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Previous research has suggested a relationship between low-frequency power of heart rate variability (HRV; LF in normalized units, LFnu) and muscle sympathetic nerve activity (MSNA). However, investigations have not systematically controlled for breathing, which can modulate both HRV and MSNA. Accordingly, the aims of this experiment were to investigate the possibility of parallel responses in MSNA and HRV (LFnu) to selected acute stressors and the effect of controlled breathing. After data were obtained at rest, 12 healthy males (28 [+ or -] 5 yr) performed isometric handgrip exercise (30% maximal voluntary contraction) and the cold pressor test in random order, and were then exposed to hypoxia (inspired fraction of [O.sub.2] = 0.105) for 7 min, during randomly assigned spontaneous and controlled breathing conditions (20 breaths/ min, constant tidal volume, isocapnic). MSNA was recorded from the peroneal nerve, whereas HRV was calculated from ECG. At rest, controlled breathing did not alter MSNA but decreased LFnu (P < 0.05 for all) relative to spontaneous breathing. MSNA increased in response to all stressors regardless of breathing. LFnu increased with exercise during both breathing conditions. During cold pressor, LFnu decreased when breathing was spontaneous, whereas in the controlled breathing condition, LFnu was unchanged from baseline. Hypoxia elicited increases in LFnu when breathing was controlled, but not during spontaneous breathing. The parallel changes observed during exercise and controlled breathing during hypoxia suggest that LFnu may be an indication of sympathetic outflow in select conditions. However, since MSNA and LFnu did not change in parallel with all stressors, a cautious approach to the use of LFnu as a marker of sympathetic activity is warranted. microneurography: autonomic nervous system; hypoxia; cold pressor test; exercise doi: 10.1152/ajpregu.00246.2009.

Neuronal activity in the paraventricular nucleus (PVN) is known to be elevated in rats with heart failure. However, the type of neurons involved and the underlying synaptic mechanisms remain unknown. Here we examined spontaneous firing activity and synaptic currents in presympathetic PVN neurons in rats with myocardial infarction (MI), using slice patch clamp combined with the retrograde labeling technique. In PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM), MI induced a significant increase in basal firing rate (1.79 to 3.02 Hz, P < 0.05) and a reduction in the frequency of spontaneous (P < 0.05) and miniature (P < 0.01) inhibitory postsynaptic currents (IPSCs). In addition, MI induced an increase in the paired-pulse ratio of evoked IPSCs (P < 0.05). Bicuculline, a [GABA.sub.A] receptor antagonist, increased the firing rate of PVN-RVLM neurons in sham-operated (1.21 to 2.74 Hz, P < 0.05) but not MI (P > 0.05) rats. In contrast, in PVN neurons projecting to the intermediolateral horn of the spinal cord (PVN-IML), MI did not induce any significant changes in the basal firing rate and the properties of spontaneous and miniature IPSCs. The properties of spontaneous excitatory postsynaptic currents (EPSCs) were not altered in either neuron group. In conclusion, our results indicate that MI induces an elevation of firing activity in PVN-RVLM but not in PVN-IML neurons and that the elevated firing rate is largely due to a decrease in GABA release. These results provide evidence for a novel target-selective synaptic plasticity in the PVN that is associated with the sympathetic hyperactivity commonly seen in heart failure. heart failure; sympathetic hyperactivity; inhibitory postsynaptic current; rostral ventrolateral medulla; intermediolateral horn of spinal cord doi: 10.1152/ajpregu.00391.2009.

Recent studies in animal and human models have revealed that free fatty acid (FFA) release from adipose tissue is oscillatory. We have shown in our laboratory that these oscillations are controlled by the sympathetic nervous system (SNS). Although FFAs have been shown to directly stimulate glucose production [endogenous glucose production (EGP)] by the liver and to reduce peripheral glucose utilization, whether the specific pattern of FFA release affects glucose metabolism is unknown. The aim of this study was to examine the effects of pulsatile vs. constant infusion of FFA on glucose homeostasis in the canine model. Euglycemic clamps with basal insulin replacement (0.1 mU x [kg.sup.-1] x [min.sup.-1] insulin) were performed in dogs (n = 8) during infusion of saline (SAL) or the medium-chain fatty acid octanoate, which was given by either pulsatile infusion (PUL: 10 mmol over 2 rain every 10 min) or continuous infusion (C-INF: 1 mmol/min) designed to achieve equivalent total FFA mass. Endogenous lipolytic pulses were suppressed with the [[beta].sub.3]-specific adrenergic receptor antagonist bupranolol. PUL infusion elicited a pulsatile pattern of FFA in circulation with average maximum pulse height of 0.82 [+ or -] 0.04 mM, whereas C-INF FFA levels reached 0.47 [+ or -] 0.03 mM (fasting levels) and were maintained throughout. Glucose uptake was not affected by PUL; however, C-INF significantly reduced glucose uptake compared with both SAL and PUL. Steady-state EGP increased by >90% from basal steady state during PUL but did not change during either SAL or C-INF. Thus, pulsatile FFA infusion led to an increase in EGP while preserving glucose disposal. These data suggest that the pattern of FFA may have a role in regulation of glucose homeostasis, which may have consequences in the obese or insulin-resistant state where the SNS is known to be altered. octanoate; oscillations; lipolysis; sympathetic nervous system doi: 10.1152/ajpendo.00427.2009.

Exercise training normalizes enhanced glutamatergic mechanisms within the paraventricular nucleus (PVN) concomitant with the normalization of increased plasma ANG II levels in rats with heart failure (HF). We tested whether ANG II type 1 ([AT.sub.1] receptors are involved in the normalization of PVN glutamatergic mechanisms using chronic [AT.sub.1] receptor blockade with losartan (Los; 50 mg x [kg.sup.-l] x [day.sup.-1] in drinking water for 3 wk). Left ventricular end-diastolic pressure was increased in both HF + vehicle (Veh) and HF + Los groups compared with sham-operated animals (Sham group), although it was significantly attenuated in the HF + Los group compared with the HF + Veh group. The effect of Los on cardiac function was similar to exercise training. At the highest dose of N-methyl-D-aspartate (NMDA; 200 pmol) injected into the PVN, the increase in renal sympathetic nerve activity was 93 [+ or -] 13% in the HF + Veh group, which was significantly higher (P < 0.05) than the increase in the Sham + Veh (45 [+ or -] 2%) and HF + Los (47 [+ or -] 2%) groups. Relative NMDA receptor subunit [NR.sub.1] mRNA expression within the PVN was increased 120% in the HF + Veh group compared with the Sham + Veh group (P < 0.05) but was significantly attenuated in the HF + Los group compared with the HF + Veh group (P < 0.05). [NR.sub.1] protein expression increased 87% in the HF + Veh group compared with the Sham + Veh group but was significantly attenuated in the HF + Los group compared with the HF + Veh group (P < 0.05). Furthermore, in in vitro experiments using neuronal NG-108 cells, we found that ANG II treatment stimulated [NR.sub.1] protein expression and that Los significantly ameliorated the [NR.sub.1] expression induced by ANG II. These data are consistent with our hypothesis that chronic [AT.sub.1] receptor blockade normalizes glutamatergic mechanisms within the PVN in rats with HF. paraventricular nucleus; N-methyl-D-aspartate receptor; angiotensin type 1 receptor; sympathetic nerve activity doi: 10.1152/ajpheart.01006.2009.

