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)

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

Endothelin (ET)-1, a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproET-1, by endothelin-converting enzyme (ECE)-1 activity. ET-1 may bind to two receptors, ETA and ETB, that mediate vasoconstriction and vasodilation in the ovine fetal lung, respectively. ET-1 contributes to high pulmonary vascular resistance in experimental perinatal pulmonary hypertension induced by ligation of the ductus arteriosus in the fetal lamb. Physiological studies in this model have demonstrated enhanced ETA- and diminished ETB-receptor activities and a threefold increase in lung immunoreactive ET-1 protein content. We hypothesized that increased ET production and an imbalance in receptor expression would favor vasoconstriction and smooth muscle cell hypertrophy in pulmonary hypertension and may be partially due to alterations in gene expression. To test this hypothesis, we studied lung mRNA expression of preproET-1, ECE-1, and the ETA and ETB receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late-gestation fetuses (135 +/- 3 days; 147 days = term) and from animals with pulmonary hypertension after ductus arteriosus ligation for 8 days (134 +/- 4 days). Ductus arteriosus ligation increased right ventricular hypertrophy [control 0.56 +/- 0.02 vs. hypertension 0.85 +/- 0.05; right ventricle/(left ventricle + septum); P < 0.05]. Northern blot analysis was performed using cDNA probes and was normalized to the signal for 18S rRNA. We found a 71 +/- 24% increase in steady-state preproET-1 mRNA (P < 0.05) and a 62 +/- 5% decrease in ETB mRNA (P < 0.05) expression in ductus arteriosus ligation. ECE-1 and ETA-receptor mRNA expression did not change. We conclude that chronic intrauterine pulmonary hypertension after ductus arteriosus ligation increases steady-state preproET-1 mRNA and decreases ETB-receptor mRNA without changing ECE-1 mRNA or ETA-receptor mRNA expression. These findings suggest that increased ET-1 production and decreased ETB-receptor expression may contribute to increased vasoconstrictor tone in this experimental model of neonatal pulmonary hypertension.
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PMID:Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension. 957 71

It has been suggested that the renin-angiotensin system (RAS) interacts with the endothelin system in the pathogenesis of cardiac remodeling. We examined endothelin system regulation in a model of chronic RAS dysfunction, which is believed to be an important factor in cardiac remodeling. We used the transgenic rat line TGR(mRen2)27, which overexpresses the mouse Renin-2 gene and shows hypertension and left ventricular hypertrophy compared to Sprague-Dawley (SD) rats. Ren-2 rats (n = 24) received either losartan (LOS), quniapril (QIN), or carvedilol (CARV) for 11 weeks, or no treatment. After 11 weeks left (LV) and right ventricular (RV) weights were determined and total RNA extracted. Ren-2 rats showed a mean systolic blood pressure of 190 mm (+/- SEM), which could be normalized to 110 +/- mm (+/- SEM) by treatment with LOS or QIN. CARV also reduced blood pressure but did not normalize it. LV end-diastolic pressure was normal in both SD and Ren-2 rats. LV weight was increased in the Ren-2 rats compared to SD rats, and was significantly reduced to normal in the LOS and QIN but not in the CARV group. RV weight was normal in all groups. Northern blot analysis of preproendothelin-1 (preproET-1) and endothelin-converting enzyme-1 (ECE-1) expression revealed a significant (p < 0.05) 20% decrease in preproET-1 mRNA in the mRen2 rats in the RV and in the LV, compared to SD rats. ECE-1 mRNA was unchanged. Treatment with LOS, but not with QIN or CARV, induced preproET-1 transcription by threefold (p < 0.01) over baseline in both the LV and RV. ECE-1 mRNA was unaltered in the CARV and LOS group and was decreased by 20% in the QIN group. Similar changes in LV and RV indicated a direct influence of a dysregulated RAS on the endothelin system. In conclusion, the activated RAS downregulates the endothelin system in this model of cardiac hypertrophy. This suggests that in chronic RAS activated, the endothelin system may have a different pathophysiologic impact as a co-factor leading to cardiac hypertrophy.
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PMID:Interaction of the renin-angiotensin system and the endothelin system in cardiac hypertrophy. 959 97

We previously reported that adenovirus-mediated overexpression of endothelin-1 (ET-1) elevates systemic blood pressure in rats. In this model, plasma big ET-1: ET-1 ratios were almost 30, whereas they were only 5 in the control group, suggesting that endothelin-converting enzyme (ECE) may be a rate-limiting step in the production of ET-1 under these conditions. To further investigate the role of ECE in vivo, we prepared recombinant adenovirus strains carrying a soluble, secretory form of bovine ECE-1 cDNA (Ad.CMV. secECE), human ET-1 cDNA (Ad.CMV.ET-1), and, as a control, E. coli lacZ (Ad.CMV.beta-gal). Ad.CMV.secECE (1-10 x 10(9) pfu/ml) was injected into the caudal vein of male Wistar rats and the animals were studied 96 h later. Immunoblot analysis of circulating plasma confirmed the expression of the soluble ECE-1. The plasma levels of big ET-1 and mature ET-1 were similar in Ad.CMV.secECE and Ad.CMV.beta-gal groups (0.3-0.5 pM). When Ad.CMV.secECE was co-injected with Ad.CMV.ET-1 (2.5 x 10(9) pfu/ml each), plasma ET-1 levels were significantly elevated compared to the control group co-injected with Ad.CMV.secECE and Ad.CMV.beta-gal (10.2 +/- 2.4 vs. 1.1 +/- 0.2 pM). Big ET-1 levels were threefold higher (3.7 +/- 1.1 vs. 1.2 +/- 0.4 pM), and systemic blood pressure was significantly elevated (132 +/- 3 vs. 90 +/- 3 mm Hg) in the Ad.CMV.secECE + Ad.CMV.ET-1 group. Administration of an ECE inhibitor (CGS 26303, 30 mg/kg) significantly reduced the blood pressure in the Ad.CMV.secECE + Ad.CMV.ET-1 group (from 125 +/- 5 to 74 +/- 6 mm Hg) but not in the control group (from 85 +/- 2 to 75 +/- 3 mm Hg). Infusion of an ETA antagonist (FR 139317; 0.2 mg/kg/min for 30 min) also significantly reduced the blood pressure only in the Ad.CMV.secECE + Ad.CMV.ET-1 group, without any significant effect in the control group. This study demonstrates that even though overexpression of ECE-1 in itself does not lead to systemic hypertension, the enzyme can be a crucial rate-limiting factor in the production of mature ET-1 in vivo. Furthermore, this model may prove to be useful for in vivo screening of ECE inhibitors.
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PMID:In vivo role of endothelin-converting enzyme-1 as examined by adenovirus-mediated overexpression in rats. 959 39

