Inhibition of L-type Ca(2+) current in Guinea pig ventricular myocytes by cisapride.
The effect of cisapride on L-type Ca(2+) 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 (IC(50)) of 46.9 microM. 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 alpha-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 Ca(2+) 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.
Chiang
Chern-En
CE
Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan, ROC. cechiang@vghtpe.gov.tw
Wang
Tsui-Min
TM
Luk
Hsiang-Ning
HN
D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D020117:Cisapride / Q000494:pharmacology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects*; D016276:Ventricular Function
D020746:Calcium Channels, L-Type; D020117:Cisapride