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 may function pathophysiologically as a counterregulatory vasoconstrictor peptide that is modified in its activity by the opposing action of endothelium-derived relaxing factor(s) (EDRF). The present study determined in part the integrated cardiorenal and endocrine actions of pathophysiologic plasma concentrations of endothelin in the anesthetized dog. In addition, nitroglycerin, which inhibits vascular smooth muscle contraction by increasing cGMP in a mechanism similar to EDRF, acts like an endogenous nitrovasodilator. Therefore, we tested the hypothesis that nitroglycerin would effectively antagonize the cardiac and renal actions of exogenous endothelin. The results confirm that endothelin-1-mediated vasoconstriction in vivo is heterogenous with a greater renal than coronary action. Further, nitroglycerin effectively blocked endothelin-1-mediated coronary flow reductions, but only partially antagonized reductions in renal blood flow. Endothelin-1-induced reduction in cardiac output also was not antagonized by nitroglycerin despite its effects to preserve coronary blood flow. Nitroglycerin did, however, antagonize endothelin-induced elevations in plasma epinephrine, norepinephrine, and aldosterone. These results would suggest that in pathophysiologic states where endothelin-1 is elevated, such as hypertension or congestive heart failure, there is a major compromising of renal function, and also the production of cardiac ischemia. Since exogenous nitroglycerin is relatively ineffective in antagonizing the renal vasoconstrictive effects of endothelin, it may be that the endogenous vasodilating systems, such as ERDF and prostacyclin, are inadequate in such pathologic states to counter the vasoconstrictor effects of endothelin.
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PMID:Endothelin-mediated cardiorenal hemodynamic and neuroendocrine effects are attenuated by nitroglycerin in vivo. 838 58

After cardiac transplantation, cyclosporine-treated patients exhibit a high incidence of systemic hypertension, the mechanism of which is not known. Endothelin, a potent vasoconstrictor peptide of endothelial origin, may be activated by cyclosporine-induced endothelial injury and therefore may mediate post-transplant hypertension. In the present study, we tested whether immunoreactive endothelin-1 could be detected by radioimmunoassay in the plasma of cardiac transplant recipients and if levels correlated with hemodynamic characteristics, cyclosporine level, or renal function as assessed by serum creatinine. Plasma endothelin was measured in 22 stable cyclosporine-treated patients 9 days to 3 years after successful orthotopic cardiac transplantation before routine hemodynamic assessment and surveillance endomyocardial biopsy. Fifteen patients were receiving chronic therapy for hypertension. Plasma endothelin-1 was 5.2 +/- 1.8 pg/ml (range 3.1 to 10.5), which was increased compared with that in 12 normal subjects (1.9 +/- 0.3 pg/ml; range 1.4 to 2.4); the difference was statistically significant (p < 0.0001). Repeated sampling in 8 patients at weekly intervals identified a persistent increase in endothelin with only modest variability. Endothelin-1 did not correlate with any hemodynamic variable, serum creatinine or cyclosporine level. Thus, endothelin-1 is increased after successful orthotopic cardiac transplantation. In the absence of discrete correlations with hemodynamic variables, serum creatinine or cyclosporine levels, both the characteristics and mechanisms for increased endothelin in recipients of cardiac transplants require further evaluation.
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PMID:Effects of successful cardiac transplantation on plasma endothelin. 842 89

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide produced in the endothelium of blood vessels that may play an important role in the control of local blood flow and could be involved in the pathogenesis of hypertension. We investigated immunoreactive ET-1 (ir-ET-1) levels in acid extracts from blood vessels of deoxycorticosterone acetate (DOCA)-salt and spontaneously hypertensive rats. We found that segments of thoracic aorta and the mesenteric vascular bed contain significantly more ir-ET-1 (11.84 +/- 0.84 and 17.30 +/- 1.89 fmol, respectively) than uninephrectomized control rats (1.78 +/- 0.20 and 9.19 +/- 0.63 fmol, respectively; p < 0.001). High performance liquid chromatography showed that ir-ET-1 of blood vessels of DOCA-salt hypertensive rats eluted in the same position as synthetic ET-1. Significantly increased ir-ET-1 was localized by immunohistochemistry in endothelial cells of aorta and large and small mesenteric arteries of DOCA-salt hypertensive rats. In contrast to the latter, in spontaneously hypertensive rats, vascular content of ir-ET-1 was similar to that of blood vessels of Wistar-Kyoto control rats, at both 6 and 16 weeks of age. High levels of vascular ET-1 may explain the downregulation of vascular endothelin receptors previously described in DOCA-salt hypertensive rats. Furthermore, this suggests that ET-1 may be involved in the maintenance of high blood pressure in mineralocorticoid hypertension.
Hypertension 1993 Mar
PMID:Increased endothelin-1 content in blood vessels of deoxycorticosterone acetate-salt hypertensive but not in spontaneously hypertensive rats. 847 38

