fMRI signal changes in response to forced expiratory loading in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show impaired ventilatory responses to CO2 and hypoxia and reduced drive to breathe during sleep but retain appropriate breathing patterns in response to volition or increased exercise. Breath-by-breath influences on heart rate are also deficient. Using functional magnetic resonance imaging techniques, we examined responses over the brain to voluntary forced expiratory loading, a task that CCHS patients can perform but that results in impaired rapid heart rate variation patterns normally associated with the loading challenge. Increased signals emerged in control (n = 14) over CCHS (n = 13; ventilator dependent during sleep but not waking) subjects in the cingulate and right parietal cortex, cerebellar cortex and fastigial nucleus, and basal ganglia, whereas anterior cerebellar cortical sites and deep nuclei, dorsal midbrain, and dorsal pons showed increased signals in the patient group. The dorsal and ventral medulla showed delayed responses in CCHS patients. Primary motor and sensory areas bordering the central sulcus showed comparable responses in both groups. The delayed responses in medullary sensory and output regions and the aberrant reactions in cerebellar and pontine sensorimotor coordination areas suggest that rapid cardiorespiratory integration deficits in CCHS may stem from defects in these sites. Additional autonomic and perceptual motor deficits may derive from cingulate and parietal cortex aberrations.     

fMRI responses to cold pressor challenges in control and obstructive sleep apnea subjects.

Obstructive sleep apnea (OSA) patients exhibit altered sympathetic outflow, which may reveal mechanisms underlying the syndrome. We used functional MRI (fMRI) in 16 control and 10 OSA subjects who were free of cardiovascular or mood-altering drugs to examine neural responses to a forehead cold pressor challenge, which elicits respiratory slowing, bradycardia, and enhanced sympathetic outflow. The magnitude of cold-induced bradycardia was smaller, and respiratory slowing showed greater intersubject variability and reached a nadir later in OSA patients. Both groups showed similar signal changes to cold stimulation in multiple brain sites. However, signal increases emerged in OSA over controls in anterior and posterior cingulate and cerebellar and frontal cortex, whereas signals markedly declined in the ventral thalamus, hippocampus, and insula rather than rising as in controls. Anomalous responses often paralleled changes in breathing and heart rate. Medullary, midbrain areas and lentiform and cerebellar dentate nuclei also showed lower signals in OSA cases. Cold pressor physiological responses are modified in OSA and may result from both diminished and exaggerated responses in multiple brain structures.     

Effects of hypoxia on vertebrate blood vessels

Hypoxia contracts mammalian respiratory vessels and increases vascular resistance in respiratory tissues of many vertebrates. In systemic vessels these responses vary, hypoxia relaxes mammalian vessels and contracts systemic arteries from cyclostomes. It has been proposed that hypoxic vasoconstriction in cyclostome systemic arteries is the antecedent to mammalian hypoxic pulmonary vasoconstriction, however, phylogenetic characterization of hypoxic responses is lacking. In this study, we characterized the hypoxic response of isolated systemic and respiratory vessels from a variety of vertebrates using standard myography. Pre-gill/respiratory (ventral aorta, afferent branchial artery, pulmonary artery) and post-gill/systemic (dorsal and thoracic aortas, efferent branchial artery) from lamprey (Petromyzon marinus), sandbar shark (Carcharhinus plumbeus), yellowfin tuna (Thunnus albacares), American bullfrog (Rana catesbeiana), American alligator (Alligator mississippiensis), Pekin duck (Anas platyrhynchos domesticus), chicken (Gallus domesticus) and rat (Rattus norvegicus) were exposed to hypoxia at rest or during pre-stimulation (elevated extracellular potassium, epinephrine or norepinephrine). Hypoxia produced a relaxation or transient contraction followed by relaxation in all pre-gill vessels, except for contraction in lamprey, and vasoconstriction or tri-phasic constriction-dilation-constriction in all pulmonary vessels. Hypoxia contracted systemic vessels from all animals except shark and rat and in pre-contracted rat aortas it produced a transient contraction followed by relaxation. These results show that while the classic "systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction" may occur in the microcirculation, the hypoxic response of the vertebrate macrocirculation is quite variable. These findings also suggest that hypoxic vasoconstriction is a phylogenetically ancient response.     

