Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In porcine aortic endothelial cells, the 21-amino acid peptide endothelin-1 (ET-1) is formed from a 39-amino acid intermediate big endothelin (big ET) by a putative endothelin-converting enzyme (ECE) that cleaves the 39-mer at the Trp21-Val22 bond. Because big ET has less than 1% of the contractile activity of ET-1, inhibition of ECE should effectively block the biological effects of big ET. Big ET injected intravenously into anesthetized rats produces a sustained pressor response that presumably is due to conversion of big ET to ET-1 by ECE. We determined the type of protease activity responsible for this conversion by evaluating the effectiveness of protease inhibitors in blocking the pressor response to big ET in ganglion-blocked anesthetized rats. The serine protease inhibitor leupeptin, the cysteinyl protease inhibitor E-64, and the metalloprotease inhibitors captopril and kelatorphan were ineffective at blocking the pressor response to big ET. However, the metalloprotease inhibitors phosphoramidon and thiorphan both dose-dependently inhibited the pressor response to big ET, although phosphoramidon was substantially more potent than thiorphan. None of the inhibitors blocked the pressor response to ET-1 and none had any effect on blood pressure when administered alone as an i.v. bolus to the ganglion-blocked anesthetized rat. However, phosphoramidon infused intravenously at 20 mg/kg/h for 4 h lowered the mean arterial pressure (MAP) in conscious spontaneously hypertensive rats (SHRs) whereas kelatorphan at the same dose did not. Our results suggest that ECE is a novel metalloprotease and that ECE inhibitors could have therapeutic potential for the treatment of hypertension.
 ...
PMID:Phosphoramidon blocks the pressor activity of big endothelin[1-39] and lowers blood pressure in spontaneously hypertensive rats. 172 58

The endothelium exerts a large influence on the underlying vascular smooth muscle, not only by the release of both contracting and relaxing factors but also by its ability to synthesize a large number of molecules that influence vascular smooth muscle growth. In addition to well-characterized growth promoters or growth inhibitors, some endothelium-derived factors, originally described as vasoactive compounds, seem to possess growth-regulatory properties. The vasoconstrictor endothelin-1 elicited a dose-dependent increase of cultured vascular smooth muscle cell DNA synthesis with a maximal effect of 57 +/- 14% over basal levels, whereas vasodilators such as prostacyclin, sodium nitroprusside, and 8-bromoguanosine 3':5'-cyclic monophosphate reduced DNA synthesis by 19 +/- 5%, 22 +/- 2%, and 31 +/- 3%, respectively. Medium conditioned by cultured bovine aortic endothelial cells markedly stimulated both DNA synthesis and proliferation of smooth muscle cells. When medium was conditioned in the presence of the endothelin-converting enzyme inhibitor phosphoramidon, the mitogenic effect was significantly reduced, thus indicating a role for endothelin in the stimulation of smooth muscle cell growth by endothelial cells. However, when both cell types were maintained in a coculture system, a 13 +/- 2% decrease of DNA synthesis was observed in smooth muscle cultures. The addition of the nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester, the cyclooxygenase inhibitor indomethacin, or both during the coculture period did not revert the antiproliferative effect of endothelial cells in coculture, thereby indicating it is not likely due to these unstable endothelium-derived vasorelaxant molecules.
Hypertension 1995 Apr
PMID:Influence of endothelium on cultured vascular smooth muscle cell proliferation. 772 27

Aspergillomarasmine-A and -B (AM-A and -B), which were isolated from the cultured broth of an unidentified fungus N877, showed apparent inhibition against endothelin-converting enzyme (ECE) from bovine endothelial cells as measured by the formation of endothelin-1 (ET-1) converted from big endothelin-1 (bET-1), with IC50 values of 3.4 and 2.5 microM for AM-A and -B, respectively. EDTA also inhibited ECE (IC50 = 1.1 microM), but the inhibitions by AM-A, AM-B and EDTA were each abolished by the addition of 10 microM Zn2+ to the reaction mixture. In mice, AM-A and -B dose-dependently (10-50 mg/kg, i.v.) caused significant prolongation of the latency to sudden death induced by i.v. bET-1 (25 nmol/kg), but not that by ET-1 (5 nmol/kg), accompanied by a decrease in plasma immunoreactive ET-1 formation, while EDTA (24 mg/kg) failed to do so. In mice, the LD50 value of AM-A was calculated to be 159.8 mg/kg, i.v., which was much larger than that of EDTA (28.5 mg/kg, i.v.), indicating the low toxicity of AM-A. AM-A (30 mg/kg, i.v.) also suppressed bET-1-induced hemoconcentration and hypertension in mice and rats, respectively. These findings suggest that although ECE inhibition by AM-A was mainly attributable to its chelating activity, it showed apparent in vivo activities due to ECE inhibition with low toxicity.
 ...
PMID:Pharmacological profiles of aspergillomarasmines as endothelin converting enzyme inhibitors. 828 29

