Dexfenfluramine protects against pulmonary hypertension in rats.
Dexfenfluramine (Dex), an appetite suppressant and serotonin reuptake inhibitor, is associated with pulmonary vascular disease (PVD) in some patients. The variability might be related to undetermined genetic abnormalities interacting with factors such as gender, weight loss, and vascular injury. We, therefore, assessed the effect of Dex (5 mg. kg(-1). day(-1)) in female obese rats, designated JCR:LA-cp or cp/cp; in lean rats, designated (+/?); and in normal Sprague-Dawley (S-D) rats under control conditions or after endothelial injury induced by monocrotaline (60 mg/kg). Pulmonary arterial pressure, right ventricular hypertrophy, percent medial wall thickness of muscular arteries, and muscularization of peripheral arteries were assessed as indexes of PVD. Although Dex reduced weight gain in cp/cp and S-D rats (P < 0.05 for both), it did not cause PVD. Moreover, PVD in S-D rats after monocrotaline injection was paradoxically ameliorated by Dex (P < 0.05) despite induction of pulmonary artery elastase (P < 0.05), which we showed is critical in inducing experimental PVD. Thus it is possible that Dex is concomitantly offsetting the sequelae of elastase activity.
Mitani
Yoshihide
Y
Division of Cardiovascular Research/Department of Laboratory Medicine and Pathobiology, The Hospital for Sick Children/University of Toronto, Toronto, Ontario M5G1X8, Canada.
Mutlu
Asuman
A
Russell
James C
JC
Brindley
David N
DN
DeAlmeida
John
J
Rabinovitch
Marlene
M
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D020372:Dexfenfluramine / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D016686:Monocrotaline; D009206:Myocardium / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000473:pathology; D009929:Organ Size / Q000235:genetics; D010196:Pancreatic Elastase / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014652:Vascular Diseases / Q000139:chemically induced / Q000503:physiopathology
D001067:Appetite Depressants; D020372:Dexfenfluramine; D016686:Monocrotaline; D019001:Nitric Oxide Synthase; D010196:Pancreatic Elastase; D017367:Selective Serotonin Reuptake Inhibitors