Interaction of lacidipine with its receptor binding site supports a slow onset and long duration of action.
[3H]lacidipine binding to its receptor was characterized to explain its 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 calcium antagonist receptor of the L-type calcium channel. The binding is allosterically modulated by verapamil and D-cis diltiazem and activated/inhibited by divalent cations. Association and dissociation kinetics of the binding of lacidipine to the receptor were significantly slower than those of isradipine. In addition, the Bmax of lacidipine binding 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 explained principally on the basis of the binding characteristics. Although no biphasic receptor binding kinetics could be detected, a fast equilibrium between the receptor and a second compartment, due to the high lipophilicity of lacidipine, cannot be excluded.
Graziani
F
F
Glaxo Research Laboratories, Verona, Italy.
Ratti
E
E
van Amsterdam
F T
FT
D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism*; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000493:pharmacokinetics; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D002540:Cerebral Cortex / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D006168:Guinea Pigs; D017275:Isradipine / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D013997:Time Factors
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; C060285:lacidipine; D017275:Isradipine