The 5-Hydroxytryptamine_(2A)Receptor Is Involved in(+)-Norfenfluramine-lnduced Arterial Contraction and Blood Pressure Increase in Deoxycorticosterone Acetate-Salt Hypertension

摘要

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-HT_(2B)receptors and that arterial 5-HT_(2B)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 stim-ulating 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-HT_(2A)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-HT_(2B)receptor antagonist,LY272015 [6-chloro-5-methyl-N-(5-quinolinyl)-2,3-dihydro-1H-indole-1-carboxamide].Ketanserin(3 mg/kg)reduced(+)-nor-fenfluramine-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.