5-Hydroxytryptamine(2B) receptor function is enhanced in the N(omega)-nitro-L-arginine hypertensive rat

J Pharmacol Exp Ther. 2002 Oct;303(1):179-87. doi: 10.1124/jpet.102.037390.

Abstract

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-HT(2B) 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-HT(2A) receptor as evidence by a parallel rightward shift in response to 5-HT by the 5-HT(2A/2C) receptor antagonist ketanserin (10 nM) and lack of shift by the 5-HT(2B) 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-HT(2B) 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-HT(2B) receptor protein was present in aortic homogenates from sham and LNNA rats, but the density of 5-HT(2B) receptor protein in LNNA homogenates was 300% that in sham. Importantly, the 5-HT(2B) 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-HT(2B) receptor in the LNNA hypertensive rats is physiologically activated to maintain elevated blood pressure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antihypertensive Agents / pharmacology
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology
  • Aorta, Thoracic / physiopathology*
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology
  • Endothelium, Vascular / physiopathology
  • Humans
  • Hypertension / chemically induced
  • Hypertension / physiopathology*
  • In Vitro Techniques
  • Ketanserin / pharmacology
  • Male
  • Nitroarginine / pharmacology*
  • Organic Chemicals
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Serotonin / pharmacology*
  • Serotonin Receptor Agonists / pharmacology
  • Vasoconstriction / drug effects*

Substances

  • Antihypertensive Agents
  • LY 272015
  • Organic Chemicals
  • Receptor, Serotonin, 5-HT2B
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Nitroarginine
  • Serotonin
  • Ketanserin