Extracellular ATP facilitates flow-induced vasodilatation in rat small mesenteric arteries

ATP can be released from endothelial cells, and this release is increased by intraluminal flow in blood vessels. In the present study, the effect of extracellular ATP (1 muM) on flow-induced vasodilatation was investigated in isolated and pressurized rat small mesenteric arteries. In the absence of extracellular ATP, only 46% of arteries developed dilatation in response to flow, and this response was both transient and unstable. In marked contrast, with ATP present, all vessels developed a prolonged and stable dilatation in response to flow. Even in the vessels that failed to respond to flow in the absence of ATP, dilatation could be stimulated once ATP was present. The ability of ATP to facilitate flow-induced vasodilatation was mimicked by UTP (1 muM), a P2Y agonist, or 3'-O-(4-benzoyl)benzoyl ATP (BzATP; 10 muM), an agonist for P2X(1), P2X(7), and P2Y(11) purinoceptors. The involvement of P2X(7) purinoceptors was further supported by the inhibitory effect of KN-62 (1 muM), a P2X(7) antagonist, on the action of BzATP. P2X(1) and P2X(3) purinoceptors were not involved because their receptor agonist alpha, beta-methylene ATP had no effect. The facilitating effect of ATP on flow dilatation was also attenuated by the combined application of reactive blue 2 (100 muM), a P2Y antagonist, and suramin (100 muM), a nonselective P2X and P2Y antagonist. Furthermore, flow-induced dilatation obtained in the presence of ATP was reproducible. In contrast, in the additional presence of the ectonucleotidase inhibitor ARL-67156 (10 muM), although the first dilatation was normal, the responses to the second and later exposures to flow were greatly attenuated. The nonhydrolyzable ATP analogs adenosine-5'-(3-thiotriphosphate)trilithium salt (1 muM) and adenosine 5'-(beta,gamma-imido) triphosphate tetralithium salt hydrate (10 muM) had similar effects to those of ARL-67156. These data suggest that ATP acts through both P2X and P2Y purinoceptors to facilitate flow-induced vasodilatation and that ectonucleotidases prevent this effect by degrading ATP on the endothelial cell surface.