Pharmacological Significance of the Blocking Action of the Intravenous General Anesthetic Propofol on the Slow Component of Cardiac Delayed Rectifier K⁺ Current

Abstract

Propofol is a widely used intravenous general anesthetic. The negative inotropic effect of propofol has been best explained by inhibition of the L-type Ca²⁺ current (I_Ca). Using guinea-pig cardiac preparations, however, we found that the propofol concentration producing a 50% decrease in force of contraction was more than 10 times higher than that producing a 50% inhibition of I_Ca, implying that a compensatory mechanism may be present to counteract the negative inotropic effect associated with the I_Ca inhibition. Consistent with I_Ca inhibition, propofol produced a shortening of action potential duration (APD) in single cardiomyocytes. Yet, the concentrations necessary to shorten APD were greater than that for 50% inhibition of I_Ca. This was associated with the potent and effective inhibition of the slowly activating component of the delayed rectifier K⁺ current (I_Ks). Thus, the I_Ks blockade with propofol may counterbalance the APD shortening evoked by its I_Ca inhibition. Taken together, the negative inotropic effect of propofol is detectable only at supratherapeutic concentrations. At clinically relevant concentrations, the action potential prolongation mechanism due to I_Ks inhibition appears to alleviate the reduction in transsarcolemmal Ca²⁺ influx through L-type Ca²⁺ channels, which may help to counteract the net negative inotropism of propofol.