Neurons In Rostral Ventrolateral Medulla Research Articles

Cardiovascular effects produced by activation of GABA receptors in the rostral ventrolateral medulla of conscious rats

The rostral ventrolateral medulla (RVLM) has been proposed as a region playing a major role in the tonic and reflex control of sympathetic vasomotor activity and blood pressure. Pharmacological activation of GABA A receptors with muscimol in the RVLM of anesthetized rats results in a large fall in mean arterial pressure (MAP), heart rate (HR) and sympathetic activity. In this study we evaluated the effects of activation of GABA receptors in the RVLM of conscious, freely moving rats. Bilateral microinjections of muscimol into the RVLM of conscious rats produced a large fall in MAP (−38±4 mm Hg, n=7) when compared with saline injections (NaCl 0.9%, 7±1 mm Hg, n=4). The decrease in MAP evoked by muscimol was accompanied by a significant increase in HR (muscimol 69±13 bpm vs. vehicle −33±12 bpm, P<0.05), an effect that was completely abolished by beta1 adrenergic receptor blockade. Conversely, bilateral microinjections of GABA B agonist, baclofen, evoked a pressor response, but in this case, the increase was not significantly different from that evoked by vehicle injections. These results 1) indicate that GABA A receptors have a powerful influence on the resting activity of RVLM neurons in conscious rats; 2) indicate that a compensatory sympathetic-mediated tachycardia is present after inhibition of RVLM neurons in conscious rats; 3) confirm and extend previous findings showing that RVLM neurons are critical for blood pressure maintenance even in normal non-anesthetized conditions.

Differential responsiveness of RVLM sympathetic premotor neurons to hypoxia in rabbits

To determine whether differential sympathetic nerve responses to hypoxia are explained by opposing effects of hypoxia upon sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), the cardiac sympathetic nerve and the renal sympathetic nerve were recorded in anesthetized and vagotomized rabbits. Renal sympathetic nerve was activated by the injection of sodium cyanide solution close to the bifurcation of the common carotid artery and/or by inhalation of hypoxic gas (3% oxygen-97% nitrogen). On the other hand, cardiac sympathetic nerve was inhibited by these stimuli. Barosensitive (inhibited by the stimulation of baroreceptor afferents) reticulospinal (antidromically activated by the stimulation of the spinal cord) neurons in the RVLM were divided into three groups according to their responses to hypoxic stimulation: neurons (Type I, n = 25), the activity of which was inhibited by the injection of sodium cyanide solution close to the bifurcation of the common carotid artery and/or by inhalation of hypoxic gas, neurons (Type II, n = 99), the activity of which was facilitated by the same stimulation, and neurons (Type III, n = 11), the activity of which was not changed. These data indicated that the differential responses of cardiac and renal sympathetic nerves might be due to opposing effects of hypoxia on individual RVLM neurons.

Repetition rates of specific interval patterns in single spike train reflect excitation level of specific receptor types, shown by high-speed favored-pattern detection method

Interval patterns in single spike train, e.g. “favored patterns (FPs, the FP is a sequence of successive intervals of action potentials that occur more often than what is reasonably expected at random.)”, may represent neural codes containing information. The present study developed a ”high-speed FP-detection method” which could qualitatively and quantitatively analyze FPs. By using this method, single spike trains of nucleus paraventricularis (NPV) and rostral ventrolateral medulla (RVL) having different firing patterns, being involved in regulation of arterial pressure, and controlled by different transmitters, were chosen for analysis. Results: (1) Corticotropin releasing factor, substance P and agonists of α-, β- and M-receptor microinjected into these brain areas, respectively, induced dominant change of specific FP. Repetition rates of specific FPs reflect excitation level of specific receptor types. It shows that chemical codes (different transmitters with their receptor types or subtypes) are transformed into electrical codes (different FPs). (2) When α-, β- and M-receptors of RVL neurons were activated simultaneously by intrinsic excitatory transmitters released due to activation of input pathway, only repetition rate of the specific FP that represented the predominant activity of the receptor type (α-adrenergic receptor) markedly increased. The activities of other receptor types (β- and M-receptors) were masked. (3) Intrinsic inhibitory transmitters (GABA, β-endorphin) in the RVL all decreased specific FP repetition rate of dominant receptor type. These results may provide a new way to further explore how information in the CNS is conveyed and processed.

Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Bötzinger complex (preBötC) is the primary site of respiratory rhythm generation in the mammal

Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Bötzinger complex (preBötC) is the primary site of respiratory rhythm generation in the mammal

Evidence that estrogen directly and indirectly modulates C1 adrenergic bulbospinal neurons in the rostral ventrolateral medulla

Blood pressure in women increases after menopause, and sympathetic tone in female rats decreases with estrogen injections in the rostral ventrolateral medulla (RVLM) region that contains bulbospinal C1 adrenergic neurons and is involved in blood pressure control. We investigated the anatomical and physiological basis for estrogen effects in the RVLM. Neurons with α- or β-subtypes of estrogen receptor (ER) immunoreactivity (-ir) overlapped in distribution with tyrosine hydroxylase (TH)-containing C1 neurons. Immunoelectron microscopy revealed that ERα- and ERβ-ir had distinct cellular and subcellular distributions. ERα-ir was most commonly in TH-lacking profiles, many of which were axons and peptide-containing afferents that contacted TH-containing dendrites. ERα-ir was also in some TH-containing dendrites. ERβ-ir was most frequently in TH-containing somata and dendrites, particularly on endoplasmic reticula, mitochondria, and plasma membranes. In whole-cell patch clamp recordings from isolated bulbospinal RVLM neurons, 17β-estradiol dose-dependently reduced voltage-gated Ca ++ currents, especially the long-lasting (L-type) component. This inhibition was reversed by washing or prevented by adding the non-subtype-selective ER antagonist ICI182780. An ERβ-selective agonist, but not an ERα-selective agonist, reproduced the Ca ++ current inhibition. The data indicate that estrogens can modulate the function of RVLM C1 bulbospinal neurons either directly, through extranuclear ERβ, or indirectly through extranuclear ERα in selected afferents. Moreover, Ca ++ current inhibition may underlie the decrease in sympathetic tone evoked by local 17β-estradiol application. These findings provide a structural and functional basis for the effects of estrogens on blood pressure control and suggest a mechanism for the modulation of cardiovascular function by estrogen in women.

A monosynaptic connection between baroinhibited neurons in the RVLM and IML in Sprague-Dawley rats

To date, few studies have examined the relationship between the firing rate of neurons in the rostral ventrolateral medulla (RVLM) and neurons in the intermediolateral cell column (IML) of the spinal cord. In 19 Sprague-Dawley rats, the relationship between 20 pairs of baroinhibited RVLM and IML units was analyzed by cross-correlation. Three criteria were applied before acceptance that the firing rate of a pair of neurons was correlated. First, at an appropriate latency following the firing of an RVLM neuron, as judged from previous studies (4–200 ms), the peak in the firing rate of an IML neuron was approximately double that of the averaged surrounding bin counts. Secondly, the peak grew steadily in the examined period. Thirdly, the peak was restricted to a 1-ms bin. With this approach, a correlation was found between RVLM and IML neurons in 3 pairs in all. In 2 pairs, a correlation was found at basal arterial pressure (AP). When AP was decreased using a caval snare, a correlation was demonstrated in a further pair. A possible potentiation of synaptic strength during hypotensive stimuli is discussed.

Central respiratory modulation of barosensitive neurones in rat caudal ventrolateral medulla

The sympathetic nerves that maintain blood pressure are modulated by the central respiratory generator. Neurones in the rostral ventrolateral medulla (RVLM) that drive this sympathetic nerve activity (SNA) also display central respiratory drive (CRD)-related activity, suggesting integration of respiratory and cardiovascular regulatory systems within the brainstem. Whether CRD-related activity in the RVLM is due to direct inputs from central respiratory neurones or modulation of cardiovascular-related neurones that influence the RVLM is not known. The caudal ventrolateral medulla (CVLM) contains GABAergic neurones that tonically inhibit presympathetic RVLM neurones and are essential for the production of numerous cardiovascular reflexes. The present study sought to determine whether cardiovascular-related GABAergic neurones in the CVLM display CRD-related activity. The firing patterns of individual barosensitive CVLM neurones were examined in relation to phrenic nerve activity in chloralose-anaesthetized, ventilated, neuromuscularly blocked, vagotomized rats. Histograms of phrenic-triggered CVLM neuronal activity showed that all baro-activated CVLM neurones displayed one of four patterns of CRD-related activity: (i) inspiratory peak (n = 15), (ii) inspiratory depression (n = 15), (iii) inspiratory peak with postinspiratory depression (n = 10), and (iv) postinspiratory peak (n = 9). A subset of each type of CVLM neurone was identified as GABAergic by individually filling the recorded neurone with biotinamide and observing expression of GAD67 mRNA by in situ hybridization (n = 10). These data suggest that the activity of GABAergic neurones in the CVLM is regulated by cardiovascular and respiratory inputs, and baro-activated GABAergic CVLM neurones may contribute to CRD-related modulation of presympathetic RVLM neurones and SNA.

