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

The present experiments describe the endothelin-1 (ET-1) antagonist activity of BQ123 (cyclic D-Asp-L-Pro-D-Val-L-Leu-D-Trp) in conscious Sprague-Dawley (SD) rats, and we also examined the effect blockade of ETA receptors had on blood pressure in four experimental models of hypertension. Rats were anesthetized with methoxyflurane and instrumented with femoral arterial and venous catheters. In SD rats, BQ123 (0.1-10.0 mg/kg i.v.) administered 5 or 60 min prior to ET-1 inhibited both the magnitude and duration of the ET-1 (0.25 nmol/kg i.v.) pressor response. In addition, BQ123 (10.0 mg/kg) inhibited the pressor response evoked by administration of the ET-1 precursor, proendothelin-1 (1.0 nmol/kg). However, BQ123 (10.0 mg/kg) had no effect on the pressor response evoked by ET-3 (0.75 nmol/kg). In Wistar-Kyoto rats, BQ123 (10.0 mg/kg) reversed the hypertension produced by an infusion of ET-1 (0.01 nmol/kg/min). Administration of BQ123 produced a mild antihypertensive effect in normal- to low-renin models of hypertension, but no blood pressure lowering was observed in high-renin models of hypertension. These studies demonstrated the selectivity of the ETA receptor antagonist, BQ123 for ET-1, but not ET-3-induced pressor responses. Furthermore, ET-1 does not appear to be a major contributing factor to the maintenance of elevated levels of blood pressure in four experimental models of hypertension.
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PMID:Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. 128 97

Endothelial cells produce the 21-amino acid peptide endothelin, which is formed from its precursor, big endothelin, via the activity of converting enzyme. The basal production of the peptide is stimulated by epinephrine, angiotensin II, arginine vasopressin, transforming growth factor beta, thrombin, interleukin-1, and hypoxia. In vascular smooth muscle, endothelin binds to a specific receptor (ETA-subtype), which activates phospholipase C, leads to the formation of inositol trisphosphate, diacylglycerol (which activates protein kinase C), and increased intracellular Ca2+. In certain blood vessels, the endothelin receptor on vascular smooth muscle is linked to a voltage-operated Ca2+ channel via a G-protein. This explains why Ca2+ antagonists inhibit endothelin-induced contractions in certain, but not all, blood vessels. In the human forearm circulation, Ca2+ antagonists do prevent endothelin-induced contractions and unmask endothelin-induced vasodilation mediated by endothelial prostacyclin production (via the ETB-receptor). The pulmonary circulation plays an important role in the metabolism of endothelin, as the lungs take up large quantities of the peptide during passage. Endothelin has profound vasoconstrictor effects in the pulmonary circulation (and also in bronchial tissue), and its production is augmented in pulmonary hypertension. In systemic hypertension, the circulating endothelin levels appear to be normal. In atherosclerosis and other forms of vascular disease, circulating endothelin levels are increased. Thus, endothelin is a potent mediator in the systemic and pulmonary circulation and, in particular, in diseases of the vasculature.
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PMID:Endothelin: systemic arterial and pulmonary effects of a new peptide with potent biologic properties. 133 60

Endothelins (ET-1, ET-2 and ET-3) are a family of 21 amino acid peptides produced by endothelial cells. They are thought to regulate the local vasomotor tone with endothelium-derived relaxing factors. ETs are the most potent vasoconstrictor substances yet identified and veins and renal vasculature are the most sensitive targets. They reduce cardiac output and have positive inotropic and chronotropic effects. ETs increase the secretion of atrial natriuretic peptide (ANP), aldosterone and catecholamines but reduce renal blood flow and glomerular filtration and they also have mitogenic properties. ETs bind to receptors (ETA and ETB), activate phospholipase C, modulate intracellular Ca2+ concentration and open Ca2+ channels. Vasoactive agents (adrenaline, angiotensin, vasopressin, thrombin, endotoxins) and hypoxia stimulate the release of ET and also ET gene expression. Raised concentrations of plasma ET have been found to occur in several clinical conditions such as hypertension, myocardial infarction, cardiogenic shock, pregnancy induced hypertension, arteriosclerosis, Raynaud's disease, subarachnoid haemorrhage, uraemia, ulcerative colitis, Crohn's disease and surgical operations suggesting that ETs have a role in several patophysiological processes.
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PMID:Endothelin peptides: biological activities, cellular signalling and clinical significance. 138 14

