Small intestine intramucosal PCO(2) and microvascular blood flow during hypoxic and ischemic hypoxia

OBJECTIVE: To determine whether small intestine intramucosal PCO(2) and mucosal blood flow changes would be different between ischemic and hypoxic hypoxia. DESIGN: Randomized animal experiment. SETTING: Research laboratory. SUBJECTS: Anesthetized, mechanically ventilated, and surgically instrumented pigs. INTERVENTIONS: Systemic oxygen delivery was lowered in a stepwise manner to decrease it beyond critical oxygen delivery by lowering either FIO(2) or blood volume. MEASUREMENTS AND MAIN RESULTS: In hypoxic hypoxia pigs (n = 6), arterial oxygen concentration and oxygen delivery decreases were achieved by progressively reducing arterial PO(2) while cardiac index remained unchanged. In ischemic hypoxia pigs (n = 5), oxygen delivery reduction was achieved by progressively reducing cardiac index while arterial PO(2) remained unchanged. In control pigs, oxygen delivery remained unchanged. The lowest oxygen delivery measured in both hypoxia and ischemia experiments was 3.60 +/- 0.26 vs. 2.93 +/- 0.77 mL x kg(-1) x min(-1), respectively (p =.23). At the lowest oxygen delivery level, differences between ischemic hypoxia and hypoxic hypoxia experiments were observed for arterial lactate concentration (468 +/- 308 vs. 1070 +/- 218 mmol/L, respectively; p =.03), mixed venous arterial PCO(2) difference (10 +/- 7 vs. 4 +/- 2 torr, respectively; p =.04), and small intestine mucosal blood flow (6.2 +/- 2.1 vs. 15.7 +/- 7.4 perfusion units, respectively; p =.02). Small intestine intramucosal-arterial difference was higher in ischemic hypoxia than in hypoxic hypoxia (52 +/- 15 vs. 31 +/- 12 torr, respectively; p =.03). CONCLUSION: Small intestine intramucosal PCO(2) increases may indicate systemic oxygen uptake supply limitation in ischemic and hypoxic hypoxia related to conditions of mucosal flow stagnation and CO(2) generation.     

Sympathoadrenal responses to acute and chronic hypoxia in the rat.

The sympathoadrenal responses to acute and chronic hypoxic exposure at 10.5 and 7.5% oxygen were determined in the rat. Cardiac norepinephrine (NE) turnover was used to assess sympathetic nervous system (SNS) activity, and urinary excretion of epinephrine (E) was measured as an index of adrenal medullary activity. The responses of the adrenal medulla and SNS were distinct and dependent upon the degree and duration of hypoxic exposure. Chronic hypoxia at 10.5% oxygen increased cardiac NE turnover by 130% after 3, 7, and 14 d of hypoxic exposure. Urinary excretion of NE was similarly increased over this time interval, while urinary E excretion was marginally elevated. In contrast, acute exposure to moderate hypoxia at 10.5% oxygen was not associated with an increase in SNS activity; in fact, decreased SNS activity was suggested by diminished cardiac NE turnover and urinary NE excretion over the first 12 h of hypoxic exposure, and by a rebound increase in NE turnover after reexposure to normal oxygen tension. Adrenal medullary activity, on the other hand, increased substantially during acute exposure to moderate hypoxia (2-fold increase in urinary E excretion) and severe hypoxia (greater than 10-fold). In distinction to the lack of effect of acute hypoxic exposure (10.5% oxygen), the SNS was markedly stimulated during the first day of hypoxia exposure at 7.5% oxygen, an increase that was sustained throughout at least 7 d at 7.5% oxygen. These results demonstrate that chronic exposure to moderate and severe hypoxia increases the activity of the SNS and adrenal medulla, the effect being greater in severe hypoxic exposure. The response to acute hypoxic exposure is more complicated; during the first 12 h of exposure at 10.5% oxygen, the SNS is not stimulated and appears to be restrained, while adrenal medullary activity is enhanced. Acute exposure to a more severe degree of hypoxia (7.5% oxygen), however, is associated with stimulation of both the SNS and adrenal medulla.     

