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

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 (TxA 2 ) 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 PGE 2 was produced after TxA 2 -receptor stimulation with U-46619. Exogenous prostaglandin E 2 (in the presence of the TxA 2 receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC 50 : 0.30 and 0.48 μmol/L, respectively). This study provides the first evidence that TxA 2 -receptor-dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE 2 formation. This mechanism of TxA 2 -dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA 2 , such as hypertension.