Stevenson Emily R, Johns Esther M C, Marques Francine Z, Jackson Kristy L, Davern Pamela J, Evans Roger G, Head Geoffrey A
aNeuropharmacology Laboratory, Baker IDI Heart and Diabetes Research Institute, Melbourne bDepartment of Pharmacology cDepartment of Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Clayton, Victoria, Australia.
J Hypertens. 2017 Mar;35(3):546-557. doi: 10.1097/HJH.0000000000001210.
Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors.
To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5 mg/kg per day), or its vehicle, for a period of 2 weeks. In addition to baseline recordings, the response to stress and ganglionic blockade with pentolinium was recorded, before and 7-14 days after minipump implantation. Following treatment, brains were processed for c-Fos immunohistochemistry and quantitative real-time polymerase chain reaction.
Administration of allopregnanolone selectively reduced mean arterial pressure (-8.0 ± 2.7 mmHg; P = 0.02) and the depressor response to pentolinium (-15.3 ± 3.2 mmHg; P = 0.001) in BPH/2J mice, with minimal effects observed in BPN/3J mice. Following allopregnanolone treatment, the diminished expression of GABAA δ, α4 and β2 subunits in the hypothalamus (-1.6 to 4.8-fold; Pstrain < 0.05) was abolished. Furthermore, in BPH/2J mice, allopregnanolone treatment reduced the pressor response to dirty cage switch stress (-26.7 ± 4.5%; P < 0.001) and abolished the elevated c-Fos expression in pre-sympathetic nuclei.
The selective antihypertensive and stress inhibitory effects of allopregnanolone in BPH/2J mice suggest that allosteric modulation of GABAA receptors, in amygdalo-hypothalamic pathways, may contribute to the development of hypertension in this model and may offer a potential new therapeutic avenue.
血压高施拉格（BPH/2J）小鼠患有神经源性高血压，与正常血压的同系物（BPN/3J）相比，其下丘脑GABAA受体存在差异。别孕烯醇酮是一种内源性神经甾体，在慢性应激时减少，给药时通过对GABAA受体的正向变构调节降低焦虑。
为了确定别孕烯醇酮是否可能是神经源性高血压的一种可行治疗方法，给雄性BPH/2J（n = 6 - 7）和BPN/3J（n = 8 - 9）小鼠植入无线电遥测探头，以比较皮下植入输送别孕烯醇酮（每天5mg/kg）或其溶媒的微型泵前后2周的心血管变量。除了基线记录外，在微型泵植入前和植入后7 - 14天记录对应激和用潘托铵进行神经节阻断的反应。治疗后，对大脑进行c-Fos免疫组织化学和定量实时聚合酶链反应处理。
别孕烯醇酮给药选择性降低了BPH/2J小鼠的平均动脉压（-8.0±2.7mmHg；P = 0.02）和对潘托铵的降压反应（-15.3±3.2mmHg；P = 0.001），在BPN/3J小鼠中观察到的影响最小。别孕烯醇酮治疗后，下丘脑GABAAδ、α4和β2亚基表达的减少（-1.6至4.8倍；P品系<0.05）被消除。此外，在BPH/2J小鼠中，别孕烯醇酮治疗降低了对脏笼转换应激的升压反应（-26.7±4.5%；P<0.001），并消除了交感神经节前核中升高的c-Fos表达。
别孕烯醇酮在BPH/2J小鼠中的选择性降压和应激抑制作用表明，杏仁核-下丘脑通路中GABAA受体的变构调节可能促成该模型中高血压的发生，并可能提供一条潜在的新治疗途径。
