Misa Yoshimoto

Acute shifts of baroreflex control of renal sympathetic nerve activity induced by treadmill exercise in rats

The present study aimed to investigate whether there was a resetting of the baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) during exercise. Wistar female rats (n= 11) were chronically implanted with catheters for the measurement of systemic arterial (Pa) and central venous pressures and with electrodes for measurement of RSNA and electrocardiogram (ECG) at least 3 days before study. The baroreflex curve for RSNA was determined by changing Pa using rapid intravenous infusions of phenylephrine and nitroprusside. The baroreflex response curves for RSNA and HR were characterized by an inverse sigmoid function curve from which the response range, gain, centring point and minimum response were estimated. Exercise shifted the Pa‐RSNA baroreflex curve upward and to the right and was associated with increases in response range of 122 ± 44 % (P < 0.05), maximum response of 173 ± 40 % (P < 0.05), maximum gain of 149 ± 66 % (P < 0.05) and midpoint pressure of 15 ± 5 mmHg (P < 0.05) compared with the pre‐exercise level. After cessation of exercise, the Pa‐RSNA baroreflex curve was suppressed vertically with a significant decrease in maximum response of 57 ± 14 % (P < 0.05) compared with the pre‐exercise level. These data suggest that the right‐upward shift of baroreflex control of sympathetic nerve activity may play a critical role in raising and stabilizing Pa during exercise. The suppression of the baroreflex control of sympathetic nerve activity may partly explain the post‐exercise inhibition of sympathetic nerve activity and contribute to the post‐exercise hypotension.

Chronic Angiotensin II Infusion Causes Differential Responses in Regional Sympathetic Nerve Activity in Rats

Angiotensin II (AngII)–induced hypertension in experimental animals has been proposed to be attributed in part to activation of the sympathetic nervous system. This sympathetic activation appears to be accentuated in animals consuming a high-salt diet (AngII-salt hypertension). However, accurate quantification of sympathetic activity is difficult, and controversy remains. It is particularly important to ask which are the critical vascular beds targeted by increased sympathetic nerve activity (SNA) in AngII-salt hypertension. To address this issue, mean arterial pressure and renal SNA or lumbar SNA were continuously recorded during a 5-day control period, 11 days of AngII (150 ng/kg per minute, SC), and a 5-day recovery period in conscious rats on a high-salt (2% NaCl) diet. Although mean arterial pressure reached a new steady-state level of 30 to 35 mm Hg above control levels by the end of the AngII period, renal SNA decreased by 40% during the first 7 days of AngII and then returned toward control levels by day 10 of AngII. In contrast, lumbar SNA remained at control levels throughout the AngII period. In another experiment we measured hindlimb norepinephrine spillover in conscious rats on normal (0.4%) or high- (2.0%) salt diets before and during 14 days of AngII administration. AngII had no significant affect on hindlimb norepinephrine spillover in either group. We conclude that chronic AngII modulates renal and lumbar SNAs differentially in rats consuming a high-salt diet and that AngII-salt hypertension in the rat is not caused by increased SNA to the renal or hindlimb vascular beds.

Lumbar sympathetic nerve activity and hindquarter blood flow during REM sleep in rats

The present study aimed to investigate the response of lumbar sympathetic nerve activity (LSNA) to the onset of rapid eye movement (REM) sleep and its contribution to the regulation of muscle blood flow during REM sleep in rats. Electrodes for the measurements of LSNA, electroencephalogram, electromyogram and electrocardiogram and a Doppler flow cuff for the measurements of blood flow in the common iliac and mesenteric arteries, also catheters for the measurements of systemic arterial and central venous pressures were implanted chronically. REM sleep resulted in a step increase in LSNA, by 22 ± 9% (mean ±s.e.m., P < 0.05), a reduction of iliac vascular conductance, by −16 ± 3% (P < 0.05) and a gradual increase in systemic arterial pressure, reaching a maximum value of 8.1 ± 2.0 mmHg (P < 0.05) at 89 s after onset of REM sleep, while mesenteric vascular conductance increased simultaneously by 5 ± 2% (P < 0.05). There was a significant (Pearsons correlation coefficient = 0.94, P < 0.05) inverse linear relationship between LSNA and the iliac blood flow. Unilateral lumbar sympathectomy blunted the reduction of iliac blood flow induced by the onset of REM sleep. The present observations suggest that the onset of REM sleep appears to be associated with a vasodilation in viscera and a vasoconstriction in skeletal muscle, such that systemic arterial pressure increases during REM sleep in rats.

Acute shifts in baroreflex control of renal sympathetic nerve activity induced by REM sleep and grooming in rats.