-Tacrolimus (FK 506) is a powerful, widely used immunosuppressant. The clinical utility of FK 506 is complicated by substantial hypertension and nephrotoxicity. To clarify the mechanisms of FK 506-induced hypertension, we studied the chronic effects of FK 506 on the synthesis of endothelin-1 (ET-1), the expression of mRNA of ET-1 and endothelin-converting enzyme-1 (ECE-1), the endothelial nitric oxide synthase (eNOS) activity, and the expression of mRNA of eNOS and C-type natriuretic peptide (CNP) in rat blood vessels. In addition, the effect of the specific endothelin type A receptor antagonist FR 139317 on FK 506-induced hypertension in rats was studied. FK 506, 5 mg. kg-1. d-1 given for 4 weeks, elevated blood pressure from 102+/-13 to 152+/-15 mm Hg and increased the synthesis of ET-1 and the levels of ET-1 mRNA in the mesenteric artery (240% and 230%, respectively). Little change was observed in the expression of ECE-1 mRNA and CNP mRNA. FK 506 decreased eNOS activity and the levels of eNOS mRNA in the aorta (48% and 55%, respectively). The administration of FR 139317 (10 mg. kg-1. d-1) prevented FK 506-induced hypertension in rats. These results indicate that FK 506 may increase blood pressure not only by increasing ET-1 production but also by decreasing NO synthesis in the vasculature.
Hypertension 1999 Jan
PMID:Mechanisms of FK 506-induced hypertension in the rat. 993 Oct 93

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

A rapidly growing body of data support the concept of endothelin as a paracrine acting endothelial regulators. The system of endothelin peptides--their chemical structure, physiological activity and role in cardiovascular pathological processes are reviewed. Molecular specificity, isoforms, and physicochemical parameters of the endothelin-converting enzyme (ECE) characterize this novel metalloproteinase as important regulator, that catalyses final step in the biosynthesis of endothelins. The role of the general endothelial system for various cardiovascular pathological states, including congestive heart failure and myocardial infarction, arterial hypertension, atherosclerotic vascular diseases is discussed. Therapeutic approaches with some endothelin receptor antagonists and ECE inhibitors are discussed, and endothelin system therefore represents a likely target for the development for the novel pharmaceutical agents.
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PMID:[The endothelin peptide system: mechanisms of cardiovascular pathology]. 1054 78

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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PMID:Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. 1106

Cyclosporin A (CsA) is a powerful, widely used immunosuppressant, but it is not devoid of serious clinical side effects such as hypertension and nephrotoxicity. To clarify the mechanisms involved in the genesis of these side effects, we studied the effects of chronic CsA administration on the expression of some endothelial vasoactive factors in the aorta and kidney. For this purpose rats were treated for 30 days with 50 mg/kg/day CsA, and hypertension and renal insufficiency developed. In rats receiving CsA, the mRNA expression of pre-pro-endothelin-1 increased, whereas that of endothelial nitric oxide (NO) synthase decreased, both in the aorta and in the renal cortex (increases in pre-pro-endothelin-1 mRNA in aorta and renal cortex, respectively: 275%+/-18%, 300%+/-27%; decreases in endothelial NO synthase mRNA in aorta and renal cortex respectively: 40%+/-8%, 42%+/-6%). Moreover, long-term CsA treatment also induced an up-regulation of the endothelin-converting enzyme 1 mRNA expression (156% vs. control rats) in the renal cortex, with a significantly increased protein content and enzyme activity. In contrast, no changes were detected in endothelin-converting enzyme 1 mRNA expression in aortas from rats receiving the drug. This imbalance between endothelin-1 and NO systems could explain the hypertension and the deranged kidney function observed after long-term CsA treatment in rats.
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PMID:Imbalance in endothelial vasoactive factors as a possible cause of cyclosporin toxicity: a role for endothelin-converting enzyme. 1107 67

Endothelins are 21 amino acid peptides that are produced ubiquitously by vascular endothelial cells, smooth muscle cells, and other cells in different organs. Endothelins are secreted as big-endothelins that are converted to active proteins by the endothelin-converting enzyme. These peptides possess many biological activities, such as vasoconstriction and mitogenesis, and are involved in numerous physiological and pathophysiological processes in humans. Elevated plasma levels of endothelin have been associated with heart failure, and increased immunoreactivity for endothelin is observed in transplant coronary artery disease. In this brief review, we will discuss the regulation of endothelin in cardiac transplantation and the pathological role this peptide plays in renal impairment, systemic hypertension, graft rejection and arteriosclerosis after heart transplantation.
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PMID:Endothelin and cardiac transplantation. 1115 88


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