Effects of glossopharyngeal insufflation on cardiac function: an echocardiographic study in elite breath-hold divers.

Glossopharyngeal insufflation (GI), a technique used by breath-hold divers to increase lung volume and augment diving depth and duration, is associated with untoward hemodynamic consequences. To study the cardiac effects of GI, we performed transthoracic echocardiography, using the subcostal window, in five elite breath-hold divers at rest and during GI. During GI, heart rate increased in all divers (mean of 53 beats/min to a mean of 100 beats/min), and blood pressure fell dramatically (mean systolic, 112 to 52 mmHg; mean diastolic, 75 mmHg to nondetectable). GI induced a 46% decrease in mean left ventricular end-diastolic area, 70% decrease in left ventricular end-diastolic volume, 49% increase in mean right ventricular end-diastolic area, and 160% increase in mean right ventricular end-diastolic volume. GI also induced biventricular systolic dysfunction; left ventricular ejection fraction decreased from 0.60 to a mean of 0.30 (P = 0.012); right ventricular ejection fraction, from 0.75 to a mean of 0.39 (P < 0.001). Wall motion of both ventricles became significantly abnormal during GI; the most prominent left ventricular abnormalities involved hypokinesis or dyskinesis of the interventricular septum, while right ventricular wall motion abnormalities involved all visible segments. In two divers, the inferior vena cava dilated with the appearance of spontaneous contrast during GI, signaling increased right atrial pressure and central venous stasis. Hypotension during GI is associated with acute biventricular systolic dysfunction. The echocardiographic pattern of right ventricular systolic dysfunction is consistent with acute pressure overload, whereas concurrent left ventricular systolic dysfunction is likely due to ventricular interdependence.     

Features of glossopharyngeal breathing in breath-hold divers.

One technique employed by competitive breath-hold divers to increase diving depth is to hyperinflate the lungs with glossopharyngeal breathing (GPB). Our aim was to assess the relationship between measured volume and pressure changes due to GPB. Seven healthy male breath-hold divers, age 33 (8) [mean (SD)] years were recruited. Subjects performed baseline body plethysmography (TLC(PRE)). Plethysmography and mouth relaxation pressure were recorded immediately following a maximal GPB maneuver at total lung capacity (TLC) (TLC(GPB)) and within 5 min after the final GPB maneuver (TLC(POST)). Mean TLC increased from TLC(PRE) to TLC(GPB) by 1.95 (0.66) liters and vital capacity (VC) by 1.92 (0.56) liters (P < 0.0001), with no change in residual volume. There was an increase in TLC(POST) compared with TLC(PRE) of 0.16 liters (0.14) (P < 0.02). Mean mouth relaxation pressure at TLC(GPB) was 65 (19) cmH(2)O and was highly correlated with the percent increase in TLC (R = 0.96). Breath-hold divers achieve substantial increases in measured lung volumes using GPB primarily from increasing VC. Approximately one-third of the additional air was accommodated by air compression.     

Scaling of swim speed in breath-hold divers

1. Breath-hold divers are widely assumed to descend and ascend at the speed that minimizes energy expenditure per distance travelled (the cost of transport (COT)) to maximize foraging duration at depth. However, measuring COT with captive animals is difficult, and empirical support for this hypothesis is sparse. 2. We examined the scaling relationship of swim speed in free-ranging diving birds, mammals and turtles (37 species; mass range, 0·5-90,000 kg) with phylogenetically informed statistical methods and derived the theoretical prediction for the allometric exponent under the COT hypothesis by constructing a biomechanical model. 3. Swim speed significantly increased with mass, despite considerable variations around the scaling line. The allometric exponent (0·09) was statistically consistent with the theoretical prediction (0·05) of the COT hypothesis. 4. Our finding suggests a previously unrecognized advantage of size in divers: larger animals swim faster and thus could travel longer distance, search larger volume of water for prey and exploit a greater range of depths during a given dive duration. 5. Furthermore, as predicted from the model, endotherms (birds and mammals) swam faster than ectotherms (turtles) for their size, suggesting that metabolic power production limits swim speed. Among endotherms, birds swam faster than mammals, which cannot be explained by the model. Reynolds numbers of small birds (<2 kg) were close to the lower limit of turbulent flow (～ 3 × 10(5) ), and they swam fast possibly to avoid the increased drag associated with flow transition.     