Distribution of somatostatinlike immunoreactivity in the brain of the little brown bat (Myotis lucifugus)

The distribution of somatostatinlike immunoreactive (SLI) perikarya, axons, and terminals was mapped in subcortical areas of the brain of the little brown bat, Myotis lucifugus, using light microscopic immunocytochemistry. A preponderance of immunoreactivity was localized in reticular, limbic, and hypothalamic areas including: 1) in the forebrain: the bed nucleus of the stria terminalis; lateral preoptic, dorsal, anterior, lateral and posterior hypothalamic areas; amygdaloid, periventricular, arcuate, supraoptic, suprachiasmatic, ventromedial, dorsomedial, paraventricular, lateral and medial mammillary, and lateral septal nuclei; the nucleus of the diagonal band of Broca and nucleus accumbens septi; 2) in the midbrain: the periaqueductal gray, interpeduncular, dorsal and ventral tegmental, pretectal, and Edinger-Westphal nuclei; and 3) in the hindbrain: the superior central and parabrachial nuclei, nucleus incertus, locus coeruleus, and nucleus reticularis gigantocellularis. Other areas containing SLI included the striatum (caudate nucleus and putamen), zona incerta, infundibulum, supramammillary and premammillary nuclei, medial and dorsal lateral geniculate nuclei, entopeduncular nucleus, lateral habenular nucleus, central medial thalamic nucleus, central tegmental field, linear and dorsal raphe nuclei, nucleus of Darkschewitsch, superior and inferior colliculi, nucleus ruber, substantia nigra, mesencephalic nucleus of V, inferior olivary nucleus, inferior central nucleus, nucleus prepositus, and deep cerebellar nuclei. While these results were similar in some respects to those previously reported in rodents, they also provided interesting contrasts.     

Regulation of breathing and body temperature of a burrowing rodent during hypoxic-hypercapnia

Burrowing mammals usually have low respiratory sensitivity to hypoxia and hypercapnia. However, the interaction between ventilation (V), metabolism and body temperature (Tb) during hypoxic-hypercapnia has never been addressed. We tested the hypothesis that Clyomys bishopi, a burrowing rodent of the Brazilian cerrado, shows a small ventilatory response to hypoxic-hypercapnia, accompanied by a marked drop in Tb and metabolism. V, Tb and O(2) consumption (V?O(2)) of C. bishopi were measured during exposure to air, hypoxia (10% and 7% O(2)), hypercapnia (3% and 5% CO(2)) and hypoxic-hypercapnia (10% O(2)+ 3% CO(2)). Hypoxia of 7% but not 10%, caused a significant increase in V, and a significant drop in Tb. Both hypoxic levels decreased V?O(2) and 7% O(2) significantly increased V/V?O(2). Hypercapnia of 5%, but not 3%, elicited a significant increase in V, although no significant change in Tb, V?O(2) or V/V?O(2) was detected. A combination of 10% O(2) and 3% CO(2) had minor effects on V and Tb, while V?O(2) decreased and V/V?O(2) tended to increase. We conclude that C. bishopi has a low sensitivity not only to hypoxia and hypercapnia, but also to hypoxic-hypercapnia, manifested by a biphasic ventilatory response, a drop in metabolism and a tendency to increase V/V?O(2). The effect of hypoxic-hypercapnia was the summation of the hypoxia and hypercapnia effects, with respiratory responses tending to have hypercapnic patterns while metabolic responses, hypoxic patterns.     

