On the mechanism of the "specific bradycardic action" of the verapamil derivative UL-FS 49.

Membrane currents were measured in single sino-atrial node cells of guinea pig and rabbit hearts as well as in guinea pig ventricular myocytes using the patch-clamp technique. UL-FS 49 blocked the L-type calcium current (ICa) in sino-atrial node cells at drug concentrations which had little or no effect on the amplitude of the hyperpolarization-activated current ih(f). In guinea pig ventricular myocytes UL-FS 49 also blocked ICa but not as strongly as in sino-atrial node cells. In a computer simulation of the sino-atrial node action potential the extent of rate reduction by block of either ih(f) or ICa was estimated. From the data obtained by single cell measurements and the computations we concluded that rate reduction in primary pacemaker cells by application of UL-FS 49 is mainly due to a use dependent block of the L-type calcium current. Voltage dependent unblock of iCa at potentials more negative than -50 mV together with the lower drug sensitivity of ventricular cells can explain the "specific bradycardic action" of UL-FS 49.