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

Inotropic and chronotropic effects of 8-substituted derivatives of cyclic AMP (8-SH, 8-SCH2C6H5, 8-N3, 8-SCH3, 8-Br, 8-N(CH3)2, 8-OCH3) were studied using guinea pig atrial and ventricular muscle preparations and correlated with the activation of the protein kinase A derived from the bovine myocardium. All the compounds 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 inotropic effect. However, after treatment of the preparation with theophylline, the positive 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-1-methylxanthine on the positive inotropic effects of 8-Br and 8-OCH3 cyclic AMPs were studied. While 3-isobutyl-1-methylxanthine potentiated 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 positive 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 phosphodiesterase and (in the atria) activation of adenosine R-receptor subserving the negative inotropic effect intervening.