Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice
It has been 45 years since Gunther Schlager used a cross breeding program in mice to develop inbred strains with high, normal, and low blood pressure (BPH/2, BPN/3, and BPL/1 respectively). Thus, it is timely to gather together the studies that have characterized and explored the mechanisms associat...
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.01311/full |
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| author | Kristy L. Jackson Geoffrey A. Head Cindy Gueguen Emily R. Stevenson Kyungjoon Lim Kyungjoon Lim Francine Z. Marques Francine Z. Marques |
| author_facet | Kristy L. Jackson Geoffrey A. Head Cindy Gueguen Emily R. Stevenson Kyungjoon Lim Kyungjoon Lim Francine Z. Marques Francine Z. Marques |
| author_sort | Kristy L. Jackson |
| collection | DOAJ |
| description | It has been 45 years since Gunther Schlager used a cross breeding program in mice to develop inbred strains with high, normal, and low blood pressure (BPH/2, BPN/3, and BPL/1 respectively). Thus, it is timely to gather together the studies that have characterized and explored the mechanisms associated with the hypertension to take stock of exactly what is known and what remains to be determined. Growing evidence supports the notion that the mechanism of hypertension in BPH/2 mice is predominantly neurogenic with some of the early studies showing aberrant brain noradrenaline levels in BPH/2 compared with BPN/3. Analysis of the adrenal gland using microarray suggested an association with the activity of the sympathetic nervous system. Indeed, in support of this, there is a larger depressor response to ganglion blockade, which reduced blood pressure in BPH/2 mice to the same level as BPN/3 mice. Greater renal tyrosine hydroxylase staining and greater renal noradrenaline levels in BPH/2 mice suggest sympathetic hyperinnervation of the kidney. Renal denervation markedly reduced the blood pressure in BPH/2 but not BPN/3 mice, confirming the importance of renal sympathetic nervous activity contributing to the hypertension. Further, there is an important contribution to the hypertension from miR-181a and renal renin in this strain. BPH/2 mice also display greater neuronal activity of amygdalo-hypothalamic cardiovascular regulatory regions. Lesions of the medial nucleus of the amygdala reduced the hypertension in BPH/2 mice and abolished the strain difference in the effect of ganglion blockade, suggesting a sympathetic mechanism. Further studies suggest that aberrant GABAergic inhibition may play a role since BPH/2 mice have low GABAA receptor δ, α4 and β2 subunit mRNA expression in the hypothalamus, which are predominantly involved in promoting tonic neuronal inhibition. Allopregnanolone, an allosteric modulator of GABAA receptors, which increase the expression of these subunits in the amygdala and hypothalamus, is shown to reduce the hypertension and sympathetic nervous system contribution in BPH/2 mice. Thus far, evidence suggests that BPH/2 mice have aberrant GABAergic inhibition, which drives neuronal overactivity within amygdalo-hypothalamic brain regions. This overactivity is responsible for the greater sympathetic contribution to the hypertension in BPH/2 mice, thus making this an ideal model of neurogenic hypertension. |
| first_indexed | 2024-12-22T01:42:49Z |
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| id | doaj.art-41885f8304da4333a475d0a2f55b216c |
| institution | Directory Open Access Journal |
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| last_indexed | 2024-12-22T01:42:49Z |
| publishDate | 2019-10-01 |
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| spelling | doaj.art-41885f8304da4333a475d0a2f55b216c2022-12-21T18:43:09ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-10-011010.3389/fphys.2019.01311494675Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 MiceKristy L. Jackson0Geoffrey A. Head1Cindy Gueguen2Emily R. Stevenson3Kyungjoon Lim4Kyungjoon Lim5Francine Z. Marques6Francine Z. Marques7Neuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, AustraliaNeuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, AustraliaNeuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, AustraliaNeuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, AustraliaNeuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, AustraliaDepartment of Physiology, Anatomy and Microbiology, School of Life Sciences, La Trobe University, Melbourne, VIC, AustraliaNeuropharmacology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, AustraliaHypertension Research Laboratory, School of Biological Sciences, Monash University, Clayton, VIC, AustraliaIt has been 45 years since Gunther Schlager used a cross breeding program in mice to develop inbred strains with high, normal, and low blood pressure (BPH/2, BPN/3, and BPL/1 respectively). Thus, it is timely to gather together the studies that have characterized and explored the mechanisms associated with the hypertension to take stock of exactly what is known and what remains to be determined. Growing evidence supports the notion that the mechanism of hypertension in BPH/2 mice is predominantly neurogenic with some of the early studies showing aberrant brain noradrenaline levels in BPH/2 compared with BPN/3. Analysis of the adrenal gland using microarray suggested an association with the activity of the sympathetic nervous system. Indeed, in support of this, there is a larger depressor response to ganglion blockade, which reduced blood pressure in BPH/2 mice to the same level as BPN/3 mice. Greater renal tyrosine hydroxylase staining and greater renal noradrenaline levels in BPH/2 mice suggest sympathetic hyperinnervation of the kidney. Renal denervation markedly reduced the blood pressure in BPH/2 but not BPN/3 mice, confirming the importance of renal sympathetic nervous activity contributing to the hypertension. Further, there is an important contribution to the hypertension from miR-181a and renal renin in this strain. BPH/2 mice also display greater neuronal activity of amygdalo-hypothalamic cardiovascular regulatory regions. Lesions of the medial nucleus of the amygdala reduced the hypertension in BPH/2 mice and abolished the strain difference in the effect of ganglion blockade, suggesting a sympathetic mechanism. Further studies suggest that aberrant GABAergic inhibition may play a role since BPH/2 mice have low GABAA receptor δ, α4 and β2 subunit mRNA expression in the hypothalamus, which are predominantly involved in promoting tonic neuronal inhibition. Allopregnanolone, an allosteric modulator of GABAA receptors, which increase the expression of these subunits in the amygdala and hypothalamus, is shown to reduce the hypertension and sympathetic nervous system contribution in BPH/2 mice. Thus far, evidence suggests that BPH/2 mice have aberrant GABAergic inhibition, which drives neuronal overactivity within amygdalo-hypothalamic brain regions. This overactivity is responsible for the greater sympathetic contribution to the hypertension in BPH/2 mice, thus making this an ideal model of neurogenic hypertension.https://www.frontiersin.org/article/10.3389/fphys.2019.01311/fullneurogenic hypertensionallopregnanoloneorexinGABA receptor Aamygdalahypothalamus |
| spellingShingle | Kristy L. Jackson Geoffrey A. Head Cindy Gueguen Emily R. Stevenson Kyungjoon Lim Kyungjoon Lim Francine Z. Marques Francine Z. Marques Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice Frontiers in Physiology neurogenic hypertension allopregnanolone orexin GABA receptor A amygdala hypothalamus |
| title | Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice |
| title_full | Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice |
| title_fullStr | Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice |
| title_full_unstemmed | Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice |
| title_short | Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice |
| title_sort | mechanisms responsible for genetic hypertension in schlager bph 2 mice |
| topic | neurogenic hypertension allopregnanolone orexin GABA receptor A amygdala hypothalamus |
| url | https://www.frontiersin.org/article/10.3389/fphys.2019.01311/full |
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