Hypoxia-induced increases in pulmonary transvascular protein escape in rats. Modulation by glucocorticoids.

Pulmonary edema after ascent to altitude is well recognized but its pathogenesis is poorly understood. To determine whether altitude exposure increases lung vascular permeability, we exposed rats to a simulated altitude of approximately 14,500 feet (barometric pressure [Pb] 450 Torr) and measured the pulmonary transvascular escape of radiolabeled 125I-albumin corrected for lung blood content with 51Cr-tagged red blood cells (protein leak index = PLI). Exposures of 24 and 48 h caused significant increases in PLI (2.30 +/- 0.08 and 2.40 +/- 0.06) compared with normoxic controls (1.76 +/- 0.06), but brief hypoxic exposures of 1-13 h produced no increase in PLI, despite comparable increases in pulmonary artery pressure. There were associated increases in gravimetric estimates of lung water in the altitude-exposed groups and perivascular edema cuffs on histologic examination. Normobaric hypoxia (48 h; fractional inspired oxygen concentration [FIO2] = 15%) also increased lung transvascular protein escape and lung water. Dexamethasone has been used to prevent and treat altitude-induced illnesses, but its mechanism of action is unclear. Dexamethasone (0.5 or 0.05 mg/kg per 12 h) started 12 h before and continued during 48 h of altitude exposure prevented the hypoxia-induced increases in transvascular protein escape and lung water. Hemodynamic measurements (mean pulmonary artery pressure and cardiac output) were unaffected by dexamethasone, suggesting that its effect was not due to a reduction in pulmonary artery pressure or flow. The role of endogenous glucocorticoid activity was assessed in adrenalectomized rats that showed augmented hypoxia-induced increases in transvascular protein escape, which were prevented by exogenous glucocorticoid replacement. In summary, subacute hypoxic exposures increased pulmonary transvascular protein escape and lung water in rats. Dexamethasone prevented these changes independent of reductions of mean pulmonary artery pressure or flow, whereas adrenalectomy increased pulmonary vascular permeability and edema at altitude. Increases in vascular permeability in hypoxia could contribute to the development of high-altitude pulmonary edema and endogenous glucocorticoids may have an important influence on pulmonary vascular permeability in hypoxia.     

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.     

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.     

Pulmonary Artery Pressure and Alveolar Gas Exchange in Man during Acclimatization to 12,470 ft

Pulmonary hemodynamics and gas exchange were studied in four physicians during 72 hr acclimatization to 12,470 ft. Pulmonary catheters were left in three subjects for 72 hr. Resting mean pulmonary arterial pressure (PAP) rose progressively during the first 24 hr from 10.3 +/-1.0 to 21.1 +/-4.0 torr and remained at this level. During this same 24 hr period cardiac output increased from 7.1 +/-1.4 to 8.4 +/-2.0 liters/min and total pulmonary resistance rose from 122 +/-16 to 209 +/-40 dynes.sec/cm(-5). Excercise at 60 w after 24 hr of hypoxia increased PAP to 28.8 +/-5.1 torr and decreased total pulmonary resistance to 155 +/-25. Shunt fractions were 11 +/-3.8% after 24 hr at altitude and fell to 7 +/-0% after 72 hr. Alveolar to arterial O(2) difference (P(A-a)(O2)) breathing oxygen fell from 116 +/-10.8 to 92 +/-33.3 torr during the same period of acclimatization, whereas dead space to tidal volume ratio (V(D)/V(T)) rose from 33 +/-4.0% to 40 +/-5.3% and P(A-a)(O2) breathing ambient air rose from 8 +/-2.6 to 11 +/-3.0 torr. Inspiratory static lung compliance decreased significantly from a control of 176 +/-8 to 141 +/-8 ml/cm H(2)O after 72 hr of hypoxia.After 4-7 days at altitude, further deterioration in gas exchange was observed after a 5 mile, 1800 ft climb to the summit (14,255 ft) and return. P(A-a)(O2) on air rose from 2.5 +/-2.1 just before starting, to 16.3 +/-2.8 at the summit (rested), and was still 9.0 +/-2.2 several hours after returning. The O(2)-breathing values paralleled these, whereas dead space appeared to fall. We speculate that the hypoxic pulmonary hypertension which develops over 24 hr in some way may be responsible for a reduction of compliance and deterioration in oxygen exchange efficiency, possibly representing a sub-clinical form of pulmonary edema of high altitude. The increased alveolar to arterial O(2) difference induced by hypoxic exercise persists for several hours of hypoxic rest.     

