It is well known that the initial reaction of monocrotaline-induced pulmonary hypertension in rats (MPH) is injury to the endothelial cells of pulmonary vascular bed by monocrotaline-pyrrole (MP), which is converted from monocrotaline (M) by cytochrome P450 monooxygenase in hepatic microsomes. It is also known that the degree of MPH differs between sexes. The mechanisms of MPH remain, however, to be elucidated. The purpose of this study is to clarify the relationship between the converting ability of hepatic microsomes and the sexual difference in MPH using castrated male rats.
A 40mg/kg dose of M was given to fifteen 6 week-old male, twelve 6 week-old female and fifteen 6 week-old castrated male, Sprague-Dawley, rats. The castration was done at three weeks of age. Four weeks after M administration, the right ventricular systolic pressure (RVSP) and the right ventricular to total ventricular weight ratio (RV/T) were measured as indices of pulmonary hypertension. Livers were taken from six 6 week-old male, six, 6 week-old female and six 6 week-old castrated male, Sprague-Dawley, rats and then homogenized and centrifuged to extract hepatic microsomes. M, at 3.3mM, was added to concentrated hepatic microsomes (0.25 to 1.5mg/ml) in order to produce MP. The concentration of the MP was measured using a modification of Mattock's method.
The mean value of RVSP was 86.5mmHg in males, 59.6mmHg in females and 73.9mmHg in castrated males.
The mean value of RV/T was 0.453 in males, 0.358 in females and 0.403 in castrated males. Both of these variables were significantly higher in males than in females and castrated males.
The mean values of absorption rates, which indicate the concentrations of the MP, are shown below.
In regard to the same microsomal protein content, the absorption rate was significantly higher in males than in females and castrated males.
These results suggest that the sexual difference in MPH may be caused a difference in the ability to convert M to MP in hepatic microsomes. Because the degree of MPH and the converting ability were decreased by castration, sex hormones and male-specific cytochrome P450s may contribute to the metabolic pathway of monocrotaline.
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