Effects of allopregnanolone, a positive allosteric modulation of GABAA receptors upon stress and hypertension in Schlager genetic hypertensive mice (697.3)

Abstract

Background: Hypertensive Schlager mice (BPH/2J) have neurogenic hypertension associated with differences in GABAA receptors compared to their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced by chronic stress and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors.Aim: To determine if allopregnanolone reduces the pressor effects of stress and basal MAP in BPH/2J mice.Methods: Male BPN/3J (n=7) and BPH/2J (n=5) mice received vehicle or allopregnanolone (5µg/hour) via subcutaneous minipumps for 2 weeks. Implanted telemetric probes enabled recording of mean arterial pressure (MAP), heart rate (HR) and activity as well as the response to aversive and non‐aversive stress tests and ganglionic blockade with pentolinium before and 7 and 14 days of treatment. Mice were perfused following stress and brains were removed for immunohistochemistry.Results: Allopregnanolone reduced systolic arterial pressure (‐8.8mmHg, P=0.01) and attenuated the depressor response to pentolinium in BPH/2J mice but had no effect upon in BPN/3J. Allopregnanolone produced marked reductions in the pressor response to both cage switch and feeding stress (‐20%, P<0.01) in BPH/2J whilst increasing the pressor response to aversive stress in BPN/3J (P<0.001). Stress induced Fos counts within the medial amygdala and paraventricular nucleus were higher in untreated BPH/2J compared to BPN/3J. Allopregnanolone reduced Fos expression and treatment abolished the difference between strains.Conclusions: The selective antihypertensive and stress inhibitory effects of allopregnanolone in BPH/2J hypertensive mice suggests that allosteric modulation of GABAA receptors at the level of the hypothalamus and amygdala may be a major cause of hypertension in this model and may offer a possible new area for the development of therapy.