Responses of ganglioglomerular nerve activity to respiratory stimuli in the cat

We studied the responses of the ganglioglomerular nerve (GGN) efferents to brief periods of hypoxia and hypercapnia and to several levels of steady-state arterial PO2 and PCO2 and to intravascular injection of cyanide in thirteen anesthetized cats. The cats breathed spontaneously. A branch of the GGN which was cut close to the carotid body was divided into several filaments, and the activity of each filament was tested until clean and identifiable action potentials were obtained. The GGN efferent activity, breath-by-breath inspiratory volume, tracheal PO2 and PCO2 and arterial blood pressure were recorded simultaneously. We found that the GGN contained spontaneously active fibers which showed a range of responses to the respiratory stimuli. Fifty-eight percent of the filaments with dominant cardiovascular rhythm showed the least response to blood gas stimuli. Forty-two percent showed clear responses to hypoxia and hypercapnia. These responses developed slowly with the onset of the stimulus but decreased promptly with the withdrawal of the stimulus. These GGN efferents were also promptly stimulated by sodium cyanide. The steady-state response curve to hypoxia was hyperbolic and to hypercapnia it was linear. Some of these fibers showed stronger respiratory rhythms than others. The responses of these GGN efferents were associated with the respiratory responses to hypoxia and hypercapnia. For the same respiratory drive, however, the steady-state hypoxic stimulus elicited a greater GGN response than did hypercapnia.     

Protein remodeling of extracellular matrix in rat myocardium during four-day hypoxia: the effect of concurrent hypercapnia

The combination of long-term hypercapnia and hypoxia decreases pulmonary vascular remodeling and attenuation of right ventricular (RV) hypertrophy. However, there is limited information in the literature regarding the first stages of acclimatization to hypercapnia/hypoxia. The purpose of this study was to investigate the effect of four-day hypoxia (10% O2) and hypoxia/hypercapnia (10% O2 + 4.4% CO2) on the protein composition of rat myocardium. Expression of the cardiac collagen types and activities of matrix metalloproteinases (MMPs) and of their tissue inhibitor TIMP-1 were followed. The four-day hypoxia changed protein composition of the right ventricle only in the hypercapnic condition; remodeling was observed in the extracellular matrix (ECM) compartments. While the concentrations of pepsin-soluble collagenous proteins in the RV were elevated, the concentrations of pepsin-insoluble proteins were decreased. Furthermore, the four-day hypoxia/hypercapnia increased the synthesis of cardiac collagen due to newly synthesized forms; the amount of cross-linked particles was not affected. This type of hypoxia increased cardiac collagen type III mRNA, while cardiac collagen type I mRNA was decreased. MMP-2 activity was detected on the zymographic gel through appearance of two bands; no differences were observed in either group. mRNA levels for MMP-2 in the RV were significantly lower in both the hypoxic and hypoxic/hypercapnic animals. mRNA levels for TIMP-1 were reduced in the RV of both the hypoxic and hypoxic/hypercapnic animals. Hypoxia with hypercapnia increased the level of mRNA (6.5 times) for the atrial natriuretic peptide (ANP) predominantly in the RV. The role of this peptide in remodeling of cardiac ECM is discussed.     

Heart rate variability responses to hypoxic and hypercapnic exposures in different mouse strains.

Heart rate variability (HRV) is a well-characterized, noninvasive means of assessing cardiac autonomic nervous system activity. This study examines the basic cardiac responses to hypoxic and hypercapnic challenges in seven strains of commonly used inbred mice (A/J, BALB/cJ, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, and FVB/J). Adult male mice, 8-12 wk of age, were chronically instrumented to a femoral artery catheter for the continuous measurement of systemic arterial blood pressure and heart rate. Mice were exposed to multiple 4-min periods of hypoxia (10% O2), hypercapnia (5% CO2), and combined hypoxia/hypercapnia (10% O2 + 5% CO2). HRV was derived from pulse intervals of the blood pressure tracings. Hypoxia induced increases in high-frequency HRV power and decreased low-frequency (LF) HRV power in most strains. Hypercapnia led to decreased high-frequency HRV power and increased LF HRV power in most strains. Strain differences were most notable in regard to the concomitant exposures of hypoxia and hypercapnia, with FVB/J mice mirroring their own response to hypercapnia alone, whereas CBA/J mice mirrored their own responses to hypoxia. As blood pressure is most likely the driving factor for heart rate changes via the baroreflex pathway, it is interesting that LF, considered to reflect cardiac sympathetic activity, was negatively correlated with heart rate, suggesting that LF changes are driven by baroreflex oscillation and not necessarily by absolute sympathetic or parasympathetic activity to the heart. These findings suggest that genetic background can influence the centrally mediated cardiovascular responses to basic hypoxic and hypercapnic challenges.     

