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.
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 35294, USA.
Huang-Ping
HP
Yu
Shaolong
S
Yang
Mashkoor A
MA
Choudhry
Ya-Ching
YC
Hsieh
Kirby I
KI
Bland
Irshad H
IH
Chaudry
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005485:Flutamide / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000235:genetics; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects
D000726:Androgen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D012333:RNA, Messenger; D011944:Receptors, Androgen; D005485:Flutamide