ABSTRACT
OBJECTIVE: 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. METHODS: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (nâ=â6-7) and BPN/3J (nâ=â8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5âmg/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. RESULTS: Administration of allopregnanolone selectively reduced mean arterial pressure (-8.0â±â2.7âmmHg; Pâ=â0.02) and the depressor response to pentolinium (-15.3â±â3.2âmmHg; Pâ=â0.001) in BPH/2J mice, with minimal effects observed in BPN/3J mice. Following allopregnanolone treatment, the diminished expression of GABAA δ, α4 and ß2 subunits in the hypothalamus (-1.6 to 4.8-fold; Pstrainâ<â0.05) was abolished. Furthermore, in BPH/2J mice, allopregnanolone treatment reduced the pressor response to dirty cage switch stress (-26.7â±â4.5%; Pâ<â0.001) and abolished the elevated c-Fos expression in pre-sympathetic nuclei. CONCLUSION: 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.
