CARDIAC CGMP-STIMULATED CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES - EFFECTS OF CGMP ANALOGS AND DRUGS

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-mu-M, 100-mu-M and 100-mu-M 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 K(i) for cAMP hydrolysis was decreased by 5-mu-M cGMP (from 30, 14 and 18 to 15, 7 and 2.6-mu-M, respectively, for the ventricular enzyme). These results show that (i) cGS-PDE is present in the canine sinoatrial node and has similar kinetic and pharmacological characteristics as in the left ventricle; (ii) the cGMP analogues, 8-bromo-cGMP and 2'-deoxy-cGMP, do not induce as potent a stimulation of cGS-PDE as cGMP itself and their structure is important for stimulation and inhibition of cGS-PDE; (iii) the mechanism of the positive inotropic and chronotropic effects of cardiotonic PDE inhibitors probably does not involve the inhibition of cGS-PDE.