INTERACTION OF LACIDIPINE WITH ITS RECEPTOR-BINDING SITE SUPPORTS A SLOW ONSET AND LONG-DURATION OF ACTION

[H-3]lacidipine binding to its receptor was characterized to explain i ts slow onset and long duration of antihypertensive activity. Binding parameters were studied in guinea pig myocardial and cerebral membrane preparations and compared with another dihydropyridine (DHP) calcium antagonist, isradipine. Lacidipine binds competitively to the DHP calc ium antagonist receptor of the L-type calcium channel. The binding is allosterically modulated by verapamil and D-cis diltiazem and activate d/inhibited by divalent cations. Association and dissociation kinetics of the binding of lacidipine to the receptor were significantly slowe r than those of isradipine. In addition, the B-max of lacidipine bindi ng in guinea pig heart microsomes was significantly higher than those of other dihydropyridine calcium antagonist. The results indicate that the slow onset and long duration of action of lacidipine can be expla ined principally on the basis of the binding characteristics. Although no biphasic receptor binding kinetics could be detected, a fast equil ibrium between the receptor and a second compartment, due to the high lipophilicity of lacidipine, cannot be excluded.