PHARMACOLOGICAL CHARACTERISTICS OF ADENOSINE-INDUCED INHIBITION OF DOG VENTRICULAR CONTRACTILITY - DEPENDENCE ON THE PREEXISTING LEVEL OF BETA-ADRENOCEPTOR ACTIVATION

Experiments were carried out to characterize the adenosine-induced negative inotropic effect in relation to the extent of beta-adrenoceptor activation in the isolated dog left ventricular myocardium. Adenosine and R-N6-phenylisopropyladenosine inhibited the positive inotropic effect of isoprenaline (10(-7) mol/l and lower) about 20% of its maximal response, which was antagonized by an A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine in a concentration-dependent manner. The negative inotropic effect of adenosine disappeared and that of R-N6-phenylisopropyl-adenosine decreased when the isoprenaline concentration was elevated to the level higher than 10(-7) mol/l. Adenosine deaminase (1.5 U/ml) that abolished the negative inotropic effect of adenosine enhanced the effect of R-N6-phenylisopropyladenosine, indicating that endogenous adenosine released by high isoprenaline concentration (10(-6) mol/l) modulates the interaction. The maximal response to adenosine and R-N6-phenylisopropyladenosine determined in the presence of 10(-7) mol/l isoprenaline was 50% of that of carbachol which elicited the maximal inhibition even in the presence of 10(-6) mol/l isoprenaline. The negative inotropic effects of R-N6-phenylisopropyladenosine and carbachol were additive to the maximal response equivalent to that of carbachol. The difference in the efficiency between the adenosine and muscarinic receptor agonists may be partly ascribed to the difference in densities of the respective receptors in the dog ventricular myocardium. The negative inotropic effect of R-N6-phenylisopropyladenosine in the presence of isoprenaline was associated with decrease in cyclic AMP levels elevated previously by isoprenaline. The elevation of cyclic AMP levels caused by isoprenaline (3 x 10(-7) mol/l) was abolished by R-N6-phenylisopropyladenosine (10(-4) mol/l), while the contractile response was reduced only by 30% with R-N6-phenylisopropyladenosine. In the absence of beta-adrenoceptor stimulation R-N6-phenylisopropyladenosine elicited a negative inotropic effect without changes in cyclic AMP levels, but this effect was less than 10% of the basal force of contraction. It is concluded that in the dog ventricular myocardium adenosine receptors play a role for the inhibitory regulation of contractility, which is influenced markedly by the pre-existing level of beta-adrenoceptor activation.