Kinetic characterization of adenosine A2 receptor-mediated relaxation in 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 alpha 1-adrenoceptors in adventitia- and endothelium-denuded rabbit thoracic aortic rings by steady-state protocols which ignore the time course of response generation. In the present communication we describe aspects of the time-dependent kinetics of relaxation responses to adenosine A2 receptor agonists in tissues pre-contracted with the alpha 1-adrenoceptor agonist phenylephrine. The results were analyzed by application of the model originally developed by Keitz et al. (1990, J. Pharmacol. Exp. Ther. 255, 650) to describe the relaxation response, to a beta-adrenoceptor agonist, as a first-order exponential decrease in tissue tension over time to estimate the apparent rate constant for relaxation (krel) and the magnitude of relaxation at equilibrium. The magnitude of the relaxation responses to adenosine, N6-cyclohexyladenosine, N6-methyladenosine, 5'-N-ethylcarboxamidoadenosine, and R(-)-N6-(2-phenylisopropyl)adenosine were agonist concentration-dependent and saturable, as were the apparent rate constants for relaxation. In addition, the magnitude of the apparent rate constants for relaxation and the relaxation responses were inversely proportional to the fractional occupancy of the alpha 1-adrenoceptor. The hypothesis put forth by Keitz et al. that the maximal value of the apparent rate constant for relaxation may serve as the kinetic definition of agonist efficacy was also tested 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 kinetic paradigms.