Interactions between responses mediated by activation of adenosine A2 receptors and α1‐adrenoceptors in the rabbit isolated aorta

1 This paper describes aspects of the functional antagonism between the responses mediated by activated α1‐adrenoceptors and adenosine A2 receptors in the adventitia‐ and endothelium‐denuded aorta of the rabbit. 2 Adenosine A2 receptor agonists relaxed aortic rings pre‐contracted with phenylephrine. The relaxation response was agonist concentration‐dependent and saturable. The respective contractile and relaxation responses were stable, reproducible, and reversible. 3 Increasing the phenylephrine concentration caused a progressive attenuation of the action of adenosine A2 receptor agonists, consisting of a decreased maximal response and a dextral shift of the adenosine agonist concentration‐response curve. This functional antagonism could be completely reversed upon removal of adenosine by either the addition of adenosine deaminase or by wash‐out of the adenosine agonist from the tissue. The relaxation response to the adenosine A2 receptor partial agonists, N6‐cyclohexyladenosine and R‐(−)‐N6‐(2‐phenylisopropyl)adenosine, was abolished 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 in the phenylephrine concentration shifted the value of the EC50 of 5′‐N‐ethylcarboxamidoadenosine four fold. 5 Analysis of the functional antagonism between the responses mediated by these receptors using the Black & Leff (1983) operational model of agonism allowed for the estimation of the agonist dissociation constant, KA, and the apparent efficacy, τ, for both phenylephrine and adenosine A2 receptor agonists. Increasing the concentration of phenylephrine reduced the value of τ for adenosine agonists in a concentration‐dependent and saturable manner. Similarly, increasing the concentration of adenosine reduced the value of τ for phenylephrine in a concentration‐dependent and saturable manner. The phenylephrine KA value obtained by the method of functional antagonism (1.9 μm) was similar to that obtained by the receptor inactivation method (2.1 μm). 6 Partial occlusion of the α1‐adrenoceptor by the alkylating agent, dibenamine, demonstrated that the magnitude of the adenosine A2 receptor‐mediated relaxation was inversely proportional to the number of functional α1‐adrenoceptors. 7 It is