Electrophysiologic properties of propoxyphene and norpropoxyphene in canine cardiac conducting tissues in vitro and in vivo

The centrally-acting analgesic, d-propoxyphene, and its N-desmethyl metabolite, d-norpropoxyphene, depressed cardiac conduction in canine myocardial tissues in vitro and in vivo. In Purkinje fibers superfused with propoxyphene or norpropoxyphene (10 −6–10 −4 m), there was a decrease in the maximal rate of rise of the upstroke of the action potential (V̇ max) and a decrease in total action potential duration and cellular refractoriness. Both agents decreased the amplitude of the compound action potential recorded from isolated rat sympathetic trunk. A significant correlation was shown between the depression of Purkinje fiber V̇ max and local anesthetic activity in vitro for propoxyphene, norpropoxyphene, and several typical membrane-active antidysrhythmic agents. In isolated guinea pig atria, both agents (10 −6–10 −4 m) decreased sinus frequency and contractility. In conscious dogs both agents (2.1–21 μmol/kg, iv) prolonged P-R interval of the ECG. His bundle electrograms recorded in anesthetized dogs revealed a 10% prolongation in H-V and A-H intervals by norproxyphene in doses of 7.5±2.8 and 6.6±1.3 μmol/kg, respectively. The corresponding values for propoxyphene were 17.1±1.2 and 3.7±0.4 μmol/kg. These observations suggest that cardiac conduction depression may be a factor in some of the cardiac toxicities associated with propoxyphene overdosage.