The present study aimed to determine the impact of  REM sleep and grooming on the baroreflex stimulus–response curve for renal sympathetic nerve activity (RSNA). At least 3 days before study, Wistar female rats (n= 12) were chronically implanted with catheters to measure systemic arterial pressure (Pa) and to intravenously infuse vasoactive drugs. In addition, electrodes were placed for measurements of RSNA, electroencephalogram, trapezius electromyogram and electrocardiogram. The baroreflex curve for RSNA was determined by changing Pa using rapid intravenous infusions of phenylephrine and nitroprusside and then fitted to an inverse sigmoid function curve. REM sleep induced a vertical suppression of the Pa–RSNA baroreflex curve, which was characterized by significant decreases in the maximum response (by 72.0%, P < 0.05) and the maximum gain (by 4.02% mmHg−1, P < 0.05) compared with NREM sleep level. Grooming shifted the Pa–RSNA baroreflex curve upward and to the right, which was associated with increases in the maximum response (by 45.2%, P < 0.05), the minimum response (by 20.7%, P < 0.05) and the pressure at the centring point (by 11.1 mmHg, P < 0.05). These data suggest that the Pa–RSNA baroreflex curve was shifted acutely and differently in a state‐dependent manner during natural sleep and wake cycle in rats.

The contribution of brain angiotensin II to the baroreflex regulation of renal sympathetic nerve activity in conscious normotensive and hypertensive rats

Angiotensin II receptor density in the brain is elevated when dietary salt intake is raised or in the state of hypertension. The aim of this study was to evaluate whether the angiotensin II modulation of the baroreceptor control of renal sympathetic nerve activity was altered under these conditions. Wistar rats, fed either a regular (0.25% w/w sodium) or high‐salt diet (3.1% w/w sodium), or stroke‐prone spontaneously hypertensive rats (SHRSPs) were implanted with cannulae in the carotid artery, jugular vein and the cerebroventricle and with recording electrodes on the renal sympathetic nerves. Three days later, baroreceptor gain curves were generated for renal sympathetic nerve activity and heart rate before and following intracerebroventricular (i.c.v.) administration of losartan (15 μg) to block angiotensin AT1 receptors. The rats fed a regular diet had a mean blood pressure of 116 ± 3 mmHg and heart rate of 467 ± 25 beats min−1, which remained unchanged after the i.c.v. administration of losartan. The sensitivity or curvature coefficient of the baroreceptor curve for renal sympathetic nerve activity was increased by 36% (P < 0.05) following losartan. In the rats fed a high‐salt diet, all cardiovascular variables and the losartan‐induced increase in the baroreceptor curvature coefficient for renal sympathetic nerve activity (29%) were similar to values in rats on the regular sodium diet. The heart rate baroreceptor curvature coefficient was not altered in either the rats fed a regular or a high‐salt diet. The slope of the renal sympathetic nerve activity baroreflex gain curve in the SHRSPs was less and the increase following administration of losartan (54%) was greater than in the Wistar rats. These data indicate that in the conscious state, the tonic inhibitory action of brain angiotensin II on the baroreflex regulation of renal sympathetic nerve activity was unaffected by raised dietary sodium, but its role was enhanced in the SHRSPs.

Functional role of diverse changes in sympathetic nerve activity in regulating arterial pressure during REM sleep.

STUDY OBJECTIVES This study aimed to investigate whether REM sleep evoked diverse changes in sympathetic outflows and, if so, to elucidate why REM sleep evokes diverse changes in sympathetic outflows. MEASUREMENTS Male Wistar rats were chronically implanted with electrodes to measure renal (RSNA) and lumbar sympathetic nerve activity (LSNA), electroencephalogram, electromyogram, and electrocardiogram, and catheters to measure systemic arterial and central venous pressure; these parameters were measured simultaneously and continuously during the sleep-awake cycle in the same rat. RESULTS REM sleep resulted in a step reduction in RNSA by 36.1% ± 2.7% (P < 0.05), while LSNA increased in a step manner by 15.3% ± 2% (P < 0.05) relative to the NREM level. Systemic arterial pressure increased gradually (P < 0.05), while heart rate decreased in a step manner (P < 0.05) during REM sleep. In contrast to REM sleep, RSNA, LSNA, systemic arterial pressure, and heart rate increased in a unidirectional manner associated with increases in physical activity levels in the order from NREM sleep, quiet awake, moving, and grooming state. Thus, the relationship between RSNA vs. LSNA and systemic arterial pressure vs. heart rate observed during REM sleep was dissociated compared with that obtained during the other behavioral states. CONCLUSIONS It is suggested that the diverse changes in sympathetic outflows during REM sleep may be needed to increase systemic arterial pressure by balancing vascular resistance between muscles and vegetative organs without depending on the heart.

