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(Circulation. 2004;110:1320-1325.)
© 2004 American Heart Association, Inc.

Original Articles

Aspirin-Triggered, Cyclooxygenase-2–Dependent Lipoxin Synthesis Modulates Vascular Tone

From the Mucosal Inflammation Research Group (P.-Y.v.d.W., M.D.H., J.L.W.), University of Calgary, Calgary, Alberta, Canada, and the Department of Gastroenterology and Hepatology (S.F.), University of Perugia, Perugia, Italy.

Correspondence to Dr John L. Wallace, Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta, T2N 4N1 Canada. E-mail wallacej{at}ucalgary.ca

Received March 31, 2004; revision received May 17, 2004; accepted May 19, 2004.

Background— Aspirin-triggered production of 15-(R)-epilipoxin A₄ (ATL) has been shown to exert potent antiinflammatory effects and gastric-protective effects, but little is known of its actions on the vasculature. In the present study, we have assessed the contribution of ATL to changes in vascular tone induced by aspirin and have examined the role of nitric oxide (NO) as a mediator of such effects.

Methods and Results— Intravenous administration of lipoxin A₄ resulted in a short-lived (3 to 4 minutes) reduction in blood pressure (BP; 13 mm Hg at 2.5 µg/kg). Aspirin administered alone resulted in a significant increase in serum ATL and an increase in BP of 10 mm Hg. When ATL synthesis was inhibited by pretreatment with a selective cyclooxygenase-2 inhibitor (celecoxib) or a 5-lipoxygenase inhibitor (zileuton), the aspirin-induced increase in BP was significantly augmented. These agents alone did not affect BP. A lipoxin receptor antagonist, Boc2, also increased the pressor effects of aspirin. Moreover, immunodepletion of neutrophils, a major source of 5-lipoxygenase, resulted in a significant reduction of ATL formation and augmented aspirin’s pressor effects. Studies of rat aortic and mesenteric artery ring segments confirmed the vasorelaxant effects of lipoxin A₄ and showed them to be endothelium dependent.

Conclusions— Aspirin-triggered lipoxin synthesis can modulate vascular tone, possibly contributing to changes in regional blood flow during inflammatory reactions, and to the modulation of systemic BP.

Key Words: inflammation • muscle, smooth • nitric oxide • vasodilation • endothelium

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