Stereoselective inhibition of calmodulin-dependent cAMP phosphodiesterase from bovine heart by (+)- and (-)-nimodipine

Abstract

The inhibitory effects of racemic (+/-)-nimodipine and of optically pure (+)- and (-)-nimodipine on the basal and calmodulin-dependent activity of a cAMP phosphodiesterase from bovine heart were investigated. The inhibition by (+/-)-nimodipine could not be overcome by an excess of calmodulin. However, increase of the cAMP concentration in the assay from 2 X 10(-4) mol/l to 2 X 10(-2) mol/l caused a shift of the IC50 for the inhibition by (+/-)-nimodipine from 2.8 X 10(-6) mol/l to 6 X 10(-5) mol/l. Dixon-plot analysis revealed an inhibitory constant of Ki = 2.3 mumol/l. Experiments with the two enantiomers showed that (+)-nimodipine is by about one order of magnitude more potent than (-)-nimodipine. This contrasts with the stereoselectivity of the Ca2+ channel inhibitory activity on isolated rings of the rabbit basilar artery where (-)-nimodipine is more effective than (+)-nimodipine in relaxing the smooth muscle contracted by K+-depolarisation. It is concluded that cAMP phosphodiesterase may be an intracellular target for nimodipine and its inhibition may contribute to the pharmacological activity of this 1,4-dihydropyridine.