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Endothelin Antagonist (endothelin + antagonist)
Selected AbstractsChemInform Abstract: Development of a Scalable Process for CI-1020 (VIII), a Novel Endothelin Antagonist.CHEMINFORM, Issue 42 2001James E. Ellis Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a "Full Text" option. The original article is trackable via the "References" option. [source] RGS4 Controls Renal Blood Flow and Inhibits Cyclosporine-Mediated NephrotoxicityAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010A. Siedlecki Calcineurin inhibitors (CNI) are powerful immunomodulatory agents that produce marked renal dysfunction due in part to endothelin-1-mediated reductions in renal blood flow. Ligand-stimulated Gq protein signaling promotes the contraction of smooth muscle cells via phospholipase C,-mediated stimulation of cytosolic calcium release. RGS4 is a GTPase activating protein that promotes the deactivation of Gq and Gi family members. To investigate the role of G protein-mediated signaling in the pathogenesis of CNI-mediated renal injury, we used mice deficient for RGS4 (rgs4,/,). Compared to congenic wild type control animals, rgs4,/, mice were intolerant of the CNI, cyclosporine (CyA), rapidly developing fatal renal failure. Rgs4,/, mice exhibited markedly reduced renal blood flow after CyA treatment when compared to congenic wild type control mice as measured by magnetic resonance imaging (MRI). Hypoperfusion was reversed by coadministration of CyA with the endothelin antagonist, bosentan. The MAPK/ERK pathway was activated by cyclosporine administration and was inhibited by cotreatment with bosentan. These results show that endothelin-1-mediated Gq protein signaling plays a key role in the pathogenesis of vasoconstrictive renal injury and that RGS4 antagonizes the deleterious effects of excess endothelin receptor activation in the kidney. [source] Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humansBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2000Marianne C. Verhaar Aims, Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT-627 in healthy humans. Methods, Healthy volunteers were included in two studies with cross-over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT-627 or matched placebo, in a dose range of 0.2,40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET-1 were assessed. Results, ABT-627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62%vs 4% during placebo, P < 0.05, for Study 1 and in 42%vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at ,,1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET-1. ABT-627 caused a significant reduction in peripheral resistance as compared with placebo (16 ± 1 vs 19 ± 1, 18 ± 2 vs 23 ± 3, 15 ± 1 vs 17 ± 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 ± 2 vs 84 ± 3, 80 ± 4 vs 90 ± 5, 75 ± 3 vs 79 ± 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate dose-dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level). Conclusions, The oral ETA receptor blocker ABT-627 is well tolerated, rapidly absorbed, effectively blocks ET-1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease. [source] Cardiovascular effects of endothelin-1 and endothelin antagonists in conscious, hypertensive ((mRen-2)27) ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2000S M Gardiner SB 209670 is a potent antagonist of the vasoconstrictor (ETA - and ETB -receptor-mediated) and vasodilator (ETB -receptor-mediated) effects of endothelin, whereas SB 234551 is relatively selective for the constrictor (ETA -receptor-mediated) effects. Since we had previously found SB 209670 exerted antihypertensive, vasodilator effects in conscious, heterozygous, transgenic ((mRen-2)27) (abbreviated to TG) rats, here we compared the two antagonists in that model, and assessed their chronic effects on responses to exogenous endothelin-1. We did this to test our global hypothesis, namely, that SB 209670, but not SB 234551, would cause inhibition of the depressor effects of exogenous endothelin-1 in vivo, and that this differential effect would be associated with a more marked antihypertensive action of SB 234551 in TG rats. SB 209670 and SB 234551 (infused for 50 h) exerted similar, sustained, antihypertensive effects in TG rats. The antihypertensive effects of the antagonists occurred at times when the pressor effects of exogenous endothelin-1 were not significantly inhibited. Furthermore, SB 234551 did not exert a greater antihypertensive effect than SB 209670 at a time (i.e., 2,4 h) when the depressor effects of endothelin-1 were abolished by the latter, but not by the former (although this differential action was lost after 24 h infusion). The results caused us to reject the hypothesis that selective antagonism of the vasoconstrictor effects of endothelin-1 would result in SB 234551 exerting a greater antihypertensive effect than SB 209670 in TG rats. British Journal of Pharmacology (2000) 131, 1732,1738; doi:10.1038/sj.bjp.0703767 [source] | ||||||||||