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The effect of cardiovascular deconditioning on central nervous system processing of baroreceptor afferent activity was evaluated following 14 days of hindlimb unloading (HU). Inactin-anesthetized rats were instrumented with catheters, renal sympathetic nerve electrodes, and aortic depressor nerve electrodes for measurement of mean arterial pressure, heart rate, renal sympathetic nerve activity (RSNA), and aortic depressor nerve activity (ADNA). Baroreceptor and baroreflex functions were assessed during infusion of phenylephrine and sodium nitroprusside. Central processing of baroreceptor afferent input was evaluated by linear regression relating RSNA to ADNA. The maximum baroreflex-elicited increase in RSNA was significantly reduced in HU rats (122 ± 3.8 vs. 144 ± 4.9% of baseline RSNA), whereas ADNA was not altered. The slope (−0.18 ± 0.04 vs. −0.40 ± 0.04) and y-intercept (121 ± 3.2 vs. 146 ± 4.3) of the linear regression relating increases in efferent RSNA to decreases in afferent ADNA during hypotension were significantly reduced in HU rats. There were no differences during increases in arterial pressure. Results demonstrate that the attenuation in baroreflex-mediated increases in RSNA following HU is due to changes in central processing of baroreceptor afferent information rather than aortic baroreceptor function.

Pulmonary surfactant, a mixture consisting of lipids and proteins and secreted by type II cells, functions to reduce the surface tension of the fluid lining of the lung, and thereby decreases the work of breathing. In mammals, surfactant secretion appears to be influenced primarily by the sympathetic nervous system and changes in ventilatory pattern. The parasympathetic nervous system is not believed to affect surfactant secretion in mammals. Very little is known about the factors that control surfactant secretion in nonmammalian vertebrates. Here, a new methodology for the isolation and culture of type II pneumocytes from the lizard Pogona vitticeps is presented. We examined the effects of the major autonomic neurotransmitters, epinephrine (Epi) and ACh, on total phospholipid (PL), disaturated PL (DSP), and cholesterol (Chol) secretion. At 37 degrees C, only Epi stimulated secretion of total PL and DSP from primary cultures of lizard type II cells, and secretion was blocked by the beta-adrenoreceptor antagonist propranolol. Neither of the agonists affected Chol secretion. At 18 degrees C, Epi and ACh both stimulated DSP and PL secretion but not Chol secretion. The secretion of surfactant Chol does not appear to be under autonomic control. It appears that the secretion of surfactant PL is predominantly controlled by the autonomic nervous system in lizards. The sympathetic nervous system may control surfactant secretion at high temperatures, whereas the parasympathetic nervous system may predominate at lower body temperatures, stimulating surfactant secretion without elevating metabolic rate.

Molecular basis of native voltage-dependent K+(Kv) channels in smooth muscle cells (SMCs) from rat mesenteric arteries was investigated. The whole cell patch-clamp study revealed that a 4-aminopyridine-sensitive delayed rectifier K+current ( IK) was the predominant K+conductance in these cells. A systematic screening of the expression of 18 Kv channel genes using RT-PCR technique showed that six IK-encoding genes (Kv1.2, Kv1.3, Kv1.5, Kv2.1, Kv2.2, and Kv3.2) were expressed in mesenteric artery. Although no transient outward Kv currents ( IA) were recorded in the studied SMCs, transcripts of multiple IA-encoding genes, including Kv1.4, Kv3.3, Kv3.4, Kv4.1, Kv4.2, and Kv4.3 as well as IA-facilitating Kv β-subunits (Kvβ1, Kvβ2, and Kvβ3), were detected in mesenteric arteries. Western blot analysis demonstrated that four IK-related Kv channel proteins (Kv1.2, Kv1.3, Kv1.5, and Kv2.1) were detected in mesenteric artery tissues. The presence of Kv1.2, Kv1.3, Kv1.5, and Kv2.1 channel proteins in isolated SMCs was further confirmed by immunocytochemistry study. Our results suggest that the native IKin rat mesenteric artery SMCs might be generated by heteromultimerization of Kv genes.

The involvement of the antilipolytic α2-adrenergic pathway and the specific role of epinephrine in the control of lipolysis during exercise in adipose tissue (AT) were investigated in healthy male subjects (age: 24.1 ± 2.2 yr; body mass index: 23.0 ± 1.6). An in vitro study carried out on isolated adipocytes showed that the weak lipolytic effect of epinephrine was potentiated after blockade of α2-adrenergic receptor (AR) by an α2-AR antagonist and reached that of isoproterenol, a β-AR agonist. The effect of the nonselective α2-AR antagonist phentolamine on the response of the extracellular glycerol concentration (EGC) in AT during two successive bouts of aerobic exercise (50% maximum O2uptake, 60 min duration) was evaluated using the microdialysis method. The metabolic responses measured in perfused probes with Ringer solution were compared with those obtained in perfused probes with Ringer plus 0.1 mmol/l phentolamine. Plasma norepinephrine level was not different during the two exercise bouts, whereas that of epinephrine was 2.5-fold higher during the second exercise. EGC in AT was twofold higher in the second compared with the first exercise, and the same response pattern was found for plasma glycerol. The exercise-induced increase in EGC was higher in the probe perfused with phentolamine compared with the control probe in both bouts of exercise. However, the potentiating effect of phentolamine on EGC was significant during the second exercise bout but did not reach a significant level during the first. These results suggest that epinephrine is involved in the control of lipid mobilization through activation of antilipolytic α2-AR in human subcutaneous AT during exercise.

To further investigate neural effects on leptin and uncoupling proteins (UCPs), we studied in vivo perturbations intended to block adrenergic input to peripheral tissues. We examined plasma leptin, leptin mRNA, and adipose and muscle UCP subtype mRNA in rats treated with α-methyl- p-tyrosine methyl ester (AMPT-ME), which inhibits catecholamine synthesis and 6-hydroxydopamine (6HDA), which is toxic to catecholinergic nerve terminals but, unlike AMPT-ME, does not enter the central nervous system. Intraperitoneal AMPT-ME, 250 mg/kg, was administered at 1800 and 0700 the following day, and rats were killed at 1200–1400. All rats were fasted with free access to water during this time. Intraperitoneal AMPT-ME increased plasma leptin by 15-fold, increased interscapular brown adipose tissue (IBAT) and epididymal fat leptin mRNA by 2- to 2.5-fold, and also increased plasma insulin and glucose concentrations. Intraperitoneal AMPT-ME decreased IBAT UCP-3 mRNA to 40% of control, while it increased epididymal adipose UCP-3 mRNA approximately twofold. Intravenous AMPT-ME, 250 mg/kg, administered to conscious rats for 5 h decreased lumbar sympathetic nerve activity, increased plasma leptin (5.89 ± 1.43 compared with 2.75 ± 0.31 ng/ml in vehicle-treated rats, n = 7, P < 0.05), and decreased cardiac rate with no sustained change in blood pressure. Intraperitoneal 6HDA, 100 mg/kg, as a single dose at 1800, increased plasma leptin approximately twofold after 18–20 h, increased IBAT (but not epididymal fat) leptin mRNA by two- to threefold, and decreased IBAT UCP-3 mRNA to 30–40% of control. Neither AMPT-ME nor 6HDA significantly altered mRNA encoding gastrocnemius muscle UCP-3, IBAT UCP-1, or IBAT and epididymal UCP-2. In summary, AMPT-ME and 6HDA increased plasma leptin and upregulated leptin mRNA expression. AMPT-ME also resulted in complex tissue and subtype-specific modulation of adipose UCP mRNA. These data are consistent with interaction between leptin and sympathetic nerve activity (SNA) in regulation of fat cell energy utilization. However, the in vivo modulation of leptin and UCPs appears complex and, beyond a causal effect of SNA per se, may depend on concurrent changes in plasma insulin, glucose, and circulatory hemodynamics.