Diving response and arterial oxygen saturation during apnea and exercise in breath-hold divers.

This study addressed the effects of apnea in air and apnea with face immersion in cold water (10 degrees C) on the diving response and arterial oxygen saturation during dynamic exercise. Eight trained breath-hold divers performed steady-state exercise on a cycle ergometer at 100 W. During exercise, each subject performed 30-s apneas in air and 30-s apneas with face immersion. The heart rate and arterial oxygen saturation decreased and blood pressure increased during the apneas. Compared with apneas in air, apneas with face immersion augmented the heart rate reduction from 21 to 33% (P < 0.001) and the blood pressure increase from 34 to 42% (P < 0.05). The reduction in arterial oxygen saturation from eupneic control was 6.8% during apneas in air and 5.2% during apneas with face immersion (P < 0.05). The results indicate that augmentation of the diving response slows down the depletion of the lung oxygen store, possibly associated with a larger reduction in peripheral venous oxygen stores and increased anaerobiosis. This mechanism delays the fall in alveolar and arterial PO(2) and, thereby, the development of hypoxia in vital organs. Accordingly, we conclude that the human diving response has an oxygen-conserving effect during exercise.     

Cardiovascular changes during underwater static and dynamic breath-hold dives in trained divers

Limited information exists concerning arterial blood pressure (BP) changes in underwater breath-hold diving. Simulated chamber dives to 50 m of freshwater (mfw) reported very high levels of invasive BP in two divers during static apnea (SA), whereas a recent study using a noninvasive subaquatic sphygmomanometer reported unchanged or mildly increased values at 10 m SA dive. In this study we investigated underwater BP changes during not only SA but, for the first time, dynamic apnea (DA) and shortened (SHT) DA in 16 trained breath-hold divers. Measurements included BP (subaquatic sphygmomanometer), ECG, and pulse oxymetry (arterial oxygen saturation, SpO?, and heart rate). BP was measured during dry conditions, at surface fully immersed (SA), and at 2 mfw (DA and SHT DA), whereas ECG and pulse oxymetry were measured continuously. We have found significantly higher mean arterial pressure (MAP) values in SA (～40%) vs. SHT DA (～30%). Postapneic recovery of BP was slightly slower after SHT DA. Significantly higher BP gain (mmHg/duration of apnea in s) was found in SHT DA vs. SA. Furthermore, DA attempts resulted in faster desaturation vs. SA. In conclusion, we have found moderate increases in BP during SA, DA, and SHT DA. These cardiovascular changes during immersed SA and DA are in agreement with those reported for dry SA and DA.     

Enhanced sympathetic outflow and decreased baroreflex sensitivity are associated with intermittent hypoxia-induced systemic hypertension in conscious rats.

Long-term exposure to intermittent hypoxia (IH), such as that occurring in association with sleep apnea, may result in systemic hypertension; however, the time course changes in arterial pressure, autonomic functions, and baroreflex sensitivity are still unclear. We investigated the changes in cardiovascular neural regulations during the development of chronic IH-induced hypertension in rats. Sprague-Dawley rats were exposed to repetitive 1.25-min cycles (30 s of N2+45 s of 21% O2) of IH or room air (RA) for 6 h/day during light phase (10 AM-4 PM) for 30 days. Arterial pressure was measured daily using the telemetry system during RA breathing. The mean arterial pressure (MAP) and interpulse interval (PPI) signals were then used to assess the autonomic functions and spontaneous baroreflex sensitivity by auto- and cross-spectral analysis, respectively. Stable MAP, low-frequency power of MAP (BLF), and low-frequency power (LF)-to-high frequency power (HF) ratio of PPI (LF/HF) were significantly higher in IH-exposed rats, compared with those of RA-exposed rats. Elevation of the MAP, BLF, LF/HF, and minute ventilation started 5 days after IH exposure and lasted until the end of the 30-day observation period. Additionally, IH-exposed rats had significant lower slope of MAP-PPI linear regression (under a successively descending and ascending) and magnitude of MAP-PPI transfer function (at frequency ranges of 0.06-0.6 Hz or 0.6-2.4 Hz) after IH exposure for 17 days. However, RA-exposed rats did not exhibit these changes. The results of this study indicate that chronic IH-induced hypertension is associated with a facilitation of cardiovascular sympathetic outflow and inhibition of baroreflex sensitivity in conscious rats.     

