Coordination between cardiovascular and respiratory control systems during and after cerebral ischemia.

The dissociation of cardiovascular (arterial hypertension) and respiratory (depression) reactions to severe cerebral ischemia seems to be inconsistent with the usual cooperative behavior of the two systems and their role in managing disturbances in the central chemical environment. In the present study the Cushing reaction was elicited by transient increase of the intracranial pressure 4-11 times in each experiment. The pressor response and changes in the vertebral sympathetic nerve discharge (SND) were compared with the respiratory reaction and with changes in the phrenic nerve activity. The reaction in both nerves developed in two phases. In the phrenic nerve, an initial hyperactivity (increased discharge amplitude and frequency) coincided with augmentation of the rhythmic SND (phase 1) and complete nerve depression developed when the SND was desynchronized (phase 2). The transition in both systems correlated in their latencies and the severity of the ischemia needed for their stimulation. Repetition of the ischemic stimuli increased the occurrence of the respiratory-related rhythmicity in the SND and later changed its character from rhythmic amplitude modulation to respiratory-related high-frequency bursting SND coinciding with the inspiration. It is concluded that, despite the apparent dissociation between the cardiovascular and respiratory reactions, there is a parallel response between the neurophysiological correlates of the two systems to increasing severity of cerebral ischemia.     

Aging alters regulation of visceral sympathetic nerve responses to acute hypothermia

Hypothermia produced by acute cooling prominently alters sympathetic nerve outflow. Skin sympathoexcitatory responses to skin cooling are attenuated in aged compared with young subjects, suggesting that advancing age influences sympathetic nerve responsiveness to hypothermia. However, regulation of skin sympathetic nerve discharge (SND) is only one component of the complex sympathetic nerve response profile to hypothermia. Whether aging alters the responsiveness of sympathetic nerves innervating other targets during acute cooling is not known. In the present study, using multifiber recordings of splenic, renal, and adrenal sympathetic nerve activity, we tested the hypothesis that hypothermia-induced changes in visceral SND would be attenuated in middle-aged and aged compared with young Fischer 344 (F344) rats. Colonic temperature (Tc) was progressively reduced from 38 degrees C to 31 degrees C in young (3 to 6 mo), middle-aged (12 mo), and aged (24 mo) baroreceptor-innervated and sinoaortic-denervated (SAD), urethane-chloralose anesthetized, F344 rats. The following observations were made. 1) Progressive hypothermia significantly (P < 0.05) reduced splenic, renal, and adrenal SND in young baroreceptor-innervated F344 rats. 2) Reductions in splenic, renal, and adrenal SND to progressive hypothermia were less consistently observed and, when observed, were generally attenuated in baroreceptor-innervated middle-aged and aged compared with young F344 rats. 3) Differences in splenic, renal, and adrenal SND responses to reduced Tc were observed in SAD young, middle-aged, and aged F344 rats, suggesting that age-associated attenuations in SND responses to acute cooling are not the result of age-dependent modifications in arterial baroreflex regulation of SND. These findings demonstrate that advancing chronological age alters the regulation of visceral SND responses to progressive hypothermia, modifications that may contribute to the inability of aged individuals to adequately respond to acute bouts of hypothermia.     

Cold stress alters characteristics of sympathetic nerve discharge bursts.

Frequency-domain analyses were used to determine the effect of cold stress on the relationships between the discharge bursts of sympathetic nerve pairs, sympathetic and aortic depressor nerve pairs, and sympathetic and phrenic nerve pairs in chloralose-anesthetized, baroreceptor-innervated rats. Sympathetic nerve discharge (SND) was recorded from the renal, lumbar, splanchnic, and adrenal nerves during decreases in core body temperature from 38 to 30 degrees C. The following observations were made. 1) Hypothermia produced nonuniform changes in the level of activity in regionally selective sympathetic nerves. Specifically, cold stress increased lumbar and decreased renal SND but did not significantly change the level of activity in splanchnic and adrenal nerves. 2) The cardiac-related pattern of renal, lumbar, and splanchnic SND bursts was transformed to a low-frequency (0-2 Hz) pattern during cooling, despite the presence of pulse-synchronous activity in arterial baroreceptor afferents. 3) Peak coherence values relating the discharges between sympathetic nerve pairs decreased at the cardiac frequency but were unchanged at low frequencies (0-2 Hz), indicating that the sources of low-frequency SND bursts remain prominently coupled during progressive reductions in core body temperature. 4) Coherence of discharge bursts in phrenic and renal sympathetic nerve pairs in the 0- to 2-Hz frequency band increased during mild hypothermia (36 degrees C) but decreased during deep hypothermia (30 degrees C). We conclude that hypothermia profoundly alters the organization of neural circuits involved in regulation of sympathetic nerve outflow to selected regional circulations.     

