Role of the Sympathetic Nervous System in Schlager Genetically Hypertensive Mice

Abstract

Early studies indicate that the hypertension observed in the Schlager inbred mouse strain may be attributed to a neurogenic mechanism. In this study, we examined the contribution of the sympathetic nervous system in maintaining hypertension in the BPH/2J mouse and used c-Fos immunohistochemistry to elucidate whether neuronal activation in specific brain regions was associated with waking blood pressure. Male hypertensive (BPH/2J; n=14), normotensive (BPN/3J; n=18), and C57/Bl6 (n=5) mice were implanted with telemetry devices, and after 10 days of recovery, recordings of blood pressure, heart rate, and locomotor activity were measured to determine circadian variation. Mean arterial pressure was higher in BPH/2J than in BPN/3J or C57/Bl6 mice (P<0.001), and BPH/2J animals showed exaggerated day-night differences (17+/-2 versus 6+/-1 mm Hg in BPN/3J or +8+/-2 mm Hg in C57/Bl6 mice; P<0.001). Acute sympathetic blockade with pentolinium (7.5 mg/kg IP) during the active and inactive phases reduced blood pressure to comparable levels in BPH/2J and BPN/3J mice. The number of c-Fos-labeled cells was greater in the amygdala (+180%; P<0.01), paraventricular nucleus (+110%; P<0.001), and dorsomedial hypothalamus (+48%; P<0.001) in the active (hypertensive) phase in BPH/2J compared with BPN/3J mice. The level of neuronal activation was mostly similar in these regions in the inactive phase. Of all of the regions studied, neuronal activation in the medial amygdala, as detected by c-Fos, was highly correlated to mean arterial pressure (r=0.98). These findings indicate that the hypertension is largely attributable to sympathetic nervous system activity, possibly generated through greater levels of arousal regulated by neurons located in the medial amygdala.

Cardiovascular Responses to Aversive and Nonaversive Stressors in Schlager Genetically Hypertensive Mice

“…9 These findings not only suggest that the hypertension observed is likely due to an overactive SNS, the pattern of night-time arousal activation is highly suggestive of the pattern associated with stress similar to that observed in human early morning BP surge. 3 Thus, we hypothesize that Schlager BPH/2J mice may respond considerably more in terms of BP rise than BPN/3J mice to a stressful stimulus.…”

“…The very high levels of BP in BPH/2J mice are most evident during the active period, but the arousal associated with nocturnal behavior would not typically be considered "aversive. " We have previously shown that the hypertension is directly correlated to the activity of the MeAm, 9 and this region is known to integrate the emotional response to stress. 17 It is known to be necessary for the manifestation of the pressor response to stress.…”

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

“…BPH/2J mice are a model of lifelong hypertension on a genetic basis and manifest some of the cardinal features of essential hypertension, i.e., neurohumoral dysfunction, sympathetic activation, cardiac hypertrophy, and kidney atrophy (58,59). Due to long-lasting hypertension, BPH/2J mice are valuable in hypertension research, akin to spontaneously hypertensive rats.…”

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

“…Thus, it is likely that there is a greater sympathetic contribution to the hypertension in BPH/2J mice. The use of radiotelemetry devices recording for 24 h identified that BPH/2J mice not only display hypertension but also have a greater day-night difference in BP compared with BPN/3J mice [3]. Interestingly, the greater BP surge in BPH/2J mice was associated with activation of neurons in the amygdala and hypothalamus indicating brain regions important for cardiovascular regulation of stress [3].…”

“…The use of radiotelemetry devices recording for 24 h identified that BPH/2J mice not only display hypertension but also have a greater day-night difference in BP compared with BPN/3J mice [3]. Interestingly, the greater BP surge in BPH/2J mice was associated with activation of neurons in the amygdala and hypothalamus indicating brain regions important for cardiovascular regulation of stress [3]. Indeed, BPH/2J mice also respond markedly more than BPN/3J mice to aversive stress demonstrated by 70-90% greater pressor responses and only small effects (þ20%) induced by non-aversive stress such as feeding indicating typical levels of arousal [4].…”