The effect of β-blockade on left ventricular (LV) remodeling, when added to angiotensin-converting enzyme inhibition (ACEI) after anterior myocardial infarction (MI), is incompletely understood. On day 2 after coronary ligation-induced anteroapical infarction, 17 sheep were randomized to ramipril (ACEI, n = 8) or ramipril and metoprolol (ACEI-β, n = 9). Magnetic resonance imaging was performed before and 8 wk after MI to measure changes in LV end-diastolic, end-systolic, and stroke volume indexes, LV mass index, ejection fraction (EF), and regional percent intramyocardial circumferential shortening.123I-labeled m-iodobenzylguanidine (MIBG) and fluorescent microspheres before and after adenosine were infused before death at 8 wk post-MI for quantitation of sympathetic innervation, blood flow, and blood flow reserve in adjacent and remote noninfarcted regions. Infarct size, regional blood flow, blood flow reserve, and the increase in LV mass and LV end-diastolic and end-systolic volume indexes were similar between groups. However, EF fell less over the 8-wk study period in the ACEI-β group (−13 ± 11 vs. −22 ± 4% in ACEI, P < 0.05). The ratio of adjacent to remote region123I-MIBG uptake was greater in ACEI-β animals than in the ACEI group (0.93 ± 0.06 vs. 0.86 ± 0.07, P < 0.04). When added to ACE inhibition after transmural anteroapical MI, β-blockade improves EF and adjacent regional sympathetic innervation but does not alter LV size.

The present study investigated the role of the renal nerves in mediating the cardiovascular and renal responses produced by the central administration of the opioid-like peptide orphanin FQ/nociceptin (OFQ/N) in conscious Sprague-Dawley rats. In conscious rats, OFQ/N (10 μg icv) produced a transient bradycardia and hypotension (nadir 20 min). Although renal sympathetic nerve activity (RSNA) initially remained unchanged, a delayed renal sympathoinhibitory response occurred after recovery (30 min) of blood pressure. By 30 and 70 min postinjection, RSNA decreased to 75 and 66% of control, respectively. Coinciding with the decrease in RSNA, central OFQ/N elicited a diuresis and antinatriuresis that occurred independent of changes in renal hemodynamics. In other studies, intracerebroventricular OFQ/N produced similar cardiovascular and renal excretory responses in bilaterally renal-denervated rats. Finally, in conscious sinoaortic deafferentiated rats, intracerebroventricular OFQ/N produced a rapid decrease in RSNA (55% of control, 10 min; 38% of control, 20 min) that paralleled the onset of the hypotension and bradycardia. These studies demonstrate that in conscious rats, intracerebroventricular OFQ/N produces a centrally mediated inhibition of RSNA which, due to activation of baroreflex mechanisms, is temporally dissociated from the hypotensive and bradycardia responses. As revealed in renal-denervated rats, the cardiovascular and renal excretory responses produced by central OFQ/N occur by a pathway that is independent of intact renal nerves or changes in renal hemodynamics.

In Inactin-anesthetized Wistar rats with an intact renal innervation, intratubular nitro-l-arginine methyl ester (l-NAME, 10−4M) increased proximal fluid uptake ( Jva, at 2.47 ± 0.61 × 10−4mm3⋅ mm−2⋅ s−1) by 17% ( P < 0.05), whereas coadministration with sodium nitroprusside (SNP, 10−4M) decreased Jvaby 18% ( P < 0.01). Similar manipulation of NO generation was without effect in groups of Wistar rats subjected to acute renal denervation. Intratubular aminoguanidine (10−4M), a selective inducible nitric oxide synthase (NOS) blocker, had no effect on Jvain intact kidneys of Wistar rats, but the neuronal NOS (nNOS) blocker, 7-nitroindazole (10−4M and 10−6M) increased Jvaby 19–23% (both P < 0.001). In stroke-prone spontaneously hypertensive rats (SHRSP), Jvavalues in the innervated kidneys were lower ( P< 0.05) than in the corresponding Wistar groups and were unchanged by intratubular l-NAME or l-NAME plus SNP. The tonic attenuation of proximal epithelial transport by NO was dependent on the renal sympathetic nerves and appeared to be generated by the nNOS isoform of the enzyme. This role of NO was not evident in the SHRSP.

Previous work in our laboratory has demonstrated impairment of cardiopulmonary reflex control of renal sympathetic nerve activity (RSNA) during the newborn period. The present study was designed to test the hypothesis that this delayed maturation is secondary to incomplete central integration of vagal afferent input. Term fetal (135–140 days; n = 6), newborn (3–7 days of age; n = 8), and young adult (6–8 wk old; n = 8) sheep anesthetized with α-chloralose underwent vagal afferent nerve stimulation. All animals had undergone prior sinoaortic denervation to eliminate influences from the arterial baroreceptors. After determination of optimal stimulation parameters, RSNA responses to gradual increases in stimulation frequency (1.0–16 Hz) were recorded and compared by one-way ANOVA. RSNA decreased progressively with increased frequency of stimulation in all three groups of animals. When comparing the three groups at any given frequency of stimulation, reflex withdrawal of RSNA tended to be more pronounced in newborn lambs ( P< 0.05 for 1 and 4 Hz). Heart rate (HR) was also noted to decrease significantly with vagal afferent stimulation in each of the groups, but no significant differences in the reflex decreases in HR were noted among the three groups of animals. These results demonstrate that central integration of vagal afferent input is intact in fetal and newborn sheep. These results suggest that the delayed maturation of cardiopulmonary reflex-mediated changes in RSNA seen early in development appears to depend on intrinsic alterations in baroreceptor function rather than incomplete central integration.

