title: Positive allosteric modulation of GABAA receptors attenuates high blood pressure in Schlager hypertensive mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Stevenson
authors.forename: Esther M C
authors.initials: EM
authors.lastname: Johns
authors.forename: Francine Z
authors.initials: FZ
authors.lastname: Marques
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Jackson
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Davern
authors.forename: Roger G
authors.initials: RG
authors.lastname: Evans
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Head
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D015870:Gene Expression; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism*; D008297:Male; D051379:Mice; D010425:Pentolinium Tartrate / Q000494:pharmacology; D011280:Pregnanolone / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000378:metabolism*; D013312:Stress, Physiological; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D016760:Proto-Oncogene Proteins c-fos; D011963:Receptors, GABA-A; D010425:Pentolinium Tartrate; D011280:Pregnanolone