Received for publication September 18, 2006.
Revised February 6, 2007.
Accepted for publication February 7, 2007.

The 5-HT_2A receptor is involved in (+)-norfenfluramine-induced arterial contraction and blood pressure increase in DOCA-salt hypertension

Abstract

The highly effective anorexigen (+)-fenfluramine was widely used to control body weight until the association with primary pulmonary hypertension and valvular heart disease. (+)-Norfenfluramine is the major hepatic metabolite of (+)-fenfluramine and is primarily responsible for the anorexic effect as well as side effects. We reported that (+)-norfenfluramine causes vasoconstriction and a blood pressure increase in rats with normal blood pressure via the 5-hydroxytryptamine (5-HT)_2A receptor. With the knowledge of (+)-norfenfluramine also has affinity for 5-HT_2B receptors and that arterial 5-HT_2B receptor expression is upregulated in deoxycorticosterone acetate (DOCA)-salt hypertension, we tested the hypothesis that (+)-norfenfluramine-induced vasoconstriction and pressor effects are potentiated in DOCA-salt hypertensive rats in a 5-HT₂ receptor-dependent manner. Contractions of arteries were measured using an isolated tissue bath system or myograph. Mean arterial blood pressure was measured in chronically-instrumented conscious rats. Effects of (+)-norfenfluramine in stimulating arterial contraction (leftward shift vs. SHAM, aorta=5.13-fold; renal artery=1.95-fold, mesenteric resistance artery=1.77-fold) and raising blood pressure were significantly enhanced in hypertension. In arteries from both normotensive and hypertensive rats, (+)-norfenfluramine-induced contraction in aorta was inhibited by 5-HT_2A receptor antagonists (ketanserin and LY53857) but not by the 5-HT_2B receptor antagonist, LY272015. Ketanserin (3 mg/kg) reduced (+)-norfenfluramine-induced pressor response in both SHAM and DOCA rats. Our results demonstrate that (+)-norfenfluramine-induced arterial contraction and blood pressure increases are potentiated in DOCA-salt hypertensive rats. However, it is the 5-HT_2A receptor and not the 5-HT_2B receptor that participates in these effects.

Key words: (+)-norfenfluramine, 5-HT, 5-HT receptors, DOCA-salt hypertensive rats, hypertension, vasoconstriction