addition to measurements in the intact circulation, myocardial function was examined by isovolumic registrations independent of peripheral vascular effects. We also studied the effect of ET-1 on myocardial high-energy phosphates. Pretreatment with molsidomine and BQ 610 attenuated the ET-induced reduction of cardiac output (ET-1: -62%; molsidomine+ET-1: -47%; BQ 610+ET-1: -27% different from controls). After a transient initial vasodilation, ET-1 raised total peripheral resistance (ET-1: +190%; molsidomine+ET-1: +171%; BQ 610+ET-1: +89%). BQ 610 was more effective in preventing ET-induced vasoconstriction. The increase of isovolumic peak first derivative of left ventricular pressure (ET-1: -2%; molsidomine+ET-1: +16%; BQ 610+ET-1: +19%) after pretreatment with molsidomine or BQ 610 indicates that these drugs unmask the positive inotropy of ET-1. ET-induced myocardial ischemia was abolished by molsidomine and BQ 610. Pretreatment with molsidomine or blockade of ETA receptors by BQ 610 can unmask the positive inotropy of ET-1 by preventing ET-induced myocardial ischemia. The positive inotropic effect of ET-1 seems to be mediated by ETB receptors.
Hypertension 1999 Jan
PMID:Inotropic effects of endothelin-1: interaction with molsidomine and with BQ 610. 993 Oct 95

Endothelin-1 (ET-1) is an important mediator of vascular tone in humans, and a number of endothelin receptor antagonists are currently in clinical development as vasodilator agents. While the vasoconstrictor role of the ETA receptor is undisputed, the role of the ETB receptor remains unclear. Hemodynamic effects of systemic doses of the ETB-selective antagonist BQ-788 were investigated in 5 healthy male volunteers (age range, 33 to 48 years) in a placebo-controlled, four-way crossover study. After a 15-minute infusion of BQ-788 (3, 30, or 300 nmol/min) or placebo, plasma ET-1 and big ET-1, blood pressure, heart rate, cardiac index, and stroke index were measured. Total peripheral vascular resistance was calculated from cardiac index and mean arterial pressure. Hemodynamic data are expressed as maximum, placebo-corrected, percentage change from baseline following BQ-788 (300 nmol/min) and were examined by ANOVA. Plasma ET-1 increased by 3.7+/-1.2 pg/mL (maximum at 15 minutes, P=0.02), whereas there was no significant change in plasma big ET-1. Although BQ-788 had no effect on mean arterial pressure, there was a reduction in heart rate (13+/-7% at 50 minutes; P=0.002), cardiac index (17+/-5% at 40 minutes; P<0. 0001), and stroke index (8+/-4% at 40 minutes; P=0.002) and an increase in total peripheral vascular resistance (24+/-5% at 40 minutes; P<0.0001). The selective ETB receptor antagonist BQ-788 causes peripheral vasoconstriction in healthy volunteers, suggesting that the overall balance of effects of endogenous ET-1 at the vascular ETB receptor favors vasodilatation. Further investigation is now clearly required to address whether selective ETA or combined ETA/ETB receptor blockade will be more effective in the clinical setting.
Hypertension 1999 Jan
PMID:Systemic blockade of the endothelin-B receptor increases peripheral vascular resistance in healthy men. 993 Nov 69

Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 +/- 6 mmHg by day 21 from control levels of 150 +/- 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg. kg-1. 24 h-1). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 +/- 6.9 mg/24 h on day 21 from 9.0 +/- 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 +/- 17 to 277 +/- 104 pg. 100 g body wt-1. 24 h-1 associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 +/- 1.1 to 12.2 +/- 1.9 ng. 100 g body wt-1. 24 h-1 (days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [3H]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [3H]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SBP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.
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PMID:Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension. 1007 Jan 37

1. Chronic inhibition of nitric oxide synthase (NOS) results in a persistent hypertension, while chronic blockade of endothelin ETA receptors has little effect on arterial pressure. These findings indicate that nitric oxide (NO) plays a more significant role than ET-1 in the long-term maintenance of arterial pressure. 2. Although endothelin (ET) appears to contribute to the hypertension in the early stages of NOS inhibition, blockade of either ETA or both ETA and ETB receptors has only a minor effect on the hypertension beyond the initial 2 weeks of NOS inhibition. 3. Endothelin may play a role in vascular lesion development associated with NOS inhibition, at least within the kidney, which may be related to angiotensin II activity. 4. The processes involved in the hypertension associated with chronic NOS inhibition appear to be dynamic and may include an evolution of ET-1 action. Variability in results from different laboratories may be related to genetic factors and choice of pharmacological agents.
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PMID:Chronic studies on the interaction between nitric oxide and endothelin in cardiovascular and renal function. 1008 24

