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

Abstract

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 mM noradrenaline. 2 Endothelial denudation abolished the dilator responses. 3 The selective P2Y 1 agonist, 2-MeSADP, induced a potent vasodilatation (pEC 50 ¼ 6.970.1). The P2Y 1 antagonist of 10 mM, 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, UTPgS and the P2Y 6 agonist, UDPbS, stimulated potent dilatations (pEC 50 ¼ 7.870.4 for UTPgS and 8.470.2 for UDPbS). 5 The 2-MeSADP-induced nitric oxide (NO)-mediated dilatation was studied in the presence of 10 mM indomethacin, 50 nM charybdotoxin and 1 mM apamin. The involvement of the endotheliumderived 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 ¼ 2575% for NO, 2576% for EDHF and 2775% 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. British Journal of Pharmacology (2003) 138, 1451-1458. doi:10.1038/sj.bjp.0705186 Keywords: coronary circulation; endothelium; endothelium-derived hyperpolarising factor; human; nitric oxide; nucleotide; P2 receptor; vasodilatationAbbreviations: 2-MeSADP, 2-methylthio adenosine 5 0 -diphosphate; 2-MeSATP, 2-methylthio adenosine 5 0 -triphosphate; abMeATP, ab-methylene adenosine 5 0 -triphosphate; Ach, acetylcholine; ADP, adenosine diphosphate; ANOVA, the one-way analysis of variance; ATP, adenosine triphosphate; EC, endothelial cells; EC 50 , effective concentration (e.g. 50% of maximum); EDHF, endothelium-derived hyperpolarising factor; LIMA, left internal mammary artery; L-NOARG, N$-nitro-L-arginine; mRNA, messenger ribonucleic acid; MRS 2179, 2 0 -deoxy-N6-methyladenosine-3 0 ,5 0 -bisphosphate; MRS 2216, 2-chloro-2 0 -deoxy-6-methyladenosine-3 0 ,5 0 -bisphosphate; NA, noradrenaline; NO, nitric oxide; t-PA, tissue-plasminogen activator; UDP, uridine diphosphate; UDPbS, uridine 5 0 -O-2-thiodiphosphate; UTP, uridine triphosphate; UTPgS, uridine 5 0 -O-3-thiotriphosphate; VSMC, vascular smooth muscle cells

Vascular stasis, intestinal hemorrhage, and heightened vascular permeability complicate acute portal hypertension in cd39-null mice

“…Similarly, adenosine did not induce significant differences in PP in either of the groups. As this is born out post-L-NNA, ATP generates a substantial increment in PPs, likely as a consequence of vascular smooth muscle cell unbalanced P2X-stimulated vasoconstriction (29,32). These data validate the previously recorded aberrant ATP-mediated hemodynamic effects in Cd39-null mice (10).…”

“…In wild-type animals, ATP infusion did not cause any significant change in PP, and L-NNA only caused a minor drop in PP in these animals. In contrast, Cd39-null mice respond to ATP by a fall in PP, likely secondary to endothelial P2Y-mediated release of NO (32). Similarly, adenosine did not induce significant differences in PP in either of the groups.…”

Selective Impairment of P2Y Signaling by Prostaglandin E2 in Macrophages: Implications for Ca2+-Dependent Responses

“…Macrophages from WT or P2X7-deficient mice (P2X7 KO) were prepared, and after the indicated time of culture in the presence or absence of LPS or IL-4/IL-13, cells were treated for 10 min with 5 mM PGE 2 , and the Ca 2+ responses to UTP (100 mM) or BzATP (300 mM) were determined using the dual excitation 340/380-nm protocol as described in nological approaches. In view of the confusion in the literature regarding the role of PGs on P2 signaling and macrophage activation (20,21,(59)(60)(61)(62)(63), we studied the role of these bioactive lipids on UTP-and ATP-dependent P2 responses. Preliminary experiments in macrophages carrying a COX-2 transgene revealed a rapid blockade of Ca 2+ mobilization induced by P2Y agonists that could be ascribed to the accumulation of PGE 2 in the culture medium.…”

Regulation of Renal Hemodyamics by Purinergic Receptors in Angiotensin II -Induced Hypertension

“…P2X receptor activation in the smooth muscle cells produces renal vasoconstriction; in the endothelial cells only P2X4 has been described as able to induce vasodilation. P2Y receptor activation in the endothelial cells induces vasodilation, and by release of nitric oxide or prostaglandin I 2 (Wihlborg et al, 2003), whereas in the smooth muscle cells induces vasoconstriction through increasing intracellular calcium release.…”