Molecular Pharmacology, Vol 14, 237-245, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Adenosine Cyclic 3',5'-Monophosphate Concentrations during the Positive Inotropic Response of Cat Cardiac Muscle to Polymeric Immobilized Isoproterenol

¹ Department of Pharmacology and Therapeutics, School of Medicine, State University of New York at Buffalo, Buffalo, New York 14214

Changes in cardiac contractility and concentrations of cyclic 3',5'-AMP in isolated cat papillary muscles in response to isoproterenol diazotized to a 12,800 mol wt random copolymer of hydroxypropylglutamine with p-aminophenylalanine (copoly-Iso) have been examined. It has been previously shown that copoly-Iso retains positive chronotropic and inotropic effects in perfused guinea pig hearts and isolated cat papillary muscles, respectively, without isoproterenol dissociation. In the present experiments, in isometrically contracting cat papillary muscles copoly-Iso (equivalent to 0.37 µmole of isoproterenol) resulted in prompt increases in the force and velocity of contraction within 20 sec. The copoly-Iso responses reached maximal levels by 180 sec and were similar in magnitude and time course to peak l-isoproterenol responses. Cat papillary muscles frozen 30-180 sec subsequent to copoly-Iso addition were subjected to cyclic AMP radioimmune assay. No detectable change in cyclic AMP concentrations were observed during increases in contractility (e.g., cyclic AMP control level was 5.54 ± 0.49 pmoles/mg of protein, n = 5). In contrast, papillary muscles frozen 60 sec after soluble l-isoproterenol addition had markedly increased cyclic AMP levels (11.56 ± 2.49 pmoles/mg of protein, n = 6). Gel permeation chromatography of muscle bath contents at the time of papillary muscle freezing indicated that no isoproterenol dissociated from the matrix during the experiments. These results confirm our previous findings for glass bead immobilized isoproterenol, where nearly maximal inotropic responses were obtained without detectable changes in cyclic AMP concentrations, and place further into question the role of cyclic AMP in catecholamine-induced beta receptor-stimulated cardiac contractility.