Vasopressor responses and hypoxemia with acutely increased intracranial pressure

We studied anesthetized dogs subjected to graded increases in intracranial pressure (ICP) to assess the role of the systemic vasopressor (Cushing) response in the arterial hypoxemia associated with increased ICP. The arterial PO2 decrement was significantly greater with rapidly increased ICP compared to slowly increased ICP (P less than 0.01). Systemic vasopressor responses generated in cats by direct electrical stimulation of the vasomotor center resulted in arterial hypoxemia during controlled ventilation. Therefore, arterial hypoxemia was coincident with increased systemic blood pressure produced by either elevation of ICP or electrical stimulation of the vasomotor center.     

Effects of midbrain and spinal cord transections on sympathetic nerve responses to heating

In the present study, we investigated the contributions of forebrain, brain stem, and spinal neural circuits to heating-induced sympathetic nerve discharge (SND) responses in chloralose-anesthetized rats. Frequency characteristics of renal and splenic SND bursts and the level of activity in these nerves were determined in midbrain-transected (superior colliculus), spinal cord-transected [first cervical vertebra (C1)], and sham-transected (midbrain and spinal cord) rats during progressive increases in colonic temperature (T(c)) from 38 to 41.6-41.7 degrees C. The following observations were made. 1) Significant increases in renal and splenic SND were observed during hyperthermia in midbrain-transected, sham midbrain-transected, C1-transected, and sham C1-transected rats. 2) Heating changed the discharge pattern of renal and splenic SND bursts and was associated with prominent coupling between renal-splenic discharge bursts in midbrain-transected, sham midbrain-transected, and sham C1-transected rats. 3) The pattern of renal and splenic SND bursts remained unchanged from posttransection recovery levels during heating in C1-transected rats. We conclude that an intact forebrain is not required for the full expression of SND responses to increased T(c) and that spinal neural systems, in the absence of supraspinal circuits, are unable to markedly alter the frequency characteristics of SND in response to acute heat stress.     

Rhythmic sympathetic nerve discharges in an in vitro neonatal rat brain stem-spinal cord preparation.

To understand the origination of sympathetic nerve discharge (SND), I developed an in vitro brain stem-spinal cord preparation from neonatal rats. Ascorbic acid (3 mM) was added into the bath solution to increase the viability of preparations. At 24 degrees C, rhythmic SND (recorded from the splanchnic nerve) was consistently observed, but it became quiescent at <16 degrees C. Respiratory-related SND (rSND) was discernible and was well correlated with C(4) root activity. Power spectral analysis of SND revealed a dominant 2-Hz oscillation. In most preparations (86%), such oscillation was persistent, whereas it only slightly reduced its magnitude after isolation from the brain stem. The removal of neural structures rostral to the superior cerebellar artery (equivalent to the level of facial nuclei) reduced rSND, increased tonic SND, but did not affect the temporal coupling between SND and C(4) root activity. Our data suggest a prominent contribution of SND from the neural mechanisms confined within the neonatal rat spinal cord. This ascorbic acid-enhanced in vitro preparation is a very useful model to study neural mechanisms underlying sympathorespiratory integration.     

