5-hydroxytryptamine2B receptor function is enhanced in the Nω-nitro-L-arginine hypertensive rat

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 N-omega-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.