Sympathoadrenal Activity in Fasting Pregnant Rats: DISSOCIATION OF ADRENAL MEDULLARY AND SYMPATHETIC NERVOUS SYSTEM RESPONSES

The pattern of urinary catecholamine excretion in fasting differs in pregnant and nonpregnant rats, which suggests that the sympathoadrenal response to fasting is altered by pregnancy. In fasting nonpregnant animals, urinary norepinephrine (NE) excretion decreases and epinephrine (E) excretion remains unchanged, whereas the excretion of both catecholamines rises significantly with refeeding. In contrast, fasting third-trimester pregnant rats exhibit a 420% increase in urinary E and a 345% increase in urinary NE, elevations which fall with refeeding. Specific evaluation of sympathoadrenal activity in fasting pregnant rats reveals stimulation of the adrenal medulla and suppression of sympathetic nerves. In fasting third-trimester rats the adrenal content of E is 37% lower in innervated adrenals as compared with contralateral denervated glands, which indicates the presence of neurally-mediated adrenal medullary activation. Adrenalectomy completely abolishes the fasting-induced rise in urinary E and NE in pregnant rats. Studies with 2-deoxy-D-glucose suggest that stimulation of the adrenal medulla results from hypoglycemia, which is present after 3 d of fasting in pregnant rats (plasma glucose 36.7 mg/dl). Sympathetic nervous system activity, as measured by [(3)H]NE turnover in the heart, decreases in fasting pregnant rats despite hypoglycemia, a response similar to that seen in fasting nonpregnant animals where plasma glucose is maintained above 50 mg/dl. The calculated NE turnover rate is 44% lower in 2-d fasted pregnant rats than in fed pregnant animals (17.6 +/- 1.3 vs. 31.3 +/- 1.8 ng NE/heart per h, respectively). Thus adrenal medullary and sympathetic nervous system responses in fasting pregnant rats appear to be dissociated, which suggests that diet-induced changes in sympathetic activity and stimulation of the adrenal medulla by hypoglycemia may be independently regulated.     

Effect of dietary fat on sympathetic nervous system activity in the rat.

Previous studies from our laboratory have demonstrated that dietary intake affects the sympathetic nervous system (SNS); carbohydrate intake, in particular, has been shown to stimulate sympathetic activity. The present studies were undertaken to characterize the effect of dietary fat on SNS activity in the rat. Sympathetic activity was assessed by measurement of norepinephrine (NE) turnover in heart, interscapular brown adipose tissue (IBAT), and pancreas and by excretion of NE in the urine. When fed a fat-enriched diet (50% chow, 50% lard), fractional NE turnover in heart (k) increased from 6.3 +/- 0.6% h in ad lib. fed controls to 14.7 +/- 1.3% h in the high-fat group (P less than 0.001); calculated NE turnover rate increased from 24.5 +/- 2.4 ng/heart per h to 36.8 +/- 3.5 (P less than 0.05). Urinary NE excretion more than doubled after 6 d of the same high fat diet (P less than 0.001). Ganglionic blockade produced a greater effect on NE turnover in fat-fed, as compared with chow-fed animals, consistent with increased sympathetic activity in the fat-fed group. When fat absorption was blocked with a bile acid binding resin (cholestyramine), the same high-fat diet did not increase cardiac NE turnover, indicating that fat absorption is required for the stimulatory effect on sympathetic activity. In another series of experiments, in which chow (and hence protein) intake was held constant, the effect of fat and isocaloric sucrose supplements on NE turnover was assessed in heart, IBAT, and pancreas. The caloric value of the supplements was 50, 100, and 335% of the chow in the different experiments. An effect of fat on NE turnover in heart and IBAT was demonstrable at the lowest level of fat supplement. Fat increased pancreatic NE turnover when added in amounts sufficient to double the caloric intake. The stimulatory effect of sucrose and fat on NE turnover in heart and IBAT was similar. These experiments demonstrate that fat increases SNS activity in the rat and that the magnitude of the effect is similar to that of sucrose. The results imply that fat may contribute to dietary thermogenesis in this species.     

