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Mechanisms of Inhibition of Calmodulin‐Stimulated Cyclic Nucleotide Phosphodiesterase by Dihydropyridine Calcium Antagonists

Abstract: Calmodulin‐dependent cyclic nucleotide phosphodiesterase (CaMPDE) is one of the key enzymes involved in the complex interaction between the cyclic nucleotide and Ca2+ second‐messenger systems. CaMPDE exists as tissue‐specific isozymes, and initially these isozymes were designated according to their respective subunit molecular mass. A variety of pharmacological agents have been used to inhibit CaMPDE, and this inhibition occurs mostly via Ca2+‐dependent association with the proteins. We have examined the effect of dihydropyridine Ca2+‐channel blockers felodipine and nicardipine on CaMPDE. The results suggest that the 63‐kDa (PDE 1B1) and 60‐kDa (PDE 1A2) CaMPDE isozymes are inhibited by felodipine and nicardipine by partial competitive inhibition and that these two Ca2+ antagonists appear to counteract each other. This study further demonstrates the existence of a specific site, distinct from the active site on CaMPDE, that exhibits high‐affinity binding of these drugs. Felodipine and nicardipine have similar affinities for 60‐kDa CaMPDE isozymes but bring about different levels of enzyme inhibition, suggesting the possibility of designing specific drugs that can protect the enzyme from inhibition by dihydropyridine Ca2+‐channel blockers.