Previous animal and human studies have suggested that a muscle reflex engaged during contraction leads to heightened levels of sympathetic activity in congestive heart failure (CHF). The present experiment was designed to test the role for bradykinin, which is produced within contracting skeletal muscle and contributes to the muscle reflex through its action on kinin [B.sub.2] receptors located on the endings of thin fiber muscle afferents. CHF was induced in rats by myocardial infarction (MI) after coronary artery ligation. Echocardiography was performed to determine fractional shortening (FS), an index of the left ventricular function. In the decerebrate rats, we examined renal sympathetic nerve activity (RSNA) during 1 min intermittent (1 to 4 s stimulation to relaxation) contraction of left triceps surae muscles. RSNA responded synchronously as tension was developed, and the response was significantly (P < 0.05) greater in MI rats [+39 [+ or -] 9% [s.sup.-1] (integrated RSNA over time); n = 16] with 20 [+ or -] 2% of FS than that in control healthy rats (+19 [+ or -] 2% [s.sup.-1]; n = 16) with 49 [+ or -] 2% of FS. Tension development did not differ significantly between the two groups of rats. Thirty minutes after intra-arterial injection into the hindlimb circulation of the kinin [B.sub.2] receptor antagonist, HOE-140 (2 [micro]g/kg), the RSNA response to contraction was significantly reduced in the MI rats (+26 [+ or -] 7% [s.sup.-1]) but not in the control rats (+ 17 [+ or -] 2% [s.-1]). These data suggest that bradykinin within contracting muscle is part of the exaggerated muscle reflex seen in CHF. kinin [B.sub.2] receptor; myocardial infarction; exercise doi: 10.1152/ajpheart.00558.2009.

The aims of this study were to determine optimal pacing parameters of electrical stimulation on different gut segments and to investigate effects and possible mechanisms of gastrointestinal electrical stimulation on gut slow waves. Twelve female hound-mix dogs were used in this study. A total of six pairs of electrodes were implanted on the stomach, duodenum, and ascending colon. Bilateral truncal vagotomy was performed in six of the dogs. One experiment was designed to study the effects of the pacing frequency on the entrainment of gut slow waves. Another experiment was designed to study the modulatory effects of the vagal and sympathetic pathways on gastrointestinal pacing. The frequency of slow waves was 4.88 [+ or -] 0.23 cpm (range, 4-6 cpm) in the stomach and 19.68 [+ or -] 0.31 cpm (range, 18-22 cpm) in the duodenum. There were no consistent or dominant frequencies of the slow waves in the colon. The optimal parameters to entrain slow waves were: frequency of 1.1 intrinsic frequency (IF; 10% higher than IF) and pulse width of 150-450 ms (mean, 320.0 [+ or -] 85.4 ms) for the stomach, and 1.1 IF and 10-20 ms for the small intestine. Electrical stimulation was not able to alter colon slow waves. The maximum entrainable frequency was 1.27 IF in the stomach and 1.21 IF in the duodenum. Gastrointestinal pacing was not blocked by vagotomy nor the application of an [alpha]- or [beta]-adrenergic receptor antagonist; whereas the induction of gastric dysrhythmia with electrical stimulation was completely blocked by the application of the [alpha]- or [beta]-adrenergic receptor antagonist. Gastrointestinal pacing is achievable in the stomach and small intestine but not the colon, and the maximal entrainable frequency of the gastric and small intestinal slow waves is about 20% higher than the IF. The entrainment of slow waves with gastrointestinal pacing is not modulated by the vagal or sympathetic pathways, suggesting a purely peripheral or muscle effect. gastrointestinal motility; slow wave dysrhythmia; sympathetic modulation; vagal nerve modulation doi: 10.1152/ajpregu.00006.2009.

Chronic heart failure (HF) is characterized by increased sympathetic drive. Enhanced angiotensin II (ANG II) activity may contribute to the increased sympathoexcitation under HF condition. The present study examined sympathoexcitation by 1) the effects of ANG II in the paraventricular nucleus (PVN) on renal sympathetic nerve activity (RSNA), and 2) the altered ANG II type 1 ([AT.sub.1]) receptor expression during HF. Left coronary artery ligation was used to induce HF. In the anesthetized Sprague-Dawley rats, microinjection of ANG II (0.05-1 nmol) into the PVN increased RSNA, mean arterial pressure (MAP), and heart rate (HR) in both sham-operated and HF rats. The responses of RSNA and HR were significantly enhanced in rats with HF compared with sham rats (RSNA: 64 [+ or -] 8% vs. 33 [+ or -] 4%, P < 0.05). Microinjection of [AT.sub.1] receptor antagonist losartan into the PVN produced a decrease of RSNA, MAP, and HR in both sham and HF rats. The RSNA and HR responses to losartan in HF rats were significantly greater (RSNA: -25 [+ or -] 4% vs. -13 [+ or -] 1%, P < 0.05). Using RT-PCR and Western blot analysis, we found that there were significant increases in the [AT.sub.1] receptor mRNA ([DELTA]186 [+ or -] 39%) and protein levels ([DELTA]88 [+ or -] 20%) in the PVN of rats with HF (P < 0.05). The immunofluorescence of [AT.sub.1] receptors was significantly higher in the PVN of rats with HF. These data support the conclusion that an increased angiotensinergic activity on sympathetic regulation, due to the upregulation of ANG II [AT.sub.1] receptors within the PVN, may contribute to the elevated sympathoexcitation that is observed during HF. angiotensin; sympathetic activity; blood pressure; [AT.sub.1] receptor doi: 10.1152/ajpregu.00149.2009.

Many heart failure (HF) patients exhibit paradoxical forearm vasodilation when central blood volume is reduced by lower body negative pressure (LBNP). We tested the hypothesis that this response results from reflex sympathetic withdrawal. We recorded simultaneously forearm blood flow, muscle sympathetic nerve activity (MSNA), and plasma norepinephrine (PNE) during four random applications of LBNP, -5, -10, -20, and -40 mmHg, in 12 men with HF (mean left ventricular ejection fraction = 24 [+ or -] 2%) and l0 healthy, normal, age-matched men (N). Compared with N, MSNA burst frequency (P = 0.001) and PNE (P = 0.005) were significantly higher in the HF group, both at rest and during LBNP. As anticipated in N, LBNP -40 mmHg significantly increased MSNA (+14.2 [+ or -] 2.5 bursts/min; P < 0.05) and PNE (+0.83 [+ or -] 0.22 nmol/1; P < 0.05) and decreased forearm vascular conductance (FVC) (-11.7 [+ or -] 3.2 ml x [min.sup.-1] x mm[Hg.sup.-1]; P < 0.05). In the HF group, LBNP elicited similar increases in MSNA (+11.5 [+ or -] 2.0; P < 0.05) and PNE (+0.85 [+ or -] 0.12; P < 0.05), without affecting FVC significantly (-4.1 [+ or -] 2.4; P = 0.01 vs. N, interaction P = 0.03). However, within the HF group, responses were bimodal: LBNP -40 mmHg increased MSNA in all subjects (P < 0.001), yet the six patients with nonischemic or dilated cardiomyopathy (DCM) exhibited significant vasoconstriction (decrease in FVC; P = 0.001), whereas the six patients with ischemic cardiomyopathy (ICM) exhibited significant vasodilation (increase in FVC; P < 0.02 vs. DCM and N; interaction P = 0.02). Cold pressor testing increased MSNA and decreased FVC in ICM (n = 4). Thus paradoxical forearm vasodilator responses to LBNP in HF are not mediated by reflex sympathetic withdrawal. ICM and DCM patients differ qualitatively in their vascular responses to hypotensive LBNP. etiology; microneurography; muscle sympathetic nerve activity; vascular conductance doi: 10.1152/ajpheart.00012.2009.

