Biochemical aspects of inhibition of cardiovascular low (K m) cyclic adenosine monophosphate phosphodiesterase

Abstract

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 (K m) 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 III c PDE) is sensitive to selective inhibition by amrinone, milrinone, imazodan, CI-930, piroximone, and numerous other PDE inhibitors. The subcellular distribution of cardiac PDE III c 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 III c 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 III c inhibitors can be linked to inhibition of PDE III c and activation of the cAMP system. These significant relations are similar to those obtained for other cAMP-related positive inotrope/vasodilators (such as β-adrenoreceptor agonists). Moreover, an increased rate of ventricular relaxation (lusitropy), which is apparent with PDE III c inhibitors, may also be attributable to activation of the cAMP system. The potency of milrinone and other PDE III c inhibitors as positive motropes and vasodilators parallels their potency as cardiac and vascular PDE III c inhibitors. Moreover, the potency of milrinone as a competitive PDE III c inhibitor in various species (K i = 0.3 to 0.4 μM) is similar to therapeutic plasma concentrations (100 to 400 ng/ml, equivalent to 0.5 to 2.0 μM). These data support the concept that a single mechanism of action, selective inhibition of cardiovascular low K m cAMP peak III PDE, may be responsible for the major cardiovascular beneficial actions (positive inotropy/lusitropy, afterload reduction and coronary vasodilation) of milrinone and other PDE III c inhibitors for the treatment of congestive heart failure.