Pharmacological Characterization of the Renovascular P2

Isolated rat kidneys, perfused at a constant flow with a nonrecir-culated medium, were used to investigate the effects of P2 punnergic receptor agonists on renal vascular resistance. A potent P2 agonist, 2-methylthio ATP, dilated the kidney in a concentration-dependent manner, a response that was similar to that elicited by acetylcholine. The vasodilator responses to 2-methylthio ATP and to acetylcholine were nearly abolished by Nwnitro/arginine methyl ester, an antagonist of nitric oxide formation by endothelial cells. A potent P agonist, a,fi-methyl-ene ATP, constricted the kidney in a concentration-dependent manner, and the effect was potentiated by N”-nitro-/-arginine methyl ester. This latter finding suggests that a,fl-methylene ATP activates P2 receptors, but with such a low potency that any tendency for vasodilation is masked by the predominant P receptor-induced constriction. Collectively, the results indicate the renal vasculature can either constrict or dilate in response to P2 punnergic receptor agonists, depending upon which subclass ofreceptor is activated, P2 (constrict)or P(dilate). Furthermore, the Ps,, receptor-induced vasodilation appears to be mediated by endothelial cell nitric oxide formation. Although several groups have investigated the renovascular effects of exogenous ATP, the results are not easy to interpret. The experimental preparations (anesthetized dogs, isolated-perfused rabbit and rat kidneys and isolated-perfused rat jux-tamedullary nephrons), the modes (bolus injections and contin-uous infusions) and routes of administration (i.v., i.a. and intrarenal arterial) and the dosages have been extremely van-able. Not unexpectedly, there are reports that ATP dilates the renal vasculature (Harvey, 1964; Hashimoto and Kumakura