Positive inotropic effect of endothelin-1 in the neonatal mouse right ventricle.
In neonatal mouse right ventricles, endothelin-1 (ET-1, 1-300 nM) induced a dose-dependent increase in twitch contractions and the dose-response curve was shifted to the right by BQ-123 (10 microM), an endothelin ET(A) receptor antagonist. The ET-1 (100 nM)-induced positive inotropy was accompanied by an increase in [Ca(2+)](i) transients without any change in the [Ca(2+)](i)-force relationship. Ryanodine (1 microM) partially decreased the [Ca(2+)](i) transients and contractile force, but did not affect the ET-1 (100 nM)-induced positive inotropy. Reduction of [Na(+)](o) elicited an increase in contractile force, and this effect was significantly inhibited by KB-R7943 (30 microM), an inhibitor of the Na(+)-Ca(2+) exchanger. KB-R7943 (30 microM) almost completely suppressed the positive inotropic effect of ET-1. Activation of protein kinase C (PKC) by phorbol 12,13-dibutylate (100 nM) decreased the contractile force, an effect which was suppressed by bisindolylmaleimide I (3 microM). On the other hand, the ET-1-induced positive inotropic effect was unaffected by bisindolylmaleimide I (3 microM). These results suggest that the positive inotropic effect of ET-1 in neonatal mouse right ventricles is caused by the increase in [Ca(2+)](i) transients through activation of the endothelin ET(A) receptor and the increase in Ca(2+) influx via the Na(+)-Ca(2+) exchanger during an action potential. Furthermore, the ET-1-induced positive inotropy is independent of the effects of PKC, which makes it distinct from the ET-1-mediated pathways reported for cardiac tissues in other species.
Nagasaka
Tsuyoshi
T
Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo, Tokyo 113-8657, Japan.
Izumi
Masanori
M
Hori
Masatoshi
M
Ozaki
Hiroshi
H
Karaki
Hideaki
H
D000818:Animals; D000831:Animals, Newborn; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D016276:Ventricular Function
D002316:Cardiotonic Agents; D019332:Endothelin-1