Transpulmonary pressures and lung mechanics with glossopharyngeal insufflation and exsufflation beyond normal lung volumes in competitive breath-hold divers.

Throughout life, most mammals breathe between maximal and minimal lung volumes determined by respiratory mechanics and muscle strength. In contrast, competitive breath-hold divers exceed these limits when they employ glossopharyngeal insufflation (GI) before a dive to increase lung gas volume (providing additional oxygen and intrapulmonary gas to prevent dangerous chest compression at depths recently greater than 100 m) and glossopharyngeal exsufflation (GE) during descent to draw air from compressed lungs into the pharynx for middle ear pressure equalization. To explore the mechanical effects of these maneuvers on the respiratory system, we measured lung volumes by helium dilution with spirometry and computed tomography and estimated transpulmonary pressures using an esophageal balloon after GI and GE in four competitive breath-hold divers. Maximal lung volume was increased after GI by 0.13-2.84 liters, resulting in volumes 1.5-7.9 SD above predicted values. The amount of gas in the lungs after GI increased by 0.59-4.16 liters, largely due to elevated intrapulmonary pressures of 52-109 cmH(2)O. The transpulmonary pressures increased after GI to values ranging from 43 to 80 cmH(2)O, 1.6-2.9 times the expected values at total lung capacity. After GE, lung volumes were reduced by 0.09-0.44 liters, and the corresponding transpulmonary pressures decreased to -15 to -31 cmH(2)O, suggesting closure of intrapulmonary airways. We conclude that the lungs of some healthy individuals are able to withstand repeated inflation to transpulmonary pressures far greater than those to which they would normally be exposed.     

Dobutamine potentiates arterial chemoreflex sensitivity in healthy normal humans

beta-Adrenergic agonists may increase chemosensitivity in humans. We tested the hypothesis that the beta1-agonist dobutamine increases peripheral chemosensitivity in a double-blind placebo-controlled randomized and crossover study. In 15 healthy subjects, we examined the effects of dobutamine on breathing, hemodynamics, and sympathetic nerve activity (measured using microneurography) during normoxia, isocapnic hypoxia (10% O2), posthypoxic maximal voluntary end-expiratory apnea, hyperoxic hypercapnia, and cold pressor test (CPT). Dobutamine increased ventilation (7.5 +/- 0.3 vs. 6.7 +/- 0.2 l/min, P = 0.0004) during normoxia, markedly enhanced the ventilatory (16.1 +/- 1.6 vs. 11.4 +/- 0.7 l/min, P < 0.0001) and sympathetic (+403 +/- 94 vs. +222 +/- 5%, P < 0.03) responses at the fifth minute of isocapnic hypoxia, and enhanced the sympathetic response to the apnea performed after hypoxia (+501 +/- 107% vs. +291 +/- 38%, P < 0.05). No differences were observed between dobutamine and placebo on the responses to hyperoxic hypercapnia and CPT. Dobutamine increases ventilation during normoxia and potentiates the ventilatory and sympathetic responses to hypoxia in healthy subjects. Dobutamine does not affect the responses to hyperoxic hypercapnia and CPT. We conclude that dobutamine enhances peripheral chemosensitivity.     

