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

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Abstract
Summary 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 × 10−4 mol/l to 2 × 10−2 mol/l caused a shift of the IC50 for the inhibition by (±)-nimodipine from 2.8 × 10−6 mol/l to 6 × 10−5 mol/l. Dixon-plot analysis revealed an inhibitory constant of K i = 2.3 μmol/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.