Effect of stellate ganglionectomy on basal cardiovascular function and responses to β1-adrenoceptor blockade in the rat

Cardiac sympathetic nerve activity is an important short-term controller of cardiac function and arterial pressure. Studies also suggest that long-term increases in cardiac sympathetic nerve activity may contribute to hypertension, coronary artery disease, and cardiac remodeling in heart failure. However, our understanding of the role of cardiac sympathetic nerves in chronic models of cardiovascular disease has been limited by inadequate experimental approaches. The present study was conducted to develop a surgical method to surgically denervate the sympathetic nerves of the rat heart for long-term cardiovascular studies. We characterized the effect of cardiac sympathetic denervation on basal levels of mean arterial pressure (MAP) and heart rate (HR) and the responses to a chronic administration of atenolol, a beta1-adrenoceptor antagonist. Rats were instrumented with telemetry transmitters for continuous recording of MAP and HR. After a 4-day baseline period, the rats were subjected to bilateral stellate ganglionectomy (SGX; n=9) or sham surgery (Sham; n=8). Seven days following SGX or Sham, the rats were administered atenolol for 5 days, followed by a 7-day recovery period. Following a transient decrease, SGX had no effect on basal MAP but decreased HR compared with baseline and Sham rats. Five days of atenolol treatment decreased MAP similarly in SGX and Sham rats. Atenolol resulted in a marked bradycardia in Sham rats but had a neglible effects on HR in SGX rats. The measurement of the content of cardiac catecholamines in all cardiac chambers at the end of the study verified a successful sympathetic denervation. This study confirms that bilateral SGX is a useful method to study the contribution of cardiac sympathetic nerves on the regulation of cardiac function. Moreover, these results suggest that cardiac sympathetic nerves are relatively unimportant in maintaining the basal level of MAP or the depressor response to atenolol in conscious, unrestrained rats.

Imaging of the closed-chest mouse pulmonary circulation using synchrotron radiation microangiography

Structural and functional changes of pulmonary circulation related to pathophysiology of pulmonary arterial hypertension (PAH) remain to be fully elucidated. Angiographic visualization in in vivo animals provided a powerful tool for assessing the major indexes associated with the pathogenesis of PAH. In this study, we have exploited the full potential of synchrotron radiation (SR) microangiography to show the ability to visualize pulmonary hemodynamics in a closed-chest mouse. Male adult mice were anesthetized and cannulated with a customized 24-gauge catheter into the right ventricle via the jugular vein for administering iodine contrast agent. The microangiography was performed on the left lung. We measured dynamic changes in vessel diameter in response to acetylcholine (ACh) and acute exposure to hypoxic gas (10% O(2)). Moreover, the pulmonary transit time was estimated by the time of contrast agent circulating. We were able to visualize the pulmonary arteries from the left pulmonary artery (LPA) to the third generation of branching (inner diameter <100 μm). ACh and acute hypoxia induced vascular responses chiefly in the second and third branching vessels rather than the LPA and the first branching vessels. The transit time was only 0.83 s. These results demonstrate the effectiveness of SR for visualizing the pulmonary circulation in a closed-chest mouse. Future studies using SR microangiography on specific gene-targeted knockout and transgenic mice will provide new insights into the pathophysiology of pulmonary dysfunction and functional adaptation to survive in hypoxic condition.

Differential control of renal and lumbar sympathetic nerve activity during freezing behavior in conscious rats

The present study was designed to document changes in sympathetic nerve activity and cardiovascular function when conscious rats were challenged with a noise stressor to induce freezing behavior. The potential contribution of the arterial baroreceptors in regulating sympathetic nerve activity and cardiovascular adjustments during the freezing behavior was then examined. Wistar male rats were assigned to sham-operated (SO) and sinoaortic-denervated (SAD) groups and instrumented chronically with electrodes for measurements of renal (RSNA) and lumbar (LSNA) sympathetic nerve activity, electroencephalogram, electromyogram, and electrocardiogram and catheters for measurements of systemic arterial and central venous pressure. Both SO and SAD rats were exposed to 90 dB of white noise for 10 min, causing freezing behavior in both groups. In SO rats, freezing behavior was associated with an immediate and significant (P < 0.05) increase in RSNA, no changes in LSNA or mean arterial pressure, and a significant (P < 0.05) decrease in heart rate. SAD attenuated the magnitude of the immediate increase in RSNA and had no influence on the response in LSNA during freezing behavior compared with SO rats. Moreover, in SAD rats, mean arterial pressure increased significantly (P < 0.05) while heart rate did not change during the freezing behavior. These data indicate that freezing behavior evokes regionally different changes in sympathetic outflows, which may be involved in generating the patterned responses of cardiovascular function to stressful or threatening sensory stimulation. Moreover, it is suggested that the arterial baroreceptors are involved in generating the differential changes in RSNA and LSNA and thus the patterned changes in cardiovascular functions observed during freezing behavior in conscious rats.

Sympathetic nerve activity during sleep, exercise, and mental stress

This brief review describes recent findings on the differential regulation of sympathetic nerve activity and its role in regulating systemic arterial pressure during rapid eye-movement sleep, non-rapid-eye movement sleep, exercise and freezing behavior (mental stress). We describe the mechanisms underlying the differential regulation of sympathetic outflows and how they act in concert to orchestrate adjustments of cardiovascular function for the whole body, which are optimized to match changes in organ activity in daily activity.