PRX-08066, a Novel 5-Hydroxytryptamine Receptor 2B Antagonist, Reduces Monocrotaline-Induced Pulmonary Arterial Hypertension and Right Ventricular Hypertrophy in Rats

Porvasnik, Stacy; Germain, Sean; Embury, Jennifer E.; Gannon, Kimberley S.; Jacques, Vincent; Murray, Justin K.; Byrne, Barry J.; Shacham, Sharon; Al-Mousily, Faris

doi:10.1124/jpet.109.165001

Cited by 43 publications

(30 citation statements)

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“…Briefly, absence of vascular remodelling during chronic hypoxia has been demonstrated in a 5-HTR 2B -/-mouse model and by pharmacological inhibition with the 5-HTR 2B antagonists RS127445 [43] and PRX-08066 [44] in animal models of chronic hypoxia or MCT-induced PH, respectively [18,44,45]. A possible clinical relevance of these findings is supported by two lines of evidence.…”

Section: Discussionsupporting

confidence: 51%

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats

et al. 2010

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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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Section: Discussionsupporting

confidence: 51%

Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats

et al. 2010

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“…16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduced pulmonary pressure, arterial wall thickening, and lumen occlusion but maintained cardiac function. [17][18][19] Independently, 5-HT was shown to stimulate human BM stromal cells and synergize with other pleiotropic growth factors that promote hematopoietic stem and progenitor cells. 20 The 5-HT action on hematopoiesis or BM microenvironment at pathophysiologic conditions warrant further investigation.…”

Section: Introductionmentioning

confidence: 99%

“…16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduced pulmonary pressure, arterial wall thickening, and lumen occlusion but maintained cardiac function. [17][18][19] Independently, Submitted June 2, 2011; accepted December 15, 2011. Prepublished online as Blood First Edition paper, December 20, 2011; DOI 10.1182 DOI 10.…”

Section: Introductionmentioning

confidence: 99%

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension

Launay

Hervé

Crinon

et al. 2012

Blood

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Pulmonary arterial hypertension (PAH) is IntroductionPulmonary arterial hypertension (PAH) is a rare but fatal disease, often of unknown origin, characterized by progressive increase in pulmonary vascular resistance and remodeling associated with vasoconstriction. 1 PAH is histologically characterized by a neomuscularization of small pulmonary arteries with intimal thickening, medial hypertrophy, adventitial proliferation, and abnormal extracellular matrix deposition. The progression of vascular remodeling results in vascular lumen narrowing, increased pulmonary artery resistance, hypoxia, and right heart hypertrophy, although the molecular pathways initiating this remodeling are not clearly established.On the one hand, stem cells, resident or not, may give rise to a significant proportion of differentiating/proliferating smooth muscle cells (SMCs) that contribute to intimal hyperplasia in lung vascular remodeling. 2 Moreover, genetic ablation of the transmembrane tyrosine kinase receptor for stem cell factor/c-kit pathway results in a marked reduction in intimal hyperplasia in animal models of vascular injury; conversely, wild-type (WT) bone marrow (BM) reconstitution in c-kit mutant mice led to intimal hyperplasia comparable with WT animals. 3 Pharmacologic antagonism of the c-kit pathway with STI-571 (imatinib mesylate; Gleevec) also results in a marked reduction in hyperplasia. 3 Mobilization of c-kit expressing cells from BM to blood circulation is a physiologic response to hypoxia. Increasing evidence supports the idea that these progenitor cells of BM origin may also contribute to vascular wall remodeling that is characteristic of PAH. [4][5][6][7][8] However, it is unclear, whether this entry of progenitors represents a protective or a worsening process in the development of PAH. 9 Other observations have also identified an association between PAH and BMrelated hematologic disorders 10 : in proliferative disorders of the hematopoietic stem cells such as myeloproliferative cancers, there is an unexplained high incidence of PAH. PAH is now a recognized complication of BM transplantation for leukemia, 11 chronic myeloproliferative disorders, 12 or in the treatment of malignant infantile osteopetrosis. 13 On the other hand, serotonin (5-hydroxytryptamine ) is associated with the pathogenesis of PAH. 14 Therapeutic drugs with PAH as a side effect, such as the amphetamine derivative and anorexigen dexfenfluramine, are potent 5-HT releasers acting at 5-HT transporter (SERT) and/or agonists at 5-HT receptors (5-HTRs). 15 An over-expression of 5-HT 2B Rs is observed in PAH. 16 Blockade of 5-HT 2B Rs using independent approaches, either genetic (5-HT 2B R knock-out mice; 5-HT 2B Ϫ/Ϫ ) or pharmacologic (5-HT 2B antagonist RS-12744) inactivation, completely prevented the development of hypoxia-induced pulmonary hypertension in mice. 16 By using the monocrotaline (MCT)-induced pulmonary hypertension rat model, recent studies confirmed that other 5-HT 2B antagonists (terguride, PRX-08066, or C-122) significantly reduc...

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“…19 A pathophysiological role of 5-HT2B receptor (5-HT2BR) was suggested by the increased binding to 5-HT2BR in lung vascular bed of the hypoxia-induced PAH mouse model and corroborated by the results that genetic or pharmacological inactivation of 5-HT2BR prevented the development of PAH in mice. [20][21][22][23][24][25][26] 5-HT2BR is currently under active investigation as a therapeutic target for PAH. However, there is currently no evidence of 5-HT2BR-mediated constriction of pulmonary arteries in PAH.…”

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confidence: 99%