Effect of sildenafil and acclimatization on cerebral oxygenation at altitude

Phosphodiesterase-5 inhibitors decrease hypoxic pulmonary vasoconstriction under hypobaric hypoxia, but are not known to affect cerebral blood flow or oxygenation. The present study was designed to evaluate the effect of sildenafil on cerebral haemodynamics during acute exposure to altitude and after acclimatization. Ten subjects were studied 1 and 3 days after rapid ascent to 3480 m before and for two consecutive hours after taking sildenafil (50 mg). Before acclimatization, HR (heart rate) rose at 1 h (76.3+/-1.0 beats/min compared with 72.5+/-1.5 beats/min at baseline; P<0.05) and had returned to baseline at 2 h (71.3+/-1.1 beats/min; P>0.05). Mean BP (blood pressure) fell from 96.0+/-2.0 mmHg at baseline to 91.7+/-2.5 (P<0.001) at 1 h and 89.8+/-1.8 mmHg (P<0.0001) at 2 h, whereas SaO2 (arterial oxygen saturation) increased from 83.9+/-0.5% at baseline to 85.3+/-0.4% (P<0.0001) at 1 h and 85.0+/-0.5% (P<0.01) at 2 h. MCAV [MCA (middle cerebral artery) velocity] and PETCO2 (end-tidal partial pressure of CO2) were unchanged, but rSO2 (regional cerebral oxygen saturation) rose progressively at 1 h (62.7+/-0.8%; P<0.05) and 2 h (65.3+/-0.9%; P<0.0001) compared with baseline (59.3+/-1.3%). After 3 days of acclimatization, resting rSO2 and RMCA (MCA resistance) increased and oxygen delivery fell. Changes in HR and mean BP after sildenafil were similar to day 1, but SaO2 did not change. However, rSO2 increased [61.7+/-0.9% at baseline to 65.0+/-1.0% (P<0.0001) at 1 h and 64.0+/-0.9% (P<0.001) at 2 h], despite a reduction in MCAV [65.3+/-1.8 cm/s at baseline to 61.3+/-1.5 cm/s (P<0.01) at 1 h and 60.9+/-1.7 cm/s (P<0.0001) at 2 h] and PETCO2 [4.1+/-0.05 kPa at baseline to 4.0+/-0.04 kPa at 2 h (P<0.01)]. These observations suggest that sildenafil improves cerebral oxygenation at altitude. Whereas the early changes before acclimatization may be largely pulmonary in origin, the later observations may be a direct cerebral effect which warrants further study.     

Effects of oxygen saturation on BOLD and arterial spin labelling perfusion fMRI signals studied in a motor activation task

