Pharmacological Evidence for Ax and A2 Adenosine Receptors in the Skin Microcirculation

To characterize adenosine-mediated vascular responses, synthetic A, and A2 receptor agonists (JV-ethyl carboxamido adenosine [NECA], 2-chloro adenosine [2CA], or cyclohexyl adenosine [CHA]), the parent compound (adenosine [ADO]), an uptake inhibitor (dipyridamole [DIPYRID]) or a nonselective, competitive antagonist (8-phenyl theophylline [8pTHEO]) were topically applied to 20-60 /*m arterioles in the subcutaneous microcirculation of the hamster. Blood flow was calculated from arteriolar diameter and red blood cell velocity using intravital microscopy. At >10~* M, the potency order for vasodilation (maximum, 170-190% of control) was NECA>2CA>ADO; these responses were attenuated by 10" M 8pTHEO. From 10" to 10"' M, 2CA evoked vasodilation whereas ADO, which has an identical affinity at A, and A2 receptors, evoked lesser responses. ADO-induced vasodilation was potentiated by 10~ M DIPYRID; this response was similar to that evoked by 2CA alone or 2CA+DIPYRID. In contrast to ADO, 2CA is a poor substrate for cellular uptake, which suggests that uptake reduces the A2 effect of exogenous ADO. From 10" 10 to 10~ M, CHA and ADO were equipotent for causing vasoconstriction (minimum, 80-90% of control); these responses were completely antagonized by SpTHEO. Norepinephrine was a more potent vasoconstrictor and 8pTH£O did not alter these responses. Since ADO is a metabolic substrate and a nonselective receptor agonist, while CHA is Arselective and a poor substrate for cellular uptake, neither A2 activation nor cellular uptake altered expression of the Aj effect of exogenous ADO. Furthermore, DIPYRID had no effect on the A, response. Thus, depending on agonist concentration, stimulation of high affinity A, receptors or low affinity A2 receptors can cause opposite responses in the skin microcirculation. The precise location or physiological role of these receptors is unknown. (Circulation Research 1989;65:176-184)