Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice

Abstract

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.

Genotypic analysis of the female BPH/5 mouse, a model of superimposed preeclampsia

“…Male BPH/2 mice have been utilized to investigate basic cardiometabolic physiology. In adulthood, they are hypertensive with a greater metabolic rate and decreased body weight compared to normotensive BPN/3 males [2], which is similar to what is observed in comparison of BPH/2 and BPN/3 females. Genome Wide Association Studies…”

“…RAS genes were considered as they are important for cardiovascular adaptations in mammals, including blood pressure regulation, and may contribute to female BPH/5 borderline hypertension before pregnancy. We hypothesized that BPH/5 and BPH/2 mice would possess similar mutations in RAS genes, specifically angiotensinogen (Agt) and kallikrein, as previously described in BPH/2 [2]. BPH/5 female mice have non-synonymous mutations in Agt, but not in angiotensinogen converting enzyme (Ace) and Agt receptor (Agtr) 1a.…”

“…The base population for this selection scheme was derived from an 8-way cross between C57Bl/6 (C57), SJL, BDP, LP, RF, CBA, BALB/c, and 129 inbred mice [1] (Fig 1). Female BPH/2 mice are lean and hypertensive with systolic blood pressure and heart rates significantly higher than BPN/3 mice [2]. Female BPL/1 mice have hypotension compared to normotensive BPN/3 [3].…”

Effect of renal denervation on long-term outcomes in patients with resistant hypertension

“…However, the mechanism responsible for the antihypertensive effect of RDN is still unclear. An elevated BP coupled to increased sympathetic drive [ 33 , 34 ]. Specifically targeting afferent renal nerves in deoxycorticosterone acetate-salt model [ 32 , 35 , 36 ] or efferent nerves in Dahl salt-sensitive rats [ 37 ] chronically lower BP.…”

Integrative Physiology: Update to the Grand Challenge 2020

“…There are a number of rat and mouse strains for example that have been bred or genetically manipulated to develop high blood pressure. Strains such as the spontaneously hypertensive rat (SHR) and Schlager BPH mouse developed in the 1960's and 1970's, respectively have been widely used (Okamoto and Aoki, 1963;Schlager, 1974;Jackson et al, 2019). Studies from our laboratory suggested that the BPH mice had a neurogenic form of hypertension involving a much greater contribution of the sympathetic nervous system (SNS) (Davern et al, 2009).…”