GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice

Pamela J Davern, Sara Chowdhury, Kristy L Jackson, Thu-Phuc Nguyen-Huu, Geoffrey A Head

Research output: Contribution to journalArticleResearchpeer-review

Abstract

OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 +/- 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 +/- 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20 (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and 50 of stress-activated neurons in these regions also expressed GABAA receptors and 45 were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.
Original languageEnglish
Pages (from-to)352 - 362
Number of pages11
JournalJournal of Hypertension
Volume32
Issue number2
DOIs
Publication statusPublished - 2014

Cite this

Davern, Pamela J ; Chowdhury, Sara ; Jackson, Kristy L ; Nguyen-Huu, Thu-Phuc ; Head, Geoffrey A. / GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice. In: Journal of Hypertension. 2014 ; Vol. 32, No. 2. pp. 352 - 362.
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abstract = "OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 +/- 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 +/- 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20 (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and 50 of stress-activated neurons in these regions also expressed GABAA receptors and 45 were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.",
author = "Davern, {Pamela J} and Sara Chowdhury and Jackson, {Kristy L} and Thu-Phuc Nguyen-Huu and Head, {Geoffrey A}",
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GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice. / Davern, Pamela J; Chowdhury, Sara; Jackson, Kristy L; Nguyen-Huu, Thu-Phuc; Head, Geoffrey A.

In: Journal of Hypertension, Vol. 32, No. 2, 2014, p. 352 - 362.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice

AU - Davern, Pamela J

AU - Chowdhury, Sara

AU - Jackson, Kristy L

AU - Nguyen-Huu, Thu-Phuc

AU - Head, Geoffrey A

PY - 2014

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N2 - OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 +/- 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 +/- 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20 (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and 50 of stress-activated neurons in these regions also expressed GABAA receptors and 45 were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.

AB - OBJECTIVE: Schlager BPH/2J hypertensive mice have high blood pressure (BP) likely due to overactivity of the sympathetic nervous system regulated by neurons in amygdala-hypothalamic pathways. These areas are normally under tonic inhibition by GABA containing neurons that may be deficient in Schlager hypertensive mice as suggested by microarray analysis. In the present study, cardiovascular effects of chronic activation of GABAA receptors were examined in BPH/2J mice. METHODS: Male normotensive BPN/3J and hypertensive BPH/2J mice were administered diazepam in drinking water for 7 days. BP, heart rate and locomotor activity were recorded by telemetry. RESULTS: Diazepam (2.5 mg/kg) reduced BP of BPN/3J mice during the night-time by -7.1 +/- 2.0 mmHg (P = 0.001) but had no effect in BPH/2J mice (+2 +/- 2 mmHg) and no effect on heart rate or locomotor activity in either strain. Diazepam reduced the responses to restraint stress in BPN/3J mice by 20 (P = 0.01) and there was no association between Fos-immunoreactive neurons and neurons expressing GABAA receptors or neuropeptide Y in the medial amygdala and paraventricular nucleus of the hypothalamus. By contrast diazepam had no effect on the pressor response to stress in BPH/2J mice and 50 of stress-activated neurons in these regions also expressed GABAA receptors and 45 were neuropeptide Y-containing. CONCLUSION: These findings show that BPH/2J mice are resistant to the effects of diazepam and suggest that GABAA receptor dysfunction in BPH/2J mice may be contributing to the neurogenic hypertension by not suppressing arousal-induced sympathetic activation within amygdala and hypothalamic nuclei.

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DO - 10.1097/HJH.0000000000000015

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