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.
Highlights
Experimental models of hypertension have been developed over the last half century and have made a major contribution to our understanding of the mechanisms underlying the development and treatment of hypertension
Neuronal activity within the medial amygdala (MeAm) of BPN/3 and BPH/2 mice strongly correlated with blood pressure (BP) and with the decrease in BP caused by ganglion blockade (Davern et al, 2009). These findings suggest that greater neuronal activity in the MeAm of BPH/2 mice may lead to elevations in BP via influences on the sympathetic nervous system (SNS)
Combining the microarray finding of altered gammaaminobutyric acid (GABA) receptor (GABAAR) subunit expression in the hypothalamus with the lower levels of GABAAR in the hypothalamus and amygdala of spontaneously hypertensive rat (SHR) (Kunkler and Hwang, 1995), we suggested that inadequate GABAergic inhibitory signaling may contribute to the higher activity in the pre-sympathetic pathways leading to the hypertension in BPH/2 (Davern et al, 2014)
Summary
Experimental models of hypertension have been developed over the last half century and have made a major contribution to our understanding of the mechanisms underlying the development and treatment of hypertension. A frequently studied model is that developed by Gunther Schlager and colleagues in the early 1970s (Schlager, 1974) They established an inbred hypertensive strain of mice (BPH/2, Blood Pressure High) that has subsequently been studied in a wide range of investigations. These have described the phenotype, including genetics (Schlager, 1994; Marques et al, 2011a), cardiovascular function (McGuire et al, 2007; Davern et al, 2009), renal function (Rosenberg et al, 1982), behavior (Elias et al, 1975a), as well as involvement of the sympathetic (Davern et al, 2009; Jackson et al, 2013) and central nervous system (Jackson et al, 2014d). The present review aims to provide an overview of the literature published on BPH/2 mice, with a particular focus on the evidence that these mice represent a unique model of neurogenic hypertension
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
