Dexfenfluramine discontinuous treatment does not worsen hypoxia-induced pulmonary vascular remodeling but activates RhoA/ROCK pathway: consequences on pulmonary hypertension.
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.
Desbuards
Nicolas
N
Laboratoire de Physiopathologie de la Paroi Artérielle, LABPART EA3852, IFR 135, Université François Rabelais, Tours Cedex 1, France.
Antier
Daniel
D
Rochefort
Gael Y
GY
Apfeldorfer
Coralie S
CS
Schenck
Emanuel
E
Hanton
Gilles
G
Hyvelin
Jean-Marc
JM
D000818:Animals; D001067:Appetite Depressants / Q000009:adverse effects; D020372:Dexfenfluramine / Q000009:adverse effects*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications*; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D001067:Appetite Depressants; D012333:RNA, Messenger; D020372:Dexfenfluramine; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein