Inhibition of adenosine 3',5'-cyclic monophosphate phosphodiesterase by CD-349, a novel 1,4-dihydropyridine derivative: Effect of EGTA on the inhibitory activity.

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CD-349 (2-nitratopropyl 3-nitratopropyl 2, 6-dimethyl-4-(3-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylate) inhibited the activity of cyclic AMP phosphodiesterase (PDE) from the porcine coronary artery more effectively than that from the myocardium. Other dihydropyridines, nicardipine and nifedipine, were not tissue selective in inhibiting the cyclic AMP PDE from both sources. CD-349 inhibited cyclic AMP PDE noncompetitively with apparent inhibition constant (K<SUB>i</SUB>) values of 6.6 and 4.6 μM for high and low affinity constant (K<SUB>m</SUB>) enzymes, respectively. Basal activity of coronary arterial cyclic AMP PDE was decreased to approximately 65% of the control value by 0.2 mM ethylene glycol bis (β-aminoethyl ether)N, N, N', N'-tetraacetic acid (EGTA). In the coronary artery, the inhibition of cyclic AMP PDE by CD-349 was weakened in the presence of EGTA, while the inhibition of nicardipine and nifedipine were not affected. EGTA had no influence on the CD-349 induced inhibition of myocardial cyclic AMP PDE. Calmodulin antagonists such as trifluoperazine (TFP) gave substantially the same results as those with CD-349. These results indicate the relative selectivity of the coronary arterial cyclic AMP PDE inhibition by CD-349 and suggest that this selective inhibition is due to blockade of calcium/calmodulin-activated cyclic AMP PDE.
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