Ventricular muscle contains a low Km, cyclic AMP-specific form of phosphodiesterase (PDE III), which is believed to represent the site of action for several of new cardiotonic agents including imazodan (CI-914), amrinone, cilostamide, and enoximone. However, species differences in the inotropic response to these agents have raised questions about the relationship between PDE III inhibition and cardiotonic activity. The present study demonstrates that these differences can be accounted for by the presence of two subclasses of PDE III in ventricular muscle and variations in the intracellular localization of these two enzymes. For these experiments, PDE III was initially isolated from canine, guinea pig, and rat left ventricular muscle. The results demonstrate that canine left ventricular muscle contains two functional subclasses of PDE III: an imazodan-sensitive form, which is membrane bound, and an imazodan-insensitive form, which is soluble. Although only weakly inhibited by imazodan, this latter enzyme is potently inhibited by the selective PDE III inhibitors, Ro 20-1724 and rolipram. Guinea pig ventricular muscle also contains the imazodan-sensitive subclass of PDE III. Unlike canine left ventricle, however, thi enzyme is soluble in the guinea pig. No membrane-bound subclass of PDE III was observed in the guinea pig. Rat left ventricle possesses only the soluble form of PDE III, which apparently represents a mixture of the imazodan-sensitive and imazodan-insensitive subclasses of PDE III. Measurement of in vivo contractility in these three species showed that imazodan exerts a potent positive inotropic effect only in the dog, in which the imazodan-sensitive subclass of PDE III is membrane bound.(ABSTRACT TRUNCATED AT 250 WORDS)
Two subclasses of cyclic guanosine monophosphate (GMP) -specific phosphodiesterases were identified in vascular tissue from several beds. The activity of one subclass (phosphodiesterase IB) was stimulated severalfold by calmodulin and selectively inhibited by the phosphodiesterase inhibitor TCV-3B. The activity of the other subclass (phosphodiesterase IC) was not stimulated by calmodulin and was selectively inhibited by the phosphodiesterase inhibitor M&B 22,948. To assess the involvement of both subclasses in regulating cyclic GMP-dependent responses, the ability of TCV-3B and M&B 22,948 to potentiate the in vitro and in vivo responses to the endogenous guanylate cyclase stimulator atrial natriuretic factor (ANF) was evaluated. Both TCV-3B and M&B 22,948 relaxed isolated rabbit aortic and pulmonary artery rings and also potentiated the relaxant effect of ANF. In addition, both inhibitors produced small increases in urine flow and sodium excretion in anesthetized rats and potentiated the diuretic and natriuretic responses to exogenous ANF. M&B 22,948 (30 /tg/kg/min) produced a threefold increase in the natriuretic response to simultaneously administered ANF, and TCV-3B (10 /tg/kg/min) produced a twofold increase in the response to ANF. The results of the present experiments suggest that both the calmodulin-sensitive and calmodulin-insensitive subclasses of cyclic GMP-specific phosphodiesterase play a role in regulating the in vitro and in vivo response to ANF. {Hypertension 1990;15:528-540) T he role of atrial natriuretic factor (ANF) in regulating vascular muscle contractile function, diuresis and natriuresis, and secretion of renin and aldosterone is well known (for reviews see References 1 and 2). Murad and others have suggested that many of these actions are because of stimulation by ANF of a membrane-bound form of guanylate cyclase, leading to an increase in intracellular levels of the second messenger cyclic guanosine monophosphate (GMP). 34 The link between cyclic GMP and ANF is supported by the observation that inhibitors of guanylate cyclase such as methylene blue block the vascular relaxant response to ANF 5 and by the observation that changes in circulating
1988.The role of cyclic AMP in modulating the contractile function of cardiac muscle has been the subject of intensive investigation for more than two decades. These studies have shown that the positive inotropic response to cyclic AMP involves multiple components, including adenylate cyclase, the enzyme that catalyzes the conversion of ATP to cyclic AMP, activation of cyclic AMP-dependent protein kinases, which are responsible for phosphorylating key intracellular proteins, and phosphodiesterase, the enzyme that hydrolyzes cyclic AMP, thereby terminating the response. Several reports have shown, however, that increases in intracellular cyclic AMP are not always accompanied by increases in myocardial contractility, suggesting that cyclic AMP may be compartmentalized within cardiac cells and that only certain compartments are involved in modulating contractility. In addition, although cardiac muscle contains only one form of adenylate cyclase, multiple forms of phosphodiesterase have been identified in ventricular muscle, which vary in their substrate specificity and their response to allosteric effectors such as calmodulin. Recent studies have also shown that these various forms of phosphodiesterase can be located in different regions within the cardiac cell and that only certain forms of the enzyme are involved in modulating the inotropic response to cyclic AMP. This review summarizes the current state of knowledge regarding the involvement of cyclic AMP with cardiac contractile function and also explores several controversial aspects of this involvement.
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