Effects of oxygen availability on blood oxygenation level dependent (BOLD) and arterial spin labelling (ASL) perfusion functional magnetic resonance imaging (fMRI) signal changes upon motor activation were studied. Mild hypoxic hypoxia was induced by reducing the inspired oxygen content (FIO(2)) to 12%, decreasing blood oxygen saturation (Y) from 0.99 +/- 0.01 to 0.85 +/- 0.03. The fMRI signal characteristics were determined during finger tapping. BOLD activation volume decreased as a function of declining Y in the brain structures involved in execution of the motor task, however, the BOLD signal increase in activated parenchyma was not influenced by Y. ASL fMRI showed that the baseline CBF of 61.8 +/- 3.6 ml/100 g/min was not affected by hypoxic hypoxia. Similar to the BOLD fMRI, the volume of motor cortex areas displaying increase in perfusion by ASL fMRI decreased, but the signal change due to perfusion increase was not influenced in hypoxia. The present fMRI results show distinct patterns of haemodynamic and metabolic responses in the brain to motor task between normoxia and hypoxia. On one hand, neither BOLD nor ASL fMRI signal changes are influenced by hypoxia during motor activation. On the other hand, hypoxia attenuates increase in both BOLD and perfusion fMRI signals upon finger tapping from the levels determined in normoxia. These observations indicate that haemodynamic and metabolic responses may be heterogeneous in brain during execution of motor functions in mild hypoxia.     

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.     

Relationship between arterial oxygen saturation and heart rate variability at high altitudes

Autonomic nervous systems have important roles for survival of victims under hypobaric hypoxic condition. In the present study, we assessed the correlation between arterial oxygen saturation (Sp O 2 ) and heart rate variability (HRV) to identify the autonomic nervous responsiveness among trekkers at high altitude (n = 21). HRV was analyzed by the maximum entropy method. Sp O 2 among subjects at 3456 m (495 mm Hg) was 80% +/- 5% (mean +/- SD; range, 69%-93%). Sp O 2 and percentile entropy, and Sp O 2 and low-frequency variability, had positive correlation ( r = 0.455 and 0.518, respectively). Sp O 2 value among subjects with mountain sickness symptoms was not different from that among subjects without the symptoms. In conclusion, autonomic responses among high-altitude trekkers may be blunted under hypobaric hypoxic conditions. Deterioration of autonomic function measured by HRV might be more sensitive to hypoxia than clinical symptoms at high altitudes.     

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.     

Effects of Aspirin During Exercise on the Incidence of High-Altitude Headache: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE: To evaluate the efficacy of aspirin for headache when exercising during acute high-altitude exposure. BACKGROUND: Aspirin effectively prevents headache when mostly resting during acute high-altitude exposure. However, the majority of individuals exposed to high altitude perform mountaineering activities, which might trigger headache. DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: Thirty-one healthy volunteers (20 men, 11 women; aged 22 to 59 years) were transported to an altitude of about 3000 meters and climbed up to 3800 meters. They then descended to a mountain hut at 3480 meters and spent 2 nights there. Tablets (placebo or 320 mg aspirin) were administered three times at 4-hour intervals, beginning 2 hours before arrival at high altitude. Headache scoring and measurements of heart rate, blood pressure, and arterial oxygen saturation were performed. RESULTS: Ninety-three percent (14 of 15) of the placebo group and 56% (9 of 16) of the aspirin group developed headache when mountaineering activities were performed during acute exposure to high altitude (P<.05). Five hours after arrival at high altitude, mean resting oxygen saturation was 86.1% +/- 2.1% with aspirin and 85.7 % +/- 2.8% with placebo (P =.66). However, subjects in the aspirin group developed headache at saturation values less than or equal to 86%, while those in the placebo group developed headache at saturation values less than 90%. CONCLUSIONS: Although the prophylactic intake of about 1 gram of aspirin reduced the headache incidence when exercising during acute high-altitude exposure, the incidence of headache was higher than previously shown for resting conditions. Aspirin resulted in tolerance to lower arterial oxygen saturation without development of headache; exercise had the opposite effect.     

Is mild normobaric hypoxia a risk factor for venous thromboembolism?

