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.