Attenuation of homeostatic responses to hypotension and glucoprivation after destruction of catecholaminergic rostral ventrolateral medulla neurons

This study determined the effect of destruction of rostral ventrolateral medulla (RVLM)-C1 cells on integrated sympathetic and hormonal responses to hypotension or glucoprivation. Injection of anti-dopamine beta-hydroxylase-saporin into the RVLM resulted in 29-99% depletion of RVLM-C1 neurons and approximately 60% reduction in the number of A5 neurons. As in our previous study in unanesthetized rats, resting mean arterial pressure (MAP) was reduced by approximately 10 mmHg in rats with >80% depletion of RVLM-C1 cells compared with control rats, although resting heart rate (HR) did not differ significantly. In the present study, resting plasma levels of norepinephrine (NE) did not differ significantly between control rats and rats with >80% depletion of RVLM-C1 cells, although there was a tendency for RVLM-C1 lesioned rats to have lower levels. Also consistent with our previous study, hydralazine (HDZ)-evoked hypotension resulted in smaller increases in HR and plasma levels of NE in rats with >80% depletion of RVLM-C1 cells compared with control rats. Furthermore, the elevated plasma levels of posterior pituitary hormones vasopressin and oxytocin evoked by HDZ were blunted in RVLM-C1 lesioned rats compared with control rats, even though MAP fell to lower levels in the lesioned rats. Plasma renin activity, plasma osmolality, and plasma protein concentrations did not differ between control rats and rats with >80% depletion of RVLM-C1 neurons. In response to systemic administration of 2-deoxyglucose, the circulating level of epinephrine and the resulting hyperglycemia were attenuated in rats with >80% depletion of RVLM-C1 cells compared with control rats. These results demonstrate that RVLM-C1 cells, in addition to playing a role in acute cardiovascular reflexes, play an important role in integrated sympathetic and hormonal responses to homeostatic challenges such as hypotension and glucoprivation.

Differential baroreceptor modulation mediated by the ventrolateral medulla

Previous studies have shown that pharmacological stimulation of a region denominated caudal pressor area (CPA), located in the caudal end of the ventrolateral medulla, induces increases in arterial blood pressure (BP). The aim of this study was to compare the responses on renal sympathetic nerve activity (rSNA) and BP responses mediated by stimulation of CPA or rostral ventrolateral medulla (RVLM), in intact or sino-aortic barodenervated rats. Male Wistar rats (300–350 g, n = 15) were anesthetized (urethane 1.2 to 1.4 g/kg, i.v.) and artificially ventilated. The mean arterial pressure (MAP) and rSNA were measured during bilateral glutamate microinjection (10 nmo/100 nl) into the CPA or into the RVLM. Glutamatergic stimulation of the RVLM increased MAP (46 ± 7 mm Hg) and rSNA (82 ± 21%); during CPA stimulation, MAP and rSNA increased 60 ± 7 mm Hg and 93 ± 9%, respectively. However, despite the similarity of responses mediated by both regions, the duration of rSNA and blood pressure responses mediated by the CPA were significantly longer than the duration of the responses mediated by the RVLM. After barodenervation, there was an increase in the time-course and magnitude of sympathetic response only in response to RVLM stimulation but not in response to CPA. The results suggest a differential baroreceptor modulation on rSNA mediated by the ventrolateral medulla neurons. Glutamatergic activation of CPA neurons can cause large increases in the rSNA and BP with a weaker baroreceptor modulation when compared to responses mediated by the RVLM neurons.

