Positive allosteric modulation of GABAA receptors attenuates high blood pressure in Schlager hypertensive mice


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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 (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.Results: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.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.

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