Molecular Pharmacology, Vol 13, 965-975, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Alpha Adrenergic Involvement in Heart Metabolism: Effects on Adenosine Cyclic 3',5'-Monophosphate, Adenosine Cyclic 3',5'-Monophosphate-Dependent Protein Kinase, Guanosine Cyclic 3',5'-Monophosphate, and Glucose Transport

¹ Department of Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

In the perfused rat heart the alpha adrenergic agonist phenylephrine, at concentrations of 0.1-50 µM, increased the adenosine cyclic 3',5'-monophosphate (cAMP)-dependent protein kinase activity ratio in a dose-dependent manner. In all cases there was a corresponding increase in glycogen phosphorylase activity. When phenylephrine concentrations greater than 1 µM were used, there was a significant increase in cAMP associated with the rise in protein kinase activity; however, the modest increase in kinase activity produced by concentrations less than 1 µM was not accompanied by any detectable increase in cAMP. The beta adrenergic blocking agent propranolol did not inhibit activation of the cAMP-dependent protein kinase in hearts treated with low concentrations (1 µM or less) of phenylephrine, but did reduce the greater activation seen in hearts treated with higher concentrations (5 µM or more) of the drug. Phentolamine (1 µM), an alpha adrenergic blocking agent, was found to potentiate the effect of phenylephrine concentrations greater than 5 µM. When animals were treated with reserpine 18 hr prior to death, activation of cAMP-dependent protein kinase by phenylephrine was still evident. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine potentiated the effect of phenylephrine on all parameters measured. Calcium was necessary for the activation of protein kinase by low (1 µM or less) but not high (5 µM or greater) concentrations of the drug. Although 1 µM phenylephrine produced a slight activation of heart protein kinase when used alone, it reduced the ability of beta adrenergic agonists (e.g., isoproterenol) to activate the enzyme. Epinephrine, which has both alpha and beta adrenergic components, was a more effective activator of heart cAMP-dependent protein kinase when its alpha component was blocked with phentolamine than when epinephrine was used alone. These observations indicate that kinase activation is principally through a beta adrenergic mechanism. Epinephrine also increased glucose transport by a process which was blocked by phentolamine but not propranolol. Phenylephrine, in the presence of 3-isobutyl-1-methylxanthine, significantly increased guanosine cyclic 3',5'-monophosphate levels. This increase was blocked by the alpha antagonist phentolamine but not by the beta antagonist propranolol.