Augmented sympathetic activation during short-term hypoxia and high-altitude exposure in subjects susceptible to high-altitude pulmonary edema. (41/5862)

BACKGROUND: Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. Cardiovascular adjustments to hypoxia are mediated, at least in part, by the sympathetic nervous system, and sympathetic activation promotes pulmonary vasoconstriction and alveolar fluid flooding in experimental animals. METHODS AND RESULTS: We measured sympathetic nerve activity (using intraneural microelectrodes) in 8 mountaineers susceptible to high-altitude pulmonary edema and 7 mountaineers resistant to this condition during short-term hypoxic breathing at low altitude and at rest at a high-altitude laboratory (4559 m). We also measured systolic pulmonary artery pressure to examine the relationship between sympathetic activation and pulmonary vasoconstriction. In subjects prone to pulmonary edema, short-term hypoxic breathing at low altitude evoked comparable hypoxemia but a 2- to 3-times-larger increase in the rate of the sympathetic nerve discharge than in subjects resistant to edema (P<0.001). At high altitude, in subjects prone to edema, the increase in the mean+/-SE sympathetic firing rate was >2 times larger than in those resistant to edema (36+/-7 versus 15+/-4 bursts per minute, P<0.001) and preceded the development of lung edema. We observed a direct relationship between sympathetic nerve activity and pulmonary artery pressure measured at low and high altitude in the 2 groups (r=0.83, P<0.0001). CONCLUSIONS: With the use of direct measurements of postganglionic sympathetic nerve discharge, these data provide the first evidence for an exaggerated sympathetic activation in subjects prone to high-altitude pulmonary edema both during short-term hypoxic breathing at low altitude and during actual high-altitude exposure. Sympathetic overactivation may contribute to high-altitude pulmonary edema.  (+info)

Sympathetic neuronal oscillators are capable of dynamic synchronization. (42/5862)

In this paper we show that the discharges of sympathetic neurons innervating an identified peripheral target are driven by multiple oscillators that undergo dynamic synchronization when an entraining force, central respiratory drive (CRD), is increased. Activity was recorded from postganglionic sympathetic neurons (PGNs) innervating the caudal ventral artery of the rat tail: (1) at the population level from the ventral collector nerve (VCN); and (2) from pairs of single PGNs recorded simultaneously using a focal recording technique. Autospectral analysis of VCN activity revealed a more prominent rhythmical component in the presence of CRD than in its absence, suggesting that (1) multiple oscillators drive the discharges of PGNs and (2) these oscillators can be entrained and therefore synchronized by CRD. This interpretation was supported by analysis of the firing behavior of PGN pairs. Autocorrelation and cross-correlation analysis showed that pairs were not synchronized in the absence of CRD but showed significant synchronization when CRD was enhanced. Time-evolving spectral analysis and raster plots demonstrated that the temporal stability of PGN-to-PGN and CRD-to-PGN interactions at a given level of CRD were also dynamic in nature, with stable constant phase relationships predominating as CRD was increased. This is the first reported example of dynamic synchronization in populations of single postganglionic sympathetic neurons, and we suggest that, as in sensory processing and motor control, temporal pattern coding may also be an important feature of neuronal discharges in sympathetic pathways.  (+info)

Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs. (43/5862)

This study was designed to evaluate the importance of sympathoadrenal activation in the acute cardiovascular response to apneas and the role of hypoxemia in this response. In addition, we evaluated the contribution of the vagus nerve to apnea responses after chemical sympathectomy. In six pigs preinstrumented with an electromagnetic flow probe and five nonpreinstrumented pigs, effects of periodic nonobstructive apneas were tested under the following six conditions: room air breathing, 100% O2 supplementation, both repeated after administration of hexamethonium (Hex), and both repeated again after bilateral vagotomy in addition to Hex. With room air apneas, during the apnea cycle, there were increases in mean arterial pressure (MAP; from baseline of 108 +/- 4 to 124 +/- 6 Torr, P < 0.01), plasma norepinephrine (from 681 +/- 99 to 1,825 +/- 578 pg/ml, P < 0.05), and epinephrine (from 191 +/- 67 to 1,245 +/- 685 pg/ml, P < 0.05) but decreases in cardiac output (CO; from 3.3 +/- 0.6 to 2.4 +/- 0.3 l/min, P < 0.01) and cervical sympathetic nerve activity. With O2 supplementation relative to baseline, apneas were associated with small increases in MAP (from 112 +/- 4 to 118 +/- 3 Torr, P < 0.01) and norepinephrine (from 675 +/- 97 to 861 +/- 170 pg/ml, P < 0.05). After Hex, apneas with room air were associated with small increases in MAP (from 103 +/- 6 to 109 +/- 6 Torr, P < 0.05) and epinephrine (from 136 +/- 45 to 666 +/- 467 pg/ml, P < 0.05) and decreases in CO (from 3.6 +/- 0.4 to 3.2 +/- 0. 5 l/min, P < 0.05). After Hex, apneas with O2 supplementation were associated with decreased MAP (from 107 +/- 5 to 100 +/- 5 Torr, P < 0.05) and no other changes. After vagotomy + Hex, with room air and O2 supplementation, apneas were associated with decreased MAP (from 98 +/- 6 to 76 +/- 7 and from 103 +/- 7 to 95 +/- 6 Torr, respectively, both P < 0.01) but increased CO [from 2.7 +/- 0.3 to 3. 2 +/- 0.4 l/min (P < 0.05) and from 2.4 +/- 0.2 to 2.7 +/- 0.2 l/min (P < 0.01), respectively]. We conclude that sympathoadrenal activation is the major pressor mechanism during apneas. Cervical sympathetic nerve activity does not reflect overall sympathoadrenal activity during apneas. Hypoxemia is an important but not the sole trigger factor for sympathoadrenal activation. There is an important vagally mediated reflex that contributes to the pressor response to apneas.  (+info)

Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. (44/5862)

The present study aimed to determine whether peripheral and/or central chemoreflex function is altered in chronic heart failure (CHF) and whether altered chemoreflex function contributes to sympathetic activation in CHF. A rabbit model of pacing-induced CHF was employed. The development of CHF (3-4 wk of pacing) was characterized by an enlarged heart, an attenuated contractility, and an elevated central venous pressure. Renal sympathetic nerve activity (RSNA) and minute volume (MV) of ventilation in response to stimulation of peripheral chemoreceptors by isocapnic/hypoxic gases were measured in the conscious state. It was found that the baseline RSNA at normoxia was higher in CHF rabbits than in sham rabbits (35. 00 +/- 4.03 vs. 20.75 +/- 2.87% of maximum, P < 0.05). Moreover, the magnitudes of changes in RSNA and MV in response to stimulation of the peripheral chemoreceptors and the slopes of RSNA-arterial PO2 and MV-arterial PO2 curves were greater in CHF than in sham rabbits. Inhibition of the peripheral chemoreceptors by inhalation of 100% O2 decreased RSNA in CHF but not in sham rabbits. The central chemoreflex function, as evaluated by the responses of RSNA and MV to hyperoxic/hypercapnic gases, was not different between sham and CHF rabbits. These data suggest that an enhancement of the peripheral chemoreflex occurs in the rabbit model of pacing-induced CHF and that the enhanced peripheral chemoreflex function contributes to the sympathetic activation in the CHF state.  (+info)

RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue. (45/5862)

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.  (+info)

Midline medullary depressor responses are mediated by inhibition of RVLM sympathoexcitatory neurons in rats. (46/5862)

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 microA) 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 microA) 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.  (+info)

Does gender influence the strength and mechanisms of the muscle metaboreflex during dynamic exercise in dogs? (47/5862)

Ischemia of active skeletal muscle stimulates neuronal afferents within the muscle, which elicits a reflex increase in sympathetic nerve activity, systemic arterial pressure (SAP), and heart rate (HR), termed the muscle metaboreflex. We retrospectively investigated whether gender influences the activation of the muscle metaboreflex and the primary mechanisms used by this reflex, augmentation of cardiac output (CO) and peripheral vasoconstriction, using 15 female and 13 male chronically instrumented dogs exercising on a treadmill (3.2 km/h, 0% grade). Metaboreflex activation was achieved via progressive partial vascular occlusion of the terminal aorta during exercise. In both females and males, hindlimb ischemia elicited similar substantial increases in SAP (56.1 +/- 3.0 and 55.1 +/- 4.2 mmHg, respectively), HR (25.8 +/- 4.8 and 33.9 +/- 2.8 beats/min, respectively), and CO (1.39 +/- 0.3 and 1.64 +/- 0.2 liters, respectively) and a similar substantial decrease in renal vascular conductance (RVC; 42.7 +/- 4.9 and 42.9 +/- 5.3%, respectively). Both groups also demonstrated similar metaboreflex thresholds and sensitivities of SAP, HR, CO, and RVC. We conclude that the strength and mechanisms mediating the metaboreflex responses during dynamic exercise in dogs are not affected by gender.  (+info)

Tonic drive to sympathetic premotor neurons of rostral ventrolateral medulla from caudal pressor area neurons. (48/5862)

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 of L-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.  (+info)