Summary.  Background : Modern air travel entails a cabin altitude between 1520 and 2440 m (5000–8000 ft) and thus exposure to mild hypoxia. There is debate as to whether hypoxia is causally related to venous thromboembolism (VTE) occurring during or after travel. One study suggested that a short period of hypobaric hypoxia causes activation of coagulation. Objectives : To test the hypothesis that hypoxia alone (normobaric hypoxia) causes activation of coagulation, possibly through endothelial cell activation. Methods : Six healthy male volunteers were exposed for 3 h, while seated, on two separate occasions to (i) dry air (control) and (ii) hypoxic gas mixture (12.8% O₂ in N₂, equivalent to breathing air at 3660 m [12000 ft]). Results : There were no differences in hemostatic or endothelial markers between control and hypoxic groups, but platelet and leukocyte counts increased and were significantly higher in the hypoxic group. There were increases in fibrinogen and von Willebrand factor, as well as rheological changes, but these were not significantly different between control and hypoxic groups. Conclusions : This small study does not support the previous suggestion that hypoxia causes activation of coagulation, and suggests that immobility-induced rheological changes may be more significant in the etiology of VTE occurring during or after travel.     

Effect of acetazolamide on leg endurance exercise at sea level and simulated altitude

Acetazolamide can be taken at sea level to prevent acute mountain sickness during subsequent altitude exposure. Acetazolamide causes metabolic acidosis at sea level and altitude, and increases SaO2 (arterial oxygen saturation) at altitude. The aim of the present study was to determine whether acetazolamide impairs muscle endurance at sea level but not simulated altitude (4300 m for <3 h). Six subjects (20+/-1 years of age; mean+/-S.E.M.) performed exhaustive constant work rate one-leg knee-extension exercise (25+/-2 W) once a week for 4 weeks, twice at sea level and twice at altitude. Each week, subjects took either acetazolamide (250 mg) or placebo orally in a double-blind fashion (three times a day) for 2 days. On day 2, all exercise bouts began approx. 2.5 h after the last dose of acetazolamide or placebo. Acetazolamide caused similar acidosis (pH) in all subjects at sea level (7.43+/-0.01 with placebo compared with 7.34+/-0.01 with acetazolamide; P<0.05) and altitude (7.48+/-0.03 with placebo compared with 7.37+/-0.01 with acetazolamide; P<0.05). However, endurance performance was impaired with acetazolamide only at sea level (48+/-4 min with placebo compared with 36+/-5 min with acetazolamide; P<0.05), but not altitude (17+/-2 min with placebo compared with 20+/-3 min with acetazolamide; P = not significant). In conclusion, lack of impairment of endurance performance by acetazolamide compared with placebo at altitude was probably due to off-setting secondary effects resulting from acidosis, e.g. ventilatory induced increase in SaO2 for acetazolamide compared with placebo (89+/-1 compared with 86+/-1% respectively; P<0.05), which resulted in an increased oxygen pressure gradient from capillary to exercising muscle.     

Hypoxia and glucose independently regulate the beta-adrenergic receptor-adenylate cyclase system in cardiac myocytes.

We explored the effects of two components of ischemia, hypoxia and glucose deprivation, on the beta-adrenergic receptor (beta AR)-adenylate cyclase system in a model of hypoxic injury in cultured neonatal rat ventricular myocytes. After 2 h of hypoxia in the presence of 5 mM glucose, cell surface beta AR density (3H-CGP-12177) decreased from 54.8 +/- 8.4 to 39 +/- 6.3 (SE) fmol/mg protein (n = 10, P less than 0.025), while cytosolic beta AR density (125I-iodocyanopindolol [ICYP]) increased by 74% (n = 5, P less than 0.05). Upon reexposure to oxygen cell surface beta AR density returned toward control levels. Cells exposed to hypoxia and reoxygenation without glucose exhibited similar alterations in beta AR density. In hypoxic cells incubated with 5 mM glucose, the addition of 1 microM (-)-norepinephrine (NE) increased cAMP generation from 29.3 +/- 10.6 to 54.2 +/- 16.1 pmol/35 mm plate (n = 5, P less than 0.025); upon reoxygenation cAMP levels remained elevated above control (n = 5, P less than 0.05). In contrast, NE-stimulated cAMP content in glucose-deprived hypoxic myocytes fell by 31% (n = 5, P less than 0.05) and did not return to control levels with reoxygenation. beta AR-agonist affinity assessed by (-)-isoproterenol displacement curves was unaltered after 2 h of hypoxia irrespective of glucose content. Addition of forskolin (100 microM) to glucose-supplemented hypoxic cells increased cAMP generation by 60% (n = 5; P less than 0.05), but in the absence of glucose this effect was not seen. In cells incubated in glucose-containing medium, the decline in intracellular ATP levels was attenuated after 2 h of hypoxia (21 vs. 40%, P less than 0.05). Similarly, glucose supplementation prevented LDH release in hypoxic myocytes. We conclude that (a) oxygen and glucose independently regulate beta AR density and agonist-stimulated cAMP accumulation; (b) hypoxia has no effect on beta AR-agonist or antagonist affinity; (c) 5 mM glucose attenuates the rate of decline in cellular ATP levels during both hypoxia and reoxygenation; and (d) glucose prevents hypoxia-induced LDH release, a marker of cell injury.     