Differential effects of hypoxia on the turnover of norepinephrine and epinephrine in the heart, adrenal gland, submaxillary gland and stomach

The authors examined the effects of hypoxia (8% O2 in N2) on the turnover rates of norepinephrine (NE) and epinephrine (E) in the heart, adrenal gland, submaxillary gland and stomach. The turnover rates were estimated by measuring the decrease in the content of NE and E after an i.p. injection of alpha-methyl-p-tyrosine (250 mg/kg), an inhibitor of tyrosine hydroxylase. After a 4-h exposure to hypoxia, the turnover rate of NE in the heart and those of NE and E in the adrenal gland were increased, whereas that of NE in the submaxillary gland was decreased. The turnover rate of NE in the stomach was unchanged. Pretreatment with hexamethonium, a ganglionic nicotinic receptor blocker, abolished the hypoxia-induced changes in the turnover rate of NE or E in the heart, adrenal gland and submaxillary gland. Furthermore, transection of the spinal cord at the level of C5-6 abolished hypoxia-induced alterations in the turnover rate of NE and E in the adrenal gland and submaxillary gland. In contrast, the hypoxia-induced changes seen in the heart persisted, although at a lower level, even after transection. These results show that the effects of hypoxia on the activities of the sympathoadrenal system differ depending on the organs; activities are increased in the heart and adrenal gland, decreased in the submaxillary gland and unchanged in the stomach. Furthermore, the present data suggest that hypoxia-induced alterations in the activities of cardiac sympathetic nerves originate in both the brain and spinal cord, including preganglionic neurons, whereas changes in the activities of the sympathetic nerves to the adrenal gland and submaxillary gland originate mainly in the brain.     

Effect of Diet and Cold Exposure on Norepinephrine Turnover in Brown Adipose Tissue of the Rat

Brown adipose tissue (BAT) is an important site of adaptive changes in thermogenesis in the rat. The sympathetic nervous system, which richly supplies BAT, is thought to play an important role in the regulation of BAT thermogenesis because catecholamines stimulate and beta adrenergic blocking agents inhibit oxygen consumption in this tissue. The present studies were carried out to assess directly sympathetic activity in BAT in response to cold exposure and to changes in dietary intake, both of which alter heat production in the rat. Sympathetic activity was determined from the rate of norepinephrine (NE) turnover in interscapular brown adipose tissue (IBAT) after preliminary experiments validated the use of NE turnover techniques in IBAT. Acute exposure to 4°C increased NE turnover in IBAT 4- to 12-fold compared with ambient temperature controls, depending upon the interval over which the turnover measurement was made, while in the heart NE turnover doubled in response to the same cold stimulus. In animals exposed to cold continuously for 10 d before study, NE turnover measurements in IBAT and in the heart were elevated comparably to those obtained during acute exposure. Alterations in feeding were also associated with changes in NE turnover in IBAT. Fasting for 2 d decreased NE turnover in IBAT (-35% from 29.2±4.2 ng NE/h to 18.9±5.9) and in heart (-52%). In animals fed a “cafeteria” diet, a model of voluntary overfeeding in the rat, NE turnover was increased in both IBAT (+108% from 24.8±4.5 ng NE/h to 51.7±6.8) and heart (+66%). Because ganglionic blockade exerted a greater effect on NE turnover in IBAT in cafeteria-fed rats than in controls, the increase in NE turnover in IBAT with this overfeeding regimen reflects enhanced central sympathetic outflow. Thus NE turnover techniques can be satisfactorily applied to the assessment of sympathetic nervous system activity in IBAT.     

Effect of protein on sympathetic nervous system activity in the rat. Evidence for nutrient-specific responses.

Increased energy intake activates the sympathetic nervous system (SNS) in animals and man. While dietary carbohydrate and fat stimulate, the impact of dietary protein on the SNS is not well defined. The present studies examine the effect of protein ingestion on sympathetic function based upon the measurement of [3H]norepinephrine (NE) turnover in heart and interscapular brown adipose tissue (IBAT) as the index of SNS activity. In these experiments, animals were pair-fed mixtures of laboratory chow and refined preparations of casein, sucrose, and lard to permit comparisons among nutrients with total energy intake held constant or with additional energy provided in the form of a single nutrient. After 5 d of eating a 2:1 mixture of chow and either casein or sucrose cardiac, [3H]NE turnover was less (P less than 0.005) in casein-fed rats (6.4%/h and 28.9 ng NE/h) than in animals given sucrose (11.2%/h and 46.5 ng NE/h). Similar results were obtained in IBAT and in experiments using 1:1 mixtures of chow and casein/sucrose. Casein-fed animals also displayed slower rates of NE turnover than lard-fed rats in both heart (7.8%/h vs. 13.2, P less than 0.001) and IBAT (7.0%/h vs. 12.8, P less than 0.01). Addition of casein (50% increase in energy intake) to a fixed chow ration raised NE turnover slightly, but not significantly, in heart (an average increase of 15% in six experiments). Thus, in distinction to SNS activation seen with dietary carbohydrate or fat, the SNS response to dietary protein is minimal in both heart and IBAT, indicating that the effect of increased energy intake on the SNS is dependent upon diet composition.     

