Inhibition of excitation-contraction coupling in the ventricular myocardium of the dog by SKF 24260.

1. The effects of SKF 24260 on the coronary vasculature and on the electrical and mechanical activities of the ventricular myocardium were studied by the use of papillary muscle preparations of the dog. The preparation was cross-circulated from a donor dog through the anterior septal artery, and driven at a rate of 120 beats/min. Drugs were injected into the anterior septal artery. 2. SKF 24260, in doses of 0-01-100 mug, caused a dose-dependent increase in the rate of blood flow through the anterior septal artery; the mean dose producing a 100% increase in blood flow rate was about 0-7 mug. 3. SKF 24260 in doses of 0-01-0-03 mug produced a slight increase in developed tension of papillary muscles. With 0-1-0-3 mug of SKF 24260 the increase was preceded by a transient decrease, and with doses larger than 1 mug the drug caused a dose-dependent decrease. The mean dose producing a 50% decrease in developed tension was about 2-8 mug. 4. SKF 24260 failed to affect the amplitude and shape of bipolar electrograms even in doses of 39-100 mug which completely abolished the developed tension. 5. The decrease in the developed tension caused by SKF 24260 was overcome by exogenous calcium; the increase in the developed tension in response to exogenous calcium was antagonized by SKF 24260. 6. These results indicate that the dilator action of SKF 24260 on the coronary vasculature is more prominent than the negative inotropic action on the ventricular myocardium, and suggest that the negative inotropic action is probably due to antagonism of the role of calcium in excitation-contraction coupling.