Dexfenfluramine discontinuous treatment does not worsen hypoxia-induced pulmonary vascular remodeling but activates RhoA/ROCK pathway: consequences on pulmonary hypertension.

Nicolas Desbuards, Daniel Antier, Gael Y Rochefort, Coralie S Apfeldorfer, Emanuel Schenck, Gilles Hanton, Jean-Marc Hyvelin, Nicolas Desbuards, Daniel Antier, Gael Y. Rochefort, Coralie S. Apfeldorfer, Emanuel Schenck, Gilles Hanton, Jean-Marc Hyvelin

Index: Eur. J. Pharmacol. 602(2-3) , 355-63, (2009)

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Abstract

The anorectic drug, dexfenfluramine has been associated with an increase in the relative risk of developing pulmonary hypertension. 5-hydroxytryptamine (5-HT) is a mitogen for smooth muscle cell, an effect that relies on 5-HT transporter expression and which has been proposed to explain pulmonary side effect of dexfenfluramine, and more particularly its effect on vascular remodeling. However recent data supported a major role of pulmonary artery vasoconstriction through the RhoA/Rho-kinase pathway. We questioned whether or not anorectic treatment aggravates pulmonary hypertension through vascular remodeling and if RhoA/Rho-kinase (ROCK) was potentially involved. In rats exposed to hypoxia, concomitant dexfenfluramine treatment (5 mg/kg/day, i.v.) for 4 weeks had no effect on pulmonary hypertension development. When exposure to 2 weeks of chronic hypoxia followed discontinuation of dexfenfluramine treatment (dexfenfluramine-hypoxic rats), echocardiographic parameters of pulmonary artery flow and right ventricle were further altered (P<0.05) as well as right ventricle systolic pressure was further increased (P<0.001) when compared to hypoxic rats treated with vehicle (hypoxic rats). However, the total number of muscularized distal pulmonary arteries artery was similar in dexfenfluramine-hypoxic vs. hypoxic rats (P>0.05). Western blot, RT-PCR and immunofluorescence analysis revealed a greater expression of 5-HT transporter and ROCK, as well as a greater activation of RhoA in dexfenfluramine-hypoxic rats compared to hypoxic rats. These data show that increased 5-HT transporter expression that follows dexfenfluramine discontinuation is not associated to a greater vascular remodeling despite worsening the development of pulmonary hypertension. Furthermore dexfenfluramine discontinuation promotes a greater RhoA/ROCK pathway activation. This pathway, involved in many cardiovascular diseases, might explain the cardiac and pulmonary toxicity of serotoninergic agonists.