Mechanism responsible for the salutary effects of flutamide on cardiac performance after trauma-hemorrhagic shock: Upregulation of cardiomyocyte estrogen receptors

BACKGROUND: Although flutamide (FTM), an androgen-receptor antagonist, normalizes the depressed immune and cardiac function in males after trauma hemorrhage (T-H), the mechanism responsible for its salutary effects remains unknown. We hypothesized that the salutary effects of FTM are mediated via upregulation of estrogen receptors (ERs). METHODS: Male Sprague-Dawley rats underwent T-H (laparotomy and 90 minutes of hemorrhage (35-40 mm Hg) and then resuscitated with 4x the volume of shed blood in the form of Ringer's lactate). FTM (25 mg/kg) or vehicle (propanediol) was injected subcutaneously 30 minutes before the end of resuscitation. At 2 hours after T-H or sham operation, cardiac output, stroke volume, heart rate, mean arterial pressure, +/- dp/dt, and total peripheral resistance were measured (n = 6 rats per group). Immediately after the measurement of cardiac function, cardiomyocytes were isolated, RNA was extracted, and expression of ER-alpha, ER-beta, and androgen-receptor (AR) mRNA in cardiomyocytes was determined by quantitative real-time polymerase chain reaction. ER-alpha, ER-beta, and AR protein levels in cardiomyocytes were also measured by Western blot analysis. RESULTS: The depressed cardiac output, stroke volume, and +/- dp/dt after T-H were significantly improved in the FTM-treated T-H group. Moreover, the decrease in expression of ER-alpha and ER-beta mRNA and protein in cardiomyocytes in the T-H group was prevented with FTM treatment after T-H. However, expression of cardiomyocytes AR mRNA and protein were not significantly different between the T-H or sham group with or without FTM treatment. CONCLUSIONS: These findings collectively suggest that, in addition to blockade of androgen receptors, flutamide-mediated ER upregulation is likely to play a role in mediating the salutary effect of flutamide on cardiac function after trauma hemorrhage.