From the Department of Physiology (G.K.D., A.D.N., L.E.C., D.R.B., B.T.A.), University of Mississippi Medical Center, Jackson.
Department of Pharmacology, Tulane University, New Orleans, LA (S.I.).
Hypertension. 2019 Oct;74(4):975-982. doi: 10.1161/HYPERTENSIONAHA.119.13257. Epub 2019 Aug 5.
Low birth weight is associated with a greater prevalence of hypertension in women by age 60; yet, the mechanisms involved are unknown. We previously reported that hypertension in female growth-restricted offspring that is associated with early reproductive senescence and a shift in the testosterone-to-estradiol ratio at 12 months of age is abolished by AR (androgen receptor) blockade in conjunction with downregulation of renal AT1aR (angiotensin type 1a receptor) mRNA expression. These data suggest androgen-mediated activation of the renin-angiotensin system contributes to the pathogenesis of hypertension that develops in female growth-restricted offspring with aging. Thus, this study tested the hypothesis that androgen-mediated increased blood pressure is specific to female growth-restricted offspring. Control and growth-restricted rats underwent sham or ovariectomy at 10 months of age. Vehicle or flutamide (8 mg/kg/day; subcutaneous), an AR antagonist, was administered at 11.5 months of age for 2 weeks followed by measurement of blood pressure. Loss of ovarian hormones was associated with a 10 mm Hg increase in blood pressure in control compared with intact counterparts accompanied by a 1.8-fold increase in renal AT1aR mRNA expression. Treatment with flutamide had no effect on blood pressure or renal AT1aR mRNA expression in ovariectomized controls. Although blood pressure was significantly decreased in flutamide-treated ovariectomized growth-restricted, flutamide had no effect on the increase in renal AT1aR mRNA expression. Therefore, these findings suggest the effect of AR blockade on blood pressure is specific to intact growth-restricted offspring and that mechanisms of postmenopausal hypertension may differ between normal and low birth weight women.
低出生体重与女性 60 岁时高血压的患病率增加有关；然而，涉及的机制尚不清楚。我们之前曾报道过，与 12 个月时生殖早期衰老和睾酮-雌二醇比值变化相关的限制生长的雌性后代的高血压，通过 AR（雄激素受体）阻断联合下调肾 AT1aR（血管紧张素 1a 受体）mRNA 表达而消除。这些数据表明，雄激素介导的肾素-血管紧张素系统的激活有助于限制生长的雌性后代随着年龄增长发生高血压的发病机制。因此，本研究检验了雄激素介导的血压升高特异性针对雌性限制生长后代的假设。对照组和限制生长组大鼠在 10 个月时进行假手术或卵巢切除术。在 11.5 个月时，用 vehicle 或 flutamide（8mg/kg/天；皮下），一种 AR 拮抗剂，给药 2 周，然后测量血压。与完整对照组相比，对照组失去卵巢激素后血压升高 10mmHg，同时肾 AT1aR mRNA 表达增加 1.8 倍。在卵巢切除的对照组中，flutamide 治疗对血压或肾 AT1aR mRNA 表达没有影响。尽管 flutamide 处理的卵巢切除限制生长组的血压显著降低，但 flutamide 对肾 AT1aR mRNA 表达的增加没有影响。因此，这些发现表明 AR 阻断对血压的影响特异性针对完整的限制生长后代，绝经后高血压的机制可能在正常出生体重和低出生体重妇女之间有所不同。