Angiotensin type 1 receptors ([AT.sub.1]Rs) play a critical role in a variety of physiological functions and pathophysiological states. They have been strongly implicated in the modulation of sympathetic outflow in the brain. An understanding of the mechanisms by which [AT.sub.1]Rs are regulated in a variety of disease states that are characterized by sympathoexcitation is pivotal in development of new strategies for the treatment of these disorders. This review concentrates on several aspects of [AT.sub.1]R regulation in the setting of chronic heart failure (CHF). There is now good evidence that [AT.sub.1]R expression in neurons is mediated by activation of the transcription factor activator protein 1 (AP-1). This transcription factor and its component proteins are upregulated in the rostral ventrolateral medulla of animals with CHF. Because the increase in [AT.sub.1]R expression and transcription factor activation can be blocked by the [AT.sub.1]R antagonist losartan, a positive feedback mechanism of [AT.sub.1]R expression in CHF is suggested. Oxidative stress has also been implicated in the regulation of receptor expression. Recent data suggest that the newly discovered catabolic enzyme angiotensin-converting enzyme 2 (ACE2) may play a role in the modulation of [AT.sub.1]R expression by altering the balance between the octapeptide ANG II and ANG(1-7). Finally, exercise training reduces both central oxidative stress and [AT.sub.1]R expression in animals with CHF. These data strongly suggest that multiple central and peripheral influences dynamically alter [AT.sub.1]R expression in CHF. sympathetic nerve activity; neuronal signaling; oxidative stress doi: 10.1152/ajpheart.00073.2009.

The paraventricular nucleus of the hypothalamus (PVH) plays an important role in energy homeostasis, regulating neuroendocrine, behavioral, and autonomic functions. However, the role of the PVH in regulating thermogenesis and energy expenditure in brown adipose tissue (BAT) is unclear. The present study investigated the effect of activating neurons within the PVH on BAT thermogenesis. In urethane- and chloralose-anesthetized, artificially ventilated rats maintained at a core body temperature of 37.0-38.0[degrees]C, microinjection of N-methyl-D-aspartate (NMDA, 12 pmol in 60 nl) in the PVH did not increase BAT sympathetic nerve activity (SNA) or BAT thermogenesis. In contrast, the increase in BAT SNA evoked by body cooling was completely reversed by microinjection of NMDA in the PVH. Additionally, the increases in BAT SNA evoked by body cooling, by microinjection of prostaglandin [E.sub.2] (170 pmol in 60 nl) in the medial preoptic area or by microinjection of bicuculline (30 pmol in 60 nl) in the dorsomedial hypothalamus were completely reversed by microinjection of bicuculline (30 pmol in 60 nl) in the PVH. Although the increases in BAT SNA and thermogenesis evoked by microinjection of NMDA (12 pmol in 60 nl) in the raphe pallidus (RPa) was markedly attenuated following microinjection of bicuculline (30 pmol) in the PVH, the increases in BAT SNA and thermogenesis evoked by microinjection of bicuculline (30 pmol in 60 nl) in the RPa were unaffected by microinjection of bicuculline in the PVH. These results demonstrate that disinhibition of neurons in the PVH inhibits BAT SNA likely via activation of a GABAergic input to BAT sympathetic premotor neurons in the RPa. thermoregulation; sympathetic premotor neurons; raphe; paraventricular nucleus; metabolism

The origins of the sympathetic nervous system (SNS) innervation of white adipose tissue (WAT) have been defined using the transneuronal viral retrograde tract tracer, pseudorabies virus. Activation of this SNS innervation is acknowledged as the principal initiator of WAT lipolysis. The central control of WAT lipolysis may require neural feedback to a brain-SNS-WAT circuit via WAT afferents. Indeed, conventional tract tracing studies have demonstrated that peripheral pseudounipolar dorsal root ganglion (DRG) sensory cells innervate WAT. The central nervous system projections of WAT afferents remain uncharted, however, and form the focus of the present study. We used the H 129 strain of the herpes simplex virus-1 (HSV-1), an anterograde transneuronal viral tract tracer, to define the afferent circuits projecting from WAT to the central nervous system. Siberian hamster inguinal (IWAT) or epididymal WAT was injected with H129 and the neuraxis processed for HSV-1 immunoreactivity. We found substantial overlap in the pattern of WAT sensory afferent projections with multiple SNS outflow sites along the neuraxis, suggesting the possibility of WAT sensory-SNS circuits that could regulate WAT SNS drive and thereby lipolysis. Previously, we demonstrated that systemic 2-deoxy-D-glucose (2DG) elicited increases in the SNS drive to IWAT. Here, we show that systemic 2DG administration also significantly increases multiunit spike activity arising from decentralized IWAT afferents. Collectively, these data provide structural and functional support for the existence of a sensory WAT pathway to the brain, important in the negative feedback control of lipid mobilization. 2-deoxy-D-glucose; lipolysis; sympathetic nervous system; electrophysiology

The arterial baroreflex is a fundamental reflex that buffers rapid changes in arterial blood pressure (BP) via regulation of the heart rate and sympathetic nerve activity to the vasculature. In adults a sigmoidal relationship between BP and both heart rate and sympathetic nerve activity is well documented. Its role in blood pressure control before birth is unclear. Preterm babies have a high incidence of low BP, especially in the first few days of life, which could be related, in part, to immaturity of the baroreflex. In the present study, we investigated the baroreflex control of fetal heart rate and renal sympathetic nerve activity (RSNA) in preterm fetal sheep in utero (102 [+ or -] 1 days of gestation; term 140 days). Phenylephrine was associated with a significant increase in BP from 38 [+ or -] 2 to 58 [+ or -] 3 mmHg and a decrease in heart rate (HR) from 177 [+ or -] 4 to 116 [+ or -] 8 beats per minute (bpm). Sodium nitroprusside was associated with a significant fall in BP from 38 [+ or -] 2 to 26 [+ or -] 1 mmHg and an increase in HR from 182 [+ or -] 4 to 274 [+ or -] 8 bpm. However, the time between the 50% changes in BP and HR was significantly greater after hypotension than hypertension (31 [+ or -] 8 s vs. 14 [+ or -] 5 s, P < 0.05). No significant changes in RSNA occurred with either stimulus. This suggests that there are different maturational tempos for the components of the central autonomic response to altered blood pressure. telemetry; renal sympathetic nerve