Central neural control of sympathetic nerve activity in heart failure following exercise training

Typical characteristics of chronic congestive heart failure (HF) are increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation. These abnormalities lead to an increased risk of mortality, particularly in the late stage of chronic HF. Recent evidence suggests that central nervous system (CNS) mechanisms may be important in these abnormalities during HF. Exercise training (ExT) has emerged as a nonpharmacological therapeutic strategy substitute with significant benefit to patients with HF. Regular ExT improves functional capacity as well as quality of life and perhaps prognosis in chronic HF patients. The mechanism(s) by which ExT improves the clinical status of HF patients is not fully known. Recent studies have provided convincing evidence that ExT significantly alleviates the increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation in HF. This review describes and highlights the studies that examine various central pathways involved in autonomic outflow that are altered in HF and are improved following ExT. The increased sympathoexcitation is due to an imbalance between inhibitory and excitatory mechanisms within specific areas in the CNS such as the paraventricular nucleus (PVN) of the hypothalamus. Studies summarized here have revealed that ExT improves the altered inhibitory pathway utilizing nitric oxide and GABA mechanisms within the PVN in HF. ExT alleviates elevated sympathetic outflow in HF through normalization of excitatory glutamatergic and angiotensinergic mechanisms within the PVN. ExT also improves volume reflex function and thus fluid balance in HF. Preliminary observations also suggest that ExT induces structural neuroplasticity in the brain of rats with HF. We conclude that improvement of the enhanced CNS-mediated increase in sympathetic outflow, specifically to the kidneys related to fluid balance, contributes to the beneficial effects of ExT in HF.     

Role of nitric oxide in central sympathetic outflow

The gaseous molecule nitric oxide (NO) plays an important role in cardiovascular homeostasis. It plays this role by its action on both the central and peripheral autonomic nervous systems. In this review, the central role of NO in the regulation of sympathetic outflow and subsequent cardiovascular control is examined. After a brief introduction concerning the location of NO synthase (NOS) containing neurons in the central nervous system (CNS), studies that demonstrate the central effect of NO by systemic administration of NO modulators will be presented. The central effects of NO as assessed by intracerebroventricular, intracisternal, or direct injection within the specific central areas is also discussed. Our studies demonstrating specific medullary and hypothalamic sites involved in sympathetic outflow are summarized. The review will be concluded with a discussion of the role of central NO mechanisms in the altered sympathetic outflow in disease states such as hypertension and heart failure.     

Orexins: a role in medullary sympathetic outflow

Orexin A and B, also known as hypocretin 1 and 2, are two recently isolated hypothalamic peptides. As orexin-containing neurons are strategically located in the lateral hypothalamus, which has long been suspected to play an important role in feeding behaviors, initial studies were focused on the involvement of orexins in positive food intake and energy metabolism. Recent studies implicate a more diverse biological role of orexins, which can be manifested at different level of the neuraxis. For example, canine narcolepsy, a disorder with close phenotypic similarity to human narcolepsy, is caused by a mutation of hypocretin receptor 2 gene. Results from our immunohistochemical and functional studies, which will be summarized here, suggest that the peptide acting on neurons in the rostral ventrolateral medulla augment sympathoexcitatory outflow to the spinal cord. This finding is discussed in the context of increased sympathetic activity frequently associated with obesity.     

Ventilatory baroreflex sensitivity in humans is not modulated by chemoreflex activation

Increasing arterial blood pressure (AP) decreases ventilation, whereas decreasing AP increases ventilation in experimental animals. To determine whether a "ventilatory baroreflex" exists in humans, we studied 12 healthy subjects aged 18-26 yr. Subjects underwent baroreflex unloading and reloading using intravenous bolus sodium nitroprusside (SNP) followed by phenylephrine ("Oxford maneuver") during the following "gas conditions:" room air, hypoxia (10% oxygen)-eucapnia, and 30% oxygen-hypercapnia to 55-60 Torr. Mean AP (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), expiratory minute ventilation (V(E)), respiratory rate (RR), and tidal volume were measured. After achieving a stable baseline for gas conditions, we performed the Oxford maneuver. V(E) increased from 8.8 ± 1.3 l/min in room air to 14.6 ± 0.8 l/min during hypoxia and to 20.1 ± 2.4 l/min during hypercapnia, primarily by increasing tidal volume. V(E) doubled during SNP. CO increased from 4.9 ± .3 l/min in room air to 6.1 ± .6 l/min during hypoxia and 6.4 ± .4 l/min during hypercapnia with decreased TPR. HR increased for hypoxia and hypercapnia. Sigmoidal ventilatory baroreflex curves of V(E) versus MAP were prepared for each subject and each gas condition. Averaged curves for a given gas condition were obtained by averaging fits over all subjects. There were no significant differences in the average fitted slopes for different gas conditions, although the operating point varied with gas conditions. We conclude that rapid baroreflex unloading during the Oxford maneuver is a potent ventilatory stimulus in healthy volunteers. Tidal volume is primarily increased. Ventilatory baroreflex sensitivity is unaffected by chemoreflex activation, although the operating point is shifted with hypoxia and hypercapnia.     