The physiologic significance of endothelin-1 (ET-1) generation in human resistance vessels is unknown. We therefore investigated whether endothelin-converting enzyme (ECE) activity could be demonstrated in human vessels, and the effects of inhibition of the generation or actions of ET-1 on vascular tone in healthy men. Brachial artery infusion of local doses of big ET-1 caused a slow-onset, dose-dependent forearm vasoconstriction that was abolished by co-infusion of the ECE inhibitor phosphoramidon. Phosphoramidon did not affect responses to ET-1. Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% (p = 0.03). Vasoconstriction to ET-1 was completely abolished by co-infusion of the ETA receptor antagonist BQ-123 (p = 0.006), with forearm blood flow tending to increase. Infusion of BQ-123 alone resulted in progressive vasodilatation, with blood flow increasing by 64% (p = 0.007). These results suggest that endogenous generation of ET-1 contributes to the maintenance of vascular tone in states of normal and elevated blood pressure. ECE inhibitors and ETA receptor antagonists may have potential as vasodilators in the treatment of diseases associated with vasoconstriction, such as hypertension and chronic heart failure.
 ...
PMID:Physiologic role of endothelin in maintenance of vascular tone in humans. 858 57

Increasing evidence suggests that endothelin, a potent vasoconstrictor, is implicated in cyclosporin A (CsA)-induced nephrotoxicity. Increased levels of urinary and circulating endothelin have been described in CsA-treated humans and animals. The exact mechanisms by which CsA induces these increases are still unknown, and no data indicate whether these elevated levels reflect increased synthesis or decreased clearance of endothelin. In the present study, we investigated the effects of CsA administration (50 mg/kg per day i.p. for 6 days) to rats on plasma and urinary levels of endothelin; expression of endothelin-1 (ET-1), ET-3, and endothelin-converting enzyme in renal tissue; clearance of infused 125I-ET-1; and degradation of 125I-ET-1 by recombinant neutral endopeptidase. Rats given CsA for 6 days developed severe renal insufficiency, as shown by a 74% decrease in creatinine clearance rate (Ccr) (P < .006). Ccr was remarkably improved in CsA-treated rats that received bosentan, the combined antagonist of both endothelin A and endothelin B receptors. Urinary excretion of endothelin increased from an undetectable level to 31.7 +/- 6.0 pg/24 h (P < .001), and plasma levels of endothelin were unchanged (2.8 +/- 0.2 to 3.1 +/- 0.2 pg/mL). Reverse transcription followed by quantitative polymerase chain reaction revealed that ET-1 mRNA in the renal medulla increased by 59% (P < .006), whereas the expression of both ET-3 and endothelin-converting enzyme was unchanged. In other rats, neither acute nor chronic treatment with CsA affected either the clearance of 125I-ET-1 from the blood or the renal and pulmonary uptake of the peptide. Moreover, CsA did not affect the degradation of 125I-ET-1 by highly purified recombinant neutral endopeptidase, a well-known endothelinase. Taken together, these data suggest that the elevated urinary endothelin levels obtained after CsA treatment originate from the kidney and reflect increased renal synthesis of ET-1. Moreover, the production of endothelin appears to be regulated at the mRNA transcription level, and expressions of ET-1 and ET-3 are regulated independently.
Hypertension 1996 May
PMID:Effects of cyclosporin A on the synthesis, excretion, and metabolism of endothelin in the rat. 862 Dec 8

Endothelins are ubiquitously produced 21-amino-acid peptides that were discovered as an endothelial product and may play important roles in cardiovescular physiology and pathophysiology. The main endothelin produced by the endothelium is endothelin-1. The vasoconstrictor role of endothelins may participate in blood pressure elevation and vascular hypertrophy in salt-dependent models of hypertension (deoxycorticosterone acetate-salt hypertensive rats, spontaneously hypertensive rats treated with deoxycorticosterone, acetate and salt, and Dehl salt-sensitive rats), and in stroke-prone spontaneously hypertensive rats. In humans, endothelins may play important roles in moderate to severe essential hypertension, and in the hypertension of African-Americans. Endothelins may be involved in cardiac hypertrophy, and there is increasing evidence of their participation in heart failure, in which acute endothelin antagonism in humans exerts beneficial effects. Endothelin expression is enhanced in smooth muscle cells migrating into the intima of arteries in atherosclerosis, suggesting a role in atherogenesis. Endothelin may participate as a vasoconstrictor in coronary artery disease, and as a contributor to intimal proliferation in restenosis after coronary angioplasty. In patients with myocardial infarction, cardiac production of endothelin is increased, particularly in those with cardiogenic shock. There is a potential for participation of endothelins in vasospasm accompanying stroke or subarachnoid hemorrhage: in the latter, endothelin antagonism has shown beneficial effects in experimental models. In neonatal and in primary pulmonary hypertension, endothelin expression is enhanced, and in experimental models endothelin antagonism resulted in favorable responses. Systemic sclerosis is another, peripheral, form of vascular disease in which endothelin may play a role and in which endothelin antagonism may be an interesting therapeutic alternative. The pathophysiologic role of endothelins is becoming increasingly apparent in cardiovascular disease, generating interesting potential therapeutic targets for the use of endothelin antagonists or endothelin-converting enzyme inhibitors.
 ...
PMID:Clinical significance of endothelin in cardiovascular disease. 926 47

