Valinomycin inhibition of the inward slow current of cardiac muscle.
Valinomycin (10(-6) M), a K+ ionophore and uncoupler of oxidative phosphorylation, produced pronounced shortening of the action potential plateau in young (3 day) and old (15-19 day) embryonic chick hearts and isolated perfused guinea pig hearts. The rate of rise of the action potential was usually not affected. Dimethylsulfoxide (DMSO) (2 percent), The vehicle for valinomycin, did not cause plateau shortening. In chick hearts, diminution of the plateau by valinomycin at 10(-6) M usually occurred by 1 hr; larger doses produced prominent effects within 15 min. Young embryonic hearts were more resistant to valinomycin, and 20x10(-6) M for 1-2 hr was necessary to produce a significant diminution in plateau. Several agents were able to partially relengthen the plateau shortened by valinomycin. In both young and old hearts, the resting potential was not increased by valinomycin, even though young hearts have a low resting potential because of a low K+ conductance (gK). In guinea pig, 10(-6) M valinomycin markedly shortened the plateau within 5-10 min. Contractions were abolished, i.e., the hearts became electromechanically uncoupled. When hearts were perfused with 27 mM K+ to depolarize the cells to about -40 mV to inactivate fast Na+ channels, catecholamines or methylxanthines rapidly induced slowly rising (about 10 V/sec), overshooting, plateau-like responses with accompanying contractions. Valinomycin rapidly (within 2-5 min) abolished these slow responses and contractions. Hearts perfused with 10(-6) M valinomycin or 10(-5) dinitrophenol became nearly entirely depleted of ATP within 2-10 min. These results suggest that valinomycin blocks the slow inward current indirectly through ATP depletion, the slow cation channels requiring metabolic energy. The possibility that resting gK or kinetics of changes in gK during the plateau is also affected by valinomycin cannot be excluded.
D000200:Action Potentials / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004140:Dinitrophenols / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010477:Perfusion; D011188:Potassium / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D012508:Sarcolemma / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology*
D004140:Dinitrophenols; D014634:Valinomycin; D002110:Caffeine; D000255:Adenosine Triphosphate; D011494:Protein Kinases; D007545:Isoproterenol; D011188:Potassium; D004121:Dimethyl Sulfoxide