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.

Abstract-We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla (RVLM) of neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and responses to angiotensin II and its type 1 receptor antagonist candesartan. Using the whole-cell patch-clamp technique, we examined the characteristics of RVLM neurons in brainstem-spinal cord preparations with a preserved sympathetic neuronal network. The baseline membrane potential of irregularly firing neurons was less negative (Ϫ50.1Ϯ0.6 versus Ϫ52.0Ϯ0.6 mV) and the firing rate was faster (3.0Ϯ0.2 versus 2.0Ϯ0. Key Words: brain Ⅲ rostral ventrolateral medulla Ⅲ angiotensin II Ⅲ receptors, angiotensin Ⅲ candesartan Ⅲ hyperpolarization R ostral ventrolateral medulla (RVLM) neurons are located at a pivotal site involved in the baroreflex pathway and play a key role in controlling peripheral sympathetic nerve activity (SNA) and blood pressure (BP). [1][2][3] We have reported impairment of the baroreflex function in hypertension based on recordings of renal SNA (RSNA) in conscious rabbits and rats and on vagal afferent nerve activity. 4,5 We have also confirmed that the angiotensin (Ang) II type 1 (AT 1 ) receptor antagonist candesartan improves the impaired baroreflex in conscious rats with congestive heart failure. 6 Earlier studies examined the responses of BP and SNA to Ang II and Ang II antagonists microinjected into the RVLM of normotensive and hypertensive animals, 7-11 because the RVLM area contains Ang II-immunoreactive nerve terminals and a moderately high density of AT 1 receptors. 12 Microinjection of Ang II increased BP and SNA, 7-10 whereas candesartan reduced BP, RSNA, and heart rate (HR). 11 However, the precise neuronal mechanisms by which RVLM neurons regulate SNA and BP and how these neurons are involved in the development of hypertension have not been fully elucidated. The firing rate of extracellular units in RVLM neurons was faster in adult spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY) in vivo. 13 Iontophoretic application of Ang II increased the extracellular activity of 30% of RVLM neurons in both strains, and the increase was greater in SHR. 14 However, very few studies have compared the intracellular properties of RVLM neurons and responses to Ang II and its antagonist between WKY and SHR. Recently, we determined the intracellular electrophysiological characteristics of RVLM bulbospinal neurons in neonatal WKY using brainstem-spinal cord preparation, in which the neuronal network is preserved from the vagal afferents to the sympathetic efferents exiting the intermediolateral cell column. 15 In the present study, we performed intracellular recordings (whole-cell patch-clamp technique) of RVLM neurons in WKY and SHR during superfusion rather than microinjection of Ang II or candesartan to precisely understand the role of the RVLM neurons. Although BP of SHR increases above that of WKY sometime between 3 and 4 weeks of age, 16 RVLM neuron activity cannot be assumed to be iden...

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Key Words: angiotensin antagonist Ⅲ angiotensin II Ⅲ brain Ⅲ central nervous system Ⅲ mice Ⅲ receptors, angiotensin II Ⅲ sympathetic nervous system R ostral ventrolateral medulla (RVLM) neurons are located at an essential site involved in the baroreflex pathway and play a key role in controlling peripheral sympathetic nerve activity (SNA) and blood pressure (BP). 1,2 Previous studies examined the responses of BP and SNA to angiotensin II (Ang II) and Ang II antagonists microinjected into the RVLM of normotensive and hypertensive animals 3,4 because the RVLM area contains Ang II-immunoreactive nerve terminals and a moderately high density of Ang II type-1 (AT 1 ) receptors. 5,6 Microinjection of Ang II into the RVLM area increased BP and SNA, 3 whereas the AT 1 receptor blocker candesartan reduced BP, renal SNA, and heart rate. 4 To elucidate the precise electrophysiological changes within RVLM neurons elicited by Ang II and candesartan, we previously performed intracellular recordings (whole-cell patch-clamp technique) of RVLM neurons in neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). 7 We demonstrated that the electrophysiological properties of RVLM neurons and their responses to Ang II and candesartan differ between neonatal WKY and SHR. These results suggest that endogenously generated Ang II binds to AT 1 receptors on RVLM bulbospinal neurons, thus tonically generating a higher membrane potential and a faster firing rate in SHR.Ang II has 2 major receptor subtypes: the AT 1 and AT 2