Impaired Suppression of Sympathetic Activity during Fasting in the Gold Thioglucose-treated Mouse

Sympathetic activity in rats and mice is diminished by fasting and increased by sucrose feeding. The central neural mechanisms coordinating changes in the functional state of sympathetic nerves with changes in dietary intake are unknown, but a role for neurons in the ventromedial hypothalamus (VMH) is suggested by the existence of sympathetic connections within the VMH and the importance of this region in the regulation of feeding behavior. To investigate the potential role of the VMH in dietary regulation of sympathetic activity [(3)H]norepinephrine turnover was measured in the hearts of fasted and sucrose-fed mice after treatment with gold thioglucose (AuTG). In control mice, norepinephrine (NE) turnover was 1.60+/-0.92 ng NE/heart per h (95% confidence limits) after 1 d of fasting and 4.58+/-0.98 after 3 d of sucrose feeding, although, in AuTG-treated mice, cardiac NE turnover in fasting was 5.45+/-1.56 and with sucrose feeding, 5.44+/-0.76. Experiments with ganglionic blockade indicate that the absence of dietary effect on NE turnover in AuTG-treated mice reflects a corresponding lack of change in central sympathetic outflow. AuTG administration, therefore, disrupts dietary regulation of sympathetic activity by abolishing the suppression of sympathetic activity that occurs with fasting. This effect of AuTG is unrelated to duration of fasting (up to 3 d) and is specific for AuTG because neither treatment with another gold thio compound (gold thiomalate) nor the presence of genetic obesity (ob/ob) prevented fasting suppression of sympathetic activity. Moreover, AuTG treatment did not impair sympathetic activation by cold exposure (4 degrees C) nor adrenal medullary stimulation by 2-deoxy-d-glucose. Thus, AuTG treatment selectively impairs dietary regulation of sympathetic activity, possibly by destruction of neurons in the VMH.     

妊娠期缺氧对子代大鼠成年后离体心肌缺血再灌注损伤的影响

目的：评价妊娠期缺氧对子代成年后心肌缺血再灌注损伤的作用。方法：在SD雌鼠妊娠期第15～21天给予氧浓度10．5％的低氧环境，建立妊娠期缺氧动物模型。缺氧组和对照组子代雄鼠同等条件下饲养至3个月龄作为实验用动物。建立离体鼠Langendorff模型，分别记录缺氧组和对照组模型平衡15rain后和缺血30min后再灌注1h内心脏机械功能变化和冠脉流量，测定再灌注1h冠脉流出液一氧化氮合酶（NOS）、内皮型一氧化氮合酶（eNOs）活性，计算梗死心肌占整个左心室质量的比例。结果：建立模型15min后，对照组和缺氧组的基础心脏机械功能和冠脉流量均无显著差异，但缺血再灌注后缺氧组心脏机械功能和冠脉流量的恢复均明显低于对照组。再灌注冠脉流出液中缺氧组NOS和eNOS活性均显著低于对照组。缺氧组心肌梗死面积明显大于对照组。结论：妊娠期缺氧可加重成年后离体心肌缺血再灌注损伤，其作用机制与eNOS活性下降有关。     

Cardiac baroreflex control in humans during and immediately after brief exposure to simulated high altitude

