Cardiac cGMP-stimulated cyclic nucleotide phosphodiesterases: effects of cGMP analogues and drugs

Abstract

The effects of cGMP analogues and phosphodiesterase inhibitors were investigated on cAMP and cGMP hydrolysis by cGMP-stimulated phosphodiesterase (cGS-PDE), isolated from a canine heart sinoatrial node-enriched preparation and from the left ventricle. There was no significant difference between the effects of drugs and cGMP analogues on cGS-PDE from the cardiac ventricle and from the sinoatrial node, suggesting that cGS-PDE has similar characteristics in the two tissues, cGMP itself, 8-bromo-cGMP and 2'-deoxy-cGMP had dual effects: at low concentrations, cAMP hydrolysis was stimulated (maximal effect at 10 microM, 100 microM and 100 microM respectively), while at higher concentrations these compounds inhibited cAMP hydrolysis. Monobutyryl-cGMP and dibutyryl-cGMP had only an inhibitory effect on cAMP hydrolysis. Inhibitors of cAMP- or cGMP-selective PDEs, including the cardiotonic drugs rolipram and zaprinast, were not effective inhibitors of cGS-PDE. Cilostamide (a selective inhibitor of cGMP-inhibited PDE). IBMX (nonspecific inhibitor of PDEs) and dipyridamole inhibited basal cGS-PDE hydrolysis of cAMP and cGMP, and their apparent Ki for cAMP hydrolysis was decreased by 5 microM cGMP (from 30, 14 and 18 to 15.7 and 2.6 microM, respectively, for the ventricular enzyme).(ABSTRACT TRUNCATED AT 250 WORDS)