Rostral ventrolateral medulla (rVLM) and parapyramidal region (PPr) serve as important medullary control sites for sympathoexcitation. rVLM and PPr have direct projections to the intermediolateral cell column (IML) that are thought to be important in maintaining mean arterial blood pressure (MAP). Substance P (SP) is found in PPr neurons and in and near the subretrofacial area of the rVLM. At least some of these cells project to the IML. We investigated the involvement of SP at the IML in mediating rVLM- and PPr-evoked pressor responses in the chloralose-anesthetized cat. Pressor responses to electrical and chemical PPr and rVLM stimulation were altered after intrathecal injection, at the level of the T1-T3 spinal cord, of either SP antagonist [d-Pro2,d-Phe7,d-Trp9]-SP, SP antagonist CP 96,345, or SP antiserum. Although MAP and heart rate responses to PPr stimulation were attenuated by intrathecal SP antagonists or antiserum, MAP responses to rVLM stimulation were augmented. Previous studies have revealed differences in transmitters associated with these two areas, even though the general response of both areas is sympathoexcitatory. The present study implies that the identical substance may increase or decrease the MAP response depending on the pathway activated.

Cardiac sympathetic nerve terminal dysfunction plays an important role in the downregulation of myocardial β-adrenoceptors in heart failure. To determine whether chronic angiotensin-converting enzyme (ACE) inhibition improved cardiac sympathetic nerve terminal function and hence increased myocardial β-adrenergic responsiveness, we administered ACE inhibitors to dogs with chronic right-sided heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. The RHF animals exhibited fluid retention, elevated right heart filling pressures, blunted inotropic response to isoproterenol, and reduced β-adrenoceptor density. These changes were accompanied by decreases in right ventricular norepinephrine (NE) uptake and neuronal NE histofluorescence and tyrosine hydroxylase immunoreactive profiles. ACE inhibitors had no effect on the production of heart failure but greatly reduced the attenuation of cardiac NE uptake, neuronal NE histofluorescence, and tyrosine hydroxylase immunoreactive profiles. ACE inhibition also improved the inotropic response to isoproterenol and restored myocardial β-adrenoceptor density. The changes probably are caused by reduction of cardiac NE release by ACE inhibition and may contribute to the beneficial effects of ACE inhibitor therapy in patients with chronic heart failure.

This experiment tested the effect of a high-salt diet on the interaction between arterial blood pressure (BP) and sympathetic nerve activity (SNA) at rest and during a controlled behavioral stress at an early stage in the development of hypertension in borderline hypertensive rats (BHR). Ten rats were maintained on a high-salt diet (8% NaCl) while 14 were fed a low-salt diet (0.8% NaCl) for 8 wk. They were trained in a Pavlovian paradigm by following a conditional stimulus tone (CS+) with a 0.5-s shock. SNA and BP were measured by implanted electrodes around the left renal nerve and a catheter in the femoral artery, respectively. There were no detectable between-group differences in BP or in BP variability in the resting animal at the end of the 8-wk dietary treatment. Moreover, there were no significant between-group differences in the changes in SNA evoked by the CS+ tone. Conversely, the amplitude of the initial conditional increase in BP was significantly ( P< 0.05) larger in the high-salt (6 ± 0.6 mmHg; mean ± SEM) compared with the low-salt (4 ± 0.4 mmHg) group. In addition, the BP excursion (peak/trough) during CS+ was larger in the high (18.2 ± 6.1 mmHg)- vs. low-salt (5.8 ± 0.4 mmHg) diet-fed subjects. The ratio of the average percent change in mean BP to the average percent change in SNA at the beginning of CS+ was 0.029 ± 0.004 for the low-salt group and 0.041 ± 0.006 for the high-salt group. We find that, before the development of overt hypertension, the enhanced conditional BP response in the high-salt BHR appears to reside at the interface between changes in SNA and the effector response and not within the central nervous system. These observations help explain the increasing BP variability typically observed with the development of hypertension in humans.

The object of this study is to quantify the very low frequency (i.e., −β. The peak magnitude squared of the coherence near 0.4 Hz was 0.82 ± 0.08, but the apparent linear coherence fell off quickly at lower frequencies so that it was close to zero for frequencies

Sympathetic modulation of cutaneous vasomotor waves in humans is most effective at frequencies up to 0.1 Hz. In contrast, sympathetic modulation of mesenteric vasomotor waves in rats is strongest in the frequency band between 0.2 and 0.75 Hz. Therefore, we addressed the question as to whether these different frequency response characteristics are due to species- or organ-specific disparities. Eleven Sprague-Dawley rats were instrumented with catheters in the carotid artery and in the jugular vein, together with electrodes on the centrally sectioned left lumbar sympathetic trunk (LST) and laser Doppler flow probes directed to the plantar surface of the skin of the left and right hind paws. In anesthetized rats, the LST was electrically stimulated at eight different stimulation frequencies, and the responses in laser Doppler blood flow were recorded in the skin of the ipsilateral and contralateral paw. At stimulation frequencies

The effects of chronic treatment with 17β-estradiol on baroreflex control of sympathetic activity were examined in conscious unrestrained ovariectomized rats. Baroreflex function was evaluated by logistic sigmoidal analysis of the relationships between changes in mean arterial pressure (MABP) and changes in heart rate (HR) and splanchnic nerve activity (SNA) when MABP was rapidly increased to 150 mmHg by intravenous phenylephrine after its reduction to 50 mmHg by intravenous nitroprusside. These baroreflex function curves were similar in vehicle- and estradiol-treated rats. However, after a 30-min infusion of vasopressin in vehicle-treated rats, the curve for HR was shifted downward, and the upper plateau and maximum gain for the SNA curve were reduced. These effects were abolished by estradiol. A 30-min phenylephrine infusion had no effect on the baroreflex curves. Thus estrogen can modulate the action of vasopressin on baroreflex control of sympathetic outflow and thereby participate in cardiovascular regulation.

We have investigated the changes in muscle sympathetic nerve activity (MSNA) from the tibial nerve during brief periods of microgravity (microG) for approximately 20 s produced by parabolic flight. MSNA was recorded microneurographically from 13 quietly seated human subjects with their knee joints extended in a jet aircraft simultaneously with the electrocardiogram, the blood pressure wave (measured with a Finapres), the respiration curve, and the thoracic fluid volume (measured by impedance plethysmography). During quiet and seated parabolic flight, MSNA was activated in hypergravity and was suppressed in microG phasically. At the entry to hypergravity at 2 G just before microG, the thoracic fluid volume was reduced by 3.2 +/- 3%, and the arterial blood pressure was lowered transiently and then gradually elevated from 89.5 +/- 1.7 to 100.2 +/- 1.7 mmHg, which caused the enhancement of MSNA by 91.4 +/- 14.2%. At the entry to microG, the thoracic fluid volume was increased by 3.4%, which lowered the mean blood pressure to 77.9 +/- 2.3 mmHg and suppressed the MSNA by 17.2%. However, this suppression lasted only approximately 10 s, followed by an enhancement of MSNA that continued for several seconds. We conclude that MSNA is suppressed and then enhanced during microG produced by parabolic flight. These changes in MSNA are in response not only to intrathoracic fluid volume changes but also to arterial blood pressure changes, both of which are caused by body fluid shifts induced by parabolic flight, and these changes are quite phasic and transient.