Cerebral glutamate decarboxylase (GAD) activity in DOCA-salt hypertensive rats showed a significant increase in the mesencephalon and a significant decrease in the cerebral cortex and in the cerebellum, compared to that observed in mononephrectomized normotensive animals. Intracerebroventricular (icv) injection of muscimol (0.5, 1 and 2 micrograms), a GABA receptor agonist, produced a dose-dependent decrease in heart rate (HR), significantly greater in freely moving hypertensive animals than in normotensive controls. Muscimol also reduced mean arterial pressure (MAP). The hypotensive effect induced by muscimol (2 micrograms) was significantly higher in hypertensive animals. Ethanolamine-O-sulphate (5, 10, 20 and 40 microM), an inhibitor of GABA breakdown, determined a decrease in MAP and in HR greater in hypertensive than in normotensive rats. Intraperitoneal injection of valproic acid (50-100 mg/Kg/die) for 6 weeks significantly reduced the development of DOCA-salt hypertension in rats. The anti-hypertensive effect became significant during the 4th week and was dose-dependent. DOCA-salt animals, daily treated with 50 mg/Kg of valproic acid, showed an increased pressor response to intravenous injection of phenylephrine (0.1, 0.5 and 1 microgram/Kg). Data strongly support an impairment of cerebral GABA control of blood pressure and heart rate in DOCA-salt hypertensive rats.
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PMID:Increased cardiovascular responsiveness to GABAergic stimulation in DOCA-salt hypertensive rats. 643 10

The purpose of this study was to characterize the receptor(s) and second messenger systems involved in prostacyclin (prostaglandin [PG] I2) synthesis elicited by endothelin (ET)-1 in the rat aorta. PGI2 synthesis, measured as immunoreactive 6-keto-PGF1 alpha, was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ETA and ETB receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ETB receptor agonist, enhanced 6-keto-PGF1 alpha synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF1 alpha synthesis. Moreover, the selective ETB receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF1 alpha synthesis. Furthermore, ET-1-induced 6-keto-PGF1 alpha synthesis was attenuated by an ETA receptor antagonist, BQ-123, in a dose-dependent manner but not by an ETB receptor antagonist, BQ-788. Depletion of extracellular Ca2+ or addition of Ca2+ channel blockers (nifedipine, verapamil, SK&F 96365) attenuated ET-1-mediated 6-keto-PGF1 alpha synthesis, while a Ca2+ channel agonist, S(-)-Bay K 8644, potentiated this effect of ET-1. Selective protein kinase C inhibitors (bisindolylmaleimide I, calphostin C) did not alter ET-1-induced 6-keto-PGF1 alpha synthesis. These data suggest that PGI2 synthesis elicited by ET-1 in the rat aorta is mediated primarily through influx of extracellular Ca2+ via activation of an ETA receptor and is independent of protein kinase C.
Hypertension 1995 Dec
PMID:Prostacyclin synthesis elicited by endothelin-1 in rat aorta is mediated by an ETA receptor via influx of calcium and is independent of protein kinase C. 749 63

The role of different endothelin (ET) receptors in the hemodynamic action of ET-1 was investigated with an ETA-receptor antagonist, BQ-123, in anesthetized Wistar rat. BQ-123 (10 mg/kg/0.1 ml) was injected 5 min before ET-1 injection (1 nmol/kg). IV injection of ET-1 induced a short period of hypotension associated with aortic vasodilation, followed by long-lasting hypertension and aortic vasoconstriction. These effects were concomitant with immediate renal and mesenteric vasoconstriction. In the presence of BQ-123, the hypotension and aortic vasodilation induced by ET-1 were prolonged and the subsequent hypertension and aortic constriction were prevented. In the renal vascular bed, BQ-123 did not significantly affect the initial ET-1-induced constriction but markedly shortened its duration. In contrast, in the mesenteric vascular bed, BQ-123 seemed initially to amplify the ET-1-induced constriction, but afterwards slightly reduced it. The hemodynamic response to ET-1 may be mediated at first by ETB receptors, which induce a reduction of systemic blood pressure and regional vasoconstriction. In a second phase, ETA receptors operate to induce a systemic pressor effect and participate with ETB receptors in regional vasoconstriction. Therefore, ETA and ETB receptors may exist in various proportions in different vessels, the renal vascular bed appearing to be richer in ETA receptors than the mesenteric bed. The results, which demonstrate that ETB receptors mediate aortic dilation and regional constriction, are unexpected and suggest the existence of another non-ETA-type receptor and/or a different localization of non-ETA receptors in the vascular wall.
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PMID:Implication of different endothelin receptors in the vascular action of a hypertensive dose of ET-1 in rat. 750 55

Until recently, a role for endothelin-1 (ET-1) in the development and/or maintenance of hypertension has been based solely on indirect findings, e.g., elevated circulating levels of peptide. However, with the development of specific ET-1 receptor antagonists it is now possible to examine this relationship directly. The present study describes the hemodynamic effects of systemic infusions of BQ-123, a selective endothelin (ETA)-receptor antagonist, in conscious, freely moving spontaneously hypertensive (SHRs) and normotensive Wistar-Kyoto (WKY) rats. Sustained infusions of BQ-123 (0.16-164 nmol/kg/min i.v. for 6 h) produced dose-dependent reductions in mean arterial pressure (approximately 30 mm Hg) in SHRs that were long-lasting (> 18 h) and reversible. Whereas cardiac output remained unaltered during BQ-123 infusion, the observed reduction in blood pressure was accompanied by a significant decrease (16%) in total peripheral resistance, indicating that the fall in blood pressure (an effect that was independent of the vehicle used and was not observed in WKY rats) was related primarily to peripheral vasodilation. Thus, the present study provides direct evidence showing that ET-1-receptor antagonists are effective antihypertensive (rather than hypotensive) agents and that endogenous ET-1 is involved in the pathophysiology of hypertension.
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PMID:Antihypertensive effects of the endothelin receptor antagonist BQ-123 in conscious spontaneously hypertensive rats. 750 76