Acquired attenuation of chemoreceptor function in chronically hypoxic man at high altitude

To determine whether chronic exposure to hypoxia during adulthood produces alterations in the control of ventilation, measurements of the resting ventilatory response to hypoxia and hypercapnia, as well as ventilatory response to hypoxia during exercise, were carried out in a group of 10 long-term (3-39 yr) non-native residents of Leadville, Colo. (elevation 3100 m). A group of 8 subjects native to Leadville was also studied and 10 low altitude subjects of Denver, Colo. (elevation 1600 m) served as controls. Hypoxic ventilatory drive was measured as the shape parameter A of isocapnic VE-PA(o2) curves. In the non-native high altitude resident this parameter averaged 43% of the value for low altitude controls (P<0.05) denoting a diminished ventilatory response to hypoxia. The degree of attenuation was related to the length of time spent at high altitude. In the high altitude natives the parameter A averaged 9.6% of control (P<0.01). Similarly hypercapnic ventilatory drive as measured by the slope of the isoxic VE-PA(co2) lines was reduced in the non-native residents to 65% of control (P<0.05) and in the natives averaged 54% of control (P<0.01).In contrast with these findings at rest induction of hypoxia during exercise produced an increase in ventilation comparable to that in the controls in both groups of highlanders.Hence chronic exposure to hypoxia during adulthood in man results in marked attenuation of the ventilatory response to hypoxia at rest and this is a function of the length of exposure to hypoxia. This attenuation of the ventilatory response to hypoxia was associated with a decrease in hypercapnic ventilatory drive. The fact that hypoxic ventilatory drive was almost completely absent while hypercapnic drive was only partially reduced parallels closely the more important role of the peripheral chemoreceptors in mediating ventilatory responses to hypoxia than to hypercapnia. This suggests that the alterations in ventilatory control at altitude are due to failure of peripheral chemoreceptor function.     

Nonresuscitated endotoxemia induces microcirculatory hypoxic areas in the renal cortex in the rat

The pathophysiology of acute renal failure (ARF) in sepsis is only partly understood. In several animal models of septic ARF, no profound tissue hypoxia or decrease in microcirculatory PO2 (microPO2) can be seen. We hypothesized that heterogeneity of microcirculatory oxygen supply to demand in the kidney is obscured when looking at the average microPO2 during endotoxemia. In 20 anesthetized and ventilated rats, MAP, renal blood flow (RBF), and creatinine clearance (CLcrea) were recorded. Renal microPO2 was measured by phosphorescence quenching, allowing measurement of microPO2 distributions. Five animals received a 1-h LPS infusion (10 mg kg h). In 5 rats, RBF was mechanically reduced to 2.1 +/- 0.2 mL min. Five animals served as time control. LPS infusion significantly reduced RBF to 2.1 +/- 0.2 mL min and induced anuria. Average cortical microPO2 decreased from 68 +/- 4 to 52 +/- 6 mmHg, with a significant left shift in the cortical oxygen histogram toward hypoxia. This shift could not be observed in animals receiving mechanical RBF reduction. In these animals, CLcrea was reduced to 50%. An additional group of rats (n = 5) received fluid resuscitation. In these animals, RBF was restored to baseline, CLcrea increased approximately 50%, and the cortical microcirculatory hypoxic areas disappeared after resuscitation. In conclusion, endotoxemia was associated with the occurrence of cortical microcirculatory hypoxic areas that are not detected in the average PO2 measurement, proving the hypothesis of our study. These observations suggest the involvement of hypoxia in the pathogenesis of endotoxemia-induced ARF.     

