Terguride ameliorates monocrotaline-induced pulmonary hypertension in rats

Abstract

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 ...

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…Although present in human pulmonary arteries, it may only participate in vasoconstriction when exposed to high 5-HT concentrations (Morecroft et al, 1999). However, given that 5-HT levels are significantly increased in PAH, this may be relevant (Dumitrascu et al, 2011). The 5-HT 2B receptor is up-regulated in pulmonary arteries removed from PAH patients and the development of hypoxia-induced PAH is inhibited in mice deficient in the 5-HT 2B receptor (Dumitrascu et al, 2011;Launay et al, 2002).…”

“…The 5-HT 2B receptor is up-regulated in pulmonary arteries removed from PAH patients and the development of hypoxia-induced PAH is inhibited in mice deficient in the 5-HT 2B receptor (Dumitrascu et al, 2011;Launay et al, 2002). Pharmacological inhibition of 5-HT 2B retards the development of PAH in hypoxic or monocrotaline exposed rodents (Dumitrascu et al, 2011;Porvasnik et al, 2010;Zopf et al, 2011).…”

“…However, unlike the 5-HT 1B receptor, there is currently no evidence that the 5-HT 2B receptor mediates vasoconstriction of human pulmonary arteries. There is continuing debate concerning the role of 5-HT 2B receptor-mediated proliferation of human pulmonary arterial smooth muscle cells or pulmonary arterial fibroblasts (Dumitrascu et al, 2011;Eddahibi et al, 2001;Marcos et al, 2003). Interestingly, there is a case report of a patient with a loss-of-function mutation in 5-HT 2B with fenfluramine-associated primary pulmonary hypertension (Blanpain et al, 2003).…”

“…The dose used in the study (1.5mg) was based on efficacy in treating hyperprolactinaemia. Studies in the rat suggest that plasma concentrations in excess of 11nM (3.74ng/ml) are necessary to inhibit 5-HT 2B (Dumitrascu et al, 2011). Published pharmacokinetic data on terguride suggest that 1.5mg achieves a peak plasma concentration of 2.3ng/ml (Lapka, Marek, Rejholec, & Franc, 1986), falling well short of the levels required to inhibit 5-HT 2B .…”

Peroxisome Proliferator-Activated Receptor-γ Ameliorates Pulmonary Arterial Hypertension by Inhibiting 5-Hydroxytryptamine 2B Receptor

“…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.…”