Mental stress consistently increases heart rate (HR) and blood pressure (BP) in humans, despite inconsistent sympathetic neural responses that include increases, decreases, or no change in muscle sympathetic nerve activity (MSNA). The purpose of the present study was to examine associations between MSNA, BP, and HR responses to mental stress. Leg MSNA, BP, HR, and perceived stress levels were recorded during 3-5 min of mental arithmetic in 82 subjects (53 men and 29 women). Subjects were divided into positive responders ([greater than or equal to][DELTA]3 bursts/min; n = 40), negative responders ([less than or equal to][DELTA]-3 bursts/min; n = 9), and nonresponders (n = 33). Mental stress increased MSNA in positive responders ([DELTA]-6 [+ or -] 1 bursts/min), decreased MSNA in negative responders ([DELTA]-6 [+ or -] 1 bursts/min), and did not change MSNA in nonresponders ([DELTA]1 [+ or -] 1 bursts/min). Mental stress increased mean BP and HR similarly in positive responders ([DELTA]15 [+ or -] 1 mmHg and [DELTA]16 [+ or -] 1 beats/min; P < 0.001), nonresponders ([DELTA]15 [+ or -] 1 mmHg and [DELTA]19 [+ or -] 2 beats/min; P < 0.001), and negative responders ([DELTA]12 [+ or -] 2 mmHg and [DELTA]19 [+ or -] 3 beats/min; P < 0.001). Perceived stress levels and sex distributions were similar across responders and nonresponders; thus, perceived stress and sex do not appear to influence MSNA during mental stress. However, men demonstrated higher increases of mean BP during mental stress when compared with women ([DELTA]16 [+ or -] 1 vs. [DELTA]12 [+ or -] 1 mmHg; P < 0.05), despite no differences in MSNA responses. In conclusion, our results demonstrate marked differences in MSNA responses to mental stress and a disassociation between MSNA and BP responses to mental stress, suggesting complex patterns of vascular responsiveness during mental stress. autonomic nervous system; blood pressure; mental arithmetic; muscle sympathetic nerve activity; cardiovascular control

Intracerebroventricular nociceptin]orphauin FQ (N/OFQ) produces cardiovascular depressor, diuretic, and renal sympathoinhibitory responses in conscious rats. These studies examined how a chronic high-NaCl intake alters these peptide-evoked responses and the activity of the endogenous central N/OFQ peptide (NOP) receptor system. In normotensive Sprague-Dawley rats fed a chronic (3-wk) high (8%)-NaCl diet, intracerebroventricular N/OFQ (5.5 nmol) produced prolonged bradycardic, hypotensive, and diuretic responses but failed to suppress renal sympathetic nerve activity. In a separate group of rats maintained on a high-NaCl diet, intracerebroventricular infusion of the NOP receptor antagonist UFP-101 significantly decreased urine output. At the tissue level, high-NaCl treatment of rats significantly increased NOP receptor density, without altering endogenous N/OFQ peptide levels in whole hypothalamus (control, 712 [+ or -] 35 fmol/mg vs. 8% NaCl, 883 [+ or -] 49 fmol/mg, P < 0.05) and paraventricular nucleus. Furthermore, in the hypothalamus, basal GTP[gamma]/S binding was increased without altering the sensitivity of N/OFQ-stimulated G protein coupling. In contrast, in whole medulla and the ventrolateral medulla (VLM), high-NaCl treatment decreased NOP receptor density (medulla: control, 1,473 [+ or -] 131 fmol/mg vs. 8% NaCl, 327 [+ or -] 31 fmol/mg, P < 0.05) and endogenous N/OFQ peptide levels (medulla: control, 35.3 [+ or -] 2 fmol/mg vs. 8% NaCl, 11.9 + 3 fmol/mg, P < 0.05), while increasing the sensitivity of G protein signaling pathways to N/OFQ stimulation. Together, these findings suggest that during a chronic high-salt intake, regional changes in the activity of the N/OFQ-NOP system in the brain may contribute to the tonic regulation of cardiovascular function and urine output and to the altered physiological responses to exogenous central N/OFQ. sodium-chloride diet; cardiovascular function; renal excretory function; central nervous system; renal sympathetic nerve activity

Glucose-mediated oxidative stress and the upregulation of cyclooxygenase (COX)-2 pathway activity have been implicated in the pathogenesis of several vascular complications of diabetes including diabetic neuropathy. However, in nondiabetic subjects, the cardiovascular safety of selective COX-2 inhibition is controversial. The aim of this study was to explore the links between hyperglycemia, oxidative stress, activation of the COX-2 pathway, cardiac sympathetic integrity, and the development of left ventricular (LV) dysfunction in experimental diabetes. R wave-to-R wave interval (R-R interval) and parameters of LV function measured by echocardiography using 1% isoflurane, LV sympathetic nerve fiber density, LV collagen content, and markers of myocardial oxidative stress, inflammation, and PG content were assessed after 6 mo in control and diabetic COX-2-deficient ([COX2.sup.-/-]) and littermate, wild-type ([COX-2.sup.+/+]) mice. There were no differences in blood glucose, LV echocardiographic measures, collagen content, sympathetic nerve fiber density, and markers of oxidative stress and inflammation between nondiabetic (ND) [COX-2.sup.+/+] and [COX-2.sup.- /-] mice at baseline and thereafter. After 6 too, diabetic [COX-2.sup.+/+] mice developed significant deteriorations in the R-R interval and signs of LV dysfunction. These were associated with a loss of LV sympathetic nerve fiber density, increased LV collagen content, and a significant increase in myocardial oxidative stress and inflammation compared with those of ND mice. Diabetic [COX-2.sup.-/-] mice were protected against all these biochemical, structural, and functional deficits. These data suggest that in experimental diabetes, selective COX-2 inactivation confers protection against sympathetic denervation and LV dysfunction by reducing intramyocardial oxidative stress, inflammation, and myocardial fibrosis. sympathetic function; oxidative stress; inflammation

Urocortin 3 (Ucn3) is a new member of the corticotropin-releasing factor (CRF) peptide family and is considered to be a specific and endogenous ligand for CRF type 2 receptors (CRF2Rs). The presence of CRF2Rs has been reported in the nucleus tractus solitarius (NTS) of the rat. It was hypothesized that the activation of CR[F.sub.2]Rs in the medial NTS (mNTS) may play a role in cardiovascular regulation. This hypothesis was tested in urethane-anesthetized, artificially ventilated, adult male Wistar rats. Microinjections (100 nl) of Ucn3 (0.03, 0.06, 0.12, and 0.25 mM) into the mNTS of anesthetized rats elicited decreases in mean arterial pressure (MAP: 5.0 [+ or -] 1.0, 21.6 2.6, 20.0 [+ or -] 2.8, and 12.7 [+ or -] 3.4 mmHg, respectively) and heart rate (HR: 7.8 [+ or -] 2.6, 46.2 [+ or -] 9.3, 34.5 [+ or -] 8.4, and 16.6 [+ or -] 4.9 beats/min, respectively). Microinjections of artificial cerebrospinal fluid (100 nl) into the mNTS did not elicit cardiovascular responses. Maximum decreases in MAP and HR were elicited by 0.06 mM concentration of Ucn3. Cardiovascular responses to Ucn3 were similar in unanesthetized midcollicular decerebrate rats. A bilateral vagotomy completely abolished Ucn3-induced bradycardia. The decreases in MAP and HR elicited by Ucn3 (0.06 mM) were completely blocked by astressin (1 mM; nonselective CRFR antagonist) and K41498 (5 mM; selective CR[F.sub.2]2R antagonist). Microinjections of Ucn3 (0.06 mM) into the mNTS decreased the efferent greater splanchnic nerve activity. After the blockade of CR[F.sub.2]Rs in the mNTS, a Ucn3-induced decrease in the efferent sympathetic nerve discharge was abolished. These results indicate that Ucn3 microinjections into the mNTS exerted excitatory effects on the mNTS neurons via CR[F.sub.2]Rs, leading to depressor and bradycardic responses. blood pressure; corticotropin-releasing factor receptor antagonists; heart rate; sympathetic nerve activity; urocortin; nucleus tractus solitarius

