Positive Inotropic and Chronotropic Effects of 8-Substituted Derivatives of Cyclic AMP and Activation of Protein Kinase A

Abstract

Inotropic and chronotropic effects of 8-substituted derivatives of cyclic AMP 8-N(CH3)2, 8-OCH3) were studied us ing guinea pig atrial and ventricular muscle preparations and correlated with the activation of the protein kinase A derived from the bovine myocardium. All the com pounds produced positive inotropic and chronotropic effects. A good correlation was found between the chronotropic effect and the activation of the enzyme, while such a good correlation was not found between the enzyme activation and the positive iso tropic effect. However, after treatment of the preparation with theophylline, the posi tive inotropic effects of some derivatives were potentiated to such a degree that the positive inotropic effects became well-correlated to the activation of the protein kinase. To elucidate the mechanism of the potentiation by theophylline, the effects of 8-phenyltheophylline and 3-isobutyl-l-methylxanthine on the positive inotropic effects of 8-Br and 8-OCH3 cyclic AMPs were studied. While 3-isobutyl-l-methylxanthine po tentiated the effects of both compounds, 8-phenyltheophylline potentiated the effect of only 8-OCH3 cyclic AMP and only in the atria. These results suggest that the posi tive inotropic and chronotropic effects of 8-substituted cyclic AMP essentially due to the activation of the protein kinase A, with the hydrolysis of the compounds by phos phodiesterase and (in the atria) activation of adenosine R-receptor subserving the negative inotropic effect intervening.