To examine the baroreflex response in humans during and immediately after acute hypoxia exposure, the cardiac baroreflex sensitivity (BRS) was studied using adaptation of RR intervals in response to spontaneous systolic blood pressure fluctuations (sequences methodology) in 11 unacclimatized subjects. All measurements were made under fixed breathing rate, and realized consecutively at baseline level (20 min), at an inspired oxygen concentration of 11% (15 min) and again under normoxic conditions (20 min; recovery period). The spontaneous baroreflex response decreases progressively during hypoxic exposure, causing a tachycardic response at this FiO2 without any significant alteration of the systolic or diastolic blood pressure. The magnitude of decrease for this variable at the end of exposure averaged 42.9 +/- 15.6%. The simultaneous spectral analysis of heart rate (HR) variability in hypoxic condition confirmed an alteration in the parasympathetic activity (HFnu: -17.8 +/- 30.9% versus basal conditions, P < 0.01) counterbalanced by an exaggerated sympathetic activity (LFnu: +33 +/- 42.4%, P < 0.05) at the sinus node. Interestingly, we could observe an enhanced cardiac baroreflex response during the period following the inhalation of the hypoxic mixture (+130.6 +/- 15.6% of basal conditions, P < 0.001). There is a relationship with a significant and abrupt increase in the parasympathetic control of HR (mean HR reached 111 +/- 8.1% of the mean basal HR, P < 0.01). These results suggest that brief exposure to hypoxia under rate-controlled ventilation is associated with a significant alteration in the spontaneous cardiac baroreflex. This important cardiac autonomic imbalance is followed by a significant increase in the cardiac parasympathetic drive even after the disappearance of the hypoxic stimulus.     

Endothelial cell tolerance to hypoxia. Potential role of purine nucleotide phosphates.

The ability of cells to tolerate hypoxia is critical to their survival, but varies greatly among different cell types. Despite alterations in many cellular responses during hypoxic exposure, pulmonary arterial endothelial cells (PAEC) retain their viability and cellular integrity. Under similar experimental conditions, other cell types, exemplified by renal tubular epithelial cells, are extremely hypoxia sensitive and are rapidly and irreversibly damaged. To investigate potential mechanisms by which PAEC maintain cellular and functional integrity under these conditions, we compared the turnover of adenine and guanine nucleotides in hypoxia tolerant PAEC and in hypoxia-sensitive renal tubular endothelial cells under various hypoxic conditions. Under several different hypoxic conditions, hypoxia-tolerant PAEC maintained or actually increased ATP levels and the percentage of these nucleotides found in the high energy phosphates, ATP and GTP. In contrast, in hypoxia-sensitive renal tubular endothelial cells, the same high energy phosphates were rapidly depleted. Yet, in both cell types, there were minor alterations in the uptake of the precusor nucleotide and its incorporation into the appropriate purine nucleotide phosphates and marked decreases in ATPase and GTPase activity. This maintenance of high energy phosphates in hypoxic PAEC suggests that there exists tight regulation of ATP and GTP turnover in these cells and that preservation of these nucleotides may contribute to the tolerance of PAEC to acute and chronic hypoxia.     

Effects of naloxone and morphine on acute hypoxic survival in mice.

OBJECTIVE: To investigate a role of the opiate system during acute hypoxic hypoxia, the effects of naloxone and morphine on hypoxic survival rate were investigated in awake adult mice. DESIGN: Prospective, randomized, animal trial. SETTING: University research laboratory. SUBJECTS: Male dd-Y mice (n = 864 in experiment I, n = 144 in experiment II, n = 30 in experiment III). INTERVENTIONS: The animals were placed in an airtight plastic chamber into which a continuous flow of 8 L/min 5% oxygen-95% nitrogen was passed. MEASUREMENTS AND MAIN RESULTS: One and 5 mg/kg naloxone had no significant effect on the survival rate of mice subjected to acute hypoxic hypoxia, whereas 10 mg/kg naloxone decreased the survival rate. On the other hand, 2 and 5 mg/kg morphine was shown to have a protective action against acute hypoxic hypoxia. The protective effects of 5 mg/kg morphine against hypoxia was even antagonized by 5 mg/kg naloxone, which did not itself show any significant effect on the survival rate. The oxygen consumption in the morphine-treated (5 mg/kg) mice was significantly (p < .05) lower (87.0% +/- 4.6%; mean +/- SE) than that in the saline-treated animals. CONCLUSIONS: The present study suggests that the endogenous opiate system does not play a significant role on the pathophysiology caused by acute hypoxic hypoxia and that the improved survival of the hypoxic animals by morphine is at least partly attributable to its depressant effect on oxygen consumption.     

