Faculty Collaboration Database

15-Lipoxygenase metabolites contribute to age-related reduction in acetylcholine-induced hypotension in rabbits. Am J Physiol Heart Circ Physiol 2008 Jul;295(1):H89-96

Date

05/06/2008

Pubmed ID

18456739

Pubmed Central ID

PMC2494760

DOI

10.1152/ajpheart.00054.2008

Scopus ID

2-s2.0-49849097364 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

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(omega)-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(omega)-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.

Author List

Aggarwal NT, Gauthier KM, Campbell WB

Author

William B. Campbell PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine
Acetylcholine
Age Factors
Aging
Animals
Apamin
Arachidonate 15-Lipoxygenase
Blood Pressure
Charybdotoxin
Cyclooxygenase Inhibitors
Dose-Response Relationship, Drug
Eicosanoids
Hypotension
In Vitro Techniques
Indomethacin
Lipoxygenase Inhibitors
Mesenteric Arteries
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase
Potassium Channel Blockers
Rabbits
Vasodilation
Vasodilator Agents