The aim of the present study was to analyze whether the cardiac endothelin system contributes to cardiac remodeling in rats with 2-kidney, 1 clip (2K1C) renovascular hypertension. The endothelin system seems to be a promising candidate for cardiac remodeling because endothelin (ET)-1 promotes growth of cardiomyocytes in vitro and induces cardiac collagen synthesis. The activity of the cardiac endothelin system was analyzed by measuring cardiac tissue big ET-1 and ET-1 concentrations as well as by estimating the cardiac expression of the ETA and ETB receptors 10 days, 4 weeks, and 12 weeks after the renal artery was clipped. The effects of long-term treatment with ETA, ETB, and combined ETA/ETB receptor antagonists on cardiac hypertrophy, media/lumen ratio of intracardiac arteries, and left ventricular fibrosis were also analyzed. This study demonstrated that the overall left ventricular cardiac endothelin system has a similar activity in the early, middle, and late stages of 2K1C renovascular hypertension compared with sham-operated controls. Fibrosis of the left ventricle and hypertrophy of intracardiac arteries, however, were markedly altered after long-term treatment with endothelin receptor antagonists in a blood pressure-independent manner. These 2 effects are mediated by different subtypes of endothelin receptors. ETA receptor blockade completely normalized the hypertrophy of intracardiac arteries (P<0. 01 compared with 2K1C without treatment) in renovascular hypertension, whereas the ETB antagonist reduced cardiac fibrosis of the left ventricle (P<0.001 compared with 2K1C without treatment) to baseline values. This study demonstrates that the cardiac endothelin system plays an important role in the development of cardiac fibrosis as well as in hypertrophy of intracardiac arteries in 2K1C renovascular hypertensive rats.
Hypertension 1999 Mar
PMID:Endothelin system-dependent cardiac remodeling in renovascular hypertension. 1008 93

The central and peripheral cardiovascular effects of endothelin (ET)-1 and ET-3 were investigated in conscious rainbow trout. Both intracerebroventricular and intra-arterial injections of ET-1 (6. 25-25 pmol) but not ET-3 (25 pmol) caused a dose-dependent increase in mean dorsal aortic blood pressure and a concomitant decrease in heart rate. The hypertensive effects induced by intra-arterial and intracerebroventricular injection of ET-1 were associated with a significant (P < 0.05) increase in systemic vascular resistance. Intracerebroventricular injection of ET-1 induced a twofold higher pressor response than that caused by intra-arterial injection of ET-1 and provoked a barostatic gain that was reduced by 2.5- to 3-fold compared with that calculated after intra-arterial administration of the peptide. The ET receptor antagonist bosentan significantly (P < 0.05) attenuated these responses regardless of the route of administration. Finally, intra-arterial injection of ET-1 did not significantly modify plasma cortisol level. The present data demonstrate that intracerebroventricular and intra-arterial administration of very low doses of ET-1 produces hypertension in conscious trout. The lack of effect of ET-3 indicates that the hemodynamic actions of ET-1 are mediated both centrally and peripherally through ETA receptors.
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PMID:Central and peripheral administration of endothelin-1 induces an increase in blood pressure in conscious trout. 1019 79

In pregnant rats during hypertension induced by NO synthase inhibition, endothelin (ET) plasma levels are increased as in some preeclamptic women. Previously, the enhanced vasodepressor effect of endothelin-1 (ET-1) has been observed in this model, thus we decided to study the relaxation induced by ET-1 on the aorta. Non-pregnant or pregnant Wistar rats (n = 7 by group) were fed for 7 days (day 13-day 20) on a nitroarginine-enriched diet (L-NNA, 0.063% i.e. 30 mg/kg/day) or a control diet. Systolic blood pressure, measured by the tail cuff method on conscious rats at day 20 of gestation, was raised by the chronic L-NNA treatment (mean +/- s.e.m., mmHg, p < 0.001: pregnant L-NNA treated, 145 +/- 1.84 vs. pregnant control, 101 +/- 2.00 and non-pregnant L-NNA treated, 148 +/- 3.11 vs. non-pregnant control, 119 +/- 1.80). On day 20 ex vivo aortic ring relaxation was produced by ET-1 in vessels previously precontracted with norepinephrine only when endothelium was present. In control rats, ET-1 (10(-8) to 5 x 10(-8) M) produced a short but significant relaxation (mean value between 4 to 19%) followed by a long-lasting contracting phase, and a higher ET-1 concentration (10(-7) M) only produced contraction. Chronic L-NNA treatment decreased the level of relaxation (at least p < 0.05, in non-pregnant and pregnant rats) and with a 30 min L-NAME (10(-4) M) preincubation, relaxation was completely inhibited in non-pregnant and pregnant rats. BQ-123, an ETA receptor antagonist, did not produce any effect on ET-1 induced relaxation. BQ-788, an ETB receptor antagonist, significantly decreased it. In conclusion, in female rats, as in male rats, ET-1 induces a transient relaxation in the preconstricted aorta which involves endothelial ETB receptors. Despite a decrease in the systemic vascular reactivity during late gestation, the vasodilating and vasoconstricting properties of ET-1 on the aorta are not changed.
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PMID:Endothelin-1 and relaxation of the rat aorta during pregnancy in nitroarginine-induced hypertension. 1022 65