Fevers are known to be suppressed near term in the mother, but the mechanism responsible for this phenomenon is not understood. We tested the hypothesis that the suppression of fever at term is a result of enhanced vasopressin-induced antipyresis. Effects of intracerebroventricular prostaglandin E2(PGE2) were examined in rats at gestational days 16–17 and 19–20 (near term) and days 1–2 postpartum. PGE2 (50 ng) elevated body and interscapular brown adipose tissue (iBAT) temperatures and increased sympathetic nerve activity to the iBAT. PGE2-induced changes in iBAT temperature and nerve activity, as well as in rectal temperature, were reduced or eliminated near term, and responses were recovered in the postpartum period. Blood pressure and heart rate changes induced by central PGE2 were also decreased at near term. Coinfusion of Manning compound, a V1 vasopressin receptor antagonist, with PGE2 throughout the peripartum period did not reverse the suppressed iBAT temperature and nerve activity or body temperature responses to PGE2. Microdialysis experiments revealed unchanged terminal release of vasopressin in the ventral septal area after PGE2 infusion in either pregnant or parturient rats. These results suggest that fever reduction at near term is not associated with enhanced vasopressin antipyresis, but may be a result of reduced sympathetic tone and in particular a reduced sympathetic drive to the iBAT. This finding may reflect a generalized reduction in autonomic output around the time of parturition.

Sympathetic vasoconstriction in working muscles during dynamic exercise has been demonstrated by intra-arterial administration of α1-adrenergic antagonists. The purpose of this study was to examine the existence of α1- and α2-adrenergic receptor-mediated vasoconstriction in active skeletal muscles during exercise. Six mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs, and a catheter was inserted in one femoral artery. All dogs ran on a motorized treadmill at three exercise intensities (3 miles/h, 6 miles/h, and 6 miles/h at 10% grade) on separate days. After 5 min of exercise, a selective α1- (prazosin) or a selective α2-adrenergic antagonist (rauwolscine) was infused as a bolus into the femoral arterial catheter (only one drug per day). The doses of the antagonists were adjusted to maintain the same effective concentration at each exercise intensity. At the mild, moderate, and heavy workloads prazosin infusion produced immediate increases in iliac conductance of 65 ± 9, 35 ± 6, and 18 ± 4% (means ± SE), respectively, and increases in blood flow of 290 ± 24, 216 ± 23, and 172 ± 18 ml/min, respectively. Rauwolscine infusion produced increases in conductance of 52 ± 5%, 36 ± 5%, and 26 ± 3%, respectively, and blood flow increases of 250 ± 34, 244 ± 39, and 259 ± 35 ml/min at the three workloads. Systemic blood pressure and blood flow in the contralateral iliac artery were unaffected by any of the antagonist infusions. These results demonstrate that there is ongoing α1- and α2-adrenergic receptor-mediated vasoconstriction in exercising skeletal muscles even at heavy workloads and that the magnitude of vasoconstriction decreases as exercise intensity increases.

Peripheral osmoreceptors monitor dietary NaCl and modify central nervous system and renal sympathetic nervous system activity accordingly. Experimental evidence suggests that these responses are dependent on the hepatic nerves. Peripheral osmoreceptors also modify arginine vasopressin (AVP) secretion. However, although hepatic denervation reportedly blunts activation of both supraoptic and paraventricular hypothalamic neurons after intraportal NaCl infusion, the role of the hepatic nerves in the AVP release has not been directly examined. The present study tests the hypothesis that the hepatic nerves modify AVP release in response to intragastric NaCl infusion. Wistar-Kyoto rats (WKY) received either hepatic denervation or a sham operation. Intragastric NaCl infusion significantly elevated plasma AVP in both sham-operated WKY and hepatic-denervated WKY, and the responses were not different between these groups. Second, previous studies suggest that both AVP secretion and baroreflexes are blunted in spontaneously hypertensive rats (SHR), deficits that contribute to the observed hypertension in SHR. We hypothesized that SHR also have a blunted peripheral osmoreceptor reflex and that this contributes to NaCl-sensitive hypertension. In contrast to our prediction, in SHR intragastric NaCl infusion induced an increase in plasma AVP that was similar to that in the WKY groups. Thus, although hepatic osmoreceptors are important for chronic regulation of arterial pressure, renal sympathetic nervous system activity, and the activity of hypothalamic neurons, they do not appear to influence plasma AVP concentration in response to intragastric NaCl.

The effect of inhibition of nitric oxide (NO) synthesis on the responses of blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) during hemorrhaging was examined with the use of an NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), in conscious rats. In the 0.9% saline group, hemorrhage (10 ml/kg body wt) did not alter BP but significantly increased HR and RSNA by 88 ± 12 beats/min and 67 ± 12%, respectively. Intravenous infusion of l-NAME (50 μg ⋅ kg−1⋅ min−1) significantly attenuated these tachycardic and sympathoexcitatory responses to hemorrhage (14 ± 7 beats/min and 26 ± 12%, respectively). Pretreatment ofl-arginine (87 mg/kg) recovered the attenuation of HR and RSNA responses induced byl-NAME (92 ± 6 beats/min and 64 ± 10%, respectively).l-NAME by itself did not alter the baroreceptor reflex control of HR and RSNA. Hemorrhage increased the plasma vasopressin concentration, and its increment in thel-NAME-treated group was significantly higher than that in the 0.9% saline group. Pretreatment with the vascular arginine vasopressin V1-receptor antagonist OPC-21268 (5 mg/kg) recovered the attenuation of RSNA response induced byl-NAME (54 ± 7%). These results indicate that NO modulated HR and RSNA responses to hemorrhage but did not directly affect the baroreceptor reflex arch. It can be assumed that NO modulated the baroreflex function by altering the secretion of vasopressin induced by hemorrhage.

Recently, studies in our laboratory involving the use of a Gaussian white noise technique demonstrated that the transfer function from sympathetic stimulation frequency to heart rate (HR) response showed dynamic characteristics of a second-order low-pass filter. However, determinants for the characteristics remain to be established. We examined the effect of an increase in mean sympathetic stimulation frequency and that of a blockade of the neuronal uptake mechanism on the transfer function in anesthetized rabbits. We found that increasing mean sympathetic stimulation frequency from 1 to 4 Hz significantly ( P < 0.01) decreased the dynamic gain of the transfer function without affecting other parameters, such as the natural frequency, lag time, or damping coefficient. In contrast, the administration of desipramine (0.3 mg/kg iv), a neuronal uptake blocking agent, significantly ( P < 0.01) decreased both the dynamic gain and the natural frequency and prolonged the lag time. These results suggest that the removal rate of norepinephrine at the neuroeffector junction, rather than the amount of available norepinephrine, plays an important role in determining the low-pass filter characteristics of the HR response to sympathetic stimulation.