Endothelins are produced by endothelial and epithelial cells, macrophages, fibroblasts, and many other types of cells. Their receptors are present in numerous cells, including smooth muscle cells, myocytes, and fibroblasts. Evidence now suggests that the three isoforms of endothelins (ET-1 and the other two related isopeptides, ET-2 and ET-3) regulate growth in several of these cells. Endothelin-1 influences DNA synthesis, the expression of protooncogenes, cell proliferation, and hypertrophy. The participation of ET in mitogenesis involves activation of multiple transduction pathways, such as the production of second messengers, the release of intracellular pools of calcium, and influx of extracellular calcium. Moreover, ET-1 acts in synergism with various factors, such as EGF, PDGF, bFGF, TGFs, insulin, etc., to potentiate cellular transformation or replication. Several of these factors may in turn stimulate the synthesis and/or the release of endothelins. The production and release of endothelins are also increased in acute and chronic pathological processes, e.g., atherosclerosis, postangioplastic restenosis, hypertension, and carcinogenesis. It is postulated that endothelins act in a paracrine/autocrine manner in growth regulation and play an important role mediating vascular remodeling in some cardiovascular diseases. The present review analyses the implication of endothelins (ET-1, -2, and -3) in physiopathology related to their growth regulatory properties.
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PMID:Growth regulatory properties of endothelins. 848 16

Endothelin-1 (ET-1) is an endothelium-derived vasoconstrictor peptide isolated from the culture supernatant of porcine aortic endothelial cells. This 21 amino-acid residue peptide has potent vasoconstrictive properties in vitro and in vivo. ET-1 action involves phosphatidylinositol turnover, calcium mobilization and protein kinase C activation. Endothelial cells have distinct receptors for different operating through hydrosoluble hormones. The aim of this study was to investigate on a possible role of angiotensin II (ANG II) to modulate the release ET-1 from human endothelial cells in vitro. These data revealed a time- and a dose-dependent increase of ET-1 production in response to ANG II. This mechanism may have important pathophysiological implications in vivo. In fact, a double-mechanism of secretion of ET-1 from endothelial cells could exist: one active in a physiological condition and an other in response to a vasoconstrictor stimuli (as well as ANG II). Furthermore, these results may suggest an additional favourable effect of ACE-inhibition in human hypertension therapy.
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PMID:[Angiotensin II stimulates endothelin-1 release from human endothelial cells]. 848 29

Endothelin-1 contracts vascular smooth muscle and inhibits release of neurotransmitter from adrenergic and cholinergic neurons. Experiments were designed to investigate the interaction of these mechanisms in a blood vessel that receives both adrenergic and cholinergic innervation. Rings cut from canine left anterior descending coronary arteries were suspended in organ chambers for the measurement of isometric force. In some rings, the endothelium was removed. Endothelin-1 caused concentration-dependent increases in tension in all rings. During electrical stimulation (1 Hz, 9 V, 2 msec), the contractions to endothelin-1 were reduced significantly. In rings without endothelium, this decrease was greater in the presence of atropine (10(-6) M) and was eliminated by a combination of phentolamine (10(-5) M) and propranolol (5 x 10(-6) M). Contractions to endothelin-1 during electrical stimulation in rings with endothelium were significantly less than those without endothelium. This difference was eliminated by atropine and NG-monomethyl L-arginine (10(-4) M). The presynaptic effects of endothelin-1 were studied by measurement of tritium-labeled norepinephrine. Phasic electrical stimulation induced release of norepinephrine; this was inhibited by endothelin-1 at high concentrations (4 x 10(-7) M) in the presence of atropine. These results suggest that the major effect of endothelin-1 is postsynaptic in canine coronary arteries. However, contractions to endothelin-1 may be modulated by the level of sympathetic and parasympathetic tone. In situations in which innervation to the coronary arteries is altered, for example, in hearts used for transplantation, the contractile effects of endothelin-1 would prevail.
Hypertension 1993 May
PMID:Autonomic modulation of contractions to endothelin-1 in canine coronary arteries. 849 2

