P2X receptors counteract the vasodilatory effects of endothelium derived hyperpolarising factor

Dilatory responses of extracellular nucleotides were examined in the precon tracted isolated rat mesenteric artery. Dilatation mediated by endothelium- derived hyperpolarising factor (EDHF) was studied in the presence of N omeg a-nitro-L-arginine (L-NOARG) and indomethacin, and was most potently induce d by the selective P2Y(1) receptor agonist adenosine 5'-O-thiodiphosphate ( ADP beta S), while 2-methylthioadenosine triphosphate (2-MeSATP) and adenos ine triphosphate (ATP) were almost inactive. However, after P2X receptor de sensitisation (with alpha beta-methylene-adenosine triphosphate, alpha beta -MeATP), 2-MeSATP and ATP potently stimulated EDHF-mediated dilatation. Thi s can be explained by simultaneous activation of endothelial P2Y receptors that release EDHF, and depolarising P2X receptors on smooth muscle cells. U ridine triphosphate (UTP) also induced potent dilatation, suggesting EDHF r elease via P2Y(2)/P2Y(4) receptors. Uridine diphosphate (UDP) had only mino r dilatory effects, and when pretreated with hexokinase it was almost inact ive, suggesting a minor role for P2Y(6) receptors. The nitric oxide (NO) me diated dilatation was studied in the presence of charybdotoxin, apamin and indomethacin. ADP beta S, 2-MeSATP, ATP and UTP were all potent relaxant ag onists suggesting NO release via P2Y(1) and P2Y(2)/P2Y(4) receptors, while UDP was much less potent and efficacious. P2X receptor desensitisation had only minor effect on the NO-mediated dilatations. In conclusion, both EDHF and NO-mediated dilatation can be induced by activation of P2Y(1) and P2Y(2 )/P2Y(4) receptors. P2X receptor stimulation of smooth muscle cells selecti vely counteracts the dilatory effect of EDHF. (C) 2000 Elsevier Science B.V . All rights reserved.