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Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2022 Feb 05; Vol. 916, pp. 174484. Date of Electronic Publication: 2021 Sep 09. - Publication Year :
- 2022
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Abstract
- Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O <subscript>2</subscript> ) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5-10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 μg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.<br /> (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Administration, Inhalation
Administration, Oral
Animals
Collagen drug effects
Disease Models, Animal
Epoprostenol administration & dosage
Epoprostenol pharmacokinetics
Epoprostenol pharmacology
Hemodynamics drug effects
Hypoxia metabolism
Indoles toxicity
Male
Myocardium pathology
Phosphodiesterase 5 Inhibitors administration & dosage
Phosphodiesterase 5 Inhibitors pharmacology
Pulmonary Arterial Hypertension chemically induced
Pulmonary Arterial Hypertension pathology
Pulmonary Artery pathology
Pyrroles toxicity
Rats, Sprague-Dawley
Sildenafil Citrate administration & dosage
Sildenafil Citrate pharmacology
Vascular Remodeling drug effects
Vasodilator Agents pharmacokinetics
Rats
Epoprostenol analogs & derivatives
Heart drug effects
Pulmonary Arterial Hypertension drug therapy
Pulmonary Artery drug effects
Vasodilator Agents administration & dosage
Vasodilator Agents pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 916
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 34508752
- Full Text :
- https://doi.org/10.1016/j.ejphar.2021.174484