Blockade of the angiotensin II (ANG II) type 1 receptor (AT1) has been shown to restore baroreflex sensitivity in rats and rabbits with experimental chronic heart failure (CHF). Because the modulation of baroreflex function in response to ANG II is mediated in part by AT1 receptors located in the area postrema, we hypothesized that lesions of the area postrema would prevent the enhancement in baroreflex function in response to AT1-receptor blockade in rabbits with pacing-induced CHF. Experiments were carried out on 24 male New Zealand White rabbits that were divided into sham ( n = 12) and lesioned ( n = 12) groups further divided into normal and CHF subgroups ( n = 6 each). All rabbits were identically instrumented to measure cardiac external dimensions, central venous pressure, arterial pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA). After 3–4 wk of pacing, baroreflex sensitivity (infusions of phenylephrine and nitroprusside) was evaluated before and after intravenous administration of the AT1-receptor antagonist L-158,809. Maximum baroreflex sensitivity in nonpaced rabbits was 5.4 ± 0.7 beats ⋅ min−1 ⋅ mmHg−1and 5.2 ± 0.5% of maximum/mmHg for HR and RSNA curves, respectively, and was not altered by L-158,809 in either intact or lesioned rabbits. In contrast, L-158,809 enhanced baroreflex sensitivity in intact rabbits with CHF (HR from 1.6 ± 0.3 to 4.1 ± 0.7 beats ⋅ min−1 ⋅ mmHg−1, P < 0.001; RSNA from 2.3 ± 0.2 to 4.9 ± 0.4% of maximum/mmHg, P < 0.001). However, in CHF rabbits with area postrema lesions, L-158,809 failed to enhance baroreflex sensitivity. Interestingly, area postrema lesions did not normalize the baroreflex in CHF rabbits. From these data we conclude that the area postrema mediates the normalization of baroreflex sensitivity after AT1 blockade in rabbits with CHF but does not modify resting baroreflex function.

The following experiments were done to determine whether changes in baroreflex sensitivity evoked by cervical vagus nerve stimulation are due to sympathoexcitation mediated by the parabrachial nucleus. The relative contribution of cardiopulmonary and general gastric afferents within the cervical vagus nerve to the depression in baroreflex sensitivity are also investigated. Male Sprague-Dawley rats anesthetized with thiobutabarbital sodium (50 mg/kg) were instrumented to measure blood pressure and heart rate or for the continuous monitoring of renal sympathetic nerve activity. Baroreflex sensitivity was measured using bolus injections of phenylephrine. Electrical stimulation of the cervical vagus (with or without the aortic depressor nerve) or the abdominal vagus nerve produced a significant increase in renal nerve activity and a decrease in baroreflex sensitivity. Both of these effects were blocked after the microinjection of lidocaine into the parabrachial nucleus before nerve stimulation. Therefore, we conclude that an increase in the activity of cardiac, pulmonary, or general gastric afferents mediated the increased sympathetic output and decreased baroreflex sensitivity via a pathway involving the parabrachial nucleus.

The sympathetic baroreflex is an important feedback system in stabilization of arterial pressure. This system can be decomposed into the controlling element (mechanoneural arc) and the controlled element (neuromechanical arc). We hypothesized that the intersection of the two operational curves representing their respective functions on an equilibrium diagram should define the operating point of the arterial baroreflex. Both carotid sinuses were isolated in 16 halothane-anesthetized rats. The vagi and aortic depressor nerves were cut bilaterally. Carotid sinus pressure (CSP) was sequentially altered in 10-mmHg increments from 80 to 160 mmHg while sympathetic efferent nerve activity (SNA) and systemic arterial pressure (SAP) were recorded simultaneously under various hemorrhagic conditions. The mechanoneural arc was characterized by the response of SNA to CSP and the neuromechanical arc by the response of SAP to SNA. We parametrically analyzed the relationship between input and output for each arc using a four-parameter logistic equation model. In baseline states, the two arcs intersected each other at the point at which the instantaneous gain of each arc attained its maximum. Severe hemorrhage lowered the gain and offset of the neuromechanical arc and moved the operating point, whereas the mechanoneural arc remained unchanged. The operating points measured under the closed-loop conditions were indistinguishable from those estimated from the intersections of the two arc curves on the equilibrium diagram. The average root mean square errors of estimate for arterial pressure and SNA were 2 and 3%, respectively. Such an analytic approach could explain a mechanism for the determination of the operating point of the sympathetic baroreflex system and thus helps us integratively understand its function.

Acute infusion of hypertonic fluid increases mean arterial pressure (MAP) in part by elevating nonrenal sympathetic activity. However, it is not known whether chronic, physiological increases in osmolality also increase sympathetic activity. To test this hypothesis, MAP, heart rate (HR), and lumbar sympathetic nerve activity (LSNA) were measured in conscious, 48-h water-deprived rats (WD) during a progressive reduction in osmolality produced by a 2-h systemic infusion (0.12 ml/min) of 5% dextrose in water (5DW). Water deprivation significantly increased osmolality (308 ± 2 vs. 290 ± 2 mosmol/kgH2O, P < 0.001), HR (453 ± 7 vs. 421 ± 10 beats/min, P < 0.05), and LSNA (63.5 ± 1.8 vs. 51.9 ± 3.8% baroreflex maximum, P < 0.01). Two hours of 5DW infusion reduced osmolality (−15 ± 5 mosmol/kgH2O), LSNA (−23 ± 3% baseline), and MAP (−10 ± 1 mmHg). To evaluate the role of vasopressin in these changes, rats were pretreated with a V1-vasopressin receptor antagonist. The antagonist lowered MAP (−5 ± 1 mmHg) and elevated HR (32 ± 7 beats/min) and LSNA (11 ± 3% baseline) in WD ( P < 0.05), but not in water-replete, rats. 5DW infusion had a similar cumulative effect on all variables in V1-blocked WD rats, but had no effect in water-replete rats. Infusion of the same volume of normal saline in WD rats did not change osmolality, LSNA or MAP. Together these data indicate that, in dehydrated rats, vasopressin supports MAP and suppresses LSNA and HR and that physiological changes in osmolality directly influence sympathetic activity and blood pressure independently of changes in vasopressin and blood volume.

Brown adipose tissue (BAT) plays a critical role in cold- and diet-induced thermogenesis. Although BAT is densely innervated by the sympathetic nervous system (SNS), little is known about the central nervous system (CNS) origins of this innervation. The purpose of the present experiment was to determine the neuroanatomic chain of functionally connected neurons from the CNS to BAT. A transneuronal viral tract tracer, Bartha’s K strain of the pseudorabies virus (PRV), was injected into the interscapular BAT of Siberian hamsters. The animals were killed 4 and 6 days postinjection, and the infected neurons were visualized by immunocytochemistry. PRV-infected neurons were found in the spinal cord, brain stem, midbrain, and forebrain. The intensity of labeled neurons in the forebrain varied from heavy infections in the medial preoptic area and paraventricular hypothalamic nucleus to few infections in the ventromedial hypothalamic nucleus, with moderate infections in the suprachiasmatic and lateral hypothalamic nuclei. These results define the SNS outflow from the brain to BAT for the first time in any species.

