Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats.
Intrauterine growth restriction induced via placental insufficiency programs a significant increase in blood pressure at 12 months of age in female growth-restricted rats that is associated with early cessation of estrous cyclicity, indicative of premature reproductive senescence. In addition, female growth-restricted rats at 12 months of age exhibit a significant increase in circulating testosterone with no change in circulating estradiol. Testosterone is positively associated with blood pressure after menopause in women. Thus, we tested the hypothesis that androgen receptor blockade would abolish the significant increase in blood pressure that develops with age in female growth-restricted rats. Mean arterial pressure was measured in animals pretreated with and without the androgen receptor antagonist, flutamide (8 mg/kg/day, SC for 2 weeks). Flutamide abolished the significant increase in blood pressure in growth-restricted rats relative to control at 12 months of age. To examine the mechanism(s) by which androgens contribute to increased blood pressure in growth-restricted rats, blood pressure was assessed in rats untreated or treated with enalapril (250 mg/L for 2 weeks). Enalapril eliminated the increase in blood pressure in growth-restricted relative to vehicle- and flutamide-treated controls. Furthermore, the increase in medullary angiotensin type 1 receptor mRNA expression was abolished in flutamide-treated growth-restricted relative to untreated counterparts and controls; cortical angiotensin-converting enzyme mRNA expression was reduced in flutamide-treated growth-restricted versus untreated counterparts. Thus, these data indicate that androgens, via activation of the renin-angiotensin system, are important mediators of increased blood pressure that develops by 12 months of age in female growth-restricted rats.
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
John Henry
JH
Dasinger
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
Suttira
S
Intapad
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
Benjamin R
BR
Rudsenske
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
Gwendolyn K
GK
Davis
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.
Ashley D
AD
Newsome
From the Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson. balexander@umc.edu.
Barbara T
BT
Alexander
D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight; D001795:Blood Pressure Determination; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D005485:Flutamide / Q000494:pharmacology*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011944:Receptors, Androgen / Q000187:drug effects* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012680:Sensitivity and Specificity
D012333:RNA, Messenger; D011944:Receptors, Androgen; D005485:Flutamide
blood pressure; low birth weight; renin–angiotensin system; testosterone; women’s health