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CARDIOVASCULAR

Characterization of the Contractile 5-Hydroxytryptamine Receptor in the Renal Artery of the Normotensive Rat

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan

Our goal was to characterize the 5-hydroxytryptamine (5-HT) receptor(s) mediating contraction in the isolated right renal artery, testing the hypothesis that the 5-HT_2A receptor would be the primary and likely only 5-HT receptor involved in contraction. Contraction of arteries was investigated in isolated tissue baths, and expression of 5-HT receptors was measured using immunohistochemical and Western analyses. Compared with endothelium-denuded rat aorta, a tissue with an established 5-HT_2A receptor, endothelium-denuded renal artery contracted to 5-HT with a 10-fold greater potency. Surprisingly, the 5-HT_2B receptor agonist -methyl-5-(2-thienylmethoxy)-1H-indole-3-ethanamine hydrochloride (BW723C86) caused a concentration-dependent contraction that was antagonized by the 5-HT_2B receptor antagonist 6-methyl-1,2,3,4-tetrahydro-1-[3,4-dimethoxyphenyl) methyl-9H-pyrido[3,4b]indole] hydrochloride (LY272015) and nonselective 5-HT₂ receptor antagonist 6-methyl-1-(1-methylethyl)-ergoline-8b-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY53857). Correlation of -log EC₅₀ values with binding affinities (pK_i) indicated that contraction of the renal artery elicited by 13 different agonists was likely consistent with activation of a 5-HT_2A (r = 0.928) and 5-HT_2B (r = 0.843) receptor. 5-HT-induced contraction was shifted by the 5-HT_2A receptor antagonist ketanserin (3 and 10 nM) and the 5-HT_2B receptor antagonist LY272015 (10 and 50 nM). Higher than expected concentrations of the 5-HT_2A/5-HT_2B receptor antagonist LY53857 were needed to antagonize 5-HT-induced contraction and the 5-HT_2B receptor antagonist 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (RS127445) was virtually inactive. Western and immunohistochemical analyses of the renal artery validated the presence of 5-HT_2A and 5-HT_2B receptor protein. These results suggest that the renal artery possesses a complex 5-HT receptor population, including ketanserin- and LY272015-sensitive receptors. This unique pharmacology may reflect differences in 5-HT receptor coupling between tissues or heterogeneity in the subtype(s) of 5-HT receptors expressed in the renal artery.

Address correspondence to: Dr. Stephanie W. Watts, Department of Pharmacology and Toxicology, B445 Life Sciences Bldg., Michigan State University, East Lansing, MI 48824-1317. E-mail: wattss{at}msu.edu

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