title: Assessment of the serotonin pathway as a therapeutic target for pulmonary hypertension.
abstract: Blockade of the serotonin reuptake transporter (5-HTT), using fluoxetine, has been identified as a potential therapeutic target for preventing and, importantly, reversing pulmonary hypertension (PH). This study utilized synchrotron radiation microangiography to determine whether fluoxetine could prevent or reverse endothelial dysfunction and vessel rarefaction, which underpin PH. PH was induced by a single injection of monocrotaline (MCT; 60 mg kg(-1)). Following MCT administration, rats received daily injections of either saline or fluoxetine (MCT+Fluox; 10 mg kg(-1)) for three weeks. A third group of rats also received the fluoxetine regime, but only three weeks after MCT (MCT+FluoxDelay). Control rats received daily injections of saline. Pulmonary microangiography was performed to assess vessel branching density and visualize dynamic changes in vessel diameter following (i) acute fluoxetine or (ii) acetylcholine, sodium nitroprusside, BQ-123 (ET-1A receptor blocker) and L-NAME (NOS inhibitor). Monocrotaline induced PH that was inevitably terminal. `Delayed' treatment of fluoxetine (MCT+FluoxDelay) was unable to reverse the progression of PH. Early fluoxetine treatment pre-PH (i.e. MCT+Fluox) attenuated but did not completely prevent vascular remodeling, vessel rarefaction and an increase in pulmonary pressure, and it did not prevent pulmonary endothelial dysfunction. Interestingly, fluoxetine treatment did counter-intuitively prevent the onset of right ventricular hypertrophy. Using synchrotron radiation microangiography, selective blockade of the serotonin reuptake transporter alone is highlighted as not being sufficient to prevent pulmonary endothelial dysfunction, which is the primary instigator for the inevitable onset of vascular remodeling and vessel rarefaction. Accordingly, potential therapeutic strategies should aim to target multiple pathways to ensure an optimal outcome.
authors: Department of Physiology, University of Otago, Dunedin, New Zealand.
authors: Emily A
authors: EA
authors: Gray
authors: Hirotsugu
authors: H
authors: Tsuchimochi
authors: James T
authors: JT
authors: Pearson
authors: Takashi
authors: T
authors: Sonobe
authors: Yutaka
authors: Y
authors: Fujii
authors: Misa
authors: M
authors: Yoshimoto
authors: Keiji
authors: K
authors: Umetani
authors: Mikiyasu
authors: M
authors: Shirai
authors: Daryl O
authors: DO
authors: Schwenke
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000792:Angiography; D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005473:Fluoxetine / Q000627:therapeutic use*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply; D008297:Male; D058990:Molecular Targeted Therapy; D016686:Monocrotaline; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014664:Vasodilation
chemical_list: D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D005473:Fluoxetine; D012701:Serotonin; D016686:Monocrotaline; D000109:Acetylcholine
keywords: endothelial dysfunction; fluoxetine; monocrotaline; pulmonary hypertension; rarefaction; rat; serotonin