Inhibition of L-Type Ca2+ Current in Guinea Pig Ventricular Myocytes by Cisapride

Abstract

The effect of cisapride on L-type Ca²⁺ current (I_Ca,L) was studied in guinea pig ventricular myocytes using a whole-cell voltage-clamp technique and a conventional action potential recording method. Myocytes were held at –40 mV, and internally dialyzed and externally perfused with Na⁺- and K⁺-free solutions; cisapride elicited a concentration-dependent block of peak I_Ca,L, with a half-maximum inhibition concentration (IC₅₀) of 46.9 µM. There was no shift in the reversal potential, nor any change in the shape of the current-voltage relationship of I_Ca,L in the presence of cisapride. Inhibition of cisapride was not associated with its binding to serotonin or to α-adrenergic receptors because ketanserin, SB203186, and prazosin had no effect on the inhibitory action of cisapride on I_Ca,L. Cisapride elicited a tonic block and a use-dependent block of I_Ca,L.These blocking effects were voltage dependent as the degree of inhibition at –40 mV was greater than that at –70 mV. Cisapride shifted the steady-state inactivation curve of I_Ca,L in the negative direction, but had no effect on the steady-state activation curve. Cisapride also delayed the kinetics of recovery of I_Ca,L from inactivation. At a slow stimulation frequency (0.1 Hz), the action potential duration in guinea pig papillary muscles showed biphasic effects; it was prolonged by lower concentrations of cisapride, but shortened by higher concentrations. These findings suggest that cisapride preferentially binds to the inactivated state of L-type Ca²⁺ channels. The inhibitory effect of cisapride on I_Ca,L might play an important role in its cardiotoxicity under pathophysiological conditions, such as myocardial ischemia.