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

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Abstract
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.