Wortmannin inhibits the increase in myofilament Ca(2+) sensitivity induced by cross-talk of endothelin-1 with norepinephrine in canine ventricular myocardium.
Endothelin-1 (ET-1) modulates cardiac contractility by cross-talk with norepinephrine (NE) in canine ventricular myocardium. The present experiments were performed to investigate the influence of wortmannin that has inhibitory action on phosphatidylinositol 3-kinase (PI3-K) (IC50 = 3 nM) and myosin light chain kinase (MLCK) (IC50 = 200 nM) on Ca(2+) signaling and the inotropic effects of ET-1 induced by cross-talk with NE. Experiments were carried out in isolated canine ventricular trabeculae and indo-1/AM-loaded single ventricular cardiomyocytes. ET-1 alone elicited a transient small negative inotropic effect (NIE). In the presence of NE at low (1-10 nM) and high (100 nM) concentrations, ET-1 induced a long-lasting positive inotropic effect (PIE) or a marked sustained NIE, respectively. Wortmannin up to 300 nM did not affect the contractility; and at 1 microM and higher, it decreased the basal contraction without suppressing Ca(2+) transients. Wortmannin (1 microM) inhibited the long-lasting PIE of ET-1 without affecting the ET-1-induced increase in Ca(2+) transients. Wortmannin at the same concentration did not affect the ET-1-induced transient and sustained NIE and the PIE mediated by beta-adrenoceptor stimulation. These results imply that wortmannin exerts selective inhibitory action on the increase in myofilament Ca(2+) sensitivity induced by cross-talk of ET-1 with NE probably through an inhibition of MLCK in canine ventricular myocardium.
Chu
Li
L
Department of Cardiovascular Pharmacology, Yamagata University School of Medicine, Japan.
Norota
Ikuo
I
Ishii
Kuniaki
K
Endoh
Masao
M
D008841:Actin Cytoskeleton / Q000187:drug effects*; D000730:Androstadienes / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D003864:Depression, Chemical; D004285:Dogs; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology*; D013268:Stimulation, Chemical; D000077191:Wortmannin
D000730:Androstadienes; D019332:Endothelin-1; D002118:Calcium; D009638:Norepinephrine; D000077191:Wortmannin