MECHANISMS OF INHIBITION OF CALMODULIN-STIMULATED CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE BY DIHYDROPYRIDINE CALCIUM-ANTAGONISTS

Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE) is o ne 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 ph armacological agents have been used to inhibit CaMPDE, and this inhibi tion occurs mostly via Ca2+-dependent association with the proteins. W e have examined the effect of dihydropyridine Ca2+-channel blockers fe lodipine and nicardipine on GaMPDE. The results suggest that the 63-kD a (PDE 1 B1) and 60-kDa (PDE 1A2) CaMPDE isozymes are inhibited by fel odipine and nicardipine by partial competitive inhibition and that the se two Ca2+ antagonists appear to counteract each other. This study fu rther demonstrates the existence of a specific site, distinct from the active site on CaMPDE, that exhibits high-affinity binding of these d rugs. Felodipine and nicardipine have similar affinities for 60-kDa Ca MPDE isozymes but bring about different levels of enzyme inhibition, s uggesting the possibility of designing specific drugs that can protect the enzyme from inhibition by dihydropyridine Ca2+-channel blockers.