Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of bosentan (Ro 47-0203), an endothelin A and B receptor antagonist, on responses to endothelin-1, sarafotoxin 6c, angiotensin II, and arginine vasopressin were investigated in the hind-limb vascular bed of the cat. Under constant-flow conditions, intraarterial injections of endothelin-1 and sarafotoxin 6c induced biphasic changes in hind-limb perfusion pressure characterized by an initial decrease followed by a secondary increase in perfusion pressure. The vasodilator and vasoconstrictor components of the biphasic responses to endothelin-1 and sarafotoxin 6c were reduced by bosentan, and the endothelin receptor antagonist reduced baseline systemic arterial and hind-limb perfusion pressures. Bosentan decreased vasoconstrictor responses to lower doses of angiotensin II, whereas responses to higher doses of angiotensin II and responses to vasopressin, U46619, BAY K8644, norepinephrine, acetylcholine, bradykinin, levcromakalim, PGE1, adrenomedullin, and calcitonin gene-related peptide were not altered. Vasoconstrictor responses to ET-1 were not altered by the angiotensin AT1 receptor antagonist DuP 532 or the AT2 receptor antagonist PD123,319. The results of the present study show that bosentan attenuates vasodilator and vasoconstrictor responses to endothelin-1 and sarafotoxin 6c and vasoconstrictor responses to lower doses of angiotensin II in the hind-limb vascular bed of the cat. These results suggest that endothelin may be involved in mediating responses to lower doses of angiotensin II and in the maintenance of baseline tone in the systemic vascular bed of the cat.
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PMID:Analysis of effects of bosentan (Ro 47-0203), a nonpeptide endothelin ETA/ETB receptor antagonist, in the hind-limb vascular bed of the cat. 963 52

Endothelin (ET) antagonists do not decrease blood pressure in normal rats. Since angiotensin II (AII) and ET both induce smooth muscle cell contraction through the same transduction pathways we designed experiments to assess whether blockade of the renin angiotensin system would unmask a vasodilatory response to ET receptor antagonists in rats. For this purpose, we tested the effect on arterial blood pressure of the mixed ETA-ETB receptor antagonist bosentan or of the ETA antagonist BQ-123 in the absence or the presence of the AII receptor antagonist losartan. In control conditions bosentan did not affect arterial blood pressure. In contrast, in losartan-pretreated rats, bosentan induced a marked, dose-dependent decrease in arterial pressure (% change after bosentan 10 mg/kg: control -3 +/- 3, losartan -32 +/- 6; cilazapril -28 +/- 3). Similarly, BQ-123 decreased blood pressure in losartan-pretreated but not in control rats. Bosentan also increased the hypotensive effect of losartan in conscious, normotensive rats. The hypotensive effect of the combination of bosentan and losartan was not associated with any changes in cardiac output or heart rate, and thus was entirely due to a decrease in total peripheral resistance. We conclude that blockade of angiotensin II, AT1 receptors unmasks a vasodilator response to ET antagonists. This suggests that endogenous ET plays an active role in the maintenance of arterial blood pressure in rats which can be unmasked by a concomitant inhibition of the renin angiotensin system.
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PMID:Angiotensin II receptor blockade unmasks a depressor response to endothelin antagonists in rats. 1079 56

Transgenic mice are useful tools to investigate the mechanisms of the renal profibrotic actions of endothelin and angiotensin II. The overexpression of angiotensinogen and renin genes induces renal sclerosis independently of changes in systemic hemodynamics. The same results are observed when the endothelin-1 gene is overexpressed. Transgenic mice harboring the luciferase gene, under the control of the collagen I alpha2 chain promoter, and made hypertensive by induction of a nitric oxide (NO) deficiency have been studied. In this strain of mice, luciferase activity is an early index of renal and vascular fibrosis. Luciferase activity was increased in preglomerular arterioles and glomeruli when mice were treated with N:(omega)-nitro-L-arginine methyl ester, an inhibitor of NO synthases. Bosentan (an endothelin receptor antagonist) was as efficient as losartan (an AT1 receptor antagonist) in preventing renal fibrosis, although it did not decrease BP. In short-term experiments, angiotensin II produced an increase in luciferase activity that was entirely prevented by losartan but also by bosentan. It can be concluded that, during chronic inhibition of NO, the collagen I gene is activated, which contributes to the development of nephroangiosclerosis and glomerulosclerosis. Angiotensin II plays a major role in this fibrogenic process, and its effect is at least partly independent of systemic hemodynamics and mediated by the profibrotic action of endothelin-1.
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PMID:Mechanisms mediating the renal profibrotic actions of vasoactive peptides in transgenic mice. 1106 43

Using angiotensin II (AngII) type 1A receptor-deficient mice [AT1(-/-)], in which we induced protein overload nephropathy, we explored the potential implication of AngII and endothelin-1 (ET-1) in the tubulointerstitial damage because of persistent proteinuria. At day 7, AT1(-/-) showed marked proteinuria to a similar extent to that of wild-type mice (WT). However, at day14, AT1(-/-) had significantly less proteinuria, renal damage, transforming growth factor-beta, and matrix mRNA expression and mortality. AT1(-/-) also showed a significant diminution in the activation of the transcriptional factors nuclear factor-kappaB and AP-1. Unexpectedly, AT1(-/-) had a higher interstitial infiltration than WT. The administration of the angiotensin-converting enzyme inhibitor quinapril to WT caused a marked improvement in proteinuria and renal lesions, resembling that seen in untreated AT1(-/-). However, the interstitial infiltration persisted in AT1(-/-) when treated with quinapril. Because ET-1 may participate in the recruitment of mononuclear cells, we also studied the implication of this peptide. AT1(-/-) had a significantly higher ET-1 expression in tubular epithelial cells than WT. The administration of the dual ETA/ETB antagonist bosentan to AT1(-/-) considerably reduced the interstitial infiltrates. Bosentan also exerted a beneficial effect on proteinuria, renal lesions, and mortality in WT. These data show that in overload nephropathy, proteinuria and renal lesions are, to a large extent, AngII-dependent. The up-regulation of ET-1 in tubular epithelial cells in AT1(-/-), associated with interstitial infiltrates, suggests that the combination of drugs interfering with both vasopeptides may be of therapeutic interest in renal diseases with severe proteinuria and tubulointerstitial damage.
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PMID:Renal tubulointerstitial damage caused by persistent proteinuria is attenuated in AT1-deficient mice: role of endothelin-1. 1169 50