Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension
| Autor: | Jeffrey Dubins, Marc Humbert, Christophe Guignabert, Vishwas Paralkar, Stéphane De Lombaert, Qing Zhang, Maria A. Cavasin, Robert J. Aiello, Timothy A. McKinsey, Daniel R. Goldberg, Patricia-Ann Bourassa |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Serotonin Ambrisentan Hypertension Pulmonary Myocytes Smooth Muscle Vasodilation 030204 cardiovascular system & hematology Biology Pulmonary Artery Tryptophan Hydroxylase Vascular Remodeling Gene Expression Regulation Enzymologic Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Animals Humans Enzyme Inhibitors Lung Semaxanib Cell Proliferation Pharmacology TPH1 Mast cell medicine.disease Pulmonary hypertension Tadalafil Rats Disease Models Animal 030104 developmental biology medicine.anatomical_structure Endocrinology HEK293 Cells Molecular Medicine medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 360(2) |
| ISSN: | 1521-0103 |
| Popis: | Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P < 0.001, r2 = 0.88). In contrast, neither ambrisentan nor tadalafil, which are vasodilators approved for the treatment of PAH, reduced mast cell number or 5-HT levels, nor were they as effective in treating the vascular remodeling as were the TPH1 inhibitors. When administered in combination with ambrisentan, the TPH1 inhibitors showed an additive effect on pulmonary vascular remodeling and pressures. 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 PH. |
| Databáze: | OpenAIRE |
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