Bacillus anthracis lethal toxin alters regulation of visceral sympathetic nerve discharge

Bacillus anthracis infection is a pathophysiological condition that is complicated by progressive decreases in mean arterial pressure (MAP). Lethal toxin (LeTx) is central to the pathogenesis of B. anthracis infection, and the sympathetic nervous system plays a critical role in physiological regulation of acute stressors. However, the effect of LeTx on sympathetic nerve discharge (SND), a critical link between central sympathetic neural circuits and MAP regulation, remains unknown. We determined visceral (renal, splenic, and adrenal) SND responses to continuous infusion of LeTx [lethal factor (100 μg/kg) + protective antigen (200 μg/kg) infused at 0.5 ml/h for ≤6 h] and vehicle (infused at 0.5 ml/h) in anesthetized, baroreceptor-intact and baroreceptor (sinoaortic)-denervated (SAD) Sprague-Dawley rats. LeTx infusions produced an initial state of cardiovascular and sympathetic nervous system activation in intact and SAD rats. Subsequent to peak LeTx-induced increases in arterial blood pressure, intact rats demonstrated a marked hypotension that was accompanied by significant reductions in SND (renal and splenic) and heart rate (HR) from peak levels. After peak LeTx-induced pressor and sympathoexcitatory responses in SAD rats, MAP, SND (renal, splenic, and adrenal), and HR were progressively and significantly reduced, supporting the hypothesis that LeTx alters the central regulation of sympathetic nerve outflow. These findings demonstrate that the regulation of visceral SND is altered in a complex manner during continuous anthrax LeTx infusions and suggest that sympathetic nervous system dysregulation may contribute to the marked hypotension accompanying B. anthracis infection.     

A severe vicious cycle in uncontrolled subarachnoid hemorrhage: the effects on cerebral blood flow and hemodynamic responses upon intracranial hypertension

In subarachnoid hemorrhage (SAH), Cushing postulated that the increase in systemic arterial pressure (SAP) in response to elevation of intracranial pressure (ICP) was beneficial to cerebral perfusion. However, in uncontrolled SAH, the increased SAP may cause more bleeding into the subarachnoid space and further increase the ICP. We created an animal model to simulate SAH by connecting a femoral arterial catheter to the subarachnoid space. The global cerebral blood flow (CBF) was measured with a venous outflow method. The purposes were to observe the CBF change under the simulated SAH, and to evaluate the effects of an adrenergic blocker and a vasodilator. In addition, spectral analysis of the aortic pressure and flow was employed for the analysis of hemodynamic changes at various ICP levels. When the femoral arterial blood was allowed to flow into the subarachnoid space, the ICP was elevated. The Cushing response to increased ICP caused an increase in SAP. A vicious cycle was generated between ICP and SAP. The CBF under the vicious cycle was greatly depressed. The dog developed pulmonary edema (PE) within 5 mins. An alpha-adrenergic blocker (phentolamine) and a vasodilator (nitroprusside) were beneficial to the reduction of SAP and ICP, improvement of CBF, and prevention of PE. Hemodynamic analysis revealed that graded increases in ICP caused increases in SAP, total peripheral resistance, arterial impedance, and pulse reflection with decreases in stroke volume, cardiac output and arterial compliance. The hemodynamic changes may contribute to acute left ventricular failure that leads to pressure and volume loading in the lung circulation, and finally acute PE.     

The effect of acute rise in intracranial pressure on the sympathetic cardiac, vertebral and phrenic nerve activities.

A transient rise of intracranial pressure in cats under chloralose-urethane anaesthesia increased the activity of the sympathetic vertebral nerve, cardiac nerve and in the first phase phrenic nerve. If the vagus nerves were intact this rise in sympathetic activity was associated with bradycardia. These effects developed with a delay, as a rule after abatement of the transient intracranial pressure rise. The authors suggest that Cushing's reaction is caused by medullary ischaemia and development of local metabolic acidosis activating simultaneously the sympathetic and parasympathetic neurons in the medulla oblongata.     

Is visceral sympathoexcitation to heat stress dependent on activation of ionotropic excitatory amino acid receptors in the rostral ventrolateral medulla?