Physiological responses at birth include increases in heart rate (HR), blood pressure, sympathetic nerve activity, and circulating vasoactive peptides. The factors mediating these responses are not known. To test the hypothesis that afferent input from peripheral mechanoreceptors (arterial and cardiopulmonary baroreceptors) and chemoreceptors contribute to the sympathoexcitatory and hormonal responses at birth, we studied the effects of sinoaortic denervation (SAD) and SAD with vagotomy (Vx) on changes in HR, mean arterial blood pressure (MABP), renal sympathetic nerve activity (RSNA), and catecholamine, arginine vasopressin (AVP), and ANG II levels at birth in term sheep. One hour after delivery by cesarean section, RSNA increased by 168 ± 49 and 192 ± 32% (relative to fetal values) in SAD and SAD-Vx animals, respectively. Significant increases in HR (18 ± 5 and 20 ± 6%) and MABP (24 ± 4 and 20 ± 5%) were also observed 1 h after delivery in SAD and SAD-Vx lambs, respectively. These responses are similar to those seen in intact sheep delivered at the same gestational age. AVP levels markedly increased after birth (19.8 ± 6.7 to 136.1 ± 75.9 pg/ml) in SAD-Vx lambs, whereas SAD animals displayed no change in AVP concentrations. Plasma ANG II also did not change after birth in either group, although levels were consistently higher ( P < 0.01) in SAD compared with SAD-Vx animals. In the presence of SAD, Vx resulted in significantly greater plasma levels of norepinephrine, although levels did not change after birth in either group. The epinephrine responses at birth were similar in both groups of animals. The present data suggest that afferent input from peripheral chemoreceptors and mechanoreceptors contributes little to the hemodynamic and sympathetic responses after delivery by cesarean section. On the other hand, these peripheral mechanisms appear to be involved in modulating endocrine responses at birth.

The brain has evolved mechanisms for sensing and regulating glucose metabolism. It receives neural inputs from glucosensors in the periphery but also contains neurons that directly sense changes in glucose levels by using glucose as a signal to alter their firing rate. Glucose-responsive (GR) neurons increase and glucose-sensitive (GS) decrease their firing rate when brain glucose levels rise. GR neurons use an ATP-sensitive K+channel to regulate their firing. The mechanism regulating GS firing is less certain. Both GR and GS neurons respond to, and participate in, the changes in food intake, sympathoadrenal activity, and energy expenditure produced by extremes of hyper- and hypoglycemia. It is less certain that they respond to the small swings in plasma glucose required for the more physiological regulation of energy homeostasis. Both obesity and diabetes are associated with several alterations in brain glucose sensing. In rats with diet-induced obesity and hyperinsulinemia, GR neurons are hyporesponsive to glucose. Insulin-dependent diabetic rats also have abnormalities of GR neurons and neurotransmitter systems potentially involved in glucose sensing. Thus the challenge for the future is to define the role of brain glucose sensing in the physiological regulation of energy balance and in the pathophysiology of obesity and diabetes.

There are complex interactions between the sympathetic and parasympathetic nervous system inputs to the sinus node. The concept of “sympathovagal balance” reflects the autonomic state resulting from the sympathetic and parasympathetic influences. Despite widespread usage of a variety of heart rate (HR) variability parameters as indexes of sympathovagal balance, no index has been validated as a measure of sympathovagal balance. This study evaluated the utility of HR, HR variability, and a new parameter termed the vagal-sympathetic effect (VSE) as indexes of sympathovagal balance. The ideal parameter had to satisfy the following criteria: 1) the index should vary similarly among subjects in response to different autonomic conditions; 2) the variability in the index among subjects exposed to the same autonomic conditions should be small; and 3) the response of the index to various autonomic conditions should reflect the underlying changes in physiological state and have a meaningful interpretation. Volunteers [8 men, 6 women; mean age 28.5 ± 4.8 (SD) yr] were evaluated for the effects of sympathetic and parasympathetic stimulation and blockade on HR and HR variability. VSE was defined as the ratio of the R-R interval to the intrinsic R-R interval. VSE and R-R interval consistently changed in the expected directions with parasympathetic and sympathetic stimulation and blockade. A general linearized model was used to evaluate the response of each parameter. VSE and R-R interval had r 2 values of 0.847 and 0.852, respectively. Natural logarithm of the low-frequency power had an r 2value of 0.781 with lower r 2 values for all the other HR variability parameters. The coefficient of variation was also lowest for each condition tested for the VSE and the R-R interval. VSE and R-R interval best satisfy the criteria for the ideal index of sympathovagal balance. Because it is impractical under most conditions to measure the VSE as the index of sympathovagal balance, the most suitable index is the R-R interval.

The responses of sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) to activation or inactivation of neurons in the caudal pressor area (CPA) were studied in urethan-anesthetized rats. Extracellular recordings were made from 32 barosensitive single units in the RVLM, of which 26 were antidromically activated from the cervical cord. Unilateral microinjections ofl-glutamate (0.5–5 nmol) into the CPA increased firing in 13 of 14 premotor neurons by 90 ± 30% while raising blood pressure. Both ipsilateral and contralateral injections were effective. Unilateral or bilateral inhibition of CPA neuron activity by microinjecting glycine (5–200 nmol/side) lowered blood pressure, while it reduced firing in 9 of 10 and 16 of 17 premotor neurons, respectively, by 45 ± 9 and 39 ± 6%. A significant proportion of tonic activity in RVLM sympathetic premotor neurons is thus driven, directly or indirectly, by neurons in the CPA.

Mechanisms underlying the depressor and sympathoinhibitory responses evoked from the caudal medullary raphe (MR) region were investigated in pentobarbital sodium-anesthetized, paralyzed rats. Intermittent electrical stimulation (0.5 Hz, 0.5-ms pulses, 200 μA) of the MR elicited a mixed sympathetic response that consisted of a long-latency sympathoexcitatory (SE) peak (onset = 146 ± 7 ms) superimposed on an inhibitory phase (onset = 59 ± 10 ms). Chemical stimulation of the MR (glutamate; Glu) most frequently elicited depressor responses accompanied by inhibition of sympathetic nerve discharge. Occasionally, these responses were preceded by transient pressor and SE responses. We examined the influence of intermittent electrical stimulation (0.5 Hz, 0.5-ms pulses, 25–200 μA) and Glu stimulation of the MR on the discharge of rostral ventrolateral medulla (RVLM) premotor SE neurons. Peristimulus-time histograms of RVLM unit discharge featured a prominent inhibitory phase in response to MR stimulation (onset = 20 ± 2 ms; duration = 42 ± 4 ms; n = 12 units). Glu stimulation of the MR reduced blood pressure (−37 ± 2 mmHg, n = 19) and inhibited the discharge of RVLM SE neurons (15 of 19 neurons). Depressor and sympathoinhibitory responses elicited by chemical and electrical stimulation of the MR region are mediated by inhibition of RVLM premotor SE neurons and withdrawal of sympathetic vasomotor discharge.