In heart failure (HF) , sympathetic nerve activity is increased. Measurements in HF patients of cardiac norepinephrine spillover, reflecting cardiac sympathetic nerve activity (CSNA), indicate that it is increased earlier and to a greater extent than sympathetic activity to other organs. This has important consequences because it worsens prognosis, provoking arrhythmias and sudden death. To elucidate the mechanisms responsible for the activation of CSNA in HF, we made simultaneous direct neural recordings of CSNA and renal SNA (RSNA) in two groups of conscious sheep: normal animals and animals in HF induced by chronic, rapid ventricular pacing. In normal animals, the level of activity, measured as burst incidence (bursts of pulse related activity/100 heart beats), was significantly lower for CSNA (30 [+ or -] 5%) than for RSNA (94 [+ or -] 2%). Furthermore, the resting level of CSNA, relative to its maximum achieved while baroreceptors were unloaded by reducing arterial pressure, was set at a much lower percentage than RSNA. In HF, burst incidence of CSNA increased from 30 to 91%, whereas burst incidence of RSNA remained unaltered at 95%. The sensitivity of the control of both CSNA and RSNA by the arterial baroreflex remained unchanged in HF. These data show that, in the normal state, the resting level of CSNA is set at a lower level than RSNA, but in HF, the resting levels of SNA to both organs are close to their maxima. This finding provides an explanation for the preferential increase in cardiac norepinephrine spillover observed in HF. arterial baroreflex | renal sympathetic nerve activity | sheep

All 5-hydroxytryptamine (5-HT; serotonin) receptors, except the [5-HT.sub.6] type, have been shown to be involved in cardiovascular regulation. In the periphery, 5-HT is stored in platelets, but the physiological role of 5-HT in the regulation of vascular tone (as opposed to its role in coagulation) remains unclear. However, central [5-HT.sub.1A], [5-HT.sub.3] and [5-HT.sub.7] receptors do play a physiological part in the regulation of cardiovascular reflexes, controlling changes in parasympathetic (vagal) drive to the heart. These reflexes also affect activity in the sympathetic nervous system, which itself can be inhibited by central [5-HT.sub.1A] receptors to cause falls in blood pressure and excited by [5-HT.sub.2] receptors to cause rises in blood pressure. The physiological role of these receptors in the central regulation of the sympathetic nervous system is unclear, although [5-HT.sub.2] receptors could be involved in the development of deoxycorticosterone-acetate-salt hypertension, which is probably related to their role in the control of vasopressin release.

Experimental endotoxemia as a model of the initial septic response affects the autonomic nervous system with profound cardiovascular sequelae. Whether the postsynaptic sympathoneural activity to the muscle vascular bed is altered in the early septic phase remains to be determined. The present study aimed to elucidate the early effects of LPS on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation in healthy humans. Young, healthy volunteers randomly received either an LPS bolus (4 ng/kg body wt, n = 11) or placebo (saline; n = 7). Experimental baroreflex assessment (baseline measurements followed by infusion of vasoactive drugs nitroprusside/phenylephrine) was done prior to and 90 min following LPS or placebo challenge. MSNA, heart rate, blood pressure, and blood levels of catecholamines, TNF-[alpha] and IL-6 were measured sequentially. Endotoxin but not placebo-induced flu-like symptoms and elevated cytokine levels. In contrast to placebo, LPS significantly suppressed MSNA burst frequency 90 min after injection [mean [+ or -] SE: 12.1 [+ or -] 2.9 vs. 27.5 [+ or -] 3.3 burst/min (post-vs. pre-LPS); P < 0.005] but increased heart rate [78.4 [+ or -] 3.1 vs. 60.6 [+ or -] 2.0 beats/min (post- vs. pre-LPS); P < 0.001]. Baseline blood pressure was not altered, but baroreflex testing demonstrated a blunted MSNA response and uncoupling of heart rate modulation to blood pressure changes in the endotoxin group. We conclude that endotoxin challenge in healthy humans has rapid suppressive effects on postsynaptic sympathetic nerve activity to the muscle vascular bed and alters baroreflex function which may contribute to the untoward cardiovascular effects of sepsis. baroreceptors; nervous system; sympathetic; MSNA; endotoxin; systemic inflammation

Hypothalamic neurons are regarded as essential for integrating thermal afferent information from skin and core and issuing commands to autonomic and behavioral effectors that maintain core temperature ([T.sub.c]) during cold exposure and for the control of energy expenditure more generally. Caudal brain stem neurons are necessary elements of the hypothalamic effector pathway and also are directly driven by skin and brain cooling. To assess whether caudal brain stem processing of thermal afferent signals is sufficient to drive endemic effectors for thermogenesis, heart rate (HR), [T.sub.c], and activity responses of chronic decerebrate (CD) and control rats adapted to 23[degrees]C were compared during cold exposure (4, 8, or 12[degrees]C) for 6 h. Other CDs and controls were exposed to 4 or 23[degrees]C for 2 h, and tissues were processed for norepinephrine turnover (NETO), a neurochemical measure of sympathetic drive. Controls maintained [T.sub.c] for all temperatures. CDs maintained [T.sub.c] for the 8 and 12[degrees]C exposures, but [T.sub.c] declined 2[degrees]C during the 4[degrees]C exposure. Cold exposure elevated HR in CDs and controls alike. Tachycardia magnitude correlated with decreases in environmental temperature for controls, but not CDs. Cold increased NETO in brown adipose tissue, heart, and some white adipose tissue pads in CDs and controls compared with their respective room temperature controls. These data demonstrate that, in neural isolation from the hypothalamus, cold exposure drives caudal brain stem neuronal activity and engages local effectors that trigger sympathetic energetic and cardiac responses that are comparable in many, but not in all, respects to those seen in neurologically intact rats. energy balance; thermoregulation; anterior hypothalamus; heart rate; body temperature; sympathetic drive; norepinephrine turnover; white adipose tissue; brown adipose tissue

Maliszewska-Scislo M, Chen H, Augustyniak RA, Seth D, Rossi NF. Subfornical organ differentially modulates baroreflex function in normotensive and two-kidney, one-clip hypertensive rats. Am J Physiol Regal Integr Comp Physiol 295: R74l-R750, 2008. First published July 2, 2008; doi:10.1152/ajpregu.00157.2008.--During activation of the renin-angiotensin system, hindbrain circumventricular organs such as the area postrema have been implicated in modulating the arterial baroreflex. This study was undertaken to test the hypothesis that the subfornical organ (SFO), a forebrain circumventricular structure, may also modulate the baroreflex. Studies were performed in rats with two-kidney, one-clip (2K, 1C) hypertension as a model of endogenously activated renin-angiotensin system. Baroreflex function was ascertained during ramp infusions of phenylephrine and nitroprusside in conscious sham-clipped and 5-wk 2K, 1C rats with either a sham or electrolytically lesioned SFO. Lesioning significantly decreased mean arterial pressure in 2K, 1C rats from 158 [+ or -] 7 to 131 [+ or -] 4 mmHg but not in sham-clipped rats. SFO-lesioned, sham-clipped rats had a significantly higher upper plateau and range of the renal sympathetic nerve activity-mean arterial pressure relationship compared with sham-clipped rats with SFO ablation. In contrast, lesioning the SFO in 2K, 1C rats significantly decreased both the upper plateau and range of the baroreflex control of renal sympathetic nerve activity, but only the range of the baroreflex response of heart rate decreased. Thus, during unloading of the baroreceptors, the SFO differentially modulates the baroreflex responses in shamclipped vs. 2K, 1C rats. Since lesioning the SFO did not influence plasma angiotensin II (ANG II), the effects of the SFO lesion are not caused by changes in circulating levels of ANG II. These findings support a pivotal role for the SFO in the sympathoexcitation observed in renovascular hypertension and in baroreflex regulation of sympathetic activity in both normal and hypertensive states. Goldblatt kidney; renal sympathetic nerve activity; angiotensin II: vasopressin