In a new model of spontaneous hypertension, namely the Prague hypertensive rat (PHR), hypertension is transferred with a kidney transplanted from the PHR to its normotensive counterpart (PNR) by an as yet unknown mechanism. One candidate may be endothelin (ET), since this potent vasoconstrictor affects vascular tone, renal haemodynamics and renal excretory function, and all members of this peptide family are located within the kidney and act in an autocrine/paracrine fashion. In the present study we investigated, in the renal tissue of PHRs and PNRs: (1) preproET-1 and preproET-3 mRNAs as well as ET-1 and ET-3 peptide distribution, (2) endothelin-converting enzyme (ECE)-1 mRNA expression, and (3) ET receptors and their characteristics in membranes of glomeruli and papillae. In addition, plasma ET concentration and urinary ET excretion were determined. Quantitative measurements by competitive reverse transcription-polymerase chain reaction revealed ET-1 mRNA levels in the renal cortex from PHRs and PNRs of 1.09+/-0.13 and 1. 29+/-0.18 amol/microgram of total RNA respectively, and in red medulla of 2.72+/-0.82 and 3.30+/-0.68 amol/microgram respectively. In contrast, renal papilla from PHRs showed significantly lower levels of preproET-1 mRNA (1.81+/-0.64 amol/microgram of total RNA, compared with 4.25+/-0.82 amol/microgram in PNRs; each n=5; P<0.05). The ET-1 peptide concentration in papillary tissue was also significantly lower in PHRs than in PNRs (120.2+/-30.8 and 491.3+/-53.4 fmol/mg of protein respectively; n=5; P<0.01), whereas it was similar in cortex and medulla from PHRs and PNRs. The preproET-3 mRNA content in renal tissue was much lower than that of preproET-1 mRNA. It was significantly higher in red medulla from PHRs compared with that from PNRs (0.25+/-0.05 and 0.13+/-0.02 amol/microgram of total RNA respectively; P<0.05), but was similar in papillae of PHRs and PNRs (0.04+/-0.02 and 0.05+/-0.01 amol/microgram respectively; n=5). Cortical preproET-3 mRNA was at the lower limit of detection. Similarly, the ET-3 peptide concentration was slightly but significantly higher in the red medulla of PHRs compared with PNRs (15.4+/-2.0 and 8.8+/-0.8 fmol/mg of protein respectively; n=5; P<0. 05), whereas no differences in ET-3 peptide concentration were found in papillae from PHRs and PNRs. ECE-1 mRNA levels were similar in the renal cortex, red medulla and papillae from PHRs and PNRs, ranging between 0.34+/-0.03 and 0.56+/-0.12 amol/microgram of total RNA. Of the total ET receptors in glomerular membranes, 39% were ETA receptors, whereas papillary membranes contained exclusively ETB receptors. PHRs and PNRs showed similar Bmax and Kd values for ET-1 in renal glomerular membranes (Bmax, 6.5+/-1.3 and 4.9+/-1.2 pmol/mg of protein respectively; Kd, 0.69+/-0.10 and 0.56+/-0.10 nM respectively) and papillary membranes (Bmax, 9.7+/-1.1 and 11.3+/-1. 6 pmol/mg of protein respectively; Kd, 0.30+/-0.04 and 0.42+/-0.07 nM respectively). Plasma ET-1/2 concentrations (10.4+/-1.3 and 12. 2+/-1.2 fmol/ml in PHRs and PNRs respectively) and urinary ET-1 excretion (3.1+/-0.3 and 3.0+/-0.2 pmol/24 h in PHRs and PNRs respectively) were similar in hypertensive and normotensive rats. In summary, although tissue levels of preproET-3 mRNA were very low in the kidney, significantly greater amounts of preproET-3 mRNA and ET-3 peptide were found in medullary tissue from PHRs compared with PNRs, a finding that awaits further investigation. In contrast, the preproET-1 mRNA content and ET-1 peptide concentration were significantly lower in papillary tissue from PHRs compared with PNRs. Decreased synthesis of ET-1, which normally antagonizes the action of [Arg8]vasopressin, may allow increased water (and sodium) reabsorption at the level of the inner medullary collecting duct. This intrinsic defect of the kidney in the PHR may contribute to hypertension in this model, and may transmit high blood pressure on transplantation of the 'hypertensive' kidney i
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PMID:The renal endothelin system in the Prague hypertensive rat, a new model of spontaneous hypertension. 1036 99


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