Acute heat stress activates visceral sympathetic nerve discharge (SND) in young rats, and the functional integrity of the rostral ventrolateral medulla (RVLM) is required for sustaining visceral sympathoexcitation during peak increases in internal body temperature (T(c)). However, RVLM mechanisms mediating SND activation to hyperthermia remain unknown. In the present study, we investigated the role of RVLM ionotropic excitatory amino acid receptors in mediating visceral SND activation to heat stress in anesthetized, young rats. The effects of bilateral RVLM kynurenic acid (Kyn; 2.7 and 5.4 nmol), saline, or muscimol (400-800 pmol) microinjections on renal SND and splenic SND responses to heat stress were determined at peak hyperthermia (T(c) 41.5°C), during progressive hyperthermia (T(c) 40°C), and at the initiation of heating (T(c) increased from 38 to 38.5°C). RVLM Kyn microinjections did not reduce renal and splenic SND recorded during progressive or peak hyperthermia and did not attenuate SND activation at the initiation of heating. In fact, renal and splenic SND tended to be or were significantly increased following RVLM Kyn microinjections at the initiation of heating and during hyperthermia (40 and 41.5°C). RVLM muscimol microinjections at 39, 40, and 41.5°C resulted in immediate reductions in SND. These data indicate that RVLM ionotropic glutamate receptors are required for mediating visceral sympathoexcitation to acute heating and suggest that acute heating activates an RVLM ionotropic excitatory amino acid receptor dependent inhibitory input, which reduces the level of visceral SND to heating.     

Sympathetic nerve and cardiovascular responses to chemical activation of the midbrain defense region

The changes in mean arterial pressure (MAP), renal (RBF) and femoral (FBF) blood flows, and inferior cardiac (CN) and vertebral nerve (VN) sympathetic nerve discharges (SND) produced by chemical activation (D,L-homocysteic acid) of the midbrain periaqueductal gray (PAG) were compared in baroreceptor-denervated and -innervated cats anesthetized with urethan. Defenselike cardiovascular responses in both states were similar in magnitude and consisted of increased MAP and FBF and decreased RBF; however, the nerve responses differed. In baroreceptor-denervated cats, PAG activation increased CN 10-Hz activity, decreased VN 10-Hz activity, and lengthened the CN-VN phase angle. In baroreceptor-innervated cats in which the rhythm in SND was cardiac related, PAG activation increased CN activity, but VN activity and the CN-VN phase angle were unchanged. These results demonstrate that chemical activation of PAG neurons induces differential patterns of sympathetic outflow generally consistent with accompanying defenselike cardiovascular responses. However, the mechanisms responsible for the changes in 10-Hz and cardiac-related SND appear to be different.     

Afferent mechanism of renal sympathetic nerve activity shutdown induced by short period of microgravity.

The present study was designed to examine acute responses of renal sympathetic nerve activity in rats to a short period of microgravity. Free drops were performed in a 100 m drop tube. Responses of atrial pressure, heart rate, aortic flow velocity and renal sympathetic nerve activity are presented. Results indicate that renal sympathetic nerve activity was suppressed during microgravity. The response was transient.     

Effects of the probiotic strain Lactobacillus johnsonii strain La1 on autonomic nerves and blood glucose in rats

Oral administration of Lactobacillus casei reportedly reduces blood glucose concentrations in a non-insulin-dependent diabetic KK-Ay mouse model. In order to determine if other lactobacillus strains affect glucose metabolism, we evaluated the effect of the probiotic strain Lactobacillus johnsonii La1 (LJLa1) strain on glucose metabolism in rats. Oral administration of LJLa1 via drinking water for 2 weeks inhibited the hyperglycemia induced by intracranial injection of 2-deoxy-D-glucose (2DG). We found that the hyperglucagonemic response induced by 2DG was also suppressed by LJLa1. Oral administration of LJLa1 for 2 weeks also reduced the elevation of blood glucose and glucagon levels after an oral glucose load in streptozotocin-diabetic rats. In addition, we recently observed that intraduodenal injection of LJLa1 reduced renal sympathetic nerve activity and enhanced gastric vagal nerve activity, suggesting that LJLa1 might affect glucose metabolism by changing autonomic nerve activity. Therefore, we evaluated the effect of intraduodenal administration of LJLa1 on adrenal sympathetic nerve activity (ASNA) in urethane-anesthetized rats, since the autonomic nervous system, including the adrenal sympathetic nerve, may be implicated in the control of the blood glucose levels. Indeed, we found that ASNA was suppressed by intraduodenal administration of LJLa1, suggesting that LJLa1 might improve glucose tolerance by reducing glucagon secretion via alteration of autonomic nerve activities.     

Forebrain and brain stem neural circuits contribute to altered sympathetic responses to heating in senescent rats.