Factors controlling cardiac sympathetic nerve activity (CSNA) in the normal state and those causing the large increase in activity in heart failure (HF) remain unclear. We hypothesized from previous clinical findings that activation of cardiac mechanoreceptors by the increased blood volume in HF may stimulate sympathetic nerve activity (SNA), particularly to the heart via cardiocardiac reflexes. To investigate the effect of volume expansion and depletion on CSNA we have made multiunit recordings of CSNA in conscious normal sheep and sheep paced into HF. In HF sheep (n = 9) compared with normal sheep (n = 9), resting levels of CSNA were significantly higher (34 [+ or -] 5 vs. 93 [+ or -] 2 bursts/100 heart beats, P < 0.05), mean arterial pressure was lower (76 [+ or -] 3 vs. 87 [+ or -] 2 mmHg; P < 0.05), and central venous pressure (CVP) was greater (3.0 [+ or -] 1.0 vs. 0.0 [+ or -] 1.0 mmHg; P < 0.05). In normal sheep (n = 6), hemorrhage (400 ml over 30 min) was associated with a significant increase in CSNA (179 [+ or -] 16%) with a decrease in CVP (2.7 [+ or -] 0.7 mmHg). Volume expansion (400 ml Gelofusine over 30 min) significantly decreased CSNA (35 [+ or -] 12%) and increased CVP (4.7 [+ or -] 1.0 mmHg). In HF sheep (n = 6) the responses of CSNA to both volume expansion and hemorrhage were severely blunted with no significant changes in CSNA or heart rate with either stimulus. In summary, these studies in a large conscious mammal demonstrate that in the normal state directly recorded CSNA increased with volume depletion and decreased with volume loading. In contrast, both of these responses were severely blunted in HF with no significant changes in CSNA during either hemorrhage or volume expansion. heart failure; sympathetic nervous system; hemorrhage; cardiac volume

Several sympathoexcitatory reflexes, such as the cardiac sympathetic afferent reflex (CSAR) and arterial chemoreflex, are significantly augmented and contribute to elevated sympathetic outflow in chronic heart failure (CHF). This study was undertaken to investigate the interaction between the CSAR and the chemoreflex in CHF and to further identify the involvement of angiotensin II type 1 receptors (AT1 Rs) in the nucleus of the tractus solitarius (NTS) in this interaction. CHF was induced in rats by coronary ligation. Acute experiments were performed in anesthetized rats. The chemoreflex-induced increase in cardiovascular responses was significantly greater in CHF than in sham-operated rats after either chemical or electrical activation of the CSAR. The inhibition of the CSAR by epicardial lidocaine reduced the chemoreflex-induced effects in CHF rats but not in sham-operated rats. Bilateral NTS injection of the [AT.sub.1]R antagonist losartan (10 and 100 pmol) dose-dependently decreased basal sympathetic nerve activity in CHF but not in sham-operated rats. This procedure also abolished the CSAR-induced enhancement of the chemoreflex. The discharge and chemosensitivity of NTS chemosensitive neurons were significantly increased following the stimulation of the CSAR in sham-operated and CHF rats, whereas CSAR inhibition by epicardial lidocaine significantly attenuated chemosensitivity of NTS neurons in CHF but not in sham-operated rats. Finally, the protein expression of [AT.sub.1]R in the NTS was significantly higher in CHF than in sham-operated rats. These results demonstrate that the enhanced cardiac sympathetic afferent input contributes to an excitatory effect of chemoreflex function in CHF, which is mediated by an NTS-[AT.sub.1]R-dependent mechanism. sympathoexcitatory reflexes; sympathetic activity; angiotensin II type 1 receptor; microinjection; extracellular recording; nucleus of tractus solitarius

Muscle metabolic by-products stimulate thin fiber muscle afferent nerves and evoke reflex increases in blood pressure and sympathetic nerve activity. Previous studies reported that chemically sensitive transient receptor potential vanilloid type 1 (TRPV1) channels present on sensory muscle afferent neurons have an important impact on sympathetically mediated cardiovascular responses. The reflex-mediated reduction in blood flow to skeletal muscle leads to limited exercise capacity in patients with peripheral arterial occlusive disease. Thus, in this study, we tested the hypothesis that the expression of enhanced TRPV1 receptor and its responsiveness in primary afferent neurons innervating muscles initiate exaggerated reflex sympathetic responses after vascular insufficiency to the muscle. Muscle vascular insufficiency was induced by the femoral artery ligation in rats for 24 h. Our data show that 1) the ligation surgery leads to the upregulation of TRPV1 expression in the dorsal root ganglion; 2) the magnitude of the dorsal root ganglion neuron TRPV1 response induced by capsaicin is greater in vascular insufficiency (4.0 [+ or -] 0.31 nA, P < 0.05 vs. sham-operated control) than that in sham-operated control (2.9 [+ or -] 0.23 nA); and 3) renal sympathetic nerve activity and mean arterial pressure responses to capsaicin (0.5 [micro]g/kg body wt) are also enhanced by vascular insufficiency (54 [+ or -] 11%, 9 [+ or -] 2 mmHg in sham-operated controls vs. 98 [+ or -] 13%, 33 [+ or -] 5 mmHg after vascular insufficiency, P < 0.05). In conclusion, sympathetic nerve responses to the activation of metabolite-sensitive TRPV1 receptors are augmented in rats with the femoral artery occlusion compared with sham-operated control animals, due to alterations in the expression of TRPV1 receptor and its responsiveness in sensory neurons. muscle afferent; claudication; peripheral vascular disease; sympathetic nervous system; exercise; transient receptor potential vanilloid type 1

Although modest elevations in pacing rate improve cardiac output and induce reflex sympathoinhibition, the threshold rate above which hemodynamic perturbations induce reflex sympathoexcitation remains unknown. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressures (MAP) and sympathetic nerve activity (SNA) were measured during normal sinus rhythm (NSR) and atrioventricular (AV) sequential pacing in 25 patients. Pacing was performed at 100, 120, and 140 beats/min with an AV interval of 100 ms. Patients were divided into two groups based on normal or abnormal left ventricular ejection fraction (LVEF): group 1 (n = 11; mean LVEF, 55%) and group 2 (n = 14; mean LVEF, 31%). In group 1, relative to NSR, SBP decreased an average of 2%, 3%, and 8% at 100, 120, and 140 beats/min (P < 0.001), respectively. DBP and MAP increased 9%, 15%, and 15% (P = 0.001) and 3%, 6%, and 5% [P = not significant (NS)], respectively. In group 2, SBP reductions were even greater, with an average decrease of 4%, 8%, and 16% (P < 0.001). Whereas DBP increased 9%, 9%, and 8% at 100, 120, and 140 heats/min (P = NS), MAP increased 3% and 2% at 100 and 120 beats/min but decreased 3% at 140 beats/min (P = 0.001). SNA recordings were obtained in 11 patients (6 in group 1 and 5 in group 2). In group 1, SNA decreased during all rates, with a mean 21% reduction. In group 2, however, SNA decreased at 100 and 120 beats/min (49% and 38%) but increased 24% at 140 beats/min. Patients with depressed LVEF exhibited altered hemodynamic and sympathetic responses to rapid sequential pacing. The implications of these findings in device programming and arrhythmia rate control await future studies. sympathetic nervous system; heart failure; hemodynamics

