CARDIAC DESENSITIZATION TO ADENOSINE-ANALOGS AFTER PROLONGED R-PIA INFUSION IN-VIVO

To determine the effects of chronic in vivo stimulation of adenosine receptors, R-(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), a selective A1 receptor agonist, was administered to rats as a continuous 7-day infusion (200 nmol/h). Inotropic and chronotropic responses of isolated atria to adenosine receptor agonists were markedly desensitized compared with the responses of atria from ap-matched control animals. Carbachol's negative chronotropic effect was also attenuated, indicating a heterologous mode of desensitization. Antagonist radioligand binding-assays indicated a 52% reduction in A1 adenosine receptor maximum binding, and competition binding assays revealed a significant loss of G protein-coupled high-affinity A1 receptors in atria from R-PIA-treated rats. Inhibitory G proteins (G(i)) were significantly reduced, as quantified by immunoblot analysis, with no change in the amount of stimulatory G proteins. Ventricular membranes from R-PIA rats showed loss of G(i) and uncoupling of A1 receptors, without a significant change in A1 receptor density. Thus chronic R-PIA infusion desensitized rat atrial muscle to the effects of adenosine receptor agonists via several regulatory adaptations, including downregulation of A1 adenosine receptors, uncoupling of A1 receptors from their associated G proteins, and loss of G(i) proteins.