Inhibition of L-type Ca2+ channels in portal vein myocytes by the enantiomers of oxodipine.
We studied the effects of the enantiomers of the dihydropyridine derivative, 4-(2,3 methylenedioxyphenyl)-1,4-dihydro-2,6-dimethyl-3 carboxyethyl-5-carboxymethyl-pyridine (oxodipine), on voltage-dependent Ca2+ channels of rat portal vein myocytes by combining electrophysiological techniques and binding studies. (+)- and (-)-oxodipine depressed the L-type Ca2+ current in a concentration-dependent manner, with similar IC50 values (around 10 nM) but had no appreciable effect on the intracellular Ca2+ stores. The steady-state inactivation curve for the Ca2+ current was shifted along the voltage axis to negative membrane potentials indicating that the block of the Ca2+ current by oxodipine enantiomers increased with depolarization. The voltage-dependent inhibitory property of oxodipine was related to an increase in [3H](+)-4-(benzo-2-oxa-1,3-diazol-4-yl)-1,4-dihydro-2,6-dimethy lpy ridine- 3,5-dicarboxylic acid 3-isopropyl, 5-methyl ester (isradipine) binding affinity without change in binding capacity. In normally polarized intact strips, interactions of (+)- and (-)-oxodipine with [3H](+)-isradipine binding indicated a stimulation of the radioligand binding at low concentrations of (-)-oxodipine while the (+) enantiomer seemed to act as a competitive ligand. Depolarization of intact strips with 135 mM K(+)-solutions increased the apparent affinity of the enantiomers of oxodipine, and abolished the stimulating effect of (-)-oxodipine on the binding of [3H](+)-isradipine. Inhibition of Ca2+ current was increased in the simultaneous presence of 1 nM of (+)- and (-)-oxodipine when compared to the inhibitions induced by 2 nM of each enantiomer.(ABSTRACT TRUNCATED AT 250 WORDS)
Baron
A
A
Laboratoire de Physiologie Cellulaire et Pharmacologie Moléculaire, URA CNRS 1489, Université de Bordeaux II, France.
Rakotoarisoa
L
L
Leprêtre
N
N
Mironneau
J
J
D000818:Animals; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003198:Computer Simulation; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D017275:Isradipine / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011169:Portal Vein / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C053783:oxodipine; D017275:Isradipine