Biochemical aspects of inhibition of cardiovascular low (Km) cyclic adenosine monophosphate phosphodiesterase.
Multiple isozymes of cyclic nucleotide phosphodiesterase (PDE) exist in mammalian cells. At least 5 major types of PDE isozymes have been identified; they differ by substrate affinity, maximal activity, intracellular regulation or mechanism of pharmacologic inhibition. A low Michaelis constant (Km) cyclic adenosine monophosphate (cAMP) PDE, whose activity is inhibited by submicromolar concentrations of cyclic guanosine monophosphate and stimulated by cAMP-mediated phosphorylation, is present in both cardiac muscle and vascular smooth muscle. This PDE isozyme (referred to as peak IIIc PDE) is sensitive to selective inhibition by amrinone, milrinone, imazodan, CI-930, piroximone, and numerous other PDE inhibitors. The subcellular distribution of cardiac PDE IIIc varies according to species; it is found in the soluble fraction of guinea pig myocardium, in the particulate fraction of canine myocardium, and in both fractions of primate (simian and human) myocardium. Another PDE isozyme, which is sensitive to inhibition by rolipram and is less sensitive to inhibition by PDE IIIc inhibitors, is found in cardiac muscle of some species (i.e., soluble fractions of rat and canine myocardium) and is apparently not related to direct regulation of positive inotropy. Both positive inotropy and vasorelaxation by milrinone and other PDE IIIc inhibitors can be linked to inhibition of PDE IIIc and activation of the cAMP system. These significant relations are similar to those obtained for other cAMP-related positive inotrope/vasodilators (such as beta-adrenoreceptor agonists). Moreover, an increased rate of ventricular relaxation (lusitropy), which is apparent with PDE IIIc inhibitors, may also be attributable to activation of the cAMP system.(ABSTRACT TRUNCATED AT 250 WORDS)
Silver
P J
PJ
Department of Pharmacology, Sterling-Winthrop Research Institute, Rensselaer, New York 12144.
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D013268:Stimulation, Chemical
D007527:Isoenzymes; D000242:Cyclic AMP; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases