Importance of rostral ventrolateral medulla neurons in determining efferent sympathetic nerve activity and blood pressure.

Accentuated sympathetic nerve activity (SNA) is a risk factor for cardiovascular events. In this review, we investigate our working hypothesis that potentiated activity of neurons in the rostral ventrolateral medulla (RVLM) is the primary cause of experimental and essential hypertension. Over the past decade, we have examined how RVLM neurons regulate peripheral SNA, how the sympathetic and renin-angiotensin systems are correlated and how the sympathetic system can be suppressed to prevent cardiovascular events in patients. Based on results of whole-cell patch-clamp studies, we report that angiotensin II (Ang II) potentiated the activity of RVLM neurons, a sympathetic nervous center, whereas Ang II receptor blocker (ARB) reduced RVLM activities. Our optical imaging demonstrated that a longitudinal rostrocaudal column, including the RVLM and the caudal end of ventrolateral medulla, acts as a sympathetic center. By organizing and analyzing these data, we hope to develop therapies for reducing SNA in our patients. Recently, 2-year depressor effects were obtained by a single procedure of renal nerve ablation in patients with essential hypertension. The ablation injured not only the efferent renal sympathetic nerves but also the afferent renal nerves and led to reduced activities of the hypothalamus, RVLM neurons and efferent systemic sympathetic nerves. These clinical results stress the importance of the RVLM neurons in blood pressure regulation. We expect renal nerve ablation to be an effective treatment for congestive heart failure and chronic kidney disease, such as diabetic nephropathy.

Candesartan and insulin reduce renal sympathetic nerve activity in hypertensive type 1 diabetic rats.

The nonlinearity of cardiovascular regulation is higher in normal physiology, whereas several diseases are characterized by a reduction in this nonlinearity. Reduced nonlinearity of heart rate regulation is a robust risk factor for high mortality in patients with myocardial infarction. We investigated the changes in linear and nonlinear correlations of cardiovascular regulation after administering drugs in hypertensive diabetic rats. Type 1 diabetes was induced in rats by intraperitoneally injecting spontaneously hypertensive rats with streptozotocin. The animals were then divided into 4 groups and each group was given vehicle, candesartan, amlodipine, or insulin for 2 weeks. Blood pressure, heart rate, renal sympathetic nerve activity, and renal blood flow were simultaneously recorded in the conscious state, and the linear and nonlinear correlations were compared by using coherence and the mutual information method. Candesartan and amlodipine decreased blood pressure to a similar extent, but renal sympathetic nerve activity was significantly lower in the candesartan group than in the vehicle group. The renal sympathetic nerve activity in the insulin group was also lower than in the vehicle group. There were no significant differences in linear correlation among the 4 groups. In contrast, the nonlinear correlations between renal sympathetic nerve activity and blood pressure in the candesartan group and the insulin group were significantly higher than in the vehicle group. Candesartan and insulin decreased renal sympathetic nerve activity and increased the nonlinearity. These results suggest that reducing the activity of renin-angiotensin system and insulin that lowers blood glucose level may improve autonomic nervous system dysfunction and neurohumoral regulation of the cardiovascular system in diabetic hypertensive rats.

Novel axonal projection from the caudal end of the ventrolateral medulla to the intermediolateral cell column.

We used an optical imaging technique to investigate whether axons of neurons in the caudal end of the ventrolateral medulla (CeVLM), as well as axons of neurons in the rostral ventrolateral medulla (RVLM), project to neurons in the intermediolateral cell column (IML) of the spinal cord. Brain stem-spinal cord preparations from neonatal normotensive Wistar-Kyoto and spontaneously hypertensive rats were stained with a voltage-sensitive dye, and responses to electrical stimulation of the IML at the Th2 level were detected as changes in fluorescence intensity with an optical imaging apparatus (MiCAM-01). The results were as follows: 1) depolarizing responses to IML stimulation during low-Ca high-Mg superfusion were detected on the ventral surface of the medulla at the level of the CeVLM, as well as at the level of the RVLM, 2) depolarizing responses were also detected on cross sections at the level of the CeVLM, and they had a latency of 24.0 +/- 5.5 (SD) ms, 3) antidromic action potentials in response to IML stimulation were demonstrated in the CeVLM neurons where optical images were detected, and 4) glutamate application to the CeVLM increased the frequency of excitatory postsynaptic potentials (EPSPs) and induced depolarization of the IML neurons. The optical imaging findings suggested a novel axonal and functional projection from neurons in the CeVLM to the IML. The increase in EPSPs of the IML neurons in response to glutamate application suggests that the CeVLM participates in the regulation of sympathetic nerve activity and blood pressure and may correspond to the caudal pressor area.

Electrophysiological properties of rostral ventrolateral medulla neurons in angiotensin II 1a receptor knockout mice.

We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla of neonatal angiotensin II type 1a receptor knockout mice and wild-type mice with responses to angiotensin II, its type-1 receptor blocker candesartan, and its type-2 receptor blocker PD123319. Using the whole-cell patch-clamp technique, we examined the characteristics of rostral ventrolateral medulla neurons in brain stem-spinal cord preparations in which the sympathetic neuronal network is preserved. Baseline membrane potential and firing rate were almost similar between angiotensin II type 1a receptor knockout mice and wild-type mice. Superfusion with angiotensin II depolarized rostral ventrolateral medulla bulbospinal neurons in wild-type mice, whereas it hyperpolarized those in angiotensin II type 1a receptor knockout mice. Because pretreatment with candesartan significantly prevented the angiotensin II-induced depolarization in wild-type mice, the angiotensin II type 1 receptor is crucial for this depolarization. Superfusion with PD123319 depolarized rostral ventrolateral medulla bulbospinal neurons in angiotensin II type 1a receptor knockout mice. PD123319 prevented the angiotensin II-induced hyperpolarization in angiotensin II type 1a receptor knockout mice, and, rather, it induced depolarization. These results suggest that the angiotensin II type 2 receptor in rostral ventrolateral medulla plays an antagonistic role against the angiotensin II type 1a receptor in controlling the neuronal activity of rostral ventrolateral medulla.

Low-order chaos in sympathetic nerve activity and scaling of heartbeat intervals.

The mechanism of 1/f scaling of heartbeat intervals remains unknown. We recorded heartbeat intervals, sympathetic nerve activity, and blood pressure in conscious rats with normal or high blood pressure. Using nonlinear analyses, we demonstrate that the dynamics of this system of three variables is low-order chaos, and that sympathetic nerve activity leads to heartbeat interval and blood pressure changes. It is suggested that impaired regulation of blood pressure by sympathetic nerve activity is likely to cause experimentally observable steeper scaling of heartbeat intervals in hypertensive (high blood pressure) rats.

[Comparison of ARB and ACEI for renoprotection in chronic glomerulonephritis].

This 1.5-year prospective study compared the effects of angiotensin II receptor blocker, candesartan(n = 21), and ACE inhibitor(ACEI, n = 23) on proteinuria and renal function in patients with moderate renal impairment due to chronic glomerulonephritis. Blood pressure reductions were comparable between both groups. Proteinuria was significantly reduced from 2.1 +/- 0.4 (mean +/- SE) to 0.6 +/- 0.2 g/day(p < 0.001) with candesartan, and the reduction was significantly larger than with ACEI(p < 0.01). Serum creatinine did not increase with candesartan or ACEI, suggesting the renoprotective effect. Serum potassium increased significantly with both drugs from 6 months. Plasma aldosterone concentrations(PAC) showed a stronger suppression with candesartan(150 pg/ml before treatment and 51 at 1.5 years) than with ACEI(104 pg/ml at 1.5 years). Plasma renin activity with candesartan(1.0 ng/ml/hr before treatment) decreased from 3.9 ng/ml/hr at 6 months to 1.3 at 1.5 years, whereas PRA remained elevated with ACEI. We speculate that the stronger reduction of PAC contributed to suppression of growth of mesangial matrix and the interstitial fibrosis in the candesartan group.

Potentiated sympathetic nervous and renin-angiotensin systems reduce nonlinear correlation between sympathetic activity and blood pressure in conscious spontaneously hypertensive rats.

BACKGROUND: Patients with a reduced nonlinear component of heart rate regulation have a poorer outcome. METHODS AND RESULTS: We investigated whether a nonlinear correlation between renal sympathetic nerve activity (RSNA) and blood pressure or renal blood flow is reduced in conscious, spontaneously hypertensive rats (SHR) by comparing them with normotensive Wistar-Kyoto rats (WKY). We also determined the linearity and nonlinearity of the correlation in SHR who were given an angiotensin II receptor blocker, candesartan, orally for 2 weeks. The RSNA value was higher in SHR than in WKY, and coherence peaks of transfer function were found at 0.05 and 0.80 Hz (ie, below respiratory- and cardiac-related fluctuations). The coherence (linearity) of the transfer function was significantly higher and gain was smaller in SHR than in WKY. Because mutual information values (linear and nonlinear correlation) were similar in both strains, we found the nonlinear correlation to be lower in SHR than in WKY. Time delay values calculated by the mutual information method demonstrated that RSNA preceded blood pressure and renal blood flow by 0.5 to 1.0 s. In SHR given candesartan, the RSNA value was lower, and the linearity was lower and nonlinearity higher than SHR given vehicle. CONCLUSIONS: Linear correlation between RSNA and blood pressure or renal blood flow was higher in SHR than in WKY, whereas the nonlinear correlation was lower. Oral treatment with candesartan increased the nonlinearity and reduced the linearity in SHR. Increased RSNA and the renin-angiotensin system may be responsible for the lower nonlinearity and higher linearity in hypertension.