Effects of cilnidipine on sympathetic outflow and sympathetic arterial pressure and heart rate regulations in rats

AimsCilnidipine is a unique Ca^2 + channel blocker that inhibits both L-type and N-type Ca^2 + channels. The present study aimed to assess the effects of intravenous cilnidipine on sympathetic outflow and sympathetic arterial pressure (AP) and heart rate (HR) regulations.Main methodsCarotid sinus baroreceptor regions were isolated from the systemic circulation in anesthetized and vagotomized Wistar Kyoto rats. Changes in efferent sympathetic nerve activity (SNA), AP and HR in response to a stepwise input of carotid sinus pressure were examined before and during intravenous cilnidipine administration (30 μg/kg bolus + 100 μg kg^? 1 h^? 1 infusion, n = 6).Key findingsCilnidipine significantly reduced the AP response range (from 68.0 ± 10.2 to 34.6 ± 4.1 mmHg, P = 0.007) but did not affect the SNA response range (from 90.4 ± 10.3 to 84.7 ± 9.5%, P = 0.297) or the HR response range (from 50.4 ± 10.1 to 48.1 ± 6.2 beats/min, P = 0.719).SignificanceCilnidipine, at a depressor dose used in the present study, does not acutely suppress sympathetic outflow from the central nervous system. Also, it spared the sympathetic HR response, suggesting that N-type Ca^2 + channel blocking action at the cardiac sympathetic nerve endings may be a modest one.     

Differential sympathetic outflow elicited by active muscle in rats

The present study was undertaken to test the hypothesis that activation of the muscle reflex elicits less sympathetic activation in skeletal muscle than in internal organs. In decerebrate rats, we examined renal and lumbar (mainly innervating hindlimb blood vessels) sympathetic nerve activities (RSNA and LSNA, respectively) during 1 min of 1) repetitive (1- to 4-s stimulation-to-relaxation) contraction of the triceps surae muscle, 2) repetitive tendon stretch, and 3) repetitive contraction with hindlimb circulatory occlusion. During these interventions, RSNA and LSNA responded synchronously as tension developed. The increase was greater in RSNA than in LSNA [+51 +/- 14 vs. +24 +/- 5% (P < 0.05) with contraction, +46 +/- 8 vs. +17 +/- 4% (P < 0.05) with stretch, +76 +/- 20 vs. 39 +/- 7% (P < 0.05) with contraction during occlusion] during all three interventions: repetitive contraction (n = 10, +508 +/- 48 g tension from baseline), tendon stretch (n = 12, +454 +/- 34 g), and contraction during occlusion (n = 9, +473 +/- 33 g). Additionally, hindlimb circulatory occlusion significantly enhanced RSNA and LSNA responses to contraction. These data demonstrate that RSNA responses to muscle contraction and stretch are greater than LSNA responses. We suggest that activation of the muscle afferents induces the differential sympathetic outflow that is directed toward the kidney as opposed to the limbs. This differential outflow contributes to the distribution of cardiac output observed during exercise. We further suggest that as exercise proceeds, muscle metabolites produced in contracting muscle sensitize muscle afferents and enhance sympathetic drive to limbs and renal beds.     

