Functional interaction of lacidipine with calcium channels in vascular smooth muscle.
We investigated the effect of lacidipine on 100-mM K(+)-evoked contractions and on 100-mM K(+)-evoked 45Ca2+ influx in rat aorta. Moreover, we compared the effect of prolonged depolarization on lacidipine inhibition and (+)isradipine inhibition of 100-mM K(+)-evoked contractions and the reversal of this inhibition by washing with a Ca(2+)-free physiological solution or with a Ca(2+)-free 40-mM K+ depolarizing solution. Lacidipine dose-dependently depressed the response to depolarization, and the pattern of inhibition was typical of voltage-dependent dihydropyridines. The concentration-inhibition curves on K(+)-evoked contraction and on K(+)-evoked 45Ca2+ influx were superimposed; the IC50 was 0.09 nM for the former and 0.11 nM for the latter. The inhibitory effect of lacidipine 60 pM or (+)isradipine 60 pM on rat aorta contraction was significantly enhanced when the preparations had been preincubated in the presence of the drugs in a K(+)-rich depolarizing solution. The inhibitory effect of lacidipine 60 pM or (+)isradipine 100 pM on rat aorta contraction was fully reversed after washing with a physiologic solution. When the washout was performed with a 40-mM K+ depolarizing solution, the inhibition was maintained in lacidipine-treated preparations, whereas it was reversed in the (+)isradipine treated ones. We conclude that lacidipine inhibits rat aorta contraction by interacting specifically with voltage-operated Ca2+ channels. Moreover, unlike with (+)isradipine, the complex formed with lacidipine and inactivated Ca2+ channels seems to not dissociate, because the inhibitory effect persisted in spite of removal of the drug from the depolarizing solution in which the arteries were immersed.
Godfraind
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Laboratory of General Pharmacodynamics and Pharmacology, Catholic University of Louvain, Brussels, Belgium.
Salomone
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D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000502:physiology; D002132:Calcium Radioisotopes; D004095:Dihydropyridines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D013997:Time Factors
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D004095:Dihydropyridines; C060285:lacidipine; D011188:Potassium; D002118:Calcium