NAFTOPIDIL, A NEW ALPHA-ADRENOCEPTOR BLOCKING-AGENT WITH CALCIUM ANTAGONISTIC PROPERTIES - CHARACTERIZATION OF CA2+ ANTAGONISTIC EFFECTS

The newly developed antihypertensive agent naftopidil blocks alpha-1-adrenoceptors and inhibits Ca2+ entry via potential-dependent channels in vascular muscle. The aim of our study was to detect possible Ca2+ channel blocking activity in various isolated preparations of the guinea pig heart. Prazosin and verapamil were used for reference. In papillary muscles, 10-mu-M of all drugs reduced the force of contraction F(c). The action potential duration and the refractory period were hardly affected by naftopidil, decreased by verapamil, and slightly increased by prazosin. In constant-flow Langendorff hearts, the drugs reduced the perfusion pressure, decreased the F(c), and slowed the spontaneous heart rate (order of potency: verapamil >> naftopidil > prazosin). In voltage-clamped ventricular cardiomyocytes, the calcium current I(Ca) was completely inhibited by verapamil (pD2 value of 6.9) and to 53.5% by naftopidil (pD2 value of 6.4). Prazosin (10-mu-M) decreased I(Ca) by little more than 10%. There were no differences in the steady-state inhibition of I(Ca) by the two enantiomers of naftopidil. The block of I(Ca) was clearly use dependent. Radioligand binding studies with ( + )-[H-3]PN 200-110, ( - )-[H-3]desmethoxyverapamil, and ( + )-cis-[H-3]diltiazem in guinea pig skeletal muscle T-tubulus membranes demonstrated that racemic naftopidil exhibited some affinity for the three distinct drug receptor domains of the L-type Ca2+ channel. In conclusion, the present data are consistent with the hypothesis that naftopidil is a weak ligand for L-type calcium channels. It partially blocks I(Ca) and shows no stereoselectivity.