Major Contribution of the Medial Amygdala to Hypertension in BPH/2J Genetically Hypertensive Mice

Abstract

BPH/2J mice are a genetic model of hypertension developed in the 1970s by Schlager et al.1 These mice were selectively bred for elevated blood pressure (BP) alongside a normotensive (BPN/3J) and hypotensive control strain (BPL/1J), from a base population of 8 inbred strains of mice. Since then a range of pathophysiological factors have been studied to determine the cause of hypertension in BPH/2J mice, and the relatively modest characterization has been increasing in recent years, possibly because of advances in technology used to study mice. 2,3 Our own findings suggest that hypertension in BPH/2J mice is sympathetically mediated, based on the greater depressor response to ganglion blockade, which ultimately abolishes the hypertension in BPH/2J mice and also greater midfrequency mean arterial pressure variability (MAP power). 4 Even the percentage depressor response to ganglion blockade is greater in BPH/2J mice compared with normotensive controls. 4 This contrasts findings in spontaneously hypertensive rats (SHRs) that are likely confounded by a vascular amplifier effect 5 caused by vascular structural changes, which contribute to hypertension in adult SHRs. 6 Recently, we have also reported that BPH/2J mice have renal sympathetic hyperinnervation and enhanced renin synthesis, which results in a greater contribution of the renin-angiotensin system (RAS) to BP maintenance during the dark period of the 24-hour light cycle in BPH/2J mice compared with BPN/3J mice. 7 Early studies indicated that BPH/2J mice have aberrant brain catecholamine levels, 8 suggesting that the hypertension may be centrally mediated. Furthermore, using Fos as a marker of neuronal activity, BPH/2J mice were also shown to have greater neuronal activity in key cardiovascular regulatory brain regions compared with normotensive control BPN/3J mice. 4 Importantly, of the limbic, hypothalamic, and medullary brain regions analyzed using Fos immunohistochemistry, the medial amygdala (MeAm) was the only region to show greater neuronal activity during the light (inactive) and the dark (active) period in BPH/2J compared with BPN/3J mice, 4 suggesting that this region may be inherently overactive in BPH/2J mice. Furthermore, neuronal activity within the MeAm correlated strongly with BP level (R=0.98), suggesting that neuronal activity in the MeAm may be related to BP level. 4 The MeAm is an important limbic region that integrates sensory information, including stress and fear as well as reproductive-related inputs, and regulates the subsequent cardiovascular, behavioral, and hormonal responses.9-11 The MeAm is activated by stressful stimuli particularly of psychological rather than a physiological nature 12 and is involved Abstract-BPH/2J mice are recognized as a neurogenic model of hypertension primarily based on overactivity of the sympathetic nervous system and greater neuronal activity in key autonomic cardiovascular regulatory brain regions. The medial amygdala (MeAm) is a forebrain region that integrates the autonomic response...

Contribution of Orexin to the Neurogenic Hypertension in BPH/2J Mice

“…4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.…”

“…2 Furthermore, lesions of the medial amygdala reduced the hypertension and SNS overactivity in BPH/2J mice. 4 Thus the central nervous system seems to play a crucial role in driving the sympathetically mediated hypertension in this model.…”

“…Spectral analysis of cardiovascular variability and the baroreceptor HR reflex gain were measured as described previously 4 in BPN/3J (n=5-6) and BPH/2J (n=7) mice treated with vehicle and almorexant (100 mg/kg, IP) during the dark period.…”

L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor

“…We questioned whether the GPR143 system was involved in phasic and daily blood pressure control. Because the sympathetic nervous system is easily modified by nociceptive stimuli and continuously activated during the active phase, we examined the tail-pinch-induced pressor response and day-and nighttime blood pressure (31,32) in WT and Gpr143 -/y mice ( Figure 7). The tail-pinch procedure elevated blood pressure in anesthetized WT mice, and the rise was suppressed by pretreatment with prazosin ( Figure 7, A and B), indicating that the nociceptive stimulation induced a pressor response through activating the sympathetic nervous system.…”

The medial amygdaloid nucleus modulates the baroreflex activity in conscious rats

“…There is functional evidence showing a possible MeA involvement in the basal control of baroreflex activity, resulting from power spectral analysis that evaluates variability of the HR and MAP (Neckel et al, 2012;Quagliotto et al, 2008), or in BPH/2J mice, a neurogenic model of hypertension, in which the MeA was proposed to participate in cardiac baroreflex sensitivity control (Jackson et al, 2014), consequently it would be relevant to evaluate the role of MeA in the modulation on baroreflex activity response evoked by intravenous infusion of phenylephrine (Phe) or sodium nitroprusside (SNP) in conscious rats.…”