Electrophysiological and radioligand binding studies of elgodipine and derivatives in portal vein myocytes

N Lepretre, S Arnaudeau, J Mironneau, L Rakotoarisoa, C Mironneau and A Galiano

Laboratoire de Physiologie Cellulaire et Pharmacologie Moleculaire, URA CNRS 1489, Universite de Bordeaux II, France.

The effects of a novel dihydropyridine, elgodipine, and of three derivatives have been studied on the calcium channel currents of isolated cells from rat portal vein by the patch-clamp technique, and on specific (+)-[3H]isradipine binding to vascular membranes. Elgodipine inhibited both T- and L-type calcium channels in a concentration-dependent manner. Half-inhibitions of T- and L-type calcium channel current were obtained at concentrations of 32 and 2.3 nM, respectively. Currents activated repetitively were similarly inhibited than those after a rest period, indicating absence of use- dependent inhibition by elgodipine. When cells were held at depolarized membrane potentials at which T- or L-type calcium channels were inactivated, the inhibitory effects of elgodipine were enhanced on both calcium channel currents, indicating that the elgodipine-induced inhibition was voltage-dependent. The elgodipine concentration which blocked the inactivated calcium channels were 5 to 7 times lower than those which blocked the resting calcium channels. The inhibition constant for elgodipine obtained from the displacement of (+)- [3H]isradipine binding to the L-type calcium channels in vascular membranes was identical to the dissociation constant calculated from electrophysiological data on inactivated calcium channels. At concentrations that completely inhibited calcium channels, elgodipine had no effect on chloride and potassium channels, and did not interfere with the intracellular calcium stores.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 271, Issue 3, pp. 1209-1215, 12/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

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