Amiloride, injected into the popliteal artery, has been reported to attenuate the reflex pressor response to static contraction of the triceps surae muscles. Both mechanical and metabolic stimuli arising in contracting skeletal muscle are believed to evoke this effect, which has been named the exercise pressor reflex. Amiloride blocks both acid-sensing ion channels, as well as epithelial sodium channels. Nevertheless, amiloride is thought to block the metabolic stimulus to the reflex, because this agent has been shown to attenuate the reflex pressor response to injection of lactic acid into the arterial supply of skeletal muscle. The possibility exists, however, that amiloride may also block mechanical stimuli evoking the exercise pressor reflex. The mechanical component of the reflex can be assessed by measuring renal sympathetic nerve activity during the first 2-5 s of contraction. During this period of time, the sudden tension developed by contraction onset briskly discharges mechanoreceptors, whereas it has little effect on the discharge of metaboreceptors. We, therefore, examined the effect of amiloride (0.5 [micro]g/kg) injected into the popliteal artery on the renal sympathetic and pressor responses to static contraction of the triceps surae muscles in decerebrated cats. We found that amiloride significantly attenuated the pressor and renal sympathetic responses to contraction; for the latter variable, the attenuation started 10 s after the onset of contraction. Our findings lead us to conclude that acid-sensing ion channels and epithelial sodium channels play little, if any, role in evoking the mechanical component of the exercise pressor reflex. group III and IV muscle afferents; renal sympathetic nerves; neural control of the circulation; cats; autonomic nervous system

Suggestions were made that increased myocardial sympathetic activity is reflected by elevated QT variability (dynamic changes in QT interval duration). However, the relationship between QT variability and the amount of norepinephrine released from the cardiac sympathetic terminals is unknown. We thus attempted to assess this relationship. The study was performed in 17 subjects (12 with major depressive disorder and 5 with panic disorder). Cardiac norepinephrine spillover (measured by direct catheter technique coupled with norepinephrine isotope dilution methodology) was assessed before and 4 mo after treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants. The distribution of the cardiac norepinephrine spillover was bimodal, with the majority of patients having values of [less than or equal to] 10 ng/min. There was a positive correlation between cardiac norepinephrine spillover and corrected QT interval (r = 0.7, P = 0.03) but not with any of the QT variability measures. However, in a subgroup of five patients who had high levels of cardiac norepinephrine spillover (>20 ng/min) a tendency for a strong positive correlation with variance of QT intervals (r = 0.9, P = 0.08) was observed. There were significant correlations between the severity of depression and QT variability indexes normalized to the heart rate [QTVi and QT interval/R-R interval (QT/RR) coherence] and between the severity of anxiety and the QT/RR residual and regression coefficient, respectively. Treatment with SSRI antidepressants substantially reduced depression score but did not affect any of the QT variability indexes. We conclude that in depression/panic disorder patients with near-normal cardiac norepinephrine levels QT variability is not correlated with cardiac norepinephrine spillover and is not affected by treatment with SSRI. sympathetic activity; antidepressants

Longterm measurement of cardiovascular variables by telemetry in laboratory animals has become indispensable in recent years. However, limited battery life and management of large volumes of recorded data are major drawbacks. These limitations can often be overcome by intermittent sampling of data. The question is, how much data does one need to collect to accurately reflect the underlying average value? To investigate this, 24-h continuous recordings of rabbit heart rate, arterial pressure, and integrated renal sympathetic nerve activity (RSNA) were resampled using a variety of protocols that differed with respect to the number of individual sampling periods used and the total amount of time that was sampled. The absolute percentage errors of estimates of the daily mean, standard deviation, and interquartile range were calculated for each sampling protocol. A similar analysis was repeated using arterial pressure data from rats. The results show that the number of sampling periods spread throughout the day had more effect than the total amount of data recorded. For example, just 2 h of total sampling time spread over 12 evenly spaced 10-min periods gave estimates of the daily mean of blood pressure and heart rate with < 1% error and RSNA with < 3% error. We show that accurate estimates of the daily mean of arterial pressure, heart rate, and RSNA can all be made using scheduled recording, and we recommend recording a minimum of 2 h/day spread over a number of periods throughout the day. blood pressure; sympathetic nerve activity; telemetry

Exercise training (ExT) normalizes the increased sympathetic outflow in heart failure (HF), but the mechanisms are not known. We hypothesized that ExT would normalize the augmented glutamatergic mechanisms mediated by N-methyl-D-aspartic acid (NMDA) receptors within the paraventricular nucleus (PVN) that occur with HF. Four groups of rats were used: 1) sham-operated (Sham) sedentary (Sed), 2) Sham ExT, 3) HF Sed, and 4) HF ExT. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In [alpha]-chloralose-urethane-anesthetized rats, the increase in renal sympathetic nerve activity in response to the highest dose of NMDA (200 pmol) injected into the PVN in the HF Sed group was approximately twice that of the Sham Sed group. In the HF ExT group the response was not different from the Sham Sed and Sham ExT groups. Relative NMDA NR1 receptor subunit mRNA expression was 63% higher in the HF Sed group compared with the Sham Sed group but in the HF ExT group was not different from the Sham Sed and Sham ExT groups. NR1 receptor subunit protein expression was increased 87% in the HF Sed group compared with the Sham Sed group but in the HF ExT group was not significantly different from the Sham Sed and Sham ExT groups. Thus one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of glutamatergic mechanisms within the PVN. paraventricular nucleus; N-methyl-D-aspartic acid receptors; sympathetic nerve activity

Surplus energy is principally stored in white adipose tissue (WAT) as triacylglycerol and mobilized via lipolysis through norepinephrine (NE) released from sympathetic nervous system terminals innervating WAT. We demonstrated that central melanocortin receptor agonism provokes differential sympathetic drives across WAT pads and interscapular brown adipose tissue (IBAT). Here we tested for differential WAT and IBAT sympathetic drive to known lipolytic stimuli {glucoprivation [2-deoxy-D-glucose (2-DG)], cold exposure (5[degrees]C), food deprivation (16 h), or both cold exposure and food deprivation} by measuring NE turnover (NETO). Only inguinal WAT NETO significantly increased across all stimuli. Dorsal subcutaneous WAT NETO only increased with glucoprivation. Retroperitoneal WAT NETO increased with glucoprivation, cold and cold + food deprivation, but not by food deprivation. Epididymal WAT NETO was unaffected by glucoprivation but increased with cold, cold + food deprivation or food deprivation, but to a small significant degree. IBAT NETO was unaffected by glucoprivation or food deprivation, but increased with cold and cold + food deprivation. Plasma glucose decreased with food deprivation and increased with 2-DG administration or cold exposure. Plasma glycerol was increased with food deprivation, cold, and their combination but not with 2-DG, whereas plasma free fatty acids increased with food deprivation, cold + food deprivation, and 2-DG. These data show differential sympathetic drive to WAT and BAT for four different lipolytic stimuli, exemplifying the fat pad-specific pattern of WAT sympathetic drive across lipid-mobilizing conditions and emphasizing the need to analyze multiple adipose depots for measures of NETO and likely most measures. norepinephrine turnover; glycerol; free fatty acids; Siberian hamsters; 2-deoxy-D-glucose

