Reductions of the phenylephrine-induced contractions of the rat aorta and mesenteric artery by the presence of intact endothelium are not mediated by same mechanisms

Abstract

Dilatory responses of extracellular nucleotides were examined in the precontracted isolated rat mesenteric artery. Dilatation mediated by endothelium-derived hyperpolarising factor (EDHF) was studied in the presence of Nω-nitro-l-arginine (l-NOARG) and indomethacin, and was most potently induced by the selective P2Y1 receptor agonist adenosine 5′-O-thiodiphosphate (ADPβS), while 2-methylthioadenosine triphosphate (2-MeSATP) and adenosine triphosphate (ATP) were almost inactive. However, after P2X receptor desensitisation (with αβ-methylene-adenosine triphosphate, αβ-MeATP), 2-MeSATP and ATP potently stimulated EDHF-mediated dilatation. This can be explained by simultaneous activation of endothelial P2Y receptors that release EDHF, and depolarising P2X receptors on smooth muscle cells. Uridine triphosphate (UTP) also induced potent dilatation, suggesting EDHF release via P2Y2/P2Y4 receptors. Uridine diphosphate (UDP) had only minor dilatory effects, and when pretreated with hexokinase it was almost inactive, suggesting a minor role for P2Y6 receptors. The nitric oxide (NO) mediated dilatation was studied in the presence of charybdotoxin, apamin and indomethacin. ADPβS, 2-MeSATP, ATP and UTP were all potent relaxant agonists suggesting NO release via P2Y1 and P2Y2/P2Y4 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 P2Y1 and P2Y2/P2Y4 receptors. P2X receptor stimulation of smooth muscle cells selectively counteracts the dilatory effect of EDHF.