Projections of the central cerebellar nuclei to the intralaminar thalamic nuclei in cats

Projections of the central cerebellar nuclei to the intralaminar thalamic nuclei were studied in cats with the use of light and electron microscopy. Almost all intralaminar nuclei were shown to obtain cerebello-thalamic projections. The entire complex of the central cerebellar nuclei serves as a source of such projections; yet, involvement of different nuclei is dissimilar. Destruction of the central and, especially, caudal regions of the fastigial nucleus evoked in the intralaminar thalamic nuclei degenerative changes in the nerve fibers (from swelling and development of varicosities up to total fragmentation). Pathological phenomena could be noticed in the most caudal regions of the above thalamic nuclear group, including the medial dorsal nucleus. Projections of the cerebellar interpositus nucleus were directed toward nearly the same regions of the intralaminar nuclei; degeneration was more intensive (covered thecentrum medianum) when posterior regions of the interpositus nucleus were destroyed. Destruction of the lateral cerebellar nucleus evoked a similar pattern of pathological changes, but degeneration was also observed in some structures of the ventral and anterior nuclear groups of the thalamus. Electron microscopic examination showed that degeneration of dark and light types developed in the fiber preterminals and terminals. It can be concluded that the central cerebellar nuclei project not only to the ventral complex of the thalamic nuclei, but also to the anterior, medial, and intralaminar nuclear groups (rostral and caudal portions).     

Ventilatory responses to hypoxia and hypercapnia in awake rats pretreated with capsaicin.

Ventilatory responses to hypoxia and hypercapnia were measured by indirect plethysmography in unanesthetized unrestrained adult rats injected neonatally with capsaicin (50 mg/kg) or vehicle. Such capsaicin treatment ablates a subpopulation of primary afferent fibers containing substance P and various other neuropeptides. Ventilation was measured while the rats breathed air, 12% O2 in N2, 8% O2 in N2, 5% CO2 in O2, or 8% CO2 in O2. Neonatal treatment with capsaicin caused marked alterations in both the magnitude and composition of the hypoxic but not hypercapnic ventilatory response. The increase in minute ventilation evoked by hypoxia in the vehicle-treated rats resulted entirely from an increase in respiratory frequency. In the capsaicin-treated rats the hypoxic ventilatory response was significantly reduced owing to an attenuation of the frequency response. Although both groups responded to hypoxia with a shortening in inspiratory and expiratory times, rats treated with capsaicin displayed less shortening of both respiratory phases. By contrast, hypercapnia induced a brisk ventilatory response in the capsaicin-treated group that was similar in magnitude and pattern to that observed in the vehicle-treated group. Analysis of the components of the hypercapnic ventilatory responses revealed no significant differences between the two groups. We, therefore, conclude that neuropeptide-containing C-fibers are essential for the tachypnic component of the ventilatory response to hypoxia but not hypercapnia.     