Sympathoexcitation in chronic heart failure: Ang II induced inhibition of voltage‐gated K + channel, an in vivo and in vitro study

We have reported that elevated central Ang II plays a critical role in sympathoexcitation of chronic heart failure (CHF) by stimulating up-regulated AT1 receptors in rostral ventrolateral medulla (RVLM). However, the link between enhanced Ang II signaling and electrophysiological characteristics of neurons in RVLM remains unclear. In the present experiments, we first screened for potentially altered genes in the brainstem of rats with CHF that relate membrane conductance in neurons using the Rat Genome 230 2.0 Array GeneChip. We found that Kv 4.3 gene was significantly down-regulated in the CHF rats (-2.1 ± 0.2 times, P < 0.05, n = 3). Second, we used real-time PCR and Western blot further to confirm this down regulation of Kv 4.3 in the RVLM of CHF rats (mRNA: 1.3 ± 0.1 to 0.7 ± 0.1, P < 0.05; protein: 2.0 ± 0.1 to 0.9 ± 0.1, P < 0.05). Finally, we used a neuronal cell line (CATH.a neurons) to explore the effect of Ang II on Kv 4.3. We found that Ang II treatment (1) down-regulated the mRNA (0.4 ± 0.1 to 0.2 ± 0.1, P < 0.05) and protein (1.5 ± 0.2 to 0.6 ± 0.1, P < 0.05) of Kv 4.3; (2) decreased the K+ peak current (Ik: 289.6 ± 31.5 to 143.3 ± 8.9 pA, P < 0.05); and (3) up-regulated the mRNA (0.7 ± 0.1 to 1.8 ± 0.2, P < 0.05) and protein (0.8 ± 0.1 to 1.5 ± 0.2, P < 0.05) of the AT1 receptor. We conclude that the sympathoexcitation of CHF may be due to, in part, the effect of Ang II down-regulating the Kv 4.3 expression and decreasing Ik, and thereby increasing the excitability of neurons in the RVLM, via the enhanced AT1 receptor expression. (Supported by NIH grant HL PO-1 62222).

Cholecytokinin activates baro‐activated neurons in rat caudal ventrolateral medulla

Cholecystokinin (CCK) is a gastointestinal hormone that produces intestinal vasodilation, which appears to be mediated by reduced sympathetic nerve activity to the gut. Intravenous injection of CCK inhibits splanchnic nerve activity (SNA) and reduces the firing of a subset of pre-sympathetic neurons in the rostral ventrolateral medulla (RVLM) in chloralose-anesthetized rats. We determined whether the inhibition of RVLM neurons could be produced by the activation of GABAergic neurons in the caudal ventrolateral medulla (CVLM). In chloralose-anesthetized, artificially ventilated, paralyzed rats, we measured the effects of CCK (10 μg/kg, iv) on arterial pressure (AP), SNA, heart rate, and the firing of baro-activated, pulse-modulated CVLM neurons. CCK decreased SNA (49±10 %), heart rate (42±7 bpm), and AP (24±10 mmHg). The firing of 3 of 5 baro-activated CVLM neurons was increased by CCK (4 to 11 spikes/sec), but 2 of 5 did not change or were inhibited during the accompanying decrease in AP. In contrast, 8 of 10 neighboring baro-inhibited neurons were inhibited by CCK (3 to 0.4 spikes/sec). Four of these cells were silenced briefly. These data suggest a subset of baro-activated CVLM neurons are activated by CCK and may produce the inhibition observed in some pre-sympathetic RVLM neurons. Furthermore, these data suggest that baro-activated CVLM neurons may be subdivided into CCK-sensitive and CCK-insensitive neurons. Supported by NIH: RO1 HL075174.