The [beta]-adrenergic pathway has been considered one important effector of circadian variation in arterial pressure. Experiments were performed in [beta]1/[beta]2-adrenergic receptor-deficient mice ([beta]1[beta]2ADR-/-) to assess whether this pathway is required for circadian variation in mean arterial pressure (MAP) and to determine the impact of its loss on the response to changes in dietary salt. Twenty-four-hour recordings of MAP, heart rate (HR), and locomotor activity were made in conscious 16- to 17-wk-old mice [wild-type, (WT), n = 7; [beta]1/[beta]2ADR-/-, n = 10] by telemetry. Both WT and [beta]1/[beta]2ADR-/- mice demonstrated robust circadian variation in MAP and HR, although 24-h mean MAP was 10% lower (102.02 [+ or -] 1.81 vs. 92.11 [+ or -] 2.62 mmHg) in [beta]/ [beta]2ADR-/- than WT, HR was 16% lower and day-night differences reduced. Both WT and [beta]1/[beta]2ADR-/- mice adapted to changed salt intake without changed MAP. However, the [beta]1/[beta]2ADR-/- mice demonstrated a striking reduction in locomotor activity in light and dark phases of the day. In WT mice, MAP was markedly affected by locomotor activity, resulting in bimodal distributions in both light and dark. When MAP was analyzed using only intervals without locomotor activity, bimodality and circadian differences were reduced, and there was no significant difference between the two genotypes. The results indicate that there is no direct effect or role for the [beta]-adrenergic system in circadian variation of arterial pressure in mice, aside from the indirect consequences of altered locomotor activity. Our results also confirm that locomotor activity contributes strongly to circadian variation in blood pressure in mice. salt intake; sympathetic nervous system

Activation of sympathetic neural traffic via the vestibular system is referred to as the vestibulosympathetic reflex. Investigations of the vestibulosympathetic reflex in humans have been limited to the past decade, and the importance of this reflex in arterial blood pressure regulation is still being determined. This review provides a summary of sympathetic neural responses to various techniques used to engage the vestibulosympathetic reflex. Studies suggest that activation of the semicircular canals using caloric stimulation and yaw rotation do not modulate muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA). In contrast, activation of the otolith organs appear to alter MSNA, but not SSNA. Specifically, head-down rotation and off-vertical axis rotation increase MSNA, while sinusoidal linear accelerations decrease MSNA. Galvanic stimulation, which results in a nonspecific activation of the vestibule, appears to increase MSNA if the mode of delivery is pulse trained. In conclusion, evidence strongly supports the existence of a vestibulosympathetic reflex in humans. Furthermore, attenuation of the vestibulosympathetic reflex is coupled with a drop in arterial blood pressure in the elderly, suggesting this reflex may be important in human blood pressure regulation. sympathetic nerve activity; blood pressure; head-down rotation

The sympathetic nervous system is an important determinant of vascular function. The effects of the sympathetic nervous system are mediated via release of neurotransmitters and neuropeptides from postganglionic sympathetic neurons. The present study tests the hypothesis that vascular smooth muscle cells (VSM) maintain adrenergic neurotransmitter/neuropeptide expression in the postganglionic sympathetic neurons that innervate them. The effects of rat aortic and tail artery VSM (AVSM and TAVSM, respectively) on neuropeptide Y (NPY) and tyrosine hydroxylase (TH) were assessed in cultures of dissociated sympathetic neurons. AVSM decreased TH (39 [+ or -] 12% of control) but did not affect NPY. TAVSM decreased TH (76 [+ or -] 10% of control) but increased NPY (153 [+ or -] 20% of control). VSM expressed leukemia inhibitory factor (LIF) and neurotrophin-3 (NT-3), which are known to modulate NPY and TH expression. Sympathetic neurons innervating blood vessels expressed LIF and NT-3 receptors. Inhibition of LIF inhibited the effect of AVSM on TH. Inhibition of neurotrophin-3 (NT-3) decreased TH and NPY in neurons grown in the presence of TAVSM. These data suggest that vascular-derived LIF decreases TH and vascular-derived NT-3 increases or maintains NPY and TH expression in postganglionic sympathetic neurons. NPY and TH in vascular sympathetic nerves are likely to modulate NPY and/or norepinephrine release from these nerves and are thus likely to affect blood flow and blood pressure. The present studies suggest a novel mechanism whereby VSM would modulate sympathetic control of vascular function. vascular smooth muscle; sympathetic nervous system; neurotrophin-3; leukemia inhibitory factor; tyrosine hydroxylase; neuropeptide Y

The present study examined whether the gain of the transfer function relating cardiac-related rhythm of renal sympathetic nerve activity (RSNA) to arterial pressure (AP) pulse might serve as a spontaneous index of sympathetic baroreflex sensitivity (BRS). AP and RSNA were simultaneously recorded in conscious rats, either baroreceptor-intact (control, n = 11) or with partial denervation of baroreflex afferents [aortic baroreceptor denervated (ABD; n = 10)] during 1-h periods of spontaneous activity. Transfer gain was calculated over 58 adjacent 61.4-s periods (segmented into 10.2-s periods). Coherence between AP and RSNA was statistically (P < 0.05) significant in 90 [+ or -] 3% and 56 [+ or -] 10% of cases in control and ABD rats, respectively. Transfer gain was higher (P = 0.0049) in control [2.39 [+ or -] 0.13 normalized units (NU)/mmHg] than in ABD (1.48 [+ or -] 0.22 NU/mmHg) rats. In the pooled study sample, transfer gain correlated with sympathetic BRS estimated by the vasoactive drug injection technique (R = 0.75; P < 0.0001) and was inversely related to both time- (standard deviation; R = -0.74; P = 0.0001) and frequency-domain [total spectral power (0.00028-2.5 Hz); R = -0.82; P < 0.0001] indices of AP variability. In control rats, transfer gain exhibited large fluctuations (coefficient of variation: 34 [+ or -] 3%) that were not consistently related to changes in the mean level of AP, heart rate, or RSNA. In conclusion, the transfer function method provides a continuous, functionally relevant index of sympathetic BRS and reveals that the latter fluctuates widely over time. arterial pressure; baroreceptor reflex; sympathetic nervous system

The finding that pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS), a P2 antagonist, attenuated the pressor response to calcaneal tendon stretch, a purely mechanical stimulus, raises the possibility that P2 receptors sensitize mechanoreceptors to static contraction of the triceps surae muscles. The mechanical component of the exercise pressor reflex, which is evoked by static contraction, can be assessed by measuring renal sympathetic nerve activity during the first 2-5 s of this maneuver. During this period of time, group III mechanoreceptors often discharge explosively in response to the sudden tension developed at the onset of contraction. In decerebrated cats, we, therefore, examined the effect of PPADS (10 mg/kg) injected into the popliteal artery on the renal sympathetic and pressor responses to contraction and stretch. We found that PPADS significantly attenuated the renal sympathetic response to contraction, with the effect starting 2 s after its onset and continuing throughout its 60-s period. PPADS also significantly attenuated the renal sympathetic nerve response to stretch, but did so after a latency of 10 s. Our findings lead us to conclude that P2 receptors sensitize group III muscle afferents to contraction. The difference in the onset latency between the PPADS-induced attenuation of the renal sympathetic response to contraction and the renal sympathetic response to stretch is probably due to the sensitivities of different populations of group III afferents to ATP released during contraction and stretch. group III muscle afferents; group 1V muscle afferents; ATP; cats; renal sympathetic nerve activity; neural control of the circulation