Morphological features of changes in target organs during pharmacological monocrotaline-induced modeling of pulmonary hypertension in rats under conditions of preliminary stimulation of liver enzymatic systems

Abstract

Pulmonary hypertension is a condition characterized by a progressive increase in pressure in the pulmonary circulation. The simplest and most common experimental model of pulmonary hypertension is the monocrotaline model. It is based on the process of transformation of monocrotaline in the liver by cytochrome P450 into endothelial toxic monocrotaline pyrrole, which in turn, damaging the endothelium of the pulmonary vessels, leads to circulatory disorders in the pulmonary circulation and the formation of pulmonary hypertension. Thus, additional prestimulation of cytochrome P450 may increase the stability and representativeness of the monocrotaline model. The purpose of this work was to determine differences in morphological changes in the myocardium and pulmonary vessels of rats in which pulmonary hypertension was modeled using monocrotaline with and without additional stimulation of liver enzymes. Material and methods. The study was conducted on 24 mature male Wistar rats. The animals were divided into 4 groups of 6 rats. Group 1 was represented by intact animals. In groups 2, 3 and 4, modeling of pulmonary hypertension in rats was carried out with a single subcutaneous injection of an aqueous-alcohol solution of monocrotaline at a dose of 60 mg/kg. In order to induce cytochrome P450 in groups 3 and 4, animals were intragastrically administered phenobarbital for one and three days, respectively. Results and discussion. The area of cardiomyocyte nuclei in the groups with one- and three-day preliminary stimulation of liver enzymes was 22.78 ± 3.4 and 23.63 ± 3.72 µm2 , respectively, significantly different from the corresponding values of the control group and group 2. Similar results were revealed when determining the index of the thickness of the medial membrane of small-caliber pulmonary arteries – 58.32 ± 10.02 and 76.44 ± 18.55 % in the groups with one- and three-day preliminary stimulation, respectively. In addition to quantitative changes, qualitative changes were also noted: with additional activation of cytochrome P450, interstitial fibrosis and myocarditis more intensively formed in the myocardium, and signs of “monocrotaline syndrome” more rapidly arose and progressed in the lungs. Conclusions. Based on the data obtained, it can be assumed that preliminary cytochrome P450 causes an increase in the stability, reproducibility and severity of morphological changes in the monocrotaline model of pulmonary hypertension.

Keywords

• pulmonary hypertension
• endothelial dysfunction
• monocrotaline
• pathological anatomy
• experimental model