期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 304, 期 1, 页码 139-144出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.102.041780
关键词
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资金
- NHLBI NIH HHS [HL30260, HL63754, HL46558, HL62984, HL66074, HL49264, HL50587] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL062984, R01HL050587, R01HL046558, R01HL066074, R01HL063754, P01HL049264, R01HL030260] Funding Source: NIH RePORTER
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 [H-3] 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.
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