To determine whether neurons in the rostral raphe pallidus (RPa) specifically control the sympathetic nerve activity to brown adipose tissue (BAT SNA), thereby regulating adipocyte metabolism and BAT thermogenesis, the responses in BAT SNA to disinhibition of RPa neurons and to disinhibition of neurons in the vasomotor region of the rostral ventrolateral medulla (RVLM) were compared with those in splanchnic (Spl) SNA, which primarily regulates visceral vasoconstriction. In urethan-chloralose-anesthetized ventilated rats, both acute hypothermia and microinjection of bicuculline into RPa produced significantly larger increases in BAT SNA (542 and 1,949% of control) than in Spl SNA (19 and 24% of control). The enhanced burst discharge in BAT SNA was not coherent with that in Spl SNA or with the arterial pressure (AP) at any frequency except the central respiratory frequency. Microinjections of bicuculline into RVLM evoked increases in Spl SNA (86% of control) and AP (32 mmHg), but reduced BAT SNA to low, normothermic levels. Microinjections of muscimol into RVLM reduced Spl SNA (−82% of control) and AP (−59 mmHg), but did not prevent the increase in BAT SNA after disinhibition of RPa neurons. These results indicate that the neural networks generating BAT SNA in response to disinhibition of RPa neurons are independent of those generating basal Spl SNA and support a model in which sympathetic outflow to tissues involved in thermoregulation and metabolism is regulated by central pathways, including neurons in RPa, that are distinct from those involved in the sympathetic control of the cardiovascular system.

We have previously demonstrated in normotensive humans an age-associated increase in sympathetic nervous system (SNS) activity combined with appropriate downregulation of α-adrenergic responsiveness. Impaired downregulation of α-adrenergic responsiveness, despite a comparable level of SNS activity, could contribute to higher blood pressure in older hypertensive humans. We measured arterial plasma norepinephrine (NE) levels and the extravascular NE release rate (NE2) derived from [3H]NE kinetics (to assess systemic SNS activity), and platelet and forearm arterial adrenergic responsiveness in 20 normotensive (N) and in 24 hypertensive (H), otherwise healthy, older subjects (60–75 yr). Although plasma NE levels were similar (N 357 ± 27 vs. H 322 ± 22 pg/ml; P = 0.37), NE2tended to be greater in the hypertensive group (H 2.23 ± 0.21 vs. N 1.64 ± 0.20 μg ⋅ min−1⋅ m−2; P = 0.11), and the NE metabolic clearance rate was greater (H 1,100 ± 30 vs. N 900 ± 50 ml/m2; P = 0.004). In the hypertensive group, there was a greater α-agonist-mediated inhibition of platelet membrane adenylyl cyclase activity and a NE- but not ANG II-mediated decrease in forearm blood flow. Compared with normotensive subjects, in older hypertensive subjects 1) NE metabolic clearance rate is increased, 2) systemic SNS activity tends to be increased, and 3) arterial and platelet α-adrenergic responsiveness is enhanced. These results suggest that heightened SNS activity coupled with enhanced α-adrenergic responsiveness may contribute to elevated blood pressure in older hypertensive humans.

The purposes of this study were to investigate the level of the sympathetic nervous system in which nitric oxide (NO) mediates regional sympathetic vasoconstriction and to determine whether neural mechanisms are involved in vasoconstriction after NO inhibition. Ganglionic blockade (hexamethonium), α1-receptor blockade (prazosin), and spinal section at T1 were used to study sympathetic involvement. NO was blocked with N ω-nitro-l-arginine methyl ester (l-NAME). Regional blood flow in the mesenteric and renal arteries and terminal aorta was monitored by electromagnetic flowmetry in conscious rats.l-NAME (3–5 mg/kg iv) increased arterial pressure and peripheral resistance. Ganglionic blockade (25 mg/kg iv) significantly reduced the increase in resistance in the mesentery and kidney in intact and spinal-sectioned rats. Ganglionic blockade significantly decreased hindquarter resistance in intact rats but not in spinal-sectioned rats. Prazosin (200 μg/kg iv) significantly reduced the increased hindquarter resistance. We concluded that NO suppresses sympathetic vasoconstriction in the mesentery and kidney at the spinal level, whereas hindquarter tone is mediated at supraspinal and synaptic levels.

We earlier reported that stimulation of either one of the sympathetic and vagal nerves augments the dynamic heart rate (HR) response to concurrent stimulation of its counterpart. We explained this phenomenon by assuming a sigmoidal static relationship between nerve activity and HR. To confirm this assumption, we stimulated the sympathetic and/or vagal nerve in anesthetized rabbits using large-amplitude Gaussian white noise and determined the static and dynamic characteristics of HR regulation by a neural network analysis. The static characteristics approximated a sigmoidal relationship between the linearly predicted and the measured HRs (response range: 212.4 ± 46.3 beats/min, minimum HR: 96.0 ± 28.4 beats/min, midpoint of operation: 196.7 ± 31.3 beats/min, maximum slope: 1.65 ± 0.51). The maximum step responses determined from the dynamic characteristics were 7.9 ± 2.9 and −14.0 ± 4.9 beats ⋅ min−1 ⋅ Hz−1for the sympathetic and the vagal system, respectively. Because of these characteristics, changes in sympathetic or vagal tone alone can alter the dynamic HR response to stimulation of the other nerve.

It has been speculated that joint instability resulting from anterior cruciate ligament (ACL) rupture could be exacerbated by changes in vasomotor activity in the remaining supporting structures. In this study, the effect of ACL transection on medial collateral ligament (MCL) basal perfusion and its responsiveness to calcitonin gene-related peptide (CGRP) and sympathetic adrenergic influences was examined. Using urethan-anesthetized rabbits, we tested the effects of CGRP and its antagonist CGRP-(8—37) by topical application of these agents to the exposed knee while sympathetic influences were tested by electrically stimulating the saphenous nerve. It was found that MCL basal perfusion was elevated in ACL-sectioned joints; however, this effect was abrogated by prior resection of the articular nerve supply. At the doses tested, the normal vasodilator response to CGRP was abolished in ACL-sectioned joints, whereas the response to CGRP-(8—37) was attenuated. Even under the influence of increased constrictor tone, MCL and capsule blood vessels still showed substantially reduced responses to exogenous CGRP administration. By contrast, nerve-mediated constrictor responses were mostly unaffected by joint instability. This study suggests that posttraumatic knee joint hyperemia is neurogenically mediated, possibly by increased secretion of CGRP.

Spike-triggered averaging, arterial pulse-triggered analysis, and coherence analysis were used to classify rostral dorsolateral pontine (RDLP) neurons into groups whose naturally occurring discharges were correlated to only the 10-Hz rhythm ( n = 29), to only the cardiac-related rhythm ( n = 15), and to both rhythms ( n = 15) in inferior cardiac sympathetic nerve discharge (SND) of urethan-anesthetized cats. Most of the neurons with activity correlated to only the cardiac-related rhythm were located medial to the other two groups of neurons. The firing rates of most RDLP neurons with activity correlated to only the 10-Hz rhythm (9 of 12) or both rhythms (7 of 8) were decreased during baroreceptor reflex-induced inhibition of SND produced by aortic obstruction; thus, they are presumed to be sympathoexcitatory. The firing rates of four of seven RDLP neurons with activity correlated to only the cardiac-related rhythm increased during baroreceptor reflex activation; thus, they may be sympathoinhibitory. We conclude that the RDLP contains a functionally heterogeneous population of neurons with sympathetic nerve-related activity. These neurons could not be antidromically activated by stimulation of the thoracic spinal cord.

