Serotonin Transporter Inhibitors Protect against Hypoxic Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) results from constriction and remodeling of pulmonary vessels. Serotonin contributes to both phenomena through different signaling pathways. The mitogenic effect of serotonin on pulmonary vascular smooth muscle cells is mediated by the serotonin transporter (5-hydroxytryptamine transporter [5-HTT]), whereas its constricting effect is mediated by 5-HT1B/1D and 5-HT2A receptors. Here, we investigated the respective roles of 5-HTT and 5-HT receptors on the development of chronic hypoxic PH in mice. During exposure to hypoxia (10% O2 for 2 weeks), the animals received one of the specific 5-HTT inhibitors citalopram and fluoxetine (10 mg/kg/day), the selective 5-HT1B/1D receptor antagonist GR127935 (2 and 10 mg/kg/day), or the 5-HT2A receptor antagonist ketanserin (2 mg/kg/day). Mice treated with the 5-HTT inhibitors showed less right ventricle hypertrophy (ratio of right ventricle/left ventricle + septum = 36.7 +/- 2.0% and 35.8 +/- 1.3% in citalopram- and fluoxetine-treated mice, respectively, vs. 41.5 +/- 1.5% in vehicle-treated mice) and less pulmonary vessel muscularization (p < 0.01) than those receiving the vehicle. Neither GR127935 nor ketanserin affected these parameters. These data indicate that 5-HTT plays a key role in hypoxia-induced pulmonary vascular remodeling. The effects of serotonin transporter inhibitors on PH in humans deserve investigation.

Potassium channels in pulmonary arterial hypertension

“…The implication that serotonin is a key determinant of vessel remodelling was further confirmed by several observations highlighting: 1) high platelet and plasma levels of serotonin in patients with PAH [22], 2) prevention of PAH in animal models following inhibition of serotonin receptors [23,24], and 3) a congenital predisposition to develop PAH in fawn-hooded rats caused by a defect in platelet serotonin storage [25]. Briefly, under pathological conditions, pulmonary endothelial cells produce high levels of serotonin that acts in a paracrine fashion on adjacent PASMCs to promote cell proliferation and contraction [26][27][28].…”

Polymorphism of the Serotonin Transporter Gene and Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

“…12 When given orally to experimental animals exposed to chronic hypoxia, these drugs attenuated the development of pulmonary vascular remodeling. 20 Whether 5-HTT inhibitors might be useful for reducing PH in selected patients with COPD deserves investigation.…”

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

“…5-HT is a pulmonary artery vasoconstrictor and induces proliferation of both pulmonary arterial fibroblasts and pulmonary arterial smooth muscle cells (Lee, Wang, Lanzillo, & Fanburg, 1994;MacLean, Herve, Eddahibi, & Adnot, 2000;Welsh, Harnett, MacLean, & Peacock, 2004). Inhibition of serotonin receptors, SERT and knockout of the rate-limiting enzyme producing 5-HT (tryptophan hydroxylase-1) have all been shown to inhibit development of PAH in animal models (Guignabert et al, 2005;Izikki et al, 2007;Keegan, Morecroft, Smillie, Hicks, & MacLean, 2001;Marcos et al, 2003;Morecroft et al, 2007).…”

“…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).…”