Cholecystokinin selectively affects presympathetic vasomotor neurons and sympathetic vasomotor outflow

Cholecystokinin (CCK) is a potential mediator of gastrointestinal vasodilatation during digestion. To determine whether CCK influences sympathetic vasomotor function, we examined the effect of systemic CCK administration on mean arterial blood pressure (MAP), heart rate (HR), lumbar sympathetic nerve discharge (LSND), splanchnic sympathetic nerve discharge (SSND), and the discharge of presympathetic neurons of the rostral ventrolateral medulla (RVLM) in alpha-chloralose-anesthetized rats. CCK (1-8 microg/kg iv) reduced MAP, HR, and SSND and transiently increased LSND. Vagotomy abolished the effects of CCK on MAP and SSND as did the CCK-A receptor antagonist devazepide (0.5 mg/kg iv). The bradycardic effect of CCK was unaltered by vagotomy but abolished by devazepide. CCK increased superior mesenteric arterial conductance but did not alter iliac conductance. CCK inhibited a subpopulation (approximately 49%) of RVLM presympathetic neurons whereas approximately 28% of neurons tested were activated by CCK. The effects of CCK on RVLM neuronal discharge were blocked by devazepide. RVLM neurons inhibited by exogenous CCK acting via CCK-A receptors on vagal afferents may control sympathetic vasomotor outflow to the gastrointestinal tract vasculature.     

Purinergic and glutamatergic interactions in the hypothalamic paraventricular nucleus modulate sympathetic outflow

P2X receptors are expressed on ventrolateral medulla projecting paraventricular nucleus (PVN) neurons. Here, we investigate the role of adenosine 5′-triphosphate (ATP) in modulating sympathetic nerve activity (SNA) at the level of the PVN. We used an in situ arterially perfused rat preparation to determine the effect of P2 receptor activation and the putative interaction between purinergic and glutamatergic neurotransmitter systems within the PVN on lumbar SNA (LSNA). Unilateral microinjection of ATP into the PVN induced a dose-related increase in the LSNA (1 nmol: 38 ± 6 %, 2.5 nmol: 72 ± 7 %, 5 nmol: 96 ± 13 %). This increase was significantly attenuated by blockade of P2 receptors (pyridoxalphosphate-6-azophenyl-20,40-disulphonic acid, PPADS) and glutamate receptors (kynurenic acid, KYN) or a combination of both. The increase in LSNA elicited by L-glutamate microinjection into the PVN was not affected by a previous injection of PPADS. Selective blockade of non-N-methyl-D-aspartate receptors (6-cyano-7-nitroquinoxaline-2,3-dione disodium salt, CNQX), but not N-methyl-D-aspartate receptors (NMDA) receptors (DL-2-amino-5-phosphonopentanoic acid, AP5), attenuated the ATP-induced sympathoexcitatory effects at the PVN level. Taken together, our data show that purinergic neurotransmission within the PVN is involved in the control of SNA via P2 receptor activation. Moreover, we show an interaction between P2 receptors and non-NMDA glutamate receptors in the PVN suggesting that these functional interactions might be important in the regulation of sympathetic outflow.     

Periods of intermittent hypoxic apnea can alter chemoreflex control of sympathetic nerve activity in humans

Obstructive sleep apnea is associated with sustained elevation of muscle sympathetic nerve activity (MSNA) and altered chemoreflex control of MSNA, both of which likely play an important role in the development of hypertension in these patients. Additionally, short-term exposure to intermittent hypoxic apneas can produce a sustained elevation of MSNA. Therefore, we tested the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Twenty-one subjects were randomly assigned to one of three groups (hypoxic apnea, hypercapnic hypoxia, and isocapnic hypoxia). Subjects were exposed to 30 s of the perturbation every minute for 20 min. Chemoreflex control of MSNA was assessed during baseline, 1 min posttreatment, and every 15 min throughout 180 min of recovery by the MSNA response to a single hypoxic apnea. Recovery hypoxic apneas were matched to a baseline hypoxic apnea with a similar nadir oxygen saturation. A significant main effect for chemoreflex control of MSNA was observed after 20 min of intermittent hypoxic apneas (P <0.001). The MSNA response to a single hypoxic apnea was attenuated 1 min postexposure compared with baseline (P <0.001), became augmented within 30 min of recovery, and remained augmented through 165 min of recovery (P <0.05). Comparison of treatment groups revealed no differences in the chemoreflex control of MSNA during recovery (P=0.69). These data support the hypothesis that 20 min of intermittent hypoxic apneas can alter chemoreflex control of MSNA. Furthermore, this response appears to be mediated by hypoxia.     

