Published Online
on April 19, 2004

A more recent version of this article appeared on June 1, 2004

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Submitted on April 23, 2003
Revised on May 14, 2003

Cyclooxygenase Involvement in Thromboxane-Dependent Contraction in Rat Mesenteric Resistance Arteries

Manlio Bolla; Dong You; Laurent Loufrani; Bernard I. Levy; Sylviane Levy-Toledano; Aïda Habib; and Daniel Henrion^*

From the Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 348 (M.B, S.L.-T., A.H.) and Unit 541 (D.Y., L.L., B.I.L., D.H.), IFR Circulation-Paris-Nord, Paris, France.

^* To whom correspondence should be addressed. E-mail: daniel.henrion{at}med.univ-angers.fr.

Abstract--The influence of cyclooxygenase pathway activation following thromboxane-endoperoxide (TP) receptor stimulation was studied in rat mesenteric resistance arteries (n=6 to 10 per group). We studied isolated, perfused, and pressurized mesenteric resistance arteries (mean internal diameter 214 µm) using an arteriograph, enabling us to study arteries in physiological conditions of flow and pressure. Changes in diameter were continuously recorded, and contractions measured as internal diameter reduction. Release of cyclooxygenase pathway metabolites was also assessed by enzyme immunoassay (EIA) analysis of mesenteric bed perfusions. The thromboxane A2 (TxA₂) analog U-46619 (1 µmol/L) induced a significant contraction (108 µm maximal diameter reduction). Inhibition by 3 chemically different cyclooxygenase inhibitors (ie, flurbiprofen, indomethacin, and aspirin) potently reduced the contraction to 27%, 25%, and 6% of control, respectively. The selective cyclooxygenase-1 inhibitor SC-58560 inhibited U-46619 contraction, whereas selective cyclooxygenase-2 inhibition (SC-58236) had no effect. Thromboxane synthase inhibition (furegrelate) did not affect U-46619-induced contraction, but it was reduced by cytosolic phospholipase A2 inhibition. Measurement of cyclooxygenase derivatives produced by the isolated mesenteric bed showed that PGE₂ was produced after TxA₂-receptor stimulation with U-46619. Exogenous prostaglandin E₂ (in the presence of the TxA₂ receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC₅₀: 0.30 and 0.48 µmol/L, respectively). This study provides the first evidence that TxA₂-receptor-dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE₂ formation. This mechanism of TxA₂-dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA₂, such as hypertension.

Key words: resistance • cyclooxygenase • prostaglandins • thromboxane

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