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Vol. 303, Issue 1, 179-187, October 2002

5-Hydroxytryptamine2B Receptor Function Is Enhanced in the Nomega -Nitro-L-arginine Hypertensive Rat

Amber Russell, Amy Banes, Hilary Berlin, Gregory D. Fink and Stephanie W. Watts

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

Arterial hyperresponsiveness to serotonin (5-hydroxytryptamine, 5-HT) is observed in experimental models and human forms of hypertension. Presently, we test the hypothesis that the 5-HT2B receptor is up-regulated and necessary for maintaining elevated blood pressure in a rat made hypertensive by the nitric-oxide synthase inhibitor Nomega -nitro-L-arginine (LNNA; 0.5 g/l). After 2 weeks of treatment, thoracic aorta were removed from LNNA hypertensive (systolic blood pressure = 189 ± 5 mm Hg) and sham normotensive rats (121 ± 1 mm Hg), denuded, and mounted into isolated tissue baths for measurement of isometric contraction. In sham tissues, 5-HT-induced contraction was mediated by the 5-HT2A receptor as evidence by a parallel rightward shift in response to 5-HT by the 5-HT2A/2C receptor antagonist ketanserin (10 nM) and lack of shift by the 5-HT2B receptor antagonist 6-methyl-1,2,3,4-tetrahydro-1-[3,4-dimethoxyphenyl)methyl]-9H-pyrido[3,4-b]indole hydrochloride (LY272015) (10 nM). In contrast, LY272015 produced a 4-fold rightward shift to 5-HT in aorta from LNNA hypertensive rats, and blockade by ketanserin did not occur at low concentrations of 5-HT. Maximal contraction to the 5-HT2B receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride was significantly greater in LNNA hypertensive rats (percentage of phenylephrine contraction in sham = 7 ± 4, and in LNNA = 61 ± 7%). 5-HT2B receptor protein was present in aortic homogenates from sham and LNNA rats, but the density of 5-HT2B receptor protein in LNNA homogenates was 300% that in sham. Importantly, the 5-HT2B receptor antagonist LY272015 reduced blood pressure of the LNNA hypertensive but not the sham normotensive rats. Thus, these data suggest that the up-regulated 5-HT2B receptor in the LNNA hypertensive rats is physiologically activated to maintain elevated blood pressure.

0022-3565/02/3031-0179$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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