Endothelin-1 (ET-1) is formed from its precursor preproET-1 via the cleavage of the intermediate bigET-1 by endothelin-converting enzyme (ECE-1). However, the subcellular site at which this step occurs is not clear: It could occur intravesicularly along the secretory pathway or bigET-1 might be released and processed extracellularly. To address this point, we have developed an integrated autocrine system that uses a recombinant Chinese hamster ovary (CHO) luciferase reporter cell line that permanently expresses the human ET(A) receptor. Into these cells we transiently transfected human ECE-1a cDNA, either together with the human preproET-1 cDNA (as an endogenous source of bigET-1), or alone (in which case exogenous bigET-1 was added). Phosphoramidon inhibited the conversion of exogenous bigET-1 (IC50 = 5 to 30 micromol/L) much better than that of endogenous bigET-1 (IC50 > 1 mmol/L). Both conversions showed similar high yields (20% to 100%) that depended on the amount of ECE-1a expressed. Thus, ECE-1a has two equally relevant activities in this recombinant system for CHO cells: (1) an intracellular, probably intravesicular activity, corresponding to the ECE-1a-mediated step of ET-1 biosynthesis and (2) an extracellular activity at the plasma membrane. If this is also the case for endothelial cells, ECE-1a inhibitors would have to cross the plasma and vesicle membranes to be effective. The present system could be useful for screening such inhibitors.
Hypertension 1997 Oct
PMID:A live-cell assay for studying extracellular and intracellular endothelin-converting enzyme activity. 933 81

Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET(A) receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET(B) antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET(B) receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET(A) receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.
Hypertension 1997 Nov
PMID:ET(B) receptor and nitric oxide synthase blockade induce BQ-123-sensitive pressor effects in the rabbit. 936 77

The potent vasoconstrictor endothelin-1 (ET-1) is secreted constitutively by endothelial cells and has been implicated in the pathophysiology of several cardiovascular diseases. It is generated from its inactive intermediate, big ET-1, through the action of endothelin-converting enzyme (ECE). Using several complementary techniques, we have demonstrated that ECE is present at the cell surface and on intracellular vesicles and that it recycles from the cell surface in endothelial cells. This is the first ultrastructural localization of ECE in lung and the first time big ET-1 and ECE have been colocalized by immunogold in a vesicular population, 50 to 100 nm in diameter. In addition, by double immunogold staining of ultrathin cryosections, we have localized ECE together with angiotensin-converting enzyme on the luminal membrane of endothelial cells. With cell surface biotinylation of a transformed rat endothelial cell line and of human umbilical vein endothelial cells, we have confirmed the presence of ECE on the plasma membrane. After treatment of endothelial cells with chloroquine, ECE and trans-Golgi network 38 protein were shown by immunofluorescence staining to localize to the same intracellular compartment.
Hypertension 1998 Jan
PMID:Endothelin-converting enzyme: ultrastructural localization and its recycling from the cell surface. 944 82

Experiments on isolated strips of rat v. portae revealed that endothelin participates in the development of myogenic reactions of vascular smooth muscles. Endothelin is known to be released by endotheliocytes and to stimulate the contraction of vascular smooth muscle cells. Rats with inherited arterial hypertension showed significant decrease of the stimulating effect of endothelin-1 upon the contraction of vascular smooth muscles. At the same time, the effect of phosphoramidon, an inhibitor of endothelin-converting enzyme, upon the length-tension curve of the strips of v. portae is more marked in hypertensive vs. control rats. The data obtained testify to the fact that the increase of vascular tone in the hypertensive rats is most likely to be conditioned by the involvement of endothelin.
 ...
PMID:[The role of endothelin in the contractile reactions of vascular smooth muscles in hypertensive rats]. 946 14


1 2 3 4 5 6 7 Next >>