Neurocardiac dysregulation and neurogenic arrhythmias in a transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is a heritable neurodegenerative disorder, with heart disease implicated as one major cause of death. While the responsible mechanism remains unknown, autonomic nervous system (ANS) dysfunction may play a role. We studied the cardiac phenotype in R6/1 transgenic mice at early (3 months old) and advanced (7 months old) stages of HD. While exhibiting a modest reduction in cardiomyocyte diameter, R6/1 mice had preserved baseline cardiac function. Conscious ECG telemetry revealed the absence of 24-h variation of heart rate (HR), and higher HR levels than wild-type littermates in young but not older R6/1 mice. Older R6/1 mice had increased plasma level of noradrenaline (NA), which was associated with reduced cardiac NA content. R6/1 mice also had unstable R-R intervals that were reversed following atropine treatment, suggesting parasympathetic nervous activation, and developed brady- and tachyarrhythmias, including paroxysmal atrial fibrillation and sudden death. c-Fos immunohistochemistry revealed greater numbers of active neurons in ANS-regulatory regions of R6/1 brains. Collectively, R6/1 mice exhibit profound ANS-cardiac dysfunction involving both sympathetic and parasympathetic limbs, that may be related to altered central autonomic pathways and lead to cardiac arrhythmias and sudden death.

Cardiovascular responses to aversive and nonaversive stressors in Schlager genetically hypertensive mice.

BACKGROUND: Schlager inbred hypertensive mice (BPH/2J) have been suggested to have high blood pressure (BP) due to an overactive sympathetic nervous system (SNS). The brain nuclei associated with the hypertension are also those involved in the integration of the cardiovascular responses to stress. Therefore, in the present study, we hypothesize that an increased contribution of the SNS in BPH/2J mice may culminate in a greater pressor response to stressful stimuli in these hypertensive mice than normotensive (BPN/3J) mice. METHODS: Male hypertensive BPH/2J and normotensive BPN/3J mice were implanted with telemetry devices and exposed to a series of behavioral "stress" tests including aversive stress (shaker, clean cage switch, and restraint) and nonaversive stress (feeding). RESULTS: Aversive stress caused a 67-88% greater pressor response in BPH/2J compared with BPN/3J mice. By contrast, the feeding-induced pressor response was not different between groups. All stressors induced tachycardia that was less in BPH/2J mice (feeding and restraint) and others were not different between groups (clean cage switch and shaker). CONCLUSIONS: These findings indicate that hypertension in BPH/2J mice is associated with greater pressor responsiveness to aversive stress but not to appetitive arousal. Thus, BPH/2J hypertensive mice may be a particularly relevant model for human hypertensive patients that overrespond to daily stressors.

The day-night difference of blood pressure is increased in AT(1A)-receptor knockout mice on a high-sodium diet.

BACKGROUND: Abnormal circadian variation of blood pressure (BP) increases cardiovascular risk. In this study, we examined the influence of angiotensin AT(1A) receptors on circadian BP variation, and specifically on its behavioral activity-related and -unrelated components. METHODS: BP and locomotor activity were recorded by radiotelemetry in AT(1A)-receptor knockout mice (AT(1A)(-/-)) and their wild-type controls (AT(1A)(+/+)) placed on a normal-salt diet (NSD) or high-salt diet (HSD, 3.1% Na). RESULTS: The 24-h BP was lower in AT(1A)(-/-) than AT(1A)(+/+) mice on a NSD (92 +/- 2 and 118 +/- 2 mm Hg, respectively), whereas the day-night BP difference (DeltaDNBP) was similar between groups (11 +/- 2 and 12 +/- 1 mm Hg, respectively). HSD increased BP by 20 +/- 2 mm Hg and DeltaDNBP by 7 +/- 1 mm Hg in AT(1A)(-/-) mice, without affecting these parameters much in AT(1A)(+/+) mice. The DeltaDNBP increase in AT(1A)(-/-) mice was caused by nondipping BP during the inactive late-dark period. Conversely, BP rise associated with circadian behavioral activation during the early dark period was not altered by HSD in AT(1A)(-/-) mice. The BP change associated with spontaneous ultradian activity-inactivity bouts was also similar between strains on HSD as was the BP rise associated with induced (cage-switch) behavioral activity. Ganglionic or alpha(1)-adrenergic blockade decreased BP in both strains; HSD did not affect this response in AT(1A)(-/-), but abolished it in AT(1A)(+/+) mice. CONCLUSIONS: AT(1A)-receptor deficiency, when combined with HSD, can increase circadian BP difference in mice. This increase is mediated principally by activity-unrelated factors, such as the nonsuppressibility of basal resting sympathetic tone by HSD, thus suggesting a form of salt-/volume-dependent hypertension.