Inhibition by opioid agonists and enhancement by antagonists of the release of catecholamines from the dog adrenal gland in response to splanchnic nerve stimulation: evidence for the functional role of opioid receptors

The aim of the present study is to examine how opioid agonists and antagonists modify the splanchnic nerve stimulation (SNS)-induced release of catecholamines from the dog adrenal gland in vivo, in an attempt to elucidate whether opioid receptors play a functional role in controlling catecholamine release. Output of epinephrine (EPI) and norepinephrine (NE) was determined from adrenal venous blood by using high-performance liquid chromatography with electrochemical detection. SNS (0.3, 1 and 3 Hz) produced increases in both EPI and NE output in a frequency-dependent manner. Leu-enkephalin (10-100 micrograms/kg i.v.) and morphine (10-100 micrograms/kg i.v.) attenuated the increase in EPI and NE output induced by 1 or 3 Hz of SNS without affecting the basal catecholamine output. A 25 to 40% reduction of the SNS-induced increase in catecholamine output was observed after the treatment with 100 micrograms/kg of leu-enkephalin or morphine. The increase in EPI and NE output induced by 1 and 3 Hz of SNS was enhanced markedly by naloxone (10-1000 micrograms/kg i.v.) and by naltrexone (10-1000 micrograms/kg i.v.). The SNS-induced increase in catecholamine output doubled after treatment with 100 and 1000 micrograms/kg of naloxone or naltrexone. Basal catecholamine output and the increase in output induced by 1 Hz of SNS were unaffected by naloxone or naltrexone. These results suggest that endogenously released opioid peptides inhibit the release of catecholamines by activating opioid receptors in the adrenal gland of the dog.     

Acute renal failure with selective medullary injury in the rat.

Since human acute renal failure (ARF) is frequently the result of multiple rather than single insults, we used a combination of treatments to induce ARF in rats. Uninephrectomized, salt-depleted rats injected with indomethacin developed ARF after administration of radiocontrast. After 24 h, the plasma creatine rose from 103 +/- 3 to 211 +/- 22 mumol/liter (mean +/- SE) and the creatinine clearance dropped from 0.7 +/- 0.1 to 0.2 +/- 0.04 ml/min (P less than 0.001). Severe injury was confined to the outer medulla and comprised necrosis of medullary thick ascending limbs (mTALs), tubular collapse, and casts. Other nephron segments were free of damage except for the proximal convoluted tubules which showed vacuole formation originating from lateral limiting membranes that resembled changes reported in human contrast nephropathy. Cell damage to mTALs included mitochondrial swelling, nuclear pyknosis, and cytoplasmic disruption with superimposed calcification; these changes were most severe in the deepest areas of the outer medulla, away from vasa recta in zones remote from oxygen supply. The fraction of mTALs with severe damage was 30 +/- 7% (range 2-68) and the extent of injury was correlated with a rise in plasma creatinine (r = 0.8, P less than 0.001). Thus, the nature of mTAL injury was similar to the selective lesions observed in isolated kidneys perfused with cell-free medium and was shown to derive from an imbalance between high oxygen demand by actively transporting mTALs and the meager oxygen supply to the renal medulla. Combined multiple renal insults in the rat produce ARF that resembles the clinical syndrome of contrast nephropathy and is characterized by selective mTAL injury conditioned by medullary hypoxia.     

Methionine-enkephalin and leucine-enkephalin in human sympathoadrenal system and pheochromocytoma.

To elucidate the physiological and pathophysiological significance of methionine- and leucine-enkephalin (Met-and Leu-enkephalin, respectively) in human sympathoadrenal system, the contents of these peptides in normal human sympathetic nervous system, adrenal medulla, and pheochromocytomas were determined by specific radioimmunoassays combined with reverse-phase high-performance liquid chromatography. Met-enkephalin-LI and Leu-enkephalin-LI, respectively) were detected by radioimmunoassay in adrenal glands, adrenal medulla, stellate ganglia, sympathetic trunks, and celiac ganglia, and their contents in adrenal medulla were highest. Existence of authentic Met- and Leu-enkephalin was confirmed by reverse-phase high-performance liquid chromatography. Met-enkephalin was approximately 74% of Met-enkephalin-LI, whereas Leu-enkephalin was approximately 30% of Leu-enkephalin-LI in human adrenal medulla. The ratio of Met- to Leu-enkephalin was 2.6 in human adrenal medulla, whereas it was higher in sympathetic ganglia or trunks. In four cases of pheochromocytoma marked difference in Met- and Leu-enkephalin contents was found between medullary and extramedullary tumors. The contents were about three orders higher and the Met- to Leu-enkephalin ratio was lower in medullary than in extramedullary pheochromocytomas, reflecting the tissues where the tumors arose. These results suggest the physiological roles of Met- and Leu-enkephalin in sympathetic nervous system and adrenal glands and their pathophysiological significances in pheochromocytomas.     