Rostral ventrolateral medulla regulates pancreatic and gastric blood flow

Premotor neurons controlling pancreatic sympathetic outflow originate from several sources including the rostral ventrolateral medulla (RVLM). This study was designed to test the hypothesis that pancreatic sympathetic vasomotor outflow is driven by RVLM neurons. Halothane-anesthetized, paralysed, male Sprague-Dawley rats received electrical stimulation (50 Hz, 25–75 μA, 0.5 ms pulse duration, 10 s) of the RVLM region which had been localised electrophysiologically. Pancreatic conductance (Gpanc) gastric conductance (Ggas), arterial blood pressure and heart rate were measured. Administration of phenylephrine (5 μg/kg, i.v.) or sodium nitroprusside (5 μg/kg, i.v.) drugs produced decreases and increases in Gpanc and Ggas, respectively. Carbachol (0.5–2.0 μg/kg, i.v., n=5) also produced increases in Gpanc and Ggas indicating the presence a muscarinic vasodilator mechanism. Stimulation of the RVLM (n=5 rats) produced increases in arterial blood pressure accompanied by marked reductions in Gpanc and Ggas. These were abolished by ganglion blockade (hexamethonium bromide, 20 mg/kg, i.v.). Cardiopulmonary vagal afferent stimulation (phenylbiguanide, 10 μg/kg, i.v., n=5) produced depressor responses and increases in Gpanc and Ggas. These data indicate that the RVLM contributes to regulation of the sympathetic vasomotor outflow to the pancreas and stomach. Presumably, non-RVLM sympathetic premotor cell groups modulate other pancreatic functions such as glucagon release.

Fractal noises and motions in time series of presympathetic and sympathetic neural activities

We used Allan factor analysis to classify time series of the discharges of single presympathetic neurons in the cat medullary lateral tegmental field (LTF) and rostral ventrolateral medulla (RVLM) and of the postganglionic vertebral sympathetic nerve. These time series fell into two classes of fractal signals characterized by statistically self-similar behavior reflecting long-range correlations among data points. Classification of a time series as either fractional Gaussian noise (fGn) or fractional Brownian motion (fBm) was based on the scaling exponent, alpha, of the power law in the Allan factor curve. fGn is defined as 0 < alpha < 1 and fBm as 1 < alpha < 3. All but one of the spike trains of 12 classifiable LTF neurons with sympathetic nerve-related activity were fGn. In contrast, the spike trains of 8 of 9 RVLM presympathetic neurons that could be classified were fBm. The time series of simultaneously recorded vertebral sympathetic nerve discharge and heart period fell into the fBm class. Because a fBm signal is the cumulative sum of the elements comprising the corresponding fGn signal, these results demonstrate smoothing of fractal time series in a feedforward direction from medullary presympathetic neurons to postganglionic sympathetic neurons. Whether this involves integration by RVLM neurons of their LTF inputs or independent fractal processes acting at different levels of the network controlling sympathetic nerve discharge remains to be determined. (Supported by NIH HL-33266.)

Elevated sympathetic outflow in hypovolemic rats depends upon the tonic activity of RVLM neurons

Elevated sympathetic outflow contributes to the maintenance of arterial blood pressure (ABP) during hypovolemia. The neural mechanisms underlying this response are not completely understood but likely involve neurons in the rostral ventrolateral medulla (RVLM). To test this hypothesis, male Sprague-Dawley rats (300–325 g) were made hypovolemic by an injection of furosemide (10 mg/kg, sc) and denied access to food and water. Control rats received an injection of isotonic saline (1 ml/kg, sc). Two hours later, rats were anesthetized with inactin (100 mg/kg, ip) and the RVLM was inhibited bilaterally with microinjection of the GABAA receptor agonist muscimol (100 pmol per 50 nl per side). Bilateral inhibition of the RVLM produced a significantly greater decrease in mean ABP of furosemide-treated rats versus control rats (50±3 vs 36±3 mmHg, respectively; P<0.05, n=4 per group) although baseline mean ABP was not different (99±3 vs 102±2 mmHg, respectively). Administration of the ganglionic blocker hexamethonium (30 mg/kg, iv) produced a significantly greater fall in mean ABP of furosemide-treated rats versus control rats (47±3 vs 35±2 mmHg, respectively; P<0.05, n=4 per group). As expected, furosemide treatment significantly increased hematocrit (51±1 vs 44±1%, P<0.05) and plasma protein concentration (7.3±0.1 vs 5.8±0.2 g/dl, P<0.01) but did not alter plasma osmolality (298±3 vs 298±2 mOsm/kg). These findings suggest that sympathetic outflow contributes more to the maintenance of ABP in hypovolemic rats and this depends, at least partly, on the tonic activity of RVLM neurons. Supported by NIH HL073661 and University of Kentucky College of Medicine.