Reflex control of vascular capacitance during hypoxia, hypercapnia, or hypoxic hypercapnia

We tested the hypothesis that the changes in venous tone induced by changes in arterial blood oxygen or carbon dioxide require intact cardiovascular reflexes. Mongrel dogs were anesthetized with sodium pentobarbital and paralyzed with veruronium bromide. Cardiac output and central blood volume were measured by indocyanine green dilution. Mean circulatory filling pressure, an index of venous tone at constant blood volume, was estimated from the central venous pressure during transient electrical fibrillation of the heart. With intact reflexes, hypoxia (arterial PaO2 = 38 mmHg), hypercapnia (PaCO2 = 72 mmHg), or hypoxic hypercapnia (PaO2 = 41; PaCO2 = 69 mmHg) (1 mmHg = 133.32 Pa) significantly increased the mean circulatory filling pressure and cardiac output. Hypoxia, but not normoxic hypercapnia, increased the mean systemic arterial pressure and maintained the control level of total peripheral resistance. With reflexes blocked with hexamethonium and atropine, systemic arterial pressure supported with a constant infusion of norepinephrine, and the mean circulatory filling pressure restored toward control with 5 mL/kg blood, each experimental gas mixture caused a decrease in total peripheral resistance and arterial pressure, while the mean circulatory filling pressure and cardiac output were unchanged or increased slightly. We conclude that hypoxia, hypercapnia, and hypoxic hypercapnia have little direct influence on vascular capacitance, but with reflexes intact, there is a significant reflex increase in mean circulatory filling pressure.     

Role of the carotid bodies in chemosensory ventilatory responses in the anesthetized mouse.

We examined the effects of carotid body denervation on ventilatory responses to normoxia (21% O2 in N2 for 240 s), hypoxic hypoxia (10 and 15% O2 in N2 for 90 and 120 s, respectively), and hyperoxic hypercapnia (5% CO2 in O2 for 240 s) in the spontaneously breathing urethane-anesthetized mouse. Respiratory measurements were made with a whole body, single-chamber plethysmograph before and after cutting both carotid sinus nerves. Baseline measurements in air showed that carotid body denervation was accompanied by lower minute ventilation with a reduction in respiratory frequency. On the basis of measurements with an open-circuit system, no significant differences in O2 consumption or CO2 production before and after chemodenervation were found. During both levels of hypoxia, animals with intact sinus nerves had increased respiratory frequency, tidal volume, and minute ventilation; however, after chemodenervation, animals experienced a drop in respiratory frequency and ventilatory depression. Tidal volume responses during 15% hypoxia were similar before and after carotid body denervation; during 10% hypoxia in chemodenervated animals, there was a sudden increase in tidal volume with an increase in the rate of inspiration, suggesting that gasping occurred. During hyperoxic hypercapnia, ventilatory responses were lower with a smaller tidal volume after chemodenervation than before. We conclude that the carotid bodies are essential for maintaining ventilation during eupnea, hypoxia, and hypercapnia in the anesthetized mouse.     

Differences in the sensory support of the anterior and posterior sections of the limbic cortex of the rat

Using retrograde axonal transport of horseradish peroxidase, studies have been made on the thalamic projections in the anterior and posterior parts of the limbic cortex with special reference to exterosensory system projections (visual, auditory and somatic). Projections of the retinorecipient nuclei of the anterior hypothalamus and classic thalamic visual relays (n. geniculatus lateralis dorsalis, n. lateralis posterior, pretectum) were found in the anterior and posterior limbic cortex. There are also inputs from the thalamic relays of the auditory (n. geniculatus medialis) and somatic (n. ventralis posterior) systems in the posterior limbic cortex The data obtained indicate: 1) that sensory supply of the limbic cortex in rats may be realized via direct pathways from sensory thalamic relays; 2) that thalamic sensory supply of the anterior limbic cortex differs from that of the posterior one. In the former, projections of the thalamic relays of the visual, auditory and somatic systems were found, whereas in the posterior cortex only visual system is presented. Topographic organization of the thalamic nuclear areas sending afferents to the anterior limbic cortex differs from that of the posterior limbic cortex.     