Chronic hyperkalemia impairs ammonium transport and accumulation in the inner medulla of the rat.

Previously we demonstrated in rats that chronic hyperkalemia had no effect on ammonium secretion by the proximal tubule in vivo but that high K+ concentrations inhibited ammonium absorption by the medullary thick ascending limb in vitro. These observations suggested that chronic hyperkalemia may reduce urinary ammonium excretion through effects on medullary transport events. To examine directly the effects of chronic hyperkalemia on medullary ammonium accumulation and collecting duct ammonium secretion, micropuncture experiments were performed in the inner medulla of Munich-Wistar rats pair fed a control or high-K+ diet for 7-13 d. In situ pH and total ammonia concentrations were measured to calculate NH3 concentrations for base and tip collecting duct and vasa recta. Chronic K+ loading was associated with significant systemic metabolic acidosis and a 40% decrease in urinary ammonium excretion. In control rats, 15% of excreted ammonium was secreted between base and tip collecting duct sites. In contrast, no net transport of ammonium was detected along the collecting duct in high-K+ rats. The decrease in collecting duct ammonium secretion in hyperkalemia was associated with a decrease in the NH3 concentration difference between vasa recta and collecting duct. The fall in the NH3 concentration difference across the collecting duct in high-K+ rats was due entirely to a decrease in [NH3] in the medullary interstitial fluid, with no change in [NH3] in the collecting duct. These results indicate that impaired accumulation of ammonium in the medullary interstitium, secondary to inhibition of ammonium absorption in the medullary thick ascending limb, may play an important role in reducing collecting duct ammonium secretion and urinary ammonium excretion during chronic hyperkalemia.     

Hypotensive effect of taurine. Possible involvement of the sympathetic nervous system and endogenous opiates.

We studied the role of diminished sympathetic nervous system (SNS) activity and endogenous opiate activation in the hypotensive action of taurine, a sulfur amino acid, in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Supplementation of taurine could prevent the development of DOCA-salt hypertension in rats, but failed to change blood pressure in vehicle-treated control rats. Cardiac NE turnover, which was determined from the rate of decline of tissue NE concentration after the administration of alpha-methyl-p-tyrosine, was markedly accelerated in DOCA-salt rats, but 1% taurine supplement restored it to normal. Moreover, naloxone (2 mg/kg), the specific opiate antagonist, increased blood pressure in taurine-treated DOCA-salt rats, restoring it to levels similar to those in the DOCA-salt rats. In contrast, taurine did not decrease cardiac NE turnover in the control rats, nor did naloxone increase blood pressure in the taurine-treated control rats. Moreover, supplementation of taurine increased both beta-endorphin-like immunoreactive material and taurine contents in the hypothalamus of DOCA-salt rats, whereas it did not increase beta-endorphin in that of control rats despite increased taurine contents. Thus, taurine not only normalized the increased cardiac SNS activity but also elicited an opiate-mediated vasodepressor response only in DOCA-salt rats. It is suggested, therefore, that endogenous opiate activation, which is intimately related to SNS suppression, may contribute to the antihypertensive effect of taurine in sodium chloride hypertension.     

Effects of oxygen withdrawal on catecholamine release in patients on home oxygen therapy

1. Long-term oxygen therapy in appropriate patients prolongs survival and corrects neuropsychological function. Some tests of mental function paradoxically improve during short periods of oxygen withdrawal in patients on long-term oxygen therapy, although the mechanism of this response is unknown. 2. To evaluate the effects of transient hypoxaemia on plasma adrenaline and noradrenaline levels, we studied eight oxygen-dependent patients who underwent either a 4 h period of oxygen withdrawal or their routine therapy, in a randomized, blinded fashion, on 2 separate days. 3. Plasma noradrenaline did not differ at baseline between study days. During normoxic conditions, plasma noradrenaline levels did not increase significantly with time. By contrast, under hypoxic conditions, plasma levels of noradrenaline rose significantly from 0 to 4 h (P less than 0.05). The magnitude of the noradrenaline response was correlated with baseline noradrenaline such that subjects with the highest resting levels had the largest increase during hypoxia (r = 0.95, P less than 0.001). 4. Plasma adrenaline did not differ at baseline between study days and there were no significant effects of hypoxia on plasma adrenaline levels. 5. We conclude that the sympathetic nervous system, but not the adrenal medulla, is stimulated in chronically oxygen-dependent subjects made acutely hypoxaemic. The magnitude of this stimulation appears to be related to the state of sympathetic nervous system activity at baseline. Improvement in some tests of mental function during transient periods of oxygen withdrawal may be due to non-specific arousal caused by a catecholamine surge.     