The present study was designed to analyze quantitatively the effects of a wide range of endothelin-1 levels on renal hemodynamics and renin release in the canine nonfiltering kidney, including their effects on glomerular hydraulic pressure. Intrarenal infusion of endothelin-1 produced dose-dependent reductions in renal blood flow, but it did not affect glomerular hydraulic pressure until the infused dose reached high rates. At the rate of 1.0 ng/kg per minute, endothelin-1 reduced renal blood flow by 23% (p < 0.01), whereas glomerular hydraulic pressure was not significantly changed from 68.1 +/- 1.3 to 67.4 +/- 1.2 mm Hg. However, with a higher rate of endothelin-1 infusion (5.0 and 10.0 ng/kg per minute), glomerular hydraulic pressure fell to 59.5 +/- 1.3 and 51.5 +/- 1.8 mm Hg (p < 0.01), whereas renal blood flow was reduced from 154.5 +/- 15 to 83.0 +/- 9.5 and 53.5 +/- 9.9 mL/min, respectively. Endothelin-1 infusion also produced an inhibitory effect on renin release. With infusion at 1.0 ng/kg per minute, renin release fell from the control level of 47.9 +/- 5.6 to 26.6 +/- 4.9 units/min per gram kidney weight (p < 0.01), and it fell further to 16.1 +/- 4.3 units/min per gram kidney weight with infusion at 10.0 ng/kg per minute. In summary, endothelin-1 infusion did not affect glomerular hydraulic pressure despite a fall in renal blood flow at low doses, but at high doses it reduced both, suggesting that endothelin-1 exerts separate, dose-dependent effects on preglomerular and postglomerular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1993 Jun
PMID:Effect of endothelin-1 on glomerular hydraulic pressure and renin release in dogs. 850 Aug 65

We previously investigated the inactivation of endothelin-1 by deamidase (lysosomal protective protein), present in many cells, including vascular smooth muscle cells. This enzyme, which we originally purified from human platelets, preferentially hydrolyzes peptides at the C-terminus with hydrophobic amino acids in the P1 or P1' position or both and thereby inactivates endothelin-1, which has a C-terminal sequence of Ile19-Ile20-Trp21-OH. We tested for the presence of deamidase in cultured bovine aortic endothelial cells. The final supernatant of the homogenized cells (S3) cleaved the deamidase substrate dansyl-Phe-Leu-Arg at a rate of 1.3 nmol/min per 10(6) cells at pH 5.5 at 37 degrees C. Endothelin-1 was completely inactivated by the S3 fraction as determined on rat thoracic aorta strips. The major site of inactivation was the Ile20-Trp21 bond, established by high performance liquid chromatography and by amino acid analysis where the main product was des-Trp21-endothelin-1. The hydrolysis of endothelin-1 (5.9 nmol/min per milligram of protein at pH 5.5 at 23 degrees C) by S3 was blocked mainly by inhibitors of deamidase, including diisopropyl fluorophosphate, but not by inhibitors of some other peptidases. This is the first report of a novel pathway of endothelin-1 metabolism in endothelial cells. Thus, endothelial cells, besides being the source of endothelin-1, contain an enzyme that inactivates it.
Hypertension 1993 Jun
PMID:Inactivation of endothelin-1 by an enzyme of the vascular endothelial cells. 850 2

Endothelin-1 (ET-1) is a potent and long-lasting vasoconstrictor peptide. In order to clarify the changes in the level of ET-1 with aging, we measured the ET-1 level in plasma by radioimmunoassay and used 74 healthy subjects including 61 males and 13 females, aged from 30 to 69, who were admitted in the health check center of Ashikaga Red Cross Hospital. None of them had risk factors related to hypertension, obesity, diabetes mellitus or cardiovascular disease. In the male group, the relationship between the level of ET-1 (Y) and age (X) was obtained as follows: Y = 0.08857 X +0.06363. The correlation between them was significant (gamma = 0.65894, p < 0.05). In the female group also, the increased level of ET-1 (Y) with age (X) showed an excellent linear relationship (Y = 0.163091 X -4.23, gamma = 0.762, p < 0.002). These studies demonstrated that the level of ET-1 increased in relation to aging and the increased ET-1 production with aging may be consistent with deterioration of endothelial function.
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PMID:[Changes in the level of endothelin-1 with aging]. 855 91

Endothelin-1, a potent vasoconstrictor produced by vascular endothelial cells, activates the hypertrophic program in cultured heart muscle cells. However, the role of endothelin-1 in cardiac hypertrophy in humans is unknown. Therefore, we studied hypertrophic cardiomyopathy patients with normal pulmonary arterial pressure, in whom cardiac hypertrophy is a specific feature of the disease. Radioimmunoassay with a monoclonal antibody to human endothelin-1 showed that the plasma level of immunoreactive endothelin was more than twofold higher in hypertrophic cardiomyopathy patients than in control subjects (P < .005). In situ hybridization analysis of endomyocardial biopsy specimens showed positive signals of endothelin-1 type A receptor mRNA in ventricular myocytes of all specimens. The receptor expression in ventricular myocytes was similar between hypertrophic cardiomyopathy patients and control subjects. We propose that endothelin-1 might represent an important factor involved in hypertrophic cardiomyopathy. Whether endothelin-1 plays a causal role in cardiac hypertrophy or is a marker of its occurrence needs to be clarified.
Hypertension 1996 Feb
PMID:Endothelin-1 and its receptor in hypertrophic cardiomyopathy. 856 49


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