Effect of catecholamines, histamine and oxyfedrine on isotonic contraction and cyclic AMP in the guinea-pig heart.

Abstract

Experiments in isolated, perfused guinea-pig hearts (Langendorff) have shown that 1. Inotropic effects of catecholamines and histamine are potentiated by the PDE-inhibitor theophylline, but antagonized by the PDE-activators imidazole or N-methyl-imidazole. 2. Maximum effective doses of isoprenaline (0.5 μg) or histamine (10 μg) increase cardiac cAMP 4–5-fold at 15 sec after injection whereas maximum effective doses of oxyfedrine (10 μg) produce a 2-fold increase in cAMP at 15 sec, along with a considerably weaker inotropic response than isoprenaline or histamine. 3. Changes in cAMP precede the increase in isotonic contractions brought about by isoprenaline, histamine or oxyfedrine in maximum effective doses, and also clearly precede the decrease in the inotropic effect of isoprenaline or histamine. 4. No dissociation between the increase in cAMP and the positive inotropic effect was observed after very small doses of isoprenaline or histamine which only increased the amplitude of contraction by about 12–14%. A significant correlation (r=0.94, p<0.01) between increases in isotonic contractions and increases in cAMP was found over the whole tested dose range of both compounds. 5. Increases in cAMP as well as in contractions induced by 2 μg of histamine—in contrast to an equieffective dose of 0.1 μg of isoprenaline—were not blocked by the β-blocking compound Ko 592 (50 μg), demonstrating again a close relationship between cAMP and inotropic effect of histamine or isoprenaline. 6. The data support the mediator role of cAMP for the inotropic effect of substances which activate the adenyl cyclase system in the heart.