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. Mate Sprague-Dawley rats underwent TH (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-a, ER-P, 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 TH were significantly improved in the FTM-treated TH group. Moreover, the decrease in expression of ER-a and ER-P mRNA and protein in cardiomyocytes in the TH 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.