KINETIC CHARACTERIZATION OF ADENOSINE-A2 RECEPTOR-MEDIATED RELAXATIONIN ISOLATED RABBIT AORTA

Previous studies in our laboratory (Wiener et al., 1991, Soc. Neurosci . Abstr. 17, 989) have addressed aspects of the functional antagonism between the responses mediated by activated adenosine A2 receptors and alpha1-adrenoceptors in adventitia- and endothelium-denuded rabbit th oracic aortic rings by steady-state protocols which ignore the time co urse of response generation. In the present communication we describe aspects of the time-dependent kinetics of relaxation responses to aden osine A2 receptor agonists in tissues pre-contracted with the alpha1-a drenoceptor agonist phenylephrine. The results were analyzed by applic ation of the model originally developed by Keitz et al. (1990, J. Phar macol. Exp. Ther. 255, 650) to describe the relaxation response, to a beta-adrenoceptor agonist, as a first-order exponential decrease in ti ssue tension over time to estimate the apparent rate constant for rela xation (k(rel)) and the magnitude of relaxation at equilibrium. The ma gnitude of the relaxation responses to adenosine, N6-cyclohexyladenosi ne, N6-methyladenosine, 5'-N-ethylcarboxamidoadenosine, and R(-)-N6-(2 -phenylisopropyl)adenosine were agonist concentration-dependent and sa turable, as were the apparent rate constants for relaxation. In additi on, the magnitude of the apparent rate constants for relaxation and th e relaxation responses were inversely proportional to the fractional o ccupancy of the al-adrenoceptor. The hypothesis put forth by Keitz et al. that the maximal value of the apparent rate constant for relaxatio n may serve as the kinetic definition of agonist efficacy was also tes ted and found to be invalid for the adenosine A2 receptor. We propose that this pair of activated receptors and tissue preparation is a good model to study quantitative aspects of functional antagonism by kinet ic paradigms.