Reversibility of the monocrotaline pulmonary hypertension rat model

Abstract

To the Editor : Pulmonary hypertension (PH) is a disease characterised by progressive remodelling of the pulmonary vasculature eventually leading to right heart failure. Various animal models have been used to mimic the disease, involving pigs, dogs, rats and mice [1]. The most commonly used model is the monocrotaline (MCT) rat model. In this model MCT is injected subcutaneously and becomes metabolically activated, as a pyrrolizidine alkaloid, by hepatic cytochrome P450 3A [2, 3]. The active MCT pyrrole is pneumotoxic and damages the pulmonary artery endothelial cells (PAECs), which leads to a disturbed barrier function [4]. Other features of MCT-induced pulmonary vascular remodelling are arterial medial hyperplasia of axial arteries, interstitial oedema, adventitial inflammation, haemorrhage and, eventually, fibrosis [1, 2, 5, 6]. As a result, pulmonary vascular resistance (PVR) increases and the right ventricle compensates by hypertrophy and eventually fails [7, 8]. Besides the MCT PH rat model, chronic hypoxia with or without Sugen 5416 and pulmonary artery banding are used to study experimental PH [1]. The PH animal model of choice is mostly dependent on the research question that needs to be answered. Ideally, an animal model would recapitulate the progressive and irreversible pulmonary vascular remodelling, which is the hallmark of human PH [1, 4, 9]. However, none of the animal models fulfil this criterion. Concerns have been raised about the MCT rat model since many therapies were successful in MCT rats but not in humans with PH [4]. We, therefore, investigated the long-term progression and reversibility of MCT-induced PH in rats over 12 weeks, using a dose of 40 mg·kg−1 in a randomised placebo-controlled study design. Since it is known that a high dose …