INTERACTIONS BETWEEN RESPONSES MEDIATED BY ACTIVATION OF ADENOSINE-A(2)-RECEPTORS AND ALPHA(1)-ADRENOCEPTORS IN THE RABBIT ISOLATED AORTA

1 This paper describes aspects of the functional antagonism between th e responses mediated by activated alpha1-adrenoceptors and adenosine A 2 receptors in the adventitia- and endothelium-denuded aorta of the ra bbit. 2 Adenosine A2 receptor agonists relaxed aortic rings pre-contra cted with phenylephrine. The relaxation response was agonist concentra tion-dependent and saturable. The respective contractile and relaxatio n responses were stable, reproducible, and reversible. 3 Increasing th e phenylephrine concentration caused a progressive attenuation of the action of adenosine A2 receptor agonists, consisting of a decreased ma ximal response and a dextral shift of the adenosine agonist concentrat ion-response curve. This functional antagonism could be completely rev ersed upon removal of adenosine by either the addition of adenosine de aminase or by wash-out of the adenosine agonist from the tissue. The r elaxation response to the adenosine A2 receptor partial agonists, N6-c yclohexyladenosine and R-(-)-N6-(2-phenylisopropyl)adenosine, was abol ished at higher phenylephrine concentrations (e.g. 30 EC50). 4 A 1000 fold increase in the adenosine concentration was required to shift the value of the EC50 of phenylephrine six fold, while a similar increase in the value of the EC50 of adenosine could be elicited by only a 32 fold increase in the phenylephrine concentration. A 30 fold increase i n the phenylephrine concentration shifted the value of the EC50 of 5'- N-ethylcarboxamidoadenosine four fold. 5 Analysis of the functional an tagonism between the responses mediated by these receptors using the B lack & Leff (1983) operational model of agonism allowed for the estima tion of the agonist dissociation constant, K(A), and the apparent effi cacy, tau, for both phenylephrine and adenosine A2 receptor agonists. Increasing the concentration of phenylephrine reduced the value of tau for adenosine agonists in a concentration-dependent and saturable man ner. Similarly, increasing the concentration of adenosine reduced the value of tau for phenylephrine in a concentration-dependent and satura ble manner. The phenylephrine K(A) value obtained by the method of fun ctional antagonism (1.9 muM) was similar to that obtained by the recep tor inactivation method (2.1 muM). 6 Partial occlusion of the alpha1-a drenoceptor by the alkylating agent, dibenamine, demonstrated that the magnitude of the adenosine A2 receptor-mediated relaxation was invers ely proportional to the number of functional alpha1-adrenoceptors. 7 I t is concluded that the magnitude of functional antagonism is proporti onal to the stimulus elicited through either receptor. We propose that this tissue preparation and pair of receptors is a good model to stud y quantitative aspects of functional antagonism between activated rece ptors.