Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats

Hironaka, Eiji; Hongo, Minoru; Sakai, Akio; Mawatari, Eiichiro; Terasawa, Fumiko; Okumura, Nobuo; Yamazaki, Akie; Ushiyama, Yoshihisa; Yazaki, Yoshikazu; Katoh, Osamu

doi:10.1016/j.cardiores.2003.09.023

Cited by 75 publications

(67 citation statements)

References 30 publications

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“…These results are somewhat discordant with previous findings showing attenuation of MCT-induced PH with 5-HT 2A antagonists. 21 However, in those studies, none of the antagonists was capable of reversing advanced disease or of completely inhibiting MCT-induced PH. Taken together with our previous findings that 5-HTT inhibitors, but not 5-HT 1D/1B or 5-HT 2A receptor antagonists, affect hypoxia-induced PH, these results provide evidence for a predominant role of 5-HTT over 5-HT receptors in both hypoxia-and MCTinduced PH.…”

Section: Discussionmentioning

confidence: 93%

“…2,4,19,20 The fact that MCT-induced PH is due chiefly to pulmonary vascular remodeling probably explains the efficacy of fluoxetine in this model. Previous findings that rats treated with selective 5-HT 1D/1B or 5-HT 2A receptor antagonists 8,21 and mice lacking the 5-HT 1B receptor gene 8 develop less severe chronic experimental PH and a milder degree of vascular remodeling than relevant paired controls probably reflect the effects of these drugs on 5-HT-mediated pulmonary vasoconstriction or on 5-HT-independent mechanisms. Recent studies have also emphasized the contribution of 5-HT 2B receptors to hypoxiainduced PH.…”

Section: Discussionmentioning

confidence: 95%

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Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats

et al. 2005

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Background-Progression of pulmonary hypertension (PH) is associated with increased lung expression of the serotonin transporter (5-HTT), which leads to hyperplasia of the pulmonary artery smooth muscle cells (PA-SMCs). Given the postulated causal relation between 5-HTT overexpression and PH, we herein investigated whether the highly selective 5-HTT inhibitor fluoxetine prevented and/or reversed PH induced by monocrotaline (MCT) in rats. Selective 5-HT 1B/1D , 5-HT 2A , and 5-HT 2B receptor antagonists were used for comparative testing. Methods and Results-MCT injection (60 mg/kg SC) was followed by an early peak in lung 5-HTT expression on day 1, which preceded the onset of PH. Established PH on day 15 was associated with a sustained 5-HTT increase. Continued fluoxetine treatment completely prevented PA-SMC proliferation and PH development and also suppressed the late 5-HTT increase, without affecting the early peak. The 5-HT receptor antagonists did not affect PH. Fluoxetine (10 mg · kg Ϫ1 · d Ϫ1 PO) started 3 weeks after MCT injection completely reversed established PH, normalizing PA pressure and structure. MCT-induced PH was also associated with increased expression of various cytokines, but only interleukin-1␤ and monocyte chemotactic protein-1 increased at the early phase and stimulated 5-HTT expression by cultured PA-SMCs. Conclusion-Upregulation

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 95%

Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats

et al. 2005

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“…However, previous studies reported decreased expression of pulmonary eNOS at 5 and 6 weeks after MCT. 22,23 Therefore, it is likely that significant modulations of eNOS expression appear at a later stage in the development of MCT-induced PH. Interestingly, although Cav-1 is well recognized for its negative regulation of eNOS activity, 24 administration of AP-Cav to both control and MCT rats did not have a significant effect on pulmonary eNOS expression.…”

Section: Cav Protein and Enos Expression In Ph Ratsmentioning

confidence: 99%

Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

et al. 2006

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Background-Caveolins (Cavs), the principal structural proteins of caveolar microdomains, have been implicated in the development of pulmonary hypertension (PH). Mice with homozygous deletion of the Cav-1 gene develop PH and right ventricular hypertrophy (RVH). Reductions in pulmonary Cav-1 expression have been shown in several animal models of PH and in patients with severe PH. Whether in vivo modulation of Cav-1 expression could affect the development of PH and RVH remains unknown. Therefore, we investigated the effect of in vivo administration of a Cav-1 mimetic peptide on the development of monocrotaline (MCT)-induced PH. Methods and Results-Thirty minutes after injection of saline or 60 mg/kg MCT, rats were assigned to receive a daily injection of saline, a peptide corresponding to the homeodomain of the Drosophila transcription factor antennapedia (AP; 2.5 mg · kg Ϫ1 · d Ϫ1 ), or a peptide consisting of the Cav-1-scaffolding domain coupled to AP (AP-Cav; 2.5 mg · kg Ϫ1 · d

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“…In the MCT model of PH, inhibition of 5-HTR 2A signalling by specific inhibitors, such as DV-7029 or sarpogrelate, with a ,100-fold selectivity over the 5-HTR 2B receptor [37] resulted in a marked suppression of the increase in Ppa, medial wall thickening and right heart hypertrophy when treatment was started immediately after MCT treatment [38][39][40]. This was not detectable when treatment was delayed for 3 weeks after MCT administration [38]. A marked improvement of pulmonary vascular endothelial activation/injury, suppression of Pselectin expression, reduction of the accumulation of mononuclear cell, macrophages and mast cells in the lung, and an upregulation of endothelial nitric oxide synthase in lung tissue have been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats

Dumitrascu

Kulcke

Königshoff

et al. 2010

European Respiratory Journal

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Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a preclinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders.Immunohistochemistry against 5-HTR 2A/B on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR 2B upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach.Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.KEYWORDS: Collagen, experimental therapeutics, inflammation, pulmonary hypertension, smooth muscle cells, vascular remodelling P ulmonary arterial hypertension (PAH) is a life-threatening disease characterised by an increase of pulmonary artery pressure resulting from endothelial injury, proliferation and hypercontraction of vascular smooth muscle cells [1]. When untreated, the disease finally results in right ventricular (RV) failure and death. Several important signalling systems have been shown to be dysregulated in pulmonary hypertension (PH). In patients with idiopathic PAH (IPAH), a reduced excretion of prostaglandin I 2 and an enhanced excretion of thromboxane metabolites have been noted [2]. Moreover, enhanced expression of phosphodiesterase (PDE)-5, which hydrolyses the NO-induced second messenger cyclic guanosine monophosphate, was observed in PH [3]. In addition, the vasoconstrictor endothelin is upregulated in PAH [4] and correlates with the degree of the disease [5]. Furthermore, an epidemic of PH in patients using anorexic agents implied a role of serotonin (5-hydroxytryptamine (5-HT)) in the pathogenesis of PH [6]. Expression analysis of lung tissues from PAH patients undergoing lung transplantation revealed an increased expression of 5-HT transporter (5-HTT) and an enhanced proliferative growth response of isolated pulmonary arterial smooth muscle cells (PASMC) to 5-HT [7]. While most of these pathways are currently addressed clinically for treatment of PAH, e.g. by infusion or inhalation of prostanoids [8,9], oral application of PDE-5 inhibitors [10,11] and endothelin antagonists [12], the 5-HT pathway is still studied only on a preclinical ...

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Serotonin receptor antagonist inhibits monocrotaline-induced pulmonary hypertension and prolongs survival in rats

Cited by 75 publications

References 30 publications

Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats

Serotonin Transporter Inhibition Prevents and Reverses Monocrotaline-Induced Pulmonary Hypertension in Rats

Short-Term Administration of a Cell-Permeable Caveolin-1 Peptide Prevents the Development of Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats

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