1. In 1988, Yanagisawa et al. reported the presence of a potent peptide from the supernatant of porcine endothelial cells. This was later named endothelin-1 (ET-1) and was found to belong to a new family of vasoconstrictor peptides. There are at least three isoforms of endothelin: ET-1, endothelin-2 and endothelin-3. 2. ET-1 is produced from a larger precursor molecule by endothelin converting enzyme (ECE); there may be a number of ECE but the most physiologically relevant appears to be a membrane-bound neutral metalloprotease. The endothelin precursor is produced on demand and is regulated at the mRNA level. 3. Two subtypes of mammalian endothelin receptors have been cloned and sequenced: ETA receptors which mediate vasoconstriction and ETB receptors which mediate both vasoconstriction and vasodilatation. However, functional studies have indicated that other subtypes of endothelin receptors may exist. 4. ET-1 has a wide range of biological actions apart from its direct effects on vascular tone, including constriction of non-vascular smooth muscle, cardiac effects, mitogenesis and stimulation of the release of hormones such as atrial natriuretic peptide and prostacyclin. At low concentrations which have no direct vasoconstrictor action, ET-1 potentiates the effect of other vasoconstrictor agonists. 5. The precise role of ET-1 in health and disease is not well defined at present; however, there are indications that it may have a role in the pathogenesis of some cardiovascular disease states, including subarachnoid haemorrhage, renal ischaemia and certain types of hypertension.
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PMID:Endothelin-1 and the regulation of vascular tone. 755 21

Endothelin is the most potent mammalian vasoconstrictor yet discovered. Its three isoforms play leading roles in regulating vascular tone and causing mitogenesis. The isoforms bind to two major receptor subtypes (ETA and ETB), which mediate a wide variety of physiologic actions in several organ systems. Endothelin may also be a disease marker or an etiologic factor in ischemic heart disease, atherosclerosis, congestive heart failure, renal failure, myocardial and vascular wall hypertrophy, systemic hypertension, pulmonary hypertension, and subarachnoid hemorrhage. Specific and nonspecific receptor antagonists and ECE inhibitors that have been developed interfere with endothelin's function. Many available cardiovascular therapeutic agents, such as angiotensin-converting-enzyme inhibitors, calcium-entry blocking drugs, and nitroglycerin, also may interfere with endothelin release or may modify its activity. The endothelin antagonists have great potential as agents for use in the treatment of a wide spectrum of disease entities and as biologic probes for understanding the actions of endothelin in human beings.
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PMID:Endothelin and endothelin antagonism: roles in cardiovascular health and disease. 766 Oct 79

1. The effects of the non-selective endothelin (ET) receptor (ETA/ETB) antagonist, bosentan, on sciatic nerve dysfunction in experimental diabetes were investigated. 2. Rats with 5-6 weeks untreated streptozotocin-diabetes exhibited characteristic slowed motor nerve conduction velocity (mean +/- s.d., 36.6 +/- 3.4 m s-1) and nerve laser Doppler flux (197 +/- 64 arbitrary units) compared to age-matched control animals (42.7 +/- 2.4 m s-1 and 398 +/- 77 arbitrary units, respectively). Preventative treatment of diabetic rats with bosentan at 100 mg kg-1 day-1 p.o. attenuated both these deficits (39.7 +/- 3.0 m s-1 and 305 +/- 56 arbitrary units, respectively) without affecting mean arterial pressure. 3. In control and untreated diabetic rats, ET-1, 1 nmol kg-1 i.v., caused an initial hypotension (duration, 30 +/- 13 and 26 +/- 9 s, respectively; change in mean arterial pressure, -27 +/- 13 and -25 +/- 7 mmHg, respectively) followed by prolonged hypertension (change in mean arterial pressure, 52 +/- 18 and 31 +/- 5 mmHg, respectively). Effectiveness of the chronic bosentan treatment was demonstrated by inhibition of the hypotensive response to ET-1 in treated diabetic rats (duration, 5 +/- 2 s; change in mean arterial pressure, -4 +/- 2 mmHg) although the hypertension was unaltered (change in mean arterial pressure, 32 +/- 9 mmHg). 4. Acute i.v. administration of 10 mg kg-1 bosentan caused variable and transient rises in nerve laser Doppler flux in control (78 +/- 63 arbitrary units) and untreated diabetic rats (93 +/- 77 arbitrary units). Acute bosentan blocked the hypotensive response to subsequent ET-1 administration and attenuated the later hypertension (change in mean arterial pressure, 21 +/-9 mmHg in control, 29 +/- 10 mmHg in diabetic).5. Our results indicate that oral treatment of diabetic rats with an ET receptor antagonist can improves ciatic nerve perfusion and conduction, suggesting that the vasoconstrictor action of endogenous ET may contribute to peripheral nerve dysfunction in experimental diabetes.
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PMID:Effects of endothelin receptor antagonism with bosentan on peripheral nerve function in experimental diabetes. 767 Jul 40


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