The following experiments were conducted to determine if peripherally administered estrogen has an effect on central autonomic tone and whether this change in tone results in an alteration in cardiovascular reflex control. Male Sprague-Dawley rats were anesthetized with thiobutabarbitol sodium (50 mg/kg) and instrumented to record blood pressure, heart rate, and vagal parasympathetic or renal sympathetic efferent nerve activity. Additional rats were instrumented to test the sensitivity of the cardiac baroreflex using intravenous injections of phenylephrine hydrochloride (0.025, 0.05, 0.1 mg/kg) or sodium nitroprusside (0.0025, 0.005, 0.01 mg/kg) and plotting the cardiovascular responses. Intravenous injection of estrogen (10−4, 10−2, and 10−1 mg/kg) produced a significant increase in vagal efferent activity and in baroreflex sensitivity. The bilateral microinjection of an estrogen receptor antagonist, ICI-182,780 (1 pM, 50 nl/side) into the nucleus ambiguus blocked both the estrogen-induced increase in vagal efferent activity and baroreflex sensitivity. These results demonstrate that in male rats estrogen acts centrally to enhance baroreflex sensitivity by increasing parasympathetic efferent tone.

Sympathetic nerve activity to brown adipose tissue (BAT) regulates adipocyte metabolism of its stored lipid fuel and thus the thermogenesis in BAT. To determine if the discharge of neurons in the rostral raphe pallidus (RPa) can influence BAT thermogenesis, changes in sympathetic nerve activity to BAT were recorded after microinjection (60 nl) of the GABAA receptor antagonist bicuculline (500 μM) into the RPa in chloralose-urethan-anesthetized, ventilated rats. Bicuculline caused a large, rapid rise in the sympathetic nerve activity to BAT (which had also increased during acute hypothermia) from very low, normothermic control levels to maximum values (mean: 1,949 ± 604% control; n = 13) after 4–6 min. The sympathetic nerve discharge to BAT had a mean burst frequency (3.5 ± 0.3 Hz) that was significantly less than the heart rate (7.3 ± 0.2 beats/min), and it was not inhibited during baroreceptor reflex activation. Bicuculline-stimulated increases in the sympathetic nerve activity to BAT and cold-evoked increases in neuronal fos expression were localized to the RPa at the level of the caudal half of the facial nucleus. This dramatic increase in sympathetic nerve activity to BAT after disinhibition of neurons in rostral RPa is consistent with a major role for RPa neurons, perhaps as sympathetic premotoneurons for BAT, in medullary control of BAT thermogenesis.

These studies examined the effects of α1- and α2-adrenoreceptor blockade in the anteroventral portion of the third cerebral ventricle (AV3V) on modification of baroreflex-induced changes in heart rate and renal sympathetic nerve activity (RSNA) induced by hyperosmolality. Local administration of hypertonic artificial cerebrospinal fluid (aCSF) in the AV3V significantly increased baroreflex-induced bradycardia during intravenous phenylephrine but did not alter changes in RSNA during the pressor response or alter tachycardia and neural responses evoked by decreased blood pressure. The enhanced cardiac response was not observed during simultaneous administration of phentolamine (α1- and α2-antagonist) or yohimbine (selective α2-antagonist) in the AV3V region. However, treatment with prazosin (α1-antagonist) did not alter the exaggerated cardiac response evoked by hypertonic aCSF to increased blood pressure. These data demonstrate that acute, local hypertonic stimulation in the AV3V region selectively enhances baroreflex-induced bradycardia by stimulation of α2-adrenergic receptors during acute pressor responses.

Mean arterial pressure (MAP), the product of cardiac output (CO) and total peripheral resistance (TPR), is reduced below preexercise levels after a single bout of mild to moderate dynamic exercise. Thus acute, dynamic exercise may be used as a safe, therapeutic approach to reduce MAP. However, the mechanisms responsible for the postexercise hypotension (PEH) are unknown. We tested the hypothesis that PEH is associated with reductions in TPR and sympathetic nerve activity (SNA). Two experimental protocols were designed to test this hypothesis in male spontaneously hypertensive rats (SHR). In protocol 1( n = 9), CO and TPR were determined before, during, and after exercise. In protocol 2 ( n = 7), lumbar SNA (LSNA) was recorded before and after exercise. Rats in protocol 1 were chronically instrumented with left carotid arterial catheters and ascending aortic Doppler ultrasonic flow probes. Rats in protocol 2 were chronically instrumented with left carotid arterial catheters and electrodes around the lumbar sympathetic trunk. Dynamic treadmill exercise (9–12 m/min, 10% grade for 40 min) resulted in a postexercise reduction in MAP (from 143 ± 5 to 128 ± 4 mmHg, P

The exact mechanisms for the decrease in R-R interval (RRI) during acute physiological hyperinsulinemia with euglycemia are unknown. Power spectral analysis of RRI and microneurographic recordings of muscle sympathetic nerve activity (MSNA) in 16 normal subjects provided markers of autonomic control during 90-min hyperinsulinemic/euglycemic clamps. By infusing propranolol and insulin ( n = 6 subjects), we also explored the contribution of heightened cardiac sympathetic activity to the insulin-induced decrease in RRI. Slight decreases in RRI ( P < 0.001) induced by sevenfold increases in plasma insulin could not be suppressed by propranolol. Insulin increased MSNA by more than twofold ( P < 0.001), decreased the high-frequency variability of RRI ( P< 0.01), but did not affect the absolute low-frequency variability of RRI. These results suggest that reductions in cardiac vagal tone and modulation contribute at least in part to the reduction in RRI during hyperinsulinemia. Moreover, more than twofold increases in MSNA occurring concurrently with a slight and not purely sympathetically mediated tachycardia suggest regionally nonuniform increases in sympathetic activity during hyperinsulinemia in humans.

Frequency-domain analyses were used to determine the effect of heat stress on the relationships between the discharge bursts of sympathetic nerve pairs and sympathetic and phrenic nerve pairs in chloralose-anesthetized rats. Sympathetic nerve discharge (SND) was recorded from the renal, splanchnic, splenic, and lumbar nerves during increases in core body temperature (Tc) from 38 to 41.4 ± 0.3°C. The following observations were made: 1) hyperthermia transformed the cardiac-related bursting pattern of SND to a pattern that contained low-frequency, non-cardiac-related bursts, 2) the pattern transformation was uniform in regionally selective sympathetic nerves, 3) hyperthermia enhanced the frequency-domain coupling between SND and phrenic nerve bursts, and 4) low-frequency SND bursts recorded during hyperthermia contained significantly more activity than cardiac-related bursts. We conclude that acute heat stress profoundly affects the organization of neural circuits responsible for the frequency components in sympathetic nerve activity and that SND pattern transformation provides an important strategy for increasing the level of activity in sympathetic nerves during increased Tc.