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

Abstract

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

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].…”

Serotonin Transporter Polymorphisms in Familial and Idiopathic Pulmonary Arterial Hypertension

“…Anorexigens have been associated with the development of PAH and the metabolites of these drugs bind to the SERT acting as 5-HT substrates, and are translocated into smooth muscle cells causing intracellular effects similar to or greater than 5-HT itself (18,19). Infusion of fluoxetine, a selective SERT inhibitor, completely reverses the PH in rats induced by monocrotaline (20). In addition to these studies, the SERT promoter L/S polymorphism has been associated with more severe PH in patients with chronic obstructive pulmonary disease (16), and the LL genotype was previously reported as more prevalent in patients with IPAH than in control subjects (15).…”

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).…”