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CARDIOVASCULAR

Hypertension Increases Contractile Responses to Hydrogen Peroxide in Resistance Arteries through Increased Thromboxane A₂, Ca²⁺, and Superoxide Anion Levels

Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., A.M.B., A.E.B., M.S.); Departamento de Ciencias de la Salud III, Universidad Rey Juan Carlos, Alcorcón, Madrid, Spain (M.J.A.); and Department of Pharmacology University of Aarhus, Aarhus C, Denmark (U.S.)

This study investigated the mechanisms underlying the response to hydrogen peroxide (H₂O₂) 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 Ca²⁺ concentration ([Ca²⁺]_i), superoxide anion () production was evaluated by dihydroethidium fluorescence and confocal microscopy, and thromboxane A₂ (TXA₂) production was evaluated by enzyme immunoassay. H₂O₂ (1–100 µM) induced biphasic responses characterized by a transient endothelium-dependent contraction followed by relaxation. Simultaneous measurements of tension and Ca²⁺ showed a greater effect of H₂O₂ 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 µM); the COX-1 inhibitor, SC-58560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl pyrazole] (1 µM); the thromboxane (TXA₂) synthase inhibitor, furegrelate [5-(3-pyridinylmethyl)-2-benzofurancarboxylic acid, sodium salt] (10 µM); and the TXA₂/prostaglandin H₂ receptor antagonist, SQ 29,548 ([1S-[1..,2..(Z),3..,4..]]-7-[3-[[2-[(phenylamino) carbonyl] hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid)) (1 µM) abolished H₂O₂ contraction in arteries from WKY rats but only reduced it in SHRs. The 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 H₂O₂ contraction in arteries from SHRs but not in WKY rats. H₂O₂ induced TXA₂ and production that was greater in SHRs than in WKY rats. The TXA₂ analog, U46619 [9,11-di-deoxy-11,9-epoxymethano prostaglandin F₂ (0.1 nM–1 µM)], also increased production in SHR vessels. H₂O₂-induced TXA₂ production was decreased by SC-58560. H₂O₂-induced production was decreased by tiron, apocynin, and SQ 29,548. In conclusion, the enhanced H₂O₂ contraction in resistance arteries from SHRs seems to be mediated by increased TXA₂ release from COX-1 followed by elevations in vascular smooth muscle [Ca²⁺]_i levels and production. This reveals a new mechanism of oxidative stress-induced vascular damage in hypertension.

Address correspondence to: Mercedes Salaices, Dpto. Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain. E-mail: mercedes.salaices{at}uam.es