EFFECTS OF PURINES AND PYRIMIDINES ON THE RAT MESENTERIC ARTERIAL BED

The effects of the purines, adenosine 5'-triphosphate (ATP) and guanosine 5'-triphosphate (GTP), and the pyrimidines, uridine 5'-triphosphate (UTP), cytidine 5'-triphosphate (CTP), and thymidine 5'-triphosphate (TTP), on vascular resistance were investigated in the rat mesenteric arterial bed. In preparations at basal tone, these agents produced dose-related vasoconstriction with a potency order of ATP > CTP > UTP >> TTP = GTP. When tone was raised with norepinephrine (30-mu-M), these agents caused dose-related vasodilatation with the potency order of UTP = ATP > TTP = GTP. CTP did not elicit vasodilatation. Removal of the endothelium with sodium deoxycholate resulted in an increased responsiveness of the mesenteric bed preparation to the vasoconstrictor effects of each of the purines and pyrimidines tested. The selective P2X-purinoceptor-desensitizing agent alpha-beta-methylene ATP inhibited vasoconstrictor responses to ATP and to CTP but had no effect on vasoconstrictor responses elicited by UTP, TTP, and GTP. In raised-tone preparations, vasodilator responses to ATP, UTP, TTP, and GTP were abolished after removal of the endothelium with sodium deoxycholate. Responses to acetylcholine were also abolished; those to sodium nitroprusside were unimpaired. An inhibitor of the formation of nitric oxide from L-arginine, N(omega)-nitro-L-arginine methyl ester (30-mu-M), which antagonizes responses mediated by endothelium-derived relaxing factor (nitric oxide), attenuated vasodilatation to ATP, UTP, and acetylcholine but not to sodium nitroprusside. In addition to confirming the presence of P2X- and P2Y-purinoceptors in the rat mesenteric arterial bed, these results demonstrate the presence of discrete "pyrimidinoceptors," which mediate vasoconstriction and vasodilatation by receptors located on the smooth muscle and on endothelial cells, respectively. Furthermore, it is shown that the vascular relaxations to ATP and UTP occur largely via production of endothelium-derived relaxing factor. It is probable that, like P2-purinoceptors, UTP pyrimidinoceptors comprise a heterogeneous population, subtypes of which have been partially characterized according to their different actions and locations within the vasculature.