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

Propofol is a widely used intravenous general anesthetic. The negative inotropic effect of propofol has been best explained by inhibition of the L-type Ca(2+) 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 Ca(2+) influx through L-type Ca(2+) channels, which may help to counteract the net negative inotropism of propofol.