Subclasses of cyclic AMP-specific phosphodiesterase in left ventricular muscle and their involvement in regulating myocardial contractility.
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)
Weishaar
R E
RE
Department of Pharmacology, Warner-Lambert/Parke Davis Pharmaceutical Research, Ann Arbor, Mich. 48105.
Kobylarz-Singer
D C
DC
Steffen
R P
RP
Kaplan
H R
HR
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000145:classification* / Q000302:isolation & purification / Q000378:metabolism / Q000502:physiology; D000818:Animals; D004285:Dogs; D006168:Guinea Pigs; D006352:Heart Ventricles; D008566:Membranes / Q000378:metabolism; D009132:Muscles / Q000201:enzymology; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D051381:Rats; D012995:Solubility
D015105:3',5'-Cyclic-AMP Phosphodiesterases