The monocrotaline model of pulmonary hypertension in perspective

Abstract

Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

Modafinil improves monocrotaline-induced pulmonary hypertension rat model

“…Many experimental animal models of PAH exist and this includes monocrotaline (MCT)-induced and chronic hypoxiainduced rats (9)(10)(11). Although the precise mechanism by which MCT leads to PAH is unknown, the MCT-induced PAH model is a mainstay in evaluating experiments of new therapeutic interventions.…”

Reversibility of the monocrotaline pulmonary hypertension rat model

“…At baseline echocardiography, 3 weeks after MCT injection, all MCT rats had a higher PVR index compared with controls (mean of the three MCT groups: 4 Body weight was significantly lower in the MCT rats sacrificed at 4 weeks (311¡21 g) compared with controls (354¡6 g; p,0.05). After 8 and 12 weeks body mass of the MCT rats (405¡27 and 455¡27 g, respectively) was similar to age-matched controls (408¡36 and 496¡46 g, respectively).…”

“…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].…”

“…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.…”

“…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].…”