Slow Breathing and Hypoxic Challenge: Cardiorespiratory Consequences and Their Central Neural Substrates

Controlled slow breathing (at 6/min, a rate frequently adopted during yoga practice) can benefit cardiovascular function, including responses to hypoxia. We tested the neural substrates of cardiorespiratory control in humans during volitional controlled breathing and hypoxic challenge using functional magnetic resonance imaging (fMRI). Twenty healthy volunteers were scanned during paced (slow and normal rate) breathing and during spontaneous breathing of normoxic and hypoxic (13% inspired O₂) air. Cardiovascular and respiratory measures were acquired concurrently, including beat-to-beat blood pressure from a subset of participants (N = 7). Slow breathing was associated with increased tidal ventilatory volume. Induced hypoxia raised heart rate and suppressed heart rate variability. Within the brain, slow breathing activated dorsal pons, periaqueductal grey matter, cerebellum, hypothalamus, thalamus and lateral and anterior insular cortices. Blocks of hypoxia activated mid pons, bilateral amygdalae, anterior insular and occipitotemporal cortices. Interaction between slow breathing and hypoxia was expressed in ventral striatal and frontal polar activity. Across conditions, within brainstem, dorsal medullary and pontine activity correlated with tidal volume and inversely with heart rate. Activity in rostroventral medulla correlated with beat-to-beat blood pressure and heart rate variability. Widespread insula and striatal activity tracked decreases in heart rate, while subregions of insular cortex correlated with momentary increases in tidal volume. Our findings define slow breathing effects on central and cardiovascular responses to hypoxic challenge. They highlight the recruitment of discrete brainstem nuclei to cardiorespiratory control, and the engagement of corticostriatal circuitry in support of physiological responses that accompany breathing regulation during hypoxic challenge.     

Effect of body position on ventilatory responses in anaesthetised mice

The effects of body position on ventilatory responses to chemical stimuli have rarely been studied in experimental animals, despite evidence that position may be a factor in respiratory results. The purpose of this study was to test whether body position could affect acute ventilatory responses to 4-min periods of moderate hypercapnia (5% CO(2) in O(2)) and poikilocapnic hypoxia (15% O(2) in N(2)) in the urethane-anaesthetised mouse. Respiratory measurements were conducted with mice in the prone and supine positions with a whole-body, single-chamber plethysmograph. During hypoxia, the time course of minute ventilation (V (E)) was similar in the two positions, but the breathing pattern was different. After the response peak, V (E) depended on respiratory frequency (f) and tidal volume (V(T)) in the prone position but mainly on V(T) in the supine position. In the supine position, f declined below the baseline values toward the end of hypoxic exposure. During hypercapnia, there were no ventilatory differences between the prone and supine positions. Brief hypoxic exposure elicited f depression in the supine position in the anaesthetised mouse. The depressive effect on f suggests that the supine position may not be optimal for sustaining ventilation, particularly during hypoxia.     

Cerebral carbohydrate metabolism during acute hypoxia and recovery

Abstract— The levels of ATP, ADP, AMP and phosphocreatine, of four amino acids, and of 11 intermediates of carbohydrate metabolism in mouse brain were determined after: (1) various degrees of hypoxia; (2) hypoxia combined with anaesthesia; and (3) recovery from severe hypoxia. Glycogen decreased and lactate rose markedly in hypoxia, but levels of ATP and phosphocreatine were normal or near normal even when convulsions and respiratory collapse appeared imminent. During 30 s of complete ischaemia (decapitation) the decline in cerebral ATP and phosphocreatine and the increase in AMP was less in mice previously rendered hypoxic than in control mice. From the changes we calculated that the metabolic rate had decreased by 15 per cent or more during 30 min of hypoxia. Hypoxia was also associated with decreases of cerebral 6-phosphogluconate and aspartate, and increases in alanine, γ-aminobutyrate, α-ketoglutarate, malate, pyruvate, and the lactate :pyruvate ratio. Following recovery in air (10 min), increases were observed in glucose (200 per cent), glucose-6-phosphate, phosphocreatine and citrate, and there was a fall in fructose-1, 6-diphosphale. Similar measurements were made in samples from cerebral cortex, cerebellum, midbrain and medulla. Severe hypoxia produced significant increases in lactate and decreases in glycogen in all areas; γ-aminobutyrate levels increased in cerebral cortex and brain stem, but not in cerebellum. No significant changes occurred in ATP and only in cerebral cortex was there a significant fall in phosphocreatine. Phosphocreatine, ATP and glycogen were determined by quantitative histochemical methods in four areas of medulla oblongata, including the physiological respiratory centre of the ventromedial portion. After hypoxia, ATP was unchanged throughout and the changes (decreases) in phosphocreatine and glycogen were principally confined to dorsal medulla, notably the lateral zone. Thus there is no evidence that respiratory failure is caused by a ‘power’ failure in the respiratory centre. It is suggested that in extremis a protective mechanism may cause neurons to cease firing before high-energy phosphate stores have been exhausted.     