Acute heating in young rats increases visceral sympathetic nerve discharge (SND); however, renal and splanchnic SND responses to hyperthermia are attenuated in senescent compared with young Fischer 344 (F344) rats (Kenney MJ and Fels RJ. Am J Physiol Regul Integr Comp Physiol 283: R513-R520, 2002). Central mechanisms by which aging alters visceral SND responses to heating are unknown. We tested the hypothesis that forebrain neural circuits are involved in suppressing sympathoexcitatory responses to heating in chloralose-anesthetized, senescent F344 rats. Renal and splanchnic SND responses to increased (38 degrees C-41 degrees C) internal temperature were determined in midbrain-transected (MT) and sham-MT young (3-mo-old), mature (12-mo-old), and senescent (24-mo-old) F344 rats and in cervical-transected (CT) and sham-CT senescent rats. Renal SND remained unchanged during heating in MT and sham-MT senescent rats but was increased in CT senescent rats. Splanchnic SND responses to heating were higher in MT vs. sham-MT senescent rats and in CT vs. MT senescent rats. SND responses to heating were similar in MT and sham-MT young and mature rats. Mean arterial pressure (MAP) was increased during heating in MT but not in sham-MT senescent rats, whereas heating-induced increases in MAP were higher in sham-MT vs. MT young rats. These data suggest that in senescent rats suppression of splanchnic SND to heating involves forebrain and brain stem neural circuits, whereas renal suppression is mediated solely by brain stem neural circuits. These results support the concept that aging alters the functional organization of pathways regulating SND and arterial blood pressure responses to acute heating.     

Interactions between inhibitions of sympathetic nerve discharge to successive stimulations of baroreceptor and cutaneous afferents

Interactions between inhibitions of sympathetic nerve discharge (SND) to consecutive stimulations of A- and C-fibres in the aortic nerve and superficial peroneal (SP) nerve have been studied in rabbits anaesthetized with urethane and chloralose. SND was recorded from the renal nerve. At interval of 10 s following conditioning stimulation of SP nerve the test response of SND to activation of C-fibres (interaction SP-C) amounts to 83.7 +/- 7.5% (means +/- SE) of control. After applying both stimulations to the same SP nerve (interaction SP-SP) the test response of SND is significantly lower amounting to 56.3 +/- 3.9%. Comparable decrease of the effect of conditioning stimulation of one type of afferents on the test response to activation of other type of fibres was observed at interval of 10 s in two other interactions (SP-A and C-A). In seven interactions the conditioning stimulation of one type of fibres had no effect on the test response to stimulation of other type of fibres. This was found in one interaction at interval of 10 s (C-SP), in four interactions at interval of 20 s (SP-A, C-SP, SP-C and C-A) and in two interactions at interval of 40 s (SP-A and SP-C). Conditioning stimulations used in above interactions depressed the test responses to activation of the same type of fibres. It is suggested that the decrease or suppression of the effect of conditioning stimulation of one type of afferents on the test response of SND to activation of other type of fibres is related to disinhibition of this response.     

Sympathoexcitation to intravenous interleukin-1beta is dependent on forebrain neural circuits

We investigated the contributions of forebrain, brain stem, and spinal neural circuits to interleukin (IL)-1beta-induced sympathetic nerve discharge (SND) responses in alpha-chloralose-anesthetized rats. Lumbar and splenic SND responses were determined in spinal cord-transected (first cervical vertebra, C1), midbrain-transected (superior colliculus), and sham-transected rats before and for 60 min after intravenous IL-1beta (285 ng/kg). The observations made were the following: 1) lumbar and splenic SND were significantly increased after IL-1beta in sham C1-transected rats but were unchanged after IL-1beta in C1-transected rats; 2) intrathecal administration of DL-homocysteic acid (10 ng) increased SND in C1-transected rats; 3) lumbar and splenic SND were significantly increased after IL-1beta in sham- but not midbrain-transected rats; and 4) midbrain transection did not alter the pattern of lumbar and splenic SND, demonstrating the integrity of brain stem sympathetic neural circuits after decerebration. These results demonstrate that an intact forebrain is required for mediating lumbar and splenic sympathoexcitatory responses to intravenous IL-1beta, thereby providing new information about the organization of neural circuits responsible for mediating sympathetic-immune interactions.     

