Association of in vivo and in vitro propranolol levels in canine Purkinje fibers with antiarrhythmic effects.

This study has determined the propranolol content of Purkinje fibers associated with antiarrhythmic and electrophysiological actions of the drug both in vivo and in vitro. The minimum effective tissue content of propranolol that consistently reversed a sustained ouabain-induced ventrivular tachycardia in vivo after i.v. propranolol was between 6.7 and 11.1 micron g/g of tissue. Propranolol doses producing Purkinje fiber contents of less than 6.7 micron g/g failed to revert the arrhythmia but did ponotropic responses to 0.5 micron g/kg of isoproterenol. The in vivo minimum effective tissue content was produced in isolated Purkinje fibers perfused with Tyrode's solution containing 1.7 X 10(-6) M propranolol. In Purkinje fibers this concentration of propranolol depressed the rate of phase 4 depolarization previously enhanced by ouabain 2.1 X 10(-7) M. Propranolol, 1.7 X 10(-6) M, did not alter membrane responsiveness and only slightly accelerated repolarization at 5 minutes. Propranolol, 0.85 X 10(-6) M, did not significantly depress the ouabain-enhanced rate of phase 4 depolarization but did attenuate the response to epinephrine through beta blockade. This study indicated that the initial direct action of propranolol in reverting a ouabain-induced ventricular tachycardia to a sinus rhythm in the dog is depression of automaticity.