Hypoxic contraction of isolated rat pulmonary artery

This study was undertaken to test if isolated rat pulmonary artery (PA) rings contract in response to hypoxia, if the response behaves similarly to previously described physiologic and pharmacologic features of hypoxic pulmonary vasoconstriction (HPV) in the isolated perfused rat lung and if the endothelium is necessary for the response. Rings (2-3 mm wide) cut from the main extrapulmonary PA branches were studied. Hypoxic contractions of up to 80 mg (mean +/- S.E. 34 +/- 5 mg, n = 20) were seen in resting rings. The contraction was more reproducible and was potentiated in rings prestimulated with either phenylephrine, norepinephrine, KCl, angiotensin II or the thromboxane mimetic U46619. The magnitude of the hypoxic contraction was proportional to the level of prestimulation and the severity of the hypoxia, with maximum hypoxic contraction seen during exposure to 0% oxygen. The hypoxic dose response showed a threshold bath pO2 of between 30 and 60 Torr, was potentiated by BAY K8644 (10(-7) M), was inhibited by both nifedipine (10(-7) M) and cooling to 29 degrees C and was not inhibited by meclofenamate (1.6 x 10(-6) M). All these characteristics are comparable to previously described features of HPV in the isolated perfused rat lung. Removal of the endothelium resulted in a 48-80% reduction in maximum PA hypoxic contraction. Similar hypoxic contraction was seen in precontracted aortic rings. We conclude that the hypoxic contraction of isolated rat PA may be a useful in vitro model of HPV, that both the endothelium and smooth muscle may be involved in the sensing of PO2 and that the direct hypoxic response is not unique to pulmonary arteries.     

Effect of high altitude and exercise on microvascular parameters in acclimatized subjects

The role of microvascular fluid shifts in the adaptation to hypobaric hypoxia and its contribution to the pathophysiology of AMS (acute mountain sickness) is unresolved. In a systematic prospective study, we investigated the effects of hypobaric hypoxia and physical exercise alone, and in combination, on microvascular fluid exchange and related factors. We used computer-assisted VCP (venous congestion plethysmography) on the calves of ten altitude-acclimatized volunteers. We investigated the effects of: (i) actively climbing to an altitude of 3196 m, (ii) airlifting these subjects to the same altitude, and (iii) exercise at low altitude. CFC (capillary filtration capacity), Pvi (isovolumetric venous pressure) and Qa (calf blood flow) were assessed before and after each procedure and then repeated after an overnight rest. Measurements of CFC showed no evidence of increased microvascular permeability after any of the procedures. Pvi was significantly decreased (P<0.001) from 20.3+/-4.4 to 8.9+/-4.3 mmHg after active ascent, and was still significantly lower (P=0.009) after overnight rest at high altitude (13.6+/-5.9 mmHg). No such changes were observed after the passive ascent (16.7+/-4.0 mmHg at baseline; 17.3+/-4.5 mmHg after passive ascent; and 19.9+/-5.3 mmHg after overnight rest) or after exercise at low altitude. After the active ascent, Qa was significantly increased. We also found a significant correlation between Qa, Pvi and the number of circulating white blood cells. In conclusion, we found evidence to support the hypothesis that increased microvascular permeability associated with AMS does not occur in acclimatized subjects. We also observed that the microvascular equilibrium pressure (Pvi) fell in inverse relation to the increase in Qa, especially in hypoxic exercise. We hypothesize that this inverse relationship reflects the haemodynamic changes at the microvascular interface, possibly attributable to the flow-induced increases in endothelial surface shear forces.