Extracellular nucleotides induce vasodilatation in human arteries via prostaglandins, nitric oxide and endothelium-derived hyperpolarising factor

1 The present study was aimed at examining P2 receptor-mediated vasodilatation in human vessels. The isometric tension was recorded in isolated segments of the human left internal mammary artery branches precontracted with 1 muM noradrenaline. 2 Endothelial denudation abolished the dilator responses. 3 The selective P2Y(1), agonist, 2-MeSADP, induced a potent vasodilatation (pEC(50) = 6.9 +/- 0. 1). The P2Y(1), antagonist of 10 muM, MRS 2216, shifted the 2-MeSADP concentration-response curve 1.1 log units to the right. The combined P2Y(1) and P2X agonist, 2-MeSATP, stimulated a dilatation with a potency similar to that of 2-MeSADP. Furthermore, MRS 2216 had a similar antagonistic effect on both 2-MeSATP and 2-MeSADP indicating that P2X receptors do not mediate vasodilatation. 4 Both the P2Y(2/4) agonist, UTPgammaS and the P2Y(6) agonist, UDPbetaS, stimulated potent dilatations (pEC(50) = 7.8 +/- 0.4 for UTPgammaS and 8.4 +/- 0.2 for UDPbetaS). 5 The 2-MeSADP-induced nitric oxide (NO)-mediated dilatation was studied in the presence of 10 muM indomethacin, 50 nm charybdotoxin and 1 muM apamin. The involvement of the endothelium-derived hyperpolarising factor (EDHF) was investigated in the presence of 0.1 MM L-NOARG and indomethacin. The involvement of prostaglandins was investigated in the presence of L-NOARG, charybdotoxin and apamin. Both NO, EDHF and prostaglandins mediated 2-MeSADP dilatation with similar efficacy (E-max = 25 +/- 5% for NO, 25 +/- 6% for EDHF and 27 +/- 5% for prostaglandins). 6 In conclusion, extracellular nucleotides induce endothelium-derived vasodilatation in human vessels by stimulating P2Y(1), P2Y(2/4) and P2Y(6) receptors, while P2X receptors are not involved. Endothelial P2Y receptors mediate dilatation by release of EDHF, NO and prostaglandins.