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

Abstract

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.

Figure 1

Schematic drawing of the central and peripheral sympathetic nervous systems (original drawing by Kumagai). Increased activity of the rostral ventrolateral medulla (RVLM) neurons is transmitted to the intermediolateral (IML) cell column of the spinal cord, where peripheral sympathetic nerves to the heart, arterioles and kidneys are activated, thus increasing blood pressure (BP). Potentiated sensitivity of the subfornical organ to plasma angiotensin II (Ang II), and that of the subfornical organ and the lamina terminalis to serum Na, increases the efferent sympathetic activity and BP through the activation of the paraventricular nucleus (PVN) and the RVLM neurons in essential hypertension. A full color version of this figure is available at the Hypertension Research journal online.

Figure 2

Top; whole-cell patch-clamp recording of membrane depolarization and increase in firing rate of an RVLM bulbospinal neuron during Ang II (6 mmol l⁻¹) superfusion in brain stem-spinal cord preparation of neonatal SHR. Bottom; average changes in membrane potential of RVLM bulbospinal neurons. Values are the means±s.e.m. ^*P<0.05 vs. before superfusion. A full color version of this figure is available at the Hypertension Research journal online.

Figure 3

Top; whole-cell patch-clamp recording of membrane hyperpolarization and decrease in the firing rate of an RVLM bulbospinal neuron during candesartan (0.12 mmol l⁻¹) superfusion in an SHR preparation. Bottom; average changes in membrane potential of RVLM bulbospinal neurons. The changes in membrane potential during candesartan superfusion were significant when compared with the values obtained before superfusion in SHR, but not in WKY rats. A full color version of this figure is available at the Hypertension Research journal online.

Figure 4

Genotypic and phenotypic (BP and heart rate) characteristics of two strains of congenic rats (WKYpch1.0 rats and SHRSPwch1.0) that were developed by Professor Nabika et al. (reproduced from Iigaya et al.). A full color version of this figure is available at the Hypertension Research journal online.

Figure 5

Depolarization of a single RVLM neuron from rats carrying the chromosome 1 QTL (quantitative trait locus) of SHRSP (WKYpch1.0 and SHRSP) in response to superfusion with Ang II (6 μmol l⁻¹) was significantly larger than that from rats without the QTL (cited from Iigaya et al.). (a) Representative traces from each strain. (b) Changes in membrane potential (depolarization) of the RVLM neurons in response to Ang II superfusion (the mean±s.d. of eight neurons from different rats of each strain).

Figure 6

Method of optical imaging for brainstem–spinal cord preparation (reproduced from Iigaya et al.). Depolarizing responses in the ventrolateral medulla in response to IML stimulation were detected as difference in color. A full color version of this figure is available at the Hypertension Research journal online.

Figure 7

Optical imaging of the ventral surface of the medulla oblongata during superfusion with low-Ca²⁺, high-Mg²⁺ solution. Depolarizing responses to IML stimulation were detected on the ventral surface at the RVLM and the caudal end of the VLM (CeVLM) region (cited from Iigaya et al.).

Figure 8

Optical imaging of a cross section at the level of the caudal end of the VLM (CeVLM) during low-Ca²⁺, high-Mg²⁺ superfusion (cited from Iigaya et al.). A depolarizing response to the IML stimulation was detected at the CeVLM region (n=8).

Figure 9

Updated version of the central and peripheral sympathetic nervous systems (original drawing by Kumagai). Afferent renal nerves detect information regarding the state of the kidney, such as hypertension, ischemia, angiotensin II and adenosine, and are important in the regulation of efferent sympathetic nerve activities and BP. The importance of RVLM neurons is also understood as a pivotal position in the determination of sympathetic nerve activities. A full color version of this figure is available at the Hypertension Research journal online.