Rostral Ventrolateral Medulla mediate the Sympathoexcitatory influence from Caudal Pressor Area in Spontaneously Hypertensive Rats

The caudal pressor area (CPA), located in the caudal extent of ventrolateral medulla, tonically activates sympathoexcitatory outflow via the rostral ventrolateral medulla (RVLM) vasomotor neurons and regulates the blood pressure in normotensive animals. However, sympathoexcitatory influence from CPA in the hypertensive status have not been well examined. The sympathoexcitation from the CPA is independent of excitatory amino acid (EAA)-sensitive RVLM neurons in normotensive rats, thus other than EAA receptors may mediate these pathway. It has been reported that, in spontaneously hypertensive rats (SHR), one of the reason for maintaining high blood pressure is over-expression of AT1 receptor in RVLM. Moreover, previously we have reported that sympathoexcitatory input from CPA is enhanced in SHR (EB2003). On the basis of these findings, we hypothesized that the sympathoexcitatory influence from CPA is mediated by AT1 receptors in SHR. In chloralose-anesthetized male SHR, injection of glutamate into the CPA elicited a pressor response (27±2 mm Hg) that was substantially larger than that of WKY. Preinjection of Valsaltan into bilateral RVLM significantly attenuated the response of CPA (7±4 mmHg). In contrast, preinjection of aCSF did not change the response. These results indicate that the sympathoexcitatory influence evoked from CPA is mediated by AT1 receptor in RVLM. According to these results, enhancement of non-EAA dependent sympathoexcitatory influence from CPA and over-expression of AT1 receptor in RVLM may participate in maintenance of high blood pressure in SHR.

Estrogen in the parabrachial nucleus attenuates the sympathoexcitation following MCAO in male rats

Recent investigations have provided evidence to suggest systemic estrogen administration prevented or reversed the sympathoexcitation observed following middle cerebral artery occlusion (MCAO) in male rats. The present investigation sought to determine the role of estrogen injected directly into the parabrachial nucleus (PBN) on the MCAO-induced sympathoexcitation as well as the role of the rostral ventrolateral medulla (RVLM) in mediating the sympathoexcitatory response. Male Sprague–Dawley rats were anesthetized with sodium thiobutabarbitol (100 mg/kg) and were instrumented to continuously record blood pressure, heart rate and renal sympathetic nerve activity (RSNA). Following occlusion of the middle cerebral artery, there was a significant increase in RSNA (from 3.8 ± 0.4 to 8.3 ± 0.6 μV/s; P < 0.05) which was significantly attenuated by the prior bilateral injection of estrogen (0.5 μM in 200 nl) into the PBN. Pre-injection of lidocaine (5% in 200 nl) directly into the RVLM resulted in only a slight reduction in the magnitude of the MCAO-induced sympathoexcitation ( P > 0.05). Extracellular electrophysiological recordings from RVLM neurons demonstrated that MCAO did not produce any significant change in neuronal activity over the experimental time course ( P > 0.05). Also, bilateral injection of estrogen into the PBN prior to MCAO or sham conditions did not result in any significant change in RVLM neuronal activity. These results indicate that estrogen receptors in the PBN play a major role in modulating the sympathoexcitatory response from ischemic forebrain nuclei, and that the pathway from the PBN to sympathetic preganglionic nuclei may not involve a synapse in the RVLM.

The mysterious role of prostaglandin E2 in the medullary raphé: a hot topic or not?

the study by tanaka and mcallen published in this issue of American Journal of Physiology–Regulatory Integrative and Comparative Physiology ([32][1]) addresses a subject of considerable interest in the field of thermoregulation and one that for many years has been central to our understanding of

Fractal Noises and Motions in Time Series of Presympathetic and Sympathetic Neural Activities

