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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/H89    most recent 00054.2008v2 00054.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Aggarwal, N. T. Articles by Campbell, W. B. PubMed PubMed Citation Articles by Aggarwal, N. T. Articles by Campbell, W. B.

15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits

Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 16 January 2008 ; accepted in final form 24 April 2008

Arachidonic acid (AA) metabolites from the 15-lipoxygenase-1 (15-LO-1) pathway, trihydroxyeicosatrienoic acids (THETAs) and hydroxy-epoxyeicosatrienoic acids (HEETAs), are endothelium-derived hyperpolarizing factors (EDHFs) and relax rabbit arteries. Rabbit vascular 15-LO-1 expression, THETA and HEETA synthesis, and nitric oxide and prostaglandin-independent relaxations to acetylcholine (ACh) and AA decreased with age (neonates to 16-wk-old). We characterized age-dependent ACh-hypotensive responses in vivo in 1-, 4-, 8-, and 16-wk-old rabbits and the contribution of THETAs and HEETAs to these responses. In anesthetized rabbits, blood pressure responses to ACh (4–4,000 ng/kg) were determined in the presence of vehicle or various inhibitors. ACh responses decreased with age (P > 0.001). In the absence or presence of N-nitro-L-arginine methyl ester (L-NAME) and indomethacin (Indo), maximum responses in 1 (–54.7 ± 7.4 and –37.9 ± 3.9%)- and 4 (–48.8 ± 2.4 and –35.5 ± 7.8%)-wk-old rabbits were higher than 8 (–30.0 ± 2.8 and –26.6 ± 4.4%)- and 16 (–36.7 ± 3.5 and –27.3 ± 10%)-wk-old rabbits. A lipoxygenase inhibitor, BW755C, reduced THETA and HEETA synthesis in mesenteric arteries. In the presence of Indo and N-nitro-L-arginine, ACh relaxations were reduced by BW755C to a greater extent in the mesenteric arteries from the younger rabbits. In 4-wk-old rabbits treated with L-NAME and Indo, the maximum ACh hypotension was reduced by the potassium channel inhibitors apamin and charybdotoxin to –6.9 ± 0.9%, by apamin alone to –19.5 ± 1.4%, and by BW755C to –18.8 ± 3.5%. The present study indicates that the age-related decrease in ACh-induced hypotension is mediated by the decreased synthesis of the 15-LO-1 metabolites THETAs and HEETAs.

endothelium-derived hyperpolarizing factor; arachidonic acid; vasodilation; mean arterial pressure