Depression of myocardial contractile function by propoxyphene and norpropoxyphene

Propoxyphene and its principal metabolite, norpropoxyphene, depressed maximum developed isometric tension (T) and its first derivative, dT/dt, in isolated cat right ventricular papillary muscles. T and dT/dt were reduced by 10^-5 M concentrations of each drug (p<0.005), and this effect was markedly intensified at 10^-4 M: propoxyphene, 49% reduction of T (p<0.001); norpropoxyphene, 36% reduction of T (p<0.001). Nonresponsiveness to electrical stimulation developed in the majority of muscles at the 10^-5 M concentration of each drug and in all muscles at 10^-4 M. The cardiac depressant actions of the two drugs administered simultaneously at a concentration of 10^-5 M each were additive, resulting in a 15.6% decline in T. The contractile actions of propoxyphene and norpropoxyphene were not altered by the specific narcotic blocking agent, naloxone, indicating these effects were produced by a nonopiate mechanism. In contrast to propoxyphene and norpropoxyphene, morphine produced no reductions in T or dT/dt at a concentration of 10^-5 M and only a slight, albeit significant (p<0.05), depression of T (-4%) and dT/dt (-6%) at 10^-4 M. The cardiac depressant effects of propoxyphene and norpropoxyphene were at least partially reversible, as indicated by substantial recovery of contractile function after drug removal (to 69-75% of control T) and by a positive inotropic response to isoproterenol. These results indicate that at high concentrations propoxyphene and norpropoxyphene have a cardiac depressant action characterized by decreased electrical excitability and reversible contractile depression, effects which are consistent with a local anesthetic action. Depression of cardiac contractile and electrophysiologic functions by propoxyphene and norpropoxyphene may play a role in the clinical toxicity associated with propoxyphene overdose.