Concepts in hypoxia reborn

The human fetus develops in a profoundly hypoxic environment. Thus, the foundations of our physiology are built in the most hypoxic conditions that we are ever likely to experience: the womb. This magnitude of exposure to hypoxia in utero is rarely experienced in adult life, with few exceptions, including severe pathophysiology in critical illness and environmental hypobaric hypoxia at high altitude. Indeed, the lowest recorded levels of arterial oxygen in adult humans are similar to those of a fetus and were recorded just below the highest attainable elevation on the Earth's surface: the summit of Mount Everest. We propose that the hypoxic intrauterine environment exerts a profound effect on human tolerance to hypoxia. Cellular mechanisms that facilitate fetal well-being may be amenable to manipulation in adults to promote survival advantage in severe hypoxemic stress. Many of these mechanisms act to modify the process of oxygen consumption rather than oxygen delivery in order to maintain adequate tissue oxygenation. The successful activation of such processes may provide a new chapter in the clinical management of hypoxemia. Thus, strategies employed to endure the relative hypoxia in utero may provide insights for the management of severe hypoxemia in adult life and ventures to high altitude may yield clues to the means by which to investigate those strategies.     

Paradoxical effects of mild hypoxia and moderate altitude on human visual perception.

1. Prolonged (> 10 h) exposure to hypoxia and high altitude (> 5000 m) invariably have detrimental effects on cognitive performance. Paradoxically, mild improvements in cognitive function in patients with chronic obstructive pulmonary disease after cessation of oxygen therapy have been reported. 2. We studied in each of 10 healthy subjects the effect of an acute altitude challenge [rapid helicopter transport to the Jungfraujoch (3450 m), experiment 1] and of an acute exposure to mild hypoxia (fractional inspiratory oxygen concentration 14.5% experiment 2) on a simple test of cognitive performance (the time needed to read briefly displayed letters). 3. Under both hypoxic conditions the time needed to read briefly presented letters decreased, from 12.1 +/- SD 3.8 ms to 8.3 +/- 1.5 ms (P < 0.01) in experiment 1, and from 11.9 +/- 1.9 ms to 8.1 +/- 1.1 ms (P < 0.01) in experiment 2. 4. A rapid and mild hypoxic challenge seems to improve a simple measure of cognitive performance above normal values. The common notion that exposure to hypoxia and altitude invariably impairs cognitive performance may have to be re-evaluated.     

Hyperoxygenated solutions in clinical practice: preventing or reducing hypoxic injury

In cases of hypoxia, oxygen can be supplied via a number of methods including face masks, nasal cannulae, hyperoxygenated oxygen chambers and mechanical ventilation. Administering oxygen via the respiratory tract is, however, limited in respiratory diseases such as pulmonary fibrosis, pneumoconiosis and severe acute respiratory syndrome, or following the inhalation of asphyxiating poisons. This has led to research into new methods of supplying oxygen that bypass the lungs. Research has investigated the efficacy of intravenous hyperoxygenated solutions (HOS) as auxiliary oxygen supplies in several hypoxic states including cardiopulmonary resuscitation, respiratory failure, cerebrovascular disease, myocardial ischaemia, severe acute respiratory syndrome, poisoning, neonatal hypoxia, altitude sickness, large burns and traumatic haemorrhagic shock. Much of the research has taken place in China and more than 3.5 million hypoxic patients have received HOS, with good therapeutic effects. This review summarizes the literature supporting the use of this novel treatment.     

Catecholamine response to light in migraine

The effect of the shift from a low to a high luminosity of the environment on the urinary excretion of norepinephrine (NE) and epinephrine (E) was studied in migraineurs (26 cases) and controls (25 cases). In the latter the shift from a low to high light exposure increased NE excretion; in contrast, in migraineurs exposure to high luminosity resulted in a depression of NE excretion and an augmentation of E excretion. The possible participation of E discharge produced by photostimulation or by other stimuli in the pathogenesis of migraine attack is discussed.