Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats

Abstract

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.

Developmental Programming of Hypertension

“…Testosterone is implicated in the activation of the RAS in the aging female spontaneously hypertensive rat (42). Thus, Dasinger and colleagues also demonstrated that intramedullary expression of the angiotensin type 1 receptor was increased in untreated female IUGR offspring at one year of age, but did not differ in female IUGR treated with flutamide relative to untreated female controls (41). Based on these findings, Dasinger and colleagues proposed that testosterone-mediated activation of the RAS contributes to the development of increased blood pressure in female IUGR offspring at one year of age (Figure).…”

“…To address the hypothesis that an increase in testosterone contributes to the pathogenesis of elevated blood pressure in female IUGR offspring at one year of age, a recent study published in Hypertension showed that chronic blockade of the androgen receptor with flutamide abolished the significant increase in blood pressure at one year of age in female IUGR rat offspring programmed by fetal exposure to placental insufficiency (41). In this study by Dasinger et al, chronic treatment with enalapril also decreased blood pressure in female IUGR offspring indicating a role for the RAS (41). Testosterone is implicated in the activation of the RAS in the aging female spontaneously hypertensive rat (42).…”

“…The recent study by Dasinger et al demonstrates that testosterone contributes to the increase in blood pressure that develops in female IUGR offspring at one year of age (41). However, previous studies using the model of IUGR induced via placental insufficiency indicate that estrogen is protective against increased blood pressure and CV risk in female IUGR offspring in young adulthood (44, 45).…”

“…Thus, studies in models of developmental programming indicate a sex difference in CV risk and suggest an age-specific role for sex steroids in the pathogenesis of increased blood pressure in female offspring (41, 44, 48). Experimental studies suggest that estradiol is protective against increased CV risk in female offspring in young adulthood whereas other studies implicate testosterone as a permissive factor in the development of increased blood pressure in female IUGR offspring in later life.…”

Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease

“…Numerous mechanisms contribute to sex differences in primary hypertension with a role for sex steroids implicated in the progression of CV risk (11. Sex steroids may also contribute to sex differences in the onset of increased blood pressure that has its origins in fetal life (12). …”