Altered frequency responses of sympathetic nerve discharge bursts after IL-1beta and mild hypothermia.

Although interleukin-1beta (IL-1beta) administration produces nonuniform changes in the level of sympathetic nerve discharge (SND), the effect of IL-1beta on the frequency-domain relationships between discharges in different sympathetic nerves is not known. Autospectral and coherence analyses were used to determine the effect of IL-1beta and mild hypothermia (60 min after IL-1beta, colonic temperature from 38 degrees C to 36 degrees C) on the relationships between renal-interscapular brown adipose tissue (IBAT) and splenic-lumbar sympathetic nerve discharges in chloralose-anesthetized rats. The following observations were made. 1) IL-1beta did not alter renal-IBAT coherence values in the 0- to 2-Hz frequency band or at the cardiac frequency (CF). 2) Peak coherence values relating splenic-lumbar discharges at the CF were significantly increased after IL-1beta and during hypothermia. 3) Hypothermia after IL-1beta significantly reduced the coupling (0-2 Hz and CF) between renal-IBAT but not splenic-lumbar SND bursts. 4) Combining IL-1beta and mild hypothermia had a greater effect on renal-IBAT SND coherence values than did mild hypothermia alone. These data demonstrate functional plasticity in sympathetic neural circuits and suggest complex relationships between immune products and SND regulation.     

Conditioning of inhibition of sympathetic nerve discharge to stimulation of A- and C-fibres in the aortic nerve

Stimulation of either A- or C-fibres in the aortic nerve inhibits sympathetic nerve discharge (SND) recorded from the renal nerve in rabbits anaesthetized with urethane. When the test inhibition of SND to stimulation of A-fibres is preceded by conditioning stimulation of the same afferents, the test response is depressed at shorter and facilitated at longer testing intervals. Facilitation of the inhibition of SND reaches 120% of control at a testing interval of 10 s. The recovery curve of inhibition of SND to activation of A-fibres has a time course of 17 s. Following conditioning activation only depression of the test inhibition of SND to stimulation of C-fibres is seen. It reaches 46% of control at an interval of 2 s and the recovery curve of inhibition of SND to stimulation of C-fibres has a time course of about 30 s. In other series of experiments the duration of the conditioning stimulation was varied while the testing intervals were fixed. At a testing interval of 2 s the reductions of the test responses are deeper and the durations of conditioning at which plateaus of depression are reached are longer with stimulation of C- than of A-fibres. Taken together with a longer recovery curve these findings suggest a more effective control of the test inhibition of SND by C-fibres. Opposite changes in the patterns of inhibition of SND to activation of either A- or C-fibres are explained by frequency-dependent post-tetanic effects of the conditioning stimulation.     

Paraventricular nucleus bicuculline alters frequency components of sympathetic nerve discharge bursts

Autospectral and coherence analyses were used to determine the effect of paraventricular nucleus (PVN) GABA(A) receptor antagonism [microinfusion or microinjections of bicuculline methiodide (BMI) 100 pmoles] on sympathetic nerve discharge (SND) frequency components (bursting pattern and relationships between discharges in regionally selective nerves) in alpha-chloralose-anesthetized rats. SND was recorded from the renal, splenic, and lumbar nerves. The following observations were made. First, PVN BMI microinjections, but not PVN saline or cortical BMI microinjections, transformed the cardiac-related SND bursting pattern in baroreceptor-innervated rats to one characterized by the presence of low-frequency bursts not synchronized to the cardiac cycle or phrenic nerve discharge bursts. Second, SND pattern changes were similar in the renal, splenic, and lumbar nerves, and peak coherence values relating low-frequency bursts in sympathetic nerve pairs (renal-splenic, renal-lumbar, and splenic-lumbar) were significantly increased from preinjection control after PVN BMI microinjection. Third, PVN BMI microinjections significantly increased the coupling between low-frequency SND bursts in baroreceptor-denervated rats. Finally, PVN BMI-induced changes in the SND bursting pattern were not observed after PVN pretreatment with muscimol (GABA agonist, 1 nmole). We conclude that PVN GABA(A) receptor antagonism profoundly alters the frequency components in sympathetic nerves.