The purpose of this investigation was to contrast the effect of glucagon and that of epinephrine on the concentration of cyclic adenosine 3',5'-monophosphate (cyclic AMP), the activity of phosphorylase a and the contractile amplitude of isolated perfused rat hearts. The two drugs were about equally effective except that the maximal augmentation of contractility by epinephrine (5 x 10 -9 moles) was twice that produced by an equivalent dose of glucagon with a fourfold greater increase in cyclic AMP concentration. Combination of large doses of the two drugs caused increases in the cyclic nucleotide considerably greater than those required for maximal phosphorylase activation or associated with a maximal inotropic response. The effects of glucagon also developed more slowly than those of epinephrine. An increase in cyclic AMP was not detectable until after phosphorylase a and contractile amplitude had increased. The beta-receptor-blocking agents dichloroisoproterenol and pronethalol did not block the biochemical responses to glucagon in doses which abolished the epinephrine-induced increases in cyclic AMP and phosphorylase a . These results, along with those obtained by other investigators, indicate that glucagon can elicit the same biochemical responses in intact heart as have been obtained with epinephrine, but by action at a different receptor site.

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The literature concerned with studies of the occurrence and function of the cyclic nucleotides in blood vessels is reviewed. Emphasis is placed on the critical evaluation of the evidence which relates to the hypothesis that cyclic nucleotides mediate the effects of drugs and neurotransmitters on vascular contractility. The hypothesis that cyclic AMP mediates vasodilation, especially that induced by β-adrenergic relaxation, is supported by many experimental approaches, but it is concluded that the evidence remains unconvincing based on the criteria established for such a mediator role. Possible sites of action of cyclic AMP are discussed. The demonstrated action of cyclic AMP on vascular membrane electrophysiology and calcium ion pumps are reviewed as possible causes of relaxation. The role of both nucleotides in vascular disease, especially hypertension is discussed. Finally the needs for further research in this area are suggested.

14 C-Labeled adenosine, inosine, hypoxanthine, and adenine were extracted by the isolated rat heart in amounts proportional to their concentration in the perfusion medium between 0.05 and 5 µM. With each of the precursor materials, nearly all of the radioactivity retained by the heart was identified as acid-soluble nucleotide. Nucleotide formation from the four isotopic precursors occurred at similar rates when the concentration of the precursors was below 1 µM. Above this concentration, the heart appeared to utilize adenosine for nucleotide synthesis at rates three to five times those for the other purines. Several experimental approaches were employed to determine the predominant enzymatic routes in the rat heart for the conversion of the nucleosides adenosine and inosine to nucleotides. The results indicated that adenosine was directly phosphorylated to 5'-adenosine monophosphate by a nucleoside kinase. Inosine appeared to proceed to the nucleotide, at least partially, through an initial conversion to hypoxanthine.