Role of the sympathetic nervous system in Schlager genetically hypertensive mice.

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.

Blood pressure reactivity to emotional stress is reduced in AT1A-receptor knockout mice on normal, but not high salt intake.

Pharmacological evidence suggests that angiotensin II type 1 (AT(1)) receptors are involved in the regulation of cardiovascular response to emotional stress and reinforcing effect of dietary salt on this response. In this study, we examined the effect of genetic deletion of AT(1A) receptors on the cardiovascular effects of stress and salt in mice. AT(1A) receptor knockout (AT(1A)(-/-)) and wild-type (AT(1A)(+/+)) mice were implanted with telemetry devices and placed on a normal (0.4%) or high (3.1%) salt diet (HSD). Resting blood pressure (BP) in AT(1A)(-/-) mice (84+/-3 mm Hg) was lower than in AT(1A)(+/+) mice (107+/-2 mm Hg). Negative emotional (restraint) stress increased BP by 33+/-3 mm Hg in AT(1A)(+/+) mice. This response was attenuated by 40% in AT(1A)(-/-) mice (18+/-3 mm Hg). Conversely, the BP increase caused by food presentation and feeding was similar in AT(1A)(-/-) (25+/-3 mm Hg) and AT(1A)(+/+) mice (26+/-3 mm Hg). HSD increased resting BP by 14+/-4 mm Hg in AT(1A)(-/-) mice without affecting it significantly in AT(1A)(+/+) mice. Under these conditions, the pressor response to restraint stress in AT(1A)(-/-) mice (30+/-3 mm Hg) was no longer different from that in wild-type animals (28+/-3 mm Hg). The BP response to feeding was not altered by HSD in either AT(1A)(-/-) or AT(1A)(+/+) mice (25+/-2 and 27+/-3 mm Hg, respectively). These results indicate that AT(1A) receptor deficiency leads to a reduction in BP reactivity to negative emotional stress, but not feeding. HSD can selectively reinforce the cardiovascular response to negative stress in AT(1A)(-/-) mice. However, there is little interaction between AT(1A) receptors, excess dietary sodium and feeding-induced cardiovascular arousal.

Reduced cardiovascular reactivity to stress but not feeding in renin enhancer knockout mice.

BACKGROUND: We have recently shown that the renin enhancer, a regulatory element of renin gene transcription, is important in the long-term control of basal blood pressure (BP). In this study, we examined whether the renin enhancer deficit alters the acute pressor response to emotional stress in mice. METHODS: Under fluothane anesthesia, wild-type (C57BL6, n=7) and the Ren-1c enhancer knockout (REKO, n=8) mice were implanted with telemetry devices to measure BP and locomotor activity. RESULTS: Resting BP in REKO mice (94+/-3 mm Hg) was lower than in wild-type mice (102+/-2 mm Hg). Shaker stress elicited prompt pressor (+25+/-2 mm Hg), tachycardic (+145+/-25 beats/min), and locomotor responses in wild-type mice. The BP and locomotor responses were decreased in REKO mice by 39%+/-12% (P=.03) and 64%+/-11% (P=.02), respectively, whereas the tachycardic response remained unchanged. Restraint stress increased BP by 27+/-1 mm Hg in wild-type mice. The BP response was attenuated in REKO mice by 21%+/-8% (P=.05), and this attenuation could not be ascribed to reduced locomotor activity during stress. Cardiovascular arousal associated with presentation and eating palatable food was similar in wild-type (+19+/-2 mm Hg and +174+/-21 beats/min) and REKO (+19+/-2 mm Hg and +147+/-17 beats/min) mice. The contractile response to the alpha-adrenoceptor agonist phenylephrine was reduced in aortas from REKO mice, whereas that to angiotensin II was not different between strains. CONCLUSIONS: The disrupted regulation of renin synthesis caused by the renin enhancer deficit in mice is associated with a selective reduction in BP reactivity to aversive stress, which may be mediated by multiple central and peripheral mechanisms.