Differential sensitivity to cardiotonic drugs of cyclic AMP phosphodiesterases isolated from canine ventricular and sinoatrial-enriched tissues.

A cardiac phosphodiesterase (PDE) which specifically hydrolyzes cAMP and is inhibited by cyclic GMP has been suggested to be the site of action of new cardiotonic drugs. To investigate the effect of inhibitors, canine cyclic nucleotide PDEs were isolated from left ventricle and from sinoatrial node-enriched tissue, using identical techniques. Four PDE forms could be chromatographically resolved from each tissue, including a peak I PDE (calmodulin-activated phosphodiesterase, CaM-PDE), a peak II PDE (cyclic GMP-stimulated phosphodiesterase, CGS-PDE) and a peak III PDE (specific for cyclic AMP). The latter was further fractionated into two forms: One was inhibited by cyclic GMP and by the platelet antiaggregant AAL 05 (CGI-PDE), and the second was insensitive to cyclic GMP and was inhibited by rolipram (ROI-PDE). Reference PDE inhibitors, isobutyl-1-methylxanthine (IBMX) and papaverine, nonselectively inhibited the four forms isolated from the two tissues. Cardiotonic drugs (CI 930, LY 181512, piroximone, enoximone, and SK&F 94120) selectively inhibited CGI-PDE from ventricular tissue but were poorly active on both CGI-PDE and ROI-PDE from the sinoatrial-enriched fraction. In contrast, milrinone inhibited CGI-PDEs and ROI-PDEs from both ventricular and sinoatrial tissues. These results are in good agreement with pharmacologic data in the literature on the positive chronotropic and inotropic effects of the studied drugs in the dog. They provide a possible basis for the dissociation of these two properties of PDE inhibitors.