title: Hypertension increases contractile responses to hydrogen peroxide in resistance arteries through increased thromboxane A2, Ca2+, and superoxide anion levels.
abstract: This study investigated the mechanisms underlying the response to hydrogen peroxide (H(2)O(2)) in mesenteric resistance arteries from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto (WKY) rats. Arteries were mounted in microvascular myographs for isometric tension recording and for simultaneous measurements of intracellular Ca(2+) concentration ([Ca(2+)](i)), superoxide anion (O(2)(.)) production was evaluated by dihydroethidium fluorescence and confocal microscopy, and thromboxane A(2) (TXA(2)) production was evaluated by enzyme immunoassay. H(2)O(2) (1-100 microM) induced biphasic responses characterized by a transient endothelium-dependent contraction followed by relaxation. Simultaneous measurements of tension and Ca(2+) showed a greater effect of H(2)O(2) in arteries from hypertensive than normotensive rats. The cyclooxygenase (cox) inhibitor, indomethacin [1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-H-indole-3-acetic acid] (1 microM); the COX-1 inhibitor, SC-58560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole] (1 microM); the thromboxane (TXA(2)) synthase inhibitor, furegrelate [5-(3-pyridinylmethyl)-2-benzofurancarboxylic acid, sodium salt] (10 microM); and the TXA(2)/prostaglandin H(2) receptor antagonist, SQ 29,548 ([1S-[1.alpha.,2.alpha.(Z),3.alpha.,4.alpha.]]-7-[3-[[2-[(phenylamino) carbonyl] hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid)) (1 microM) abolished H(2)O(2) contraction in arteries from WKY rats but only reduced it in SHRs. The O(2)(.) scavenger, tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt) (1 mM), and the NADPH oxidase inhibitor, apocynin (4'-hydroxy-3'-methoxyacetophenone) (0.3 mM), decreased H(2)O(2) contraction in arteries from SHRs but not in WKY rats. H(2)O(2) induced TXA(2) and O(2)(.) production that was greater in SHRs than in WKY rats. The TXA(2) analog, U46619 [9,11-di-deoxy-11 alpha,9 alpha-epoxymethano prostaglandin F(2 alpha) (0.1 nM-1 microM)], also increased O(2)(.) production in SHR vessels. H(2)O(2)-induced TXA(2) production was decreased by SC-58560. H(2)O(2)-induced O(2)(.) production was decreased by tiron, apocynin, and SQ 29,548. In conclusion, the enhanced H(2)O(2) contraction in resistance arteries from SHRs seems to be mediated by increased TXA(2) release from COX-1 followed by elevations in vascular smooth muscle [Ca(2+)](i) levels and O(2)(.) production. This reveals a new mechanism of oxidative stress-induced vascular damage in hypertension.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: García-Redondo
authors.forename: Ana María
authors.initials: AM
authors.lastname: Briones
authors.forename: Amada Elia
authors.initials: AE
authors.lastname: Beltrán
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Alonso
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.forename: Mercedes
authors.initials: M
authors.lastname: Salaices
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D006973:Hypertension / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009930:Organic Chemicals / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D001572:Benzofurans; D004791:Enzyme Inhibitors; D009930:Organic Chemicals; C404729:SC 58560; D013481:Superoxides; D013928:Thromboxane A2; D006861:Hydrogen Peroxide; D013930:Thromboxane-A Synthase; C039936:furegrelate; D002118:Calcium; D007213:Indomethacin