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.

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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.

Abstract-Genetic factors that induce essential hypertension have been examined using genome-wide linkage analyses. A quantitative trait locus (QTL) region that is closely linked to hypertension has been found on chromosome 1 in stroke-prone spontaneously hypertensive rats (SHRSPs). We used 2 congenic rats in which the blood pressure QTL on rat chromosome 1 was introgressed from SHRSP/Izm to Wistar-Kyoto (WKY)/Izm (WKYpch1.0) and from WKY/Izm to SHRSP/Izm (SHRSPwch1.0) rats by repeated backcrossing. Previous studies reported that the intermediate phenotype of this QTL for hypertension is characterized by the hyperactivity of the sympathetic nervous system in response to physiological and psychological stress. We performed intracellular patch-clamp recordings of rostral ventrolateral medulla (RVLM) neurons from WKY, WKYpch1.0, SHRSPwch1.0, and SHRSPs and compared the basal electrophysiological activities of RVLM neurons and the responses of these neurons to angiotensin II. The basal membrane potential of RVLM neurons from WKYpch1.0 was significantly "shallower" than that of the neurons from WKY. The depolarization of RVLM neurons from WKYpch1.0 in response to angiotensin II was significantly larger than that in neurons from WKY rats, whereas the depolarization of RVLM neurons from SHRSPwch1.0 was significantly smaller than that in neurons from SHRSPs. The response to angiotensin II of RVLM neurons from WKYpch1.0 and SHRSPs was sustained even after the blockade of all of the synaptic transmissions using tetrodotoxin. The QTL on rat chromosome 1 was primarily related to the postsynaptic response of RVLM bulbospinal neurons to brain angiotensin II, whereas both the QTL and other genomic regions influenced the basal activity of RVLM neurons. Key Words: sympathetic nervous system Ⅲ congenic rat Ⅲ angiotensin II Ⅲ stress Ⅲ RVLM neurons .T he stroke-prone spontaneously hypertensive rat (SHRSP) is a useful model for the study of human essential hypertension. 1 Previous genome-wide analyses identified a potent quantitative trait locus (QTL) on rat chromosome 1 (Chr-1) that is responsible for hypertension in SHRSPs; this trait was confirmed in congenic strains for the QTLs. [2][3][4][5] Further analyses of the congenic strains suggested that this QTL harbored a gene (or genes) that regulated sympathetic responses to various stresses, such as restraint, cold, and air-jet stress. [5][6][7] Because the stressors used were either physical or emotional in nature, we hypothesized that a common pathway regulating sympathetic responses to stress might be responsible for this phenomenon. In this regard, the genetic effects of the Chr-1 QTL on the neuronal activity of the rostral ventrolateral medulla (RVLM), which is thought to determine the basal sympathetic nervous tone in response to various inputs from higher brain centers, 8,9 were explored in this study. In addition, among various modulators of RVLM activity, we particularly focused on the role of angiotensin II (Ang II) based on the following observations: physiological studi...

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