Mechanism of the Positive Inotropic Effect of Ketamine in Isolated Ferret Ventricular Papillary Muscle

Abstract

Ketamine is a cardiovascular stimulant through its sympathomimetic effects; however, its direct inotropic effect has been reported as positive in rat and negative in rabbit ventricular myocardium. This study reexamines the effect of ketamine on the contractile properties of mammalian ventricular myocardium. In isolated, electrically stimulated ferret right ventricular papillary muscles, the authors assessed the inotropic effect of ketamine (10(-6) M to 3 x 10(-4) M in 0.5 log M increments) alone and in various pharmacologic conditions designed to delineate ketamine's site(s) of action. Ketamine exerted a positive inotropic effect that was maximal at 10(-4) M. Bupranolol (10(-7) M) abolished this positive inotropic effect, whereas phentolamine (10(-6) M) did not. Depletion of norepinephrine stores by reserpine also eliminated ketamine's positive inotropic effect, indicating that ketamine caused indirect activation of the beta-adrenoceptor. Ketamine did not exert a positive inotropic effect in the presence of simultaneous inhibition of neuronal norepinephrine uptake with desmethylimipramine (DMI) (5 x 10(-6) M) and extraneuronal uptake with corticosterone (5 x 10(-5) M). It is likely that ketamine's action is to inhibit norepinephrine uptake at the neuroeffector junction rather than to augment norepinephrine release. In the presence of corticosterone, ketamine exerted a smaller positive inotropic effect than that seen with ketamine alone. Ketamine produced a small increase in force development in the presence of DMI, but this did not reach statistical significance. Inhibition of neuronal catecholamine uptake appears to be the predominant mechanism of ketamine's positive inotropic effect.