title: Mechanisms underlying ATP-induced endothelium-dependent contractions in the SHR aorta.
abstract: In mature spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats, acetylcholine, the calcium ionophore A 23187 and ATP release endothelium-derived contracting factor (EDCF), cyclooxygenase (COX) derivatives that activate thromboxane-endoperoxide (TP) receptors on vascular smooth muscle. The EDCFs released by acetylcholine have been identified as prostacyclin and prostaglandin (PG) H(2) while in response to A 23187 thromboxane A(2), along with the two other prostaglandins, contributes to the endothelium-dependent contractions. The purpose of the present study was to identify the EDCFs produced by ATP. Isometric tension and the release of prostaglandins were measured in isolated aortic rings of WKY rats and SHR. ATP produced the endothelium-dependent release of prostacyclin, thromboxane A(2) and PGE(2) (PGI(2)>>TXA(2)> or =PGE(2)>PGF(2alpha)) in a similar manner in aorta from WKY rats and SHR. In SHR aortas, the release of thromboxane A(2) was significantly larger in response to ATP than to acetylcholine while that to prostacyclin was significantly smaller. The inhibition of cyclooxygenase with indomethacin prevented the release of prostaglandins and the occurrence of endothelium-dependent contractions. The thromboxane synthase inhibitor dazoxiben selectively abolished the ATP-dependent production of thromboxane A(2) and partially inhibited the corresponding endothelium-dependent contractions. U 51605, a non-selective inhibitor of PGI-synthase, reduced the release of prostacyclin elicited by ATP but induced a parallel increase in the production of PGE(2) and PGF(2alpha), suggestive of a PGH(2)-spillover, which was associated with the enhancement of the endothelium-dependent contractions. Thus, in the aorta of SHR, endothelium-dependent contractions elicited by ATP involve the release of thromboxane A(2) and prostacyclin with a possible contribution of PGH(2).
authors.affiliation: Institut de Recherches Servier, 92150 Suresnes, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Gluais
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Michel
authors.initials: M
authors.lastname: Félétou
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D015232:Dinoprostone / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011463:Prostaglandins H / Q000494:pharmacology; D044062:Prostaglandins I / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013928:Thromboxane A2 / Q000096:biosynthesis
chemical_list: D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D011463:Prostaglandins H; D044062:Prostaglandins I; D013928:Thromboxane A2; C015014:azo analog I; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase; D015232:Dinoprostone; D000109:Acetylcholine; D007213:Indomethacin