Systemic hypoxia causes cutaneous vasodilation in healthy humans.

Hypoxia and hypercapnia represent special challenges to homeostasis because of their effects on sympathetic outflow and vascular smooth muscle. In the cutaneous vasculature, even small changes in perfusion can shift considerable blood volume to the periphery and thereby impact both blood pressure regulation and thermoregulation. However, little is known about the influence of hypoxia and hypercapnia on this circulation. In the present study, 35 healthy subjects were instrumented with two microdialysis fibers in the ventral forearm. Each site was continuously perfused with saline (control) or bretylium tosylate (10 mM) to prevent sympathetically mediated vasoconstriction. Skin blood flow was assessed at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC) was calculated as red blood cell flux/mean arterial pressure and normalized to baseline. In 13 subjects, isocapnic hypoxia (85 and 80% O(2) saturation) increased CVC to 120 +/- 10 and 126 +/- 7% baseline in the control site (both P < 0.05) and 113 +/- 3 (P = 0.087) and 121 +/- 4% baseline (P < 0.05) in the bretylium site. Adrenergic blockade did not affect the magnitude of this response (P > 0.05). In nine subjects, hyperpnea (matching hypoxic increases in tidal volume) caused no change in CVC in either site (both P > 0.05). In 13 subjects, hypercapnia (+5 and +9 Torr) increased CVC to 111 +/- 4 and 111 +/- 4% baseline, respectively, in the control site (both P < 0.05), whereas the bretylium site remained unchanged (both P > 0.05). Thus both hypoxia and hypercapnia cause modest vasodilation in nonacral skin. Adrenergic vasoconstriction of neural origin does not restrain hypoxic vasodilation, but may be important in hypercapnic vasodilation.     

Cerebellar GABA(A) receptor alterations in hypoxic neonatal rats: Role of glucose, oxygen and epinephrine supplementation

Hypoxia in neonates causes dysfunction of excitatory and inhibitory neurotransmission resulting in permanent brain damage. The present study is to understand the cerebellar GABA(A) receptor alterations and neuroprotective effect of glucose supplementation prior to current sequence of resuscitation - oxygen and epinephrine supplementation in hypoxic neonatal rats. Hypoxic insult caused a significant decrease in GABA(A) receptor number along with down regulated expression of GABA(Aα1,) GABA(Aα5), GABA(Aδ) and GABA(Aγ3) receptor subunits in the cerebellum which accounts for the respiratory inhibition. Hypoxic rats supplemented with glucose alone and with oxygen showed a reversal of the receptor alterations and changes in GABA(A) receptor subunits expression to near control. Glucose can reduce ATP-depletion-induced alterations in GABA receptors, thereby assisting in overcoming the neuronal damage caused by hypoxia. Resuscitation with oxygen alone and epinephrine was less effective in reversing the receptor alterations. The reduction in the GABA(A) receptors functional regulation during hypoxia plays an important role in cerebellar damage. Resuscitation with glucose alone and glucose with oxygenation to hypoxic neonatal rats helps in protecting the brain from severe hypoxic damage.