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 that (+)-norfenfluramine also has affinity for 5-HT2B receptors and that arterial 5-HT2B receptor expression is up-regulated 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 versus 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-HT2A receptor antagonists, ketanserin and LY53857 (4-isopropyl-7-methyl-9-(2-hydroxy-1-meth ylpropoxycarbonyl)4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline), but not by the 5-HT2B receptor antagonist, LY272015 [6-chloro-5-methyl-N-(5-quinolinyl)-2,3-dihydro-1H-indole-1-carboxamide]. 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-HT2A receptor and not the 5-HT2B receptor that participates in these effects.