Abstract
Pulmonary arterial hypertension (PAH) is a progressive disease defined by an elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular mast cell accumulation. While the exact etiology of the disease is unknown, experimental as well as clinical data strongly implicate a role for serotonin in the remodeling process. Here we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase (TPH1), the rate-limiting enzyme in serotonin biosynthesis, on serotonin levels, pulmonary vascular remodeling, mast cell number, and histamine levels in rats treated with monocrotaline (MCT). PAH was induced in Sprague-Dawley rats by administering a single subcutaneous 60 mg/kg dose of MCT. Novel, small molecule TPH1 inhibitors with nM in vitro potency were orally administered for 21 days. At the conclusion of the studies, perfusion fixed lungs were stained for mast cells with toluidine blue. Tissue levels of serotonin were analyzed via HLPC/fluorescence detection and histamine via ELISA. Lung 5-HT was markedly elevated 2-3 fold in the MCT-treated rats when compared to normal controls. TPH1 inhibitor treatment significantly reduced both lung 5-HT levels and vessel wall thickness. The decrease in lung serotonin significantly correlated with a reduction in histamine levels and mast cell number (p<0.0001, r2=0.88). Neither ambrisentan nor tadalafil reduced mast cell number or 5-HT levels in the lungs of MCT treated rats. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PAH.
- Copyright ©ERS 2015