GABAB-receptor-mediated suppression of sympathetic outflow from the spinal cord of neonatal rats.

Using a splanchnic nerve-spinal cord preparation in vitro that could spontaneously generate sympathetic nerve discharge (SND), we investigated the roles of intraspinal GABA(B) receptors in the regulation of SND. Despite an age-dependent difference in sensitivity, bath applications of baclofen (Bac; GABA(B)-receptor agonist) consistently reduced SND in a concentration-dependent manner. The drug specificity of Bac in activation of GABA(B) receptors was verified by application of its antagonist saclofen (Sac) or CGP-46381 (CGP). Sac or CGP alone did not change SND. However, in the presence of Sac or CGP, the effects of Bac on SND inhibition were reversibly attenuated. The splanchnic sympathetic preganglionic neuron (SPN) was recorded by blind whole cell, patch-clamp techniques. We examined Bac effects on electrical membrane properties of SPNs. Applications of Bac reduced excitatory synaptic events, induced membrane hyperpolarizations, and inhibited SPN firing. In the presence of 12 mM Mg2+ or 0.5 microM TTX to block Ca2+- or action potential-dependent synaptic transmissions, applications of Bac induced an outward baseline current that reversed at -29 +/- 6 mV. Because the K+ equilibrium potential in our experimental conditions was -100 mV, the Bac-induced currents could not simply be attributed to an alteration of K+ conductance. On the other hand, applications of Bac to Cs+-loaded SPNs reduced Cd2+-sensitive and high-voltage-activated inward currents, indicating an inhibition of voltage-gated Ca2+ currents. Our results suggest that the activation of intraspinal GABA(B) receptors suppresses SND via a mixture of ion events that may link to a change in Ca2+ conductance.     

Feedback effects of circulating norepinephrine on sympathetic outflow in healthy subjects

The amplitude of low-frequency (LF) oscillations of heart rate (HR) usually reflects the magnitude of sympathetic activity, but during some conditions, e.g., physical exercise, high sympathetic activity results in a paradoxical decrease of LF oscillations of HR. We tested the hypothesis that this phenomenon may result from a feedback inhibition of sympathetic outflow caused by circulating norepinephrine (NE). A physiological dose of NE (100 ng.kg(-1).min(-1)) was infused into eight healthy subjects, and infusion was continued after alpha-adrenergic blockade [with phentolamine (Phe)]. Muscle sympathetic nervous activity (MSNA) from the peroneal nerve, LF (0.04-0.15 Hz) and high frequency (HF; 0.15-0.40 Hz) spectral components of HR variability, and systolic blood pressure variability were analyzed at baseline, during NE infusion, and during NE infusion after Phe administration. The NE infusion increased the mean blood pressure and decreased the average HR (P < 0.01 for both). MSNA (10 +/- 2 vs. 2 +/- 1 bursts/min, P < 0.01), LF oscillations of HR (43 +/- 13 vs. 35 +/- 13 normalized units, P < 0.05), and systolic blood pressure (3.1 +/- 2.3 vs. 2.0 +/- 1.1 mmHg2, P < 0.05) decreased significantly during the NE infusion. During the NE infusion after PHE, average HR and mean blood pressure returned to baseline levels. However, MSNA (4 +/- 2 bursts/min), LF power of HR (33 +/- 9 normalized units), and systolic blood pressure variability (1.7 +/- 1.1 mmHg2) remained significantly (P < 0.05 for all) below baseline values. Baroreflex gain did not change significantly during the interventions. Elevated levels of circulating NE cause a feedback inhibition on sympathetic outflow in healthy subjects. These inhibitory effects do not seem to be mediated by pressor effects on the baroreflex loop but perhaps by a presynaptic autoregulatory feedback mechanism or some other mechanism that is not prevented by a nonselective alpha-adrenergic blockade.     

Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation

Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ～21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.