Cardiac cGMP-stimulated cyclic nucleotide phosphodiesterases: effects of cGMP analogues 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 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)
Komas
N
N
Laboratoire de Pharmacologie Cellulaire et Moléculaire, CNRS URA 600, Université Louis Pasteur de Strasbourg, Illkirch, France.
Le Bec
A
A
Stoclet
J C
JC
Lugnier
C
C
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002848:Chromatography, DEAE-Cellulose; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004285:Dogs; D006352:Heart Ventricles / Q000201:enzymology; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012849:Sinoatrial Node / Q000201:enzymology; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D006152:Cyclic GMP