We used Allan factor analysis to classify time series of the discharges of single presympathetic neurons in the cat medullary lateral tegmental field (LTF) and rostral ventrolateral medulla (RVLM) and of the postganglionic vertebral sympathetic nerve. These time series fell into two classes of fractal-based point processes characterized by statistically self-similar behavior reflecting long-range correlations among data points. Classification of a time series as either a fractional Gaussian noise (fGn)-or fractional Brownian motion (fBm)-based point process depended on the scaling exponent, alpha, of the power law in the Allan factor curve. fGn is defined as 0 < alpha < 1 and fBm as 1 < alpha < 3. The process responsible for the fractal spike trains of 11 of 12 classifiable LTF neurons with sympathetic nerve-related activity was fGn. In contrast, the process responsible for the fractal spike trains of eight of nine classifiable RVLM presympathetic neurons was fBm. The time series of simultaneously recorded vertebral sympathetic nerve discharge and the arterial pulse also were fBm-based signals. Because a fBm signal is the cumulative sum of the elements comprising the corresponding fGn signal, these results show smoothing of fractal time series in a feedforward direction from medullary presympathetic neurons to postganglionic sympathetic neurons. This may involve integration by RVLM neurons of their LTF inputs or independent fractal processes acting at different levels of the network controlling sympathetic nerve discharge. Whether feedforward smoothing of fractal signals is a feature in other neural systems is open to investigation.

Reticulospinal neurons inactivated by warming of the preoptic area and anterior hypothalamus of rabbits

To identify the premotor neurons for vasoconstrictors of the skin, activities of reticulospinal neurons in the rostroventral medulla, the ear sympathetic nerve (ESNA) and the renal sympathetic nerve (RSNA) were recorded in anesthetized and immobilized Japanese White or New Zealand White rabbits. Two groups of neurons were identified according to their responses to thermal stimulation of the preoptic area and the anterior hypothalamus (POAH) and to electrical stimulation of baroreceptor afferents, the aortic nerve (AN). Neurons (Type I neurons, n = 21) whose activity was inhibited by warm stimulation of the POAH but not inhibited by the AN stimulation were located in sites medial to the rostral ventrolateral medulla (RVLM). The other neurons (Type II neurons, n = 20) whose activity was not inhibited by warm stimulation of the POAH but inhibited by the AN stimulation were located in the RVLM. Because the time course of the inhibitory response of Type I neurons to warm stimulation of the POAH was very similar to that of the inhibitory response of the ESNA and activities of these neurons and the ESNA were not inhibited by the stimulation of the AN, it was suggested the Type I neurons might participate in regulation of activity of the vasoconstrictors of the ear skin. The Type II neurons are considered to be the barosensitive RVLM neurons that regulate systemic arterial pressure by controlling the activity of visceral or muscular sympathetic vasoconstrictors or cardiac sympathetic fibers.

NADPH Oxidase–Derived Superoxide Anion Mediates Angiotensin II–Induced Pressor Effect via Activation of p38 Mitogen–Activated Protein Kinase in the Rostral Ventrolateral Medulla

The rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons are located, is a central site via which angiotensin II (Ang II) elicits its pressor effect. We tested the hypothesis that NADPH oxidase-derived superoxide anion (O2*-) in the RVLM mediates Ang II-induced pressor response via activation of mitogen-activated protein kinase (MAPK) signaling pathways. Bilateral microinjection of Ang II into the RVLM resulted in an angiotensin subtype 1 (AT1) receptor-dependent phosphorylation of p38 MAPK and extracellular signal-regulated protein kinase (ERK)1/2, but not stress-activated protein kinase/Jun N-terminal kinase (SAPK/JNK), in the ventrolateral medulla. The Ang II-induced p38 MAPK or ERK1/2 phosphorylation was attenuated by application into the RVLM of a NADPH oxidase inhibitor, diphenyleneiodonium chloride (DPI), an antisense oligonucleotide that targets against p22phox or p47phox subunit of NADPH oxidase mRNA, or the superoxide dismutase mimetic tempol. DPI or antisense p22phox or p47phox oligonucleotide treatment also attenuated the AT1 receptor-dependent increase in O2*- production in the ventrolateral medulla elicited by Ang II at the RVLM. Functionally, Ang II-elicited pressor response in the RVLM was attenuated by DPI, tempol, or a p38 MAPK inhibitor, SB203580. The AT1 receptor-mediated enhancement of the frequency of glutamate-sensitive spontaneous excitatory postsynaptic currents induced by Ang II in RVLM neurons was also abolished by SB203580. These results suggest that NADPH oxidase-derived O2*- underlies the activation of p38 MAPK or ERK1/2 by Ang II in the ventrolateral medulla. Furthermore, the p38 MAPK signaling pathway may mediate Ang II-induced pressor response via enhancement of presynaptic release of glutamate to RVLM neurons.