Abstract
We examined the mechanism of arachidonic acid-induced vasodilation in rat small mesenteric arteries and determined the primary arachidonic acid metabolites produced by these arteries. Responses to arachidonic acid in small mesenteric arteries from Sprague-Dawley rats were investigated in vitro in the presence or absence of endothelium or after pretreatment with inhibitors of nitric oxide (NO), cyclooxygenase, cytochrome P450, lipoxygenase, or K+channels. In addition, the metabolism of arachidonic acid was examined by incubating arteries with [3H]arachidonic acid in the presence and absence of cyclooxygenase, cytochrome P450, or lipoxygenase inhibitors. Finally, the vascular response to both 12(S)-hydroxyeicosatetraenoic acid (HETE) and 12(S)-hydroperoxyeicosatetraenoic acid (HPETE) was determined. Arachidonic acid induced an endothelium-dependent vasodilation that was abolished by lipoxygenase inhibitors [cin-namyl-3,4-dihydroxy-cyanocinnamate (CDC) or 5,8,11-eicosatriynoic acid (ETI)] and KCl, whereas it was partially inhibited by either tetraethylammonium or iberiotoxin. In contrast, neither NO nor cytochrome P450 enzyme inhibitors affected arachidonic acid-mediated dilation, whereas inhibition of cyclooxygenase enhanced dilation. Biochemical analysis revealed that small mesenteric arteries primarily produce 12-HETE, a lipoxygenase metabolite. Moreover, CDC and ETI inhibited the production of 12-HETE. Finally, both 12(S)-HETE and 12(S)-HPETE induced a concentration-dependent vasodilation in mesenteric arteries. These findings provide functional and biochemical evidence that the lipoxygenase pathway mediates arachidonic acid-induced vasodilation in rat small mesenteric arteries through a K+channel-dependent mechanism.
Footnotes
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This work was supported by the American Heart Association (0140212N to A.W.M.; 0270114N to D.W.B.) and the National Institutes of Health (HL66074 to A.W.M.; HL30260, HL46558, and HL50587 to D.W.B.; HL49264 and HL62984 to N.L.W.; and HL63754 to H.C.L.).
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DOI: 10.1124/jpet.102.041780
- Abbreviations:
- NO
- nitric oxide
- EDHF
- endothelium-dependent hyperpolarizing factor
- HPETE
- hydroperoxyeicosatetraenoic acid
- HETE
- hydroxyeicosatetraenoic acid
- PE
- phenylephrine
- CDC
- cinnamyl-3,4-dihydroxy-cyanocinnamate
- ETI
- 5,8,11-eicosatriynoic acid
- KCa
- calcium-dependent potassium channel
- HPLC
- high-performance liquid chromatography
- Received July 16, 2002.
- Accepted September 10, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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