CO2 sensitivity of cat phrenic neurogram during hypoxic respiratory depression

The CO2 response of the phrenic neurogram before and during CO-induced isocapnic brain hypoxia was studied in peripherally chemodenervated, vagotomized, paralyzed, ventilated cats with blood pressure held constant. During inhalation of 0.5% CO in 40% O2, arterial O2 content (CaO2) was reduced to 40% and minute phrenic activity to 38.4 +/- 9.4% (SE; n = 9) of prehypoxic levels, primarily due to depression of peak phrenic amplitude (PP). CO2 response, defined as the slope of the plot of PP vs. end-tidal PCO2 during CO2 rebreathing, was unaffected by phrenic depression even to the point of total suppression of phrenic activity in two cats. The effect of the tissue metabolic acidosis associated with hypoxia on phrenic CO2 sensitivity was assessed in a separate group of cats by blocking lactate formation during hypoxia with dichloroacetate (DCA). Preventing lactic acidosis during hypoxia did not affect the CO2 response of the phrenic activity during hypoxia. We conclude that 1) hypoxic depression does not limit the ability of central respiratory neurons to respond to CO2, and 2) the failure of DCA to affect the CO2 response of the phrenic neurogram suggests that brain intracellular lactic acidosis does not modify the phrenic response to hypercapnia.     

Naloxone reduces ventilatory depression of brain hypoxia

To assess whether endogenous opioids participate in respiratory depression due to brain hypoxia, we determined the ventilatory response to progressive carboxyhemoglobinemia (1% CO, 40% O2) before and after administration of naloxone (NLX, 0.1 mg/kg iv). Minute ventilation (VI) and ventral medullary surface pH (Vm pH) were measured in six anesthetized, peripherally chemodenervated cats. NLX consistently increased base-line hyperoxic VI from 618 +/- 99 to 729 +/- 126 ml/min (P less than 0.05). Although NLX did not alter the Vm pH response to CO [initial alkalosis, Vm pH +0.011 +/- 0.003 pH units, followed by acidosis, Vm pH -0.082 +/- 0.036 at carboxyhemoglobin (HbCO) 55%], NLX attenuated the amount of ventilatory depression; increasing HbCO to 55% decreased VI to 66 +/- 6% of base line before NLX and to 81 +/- 9% of base line after NLX (P less than 0.05). The difference in response after NLX was primarily the result of a linear increase in tidal volume (VT) with decreasing Vm pH (delta VT = 60.3 ml/-pH unit) which was absent before NLX. To assess whether the site of action of the endogenous opioid effect was the central chemosensors, the ventilatory and Vm pH response to progressive HbCO was determined in three additional cats before and after topical application of NLX (3 X 10(-4) M) to the ventral medullary surface. The effect of topical NLX was similar to systemic NLX; significant attenuation of the reduction in VI with increasing HbCO. We conclude that 1) endogenous opioids mediate a portion of the depression of ventilation due to acute brain hypoxia, and 2) this effect is probably at the central chemosensitive regions.     

Triangularis sterni and phrenic nerve responses to progressive brain hypoxia.

Activity of the respiratory muscles that are not normally active during eupnea (genioglossal and abdominal) has been shown to be more vulnerable to hypoxic depression than inspiratory diaphragmatic activity. We hypothesized that respiratory muscles that are active at eupnea would be equally vulnerable to isocapnic progressive brain hypoxia (PBH). Phrenic (PHR) and triangularis sterni nerve (TSN) activity were recorded in anesthetized peripherally chemodenervated vagotomized ventilated cats. Hypercapnia [arterial PCO2 (PaCO2) = 57 +/- 3 (SE) Torr] produced parallel increases in peak PHR and TSN activity. PBH [0.5% CO-40% O2-59.5% N2, arterial O2 content (CaO2) reduced from 13.1 +/- 1.0 to 3.7 +/- 0.3 vol%] resulted in parallel decreases of peak PHR and TSN activity to neural apnea. PBH was continued until PHR gasping ensued (CaO2 = 2.9 +/- 0.2 vol%); TSN activity remained silent during gasping. After 6-12 min of recovery (95% O2-5% CO2; CaO2 = 7.8 +/- 0.8 vol%; PaCO2 = 55 +/- 2 Torr), peak PHR activity was increased to 110 +/- 18% (% of activity at 9% CO2) whereas peak TSN activity was augmented to 269 +/- 89%. The greater augmentation of TSN activity during the recovery period could not be explained solely by hypercapnia. In conclusion, we found that 1) TSN expiratory and PHR inspiratory activities are equally vulnerable to hypoxic depression and 2) recovery from severe hypoxia is characterized by a profound augmentation of TSN expiratory activity.     

Cervical sympathetic and phrenic nerve responses to progressive brain hypoxia

To determine if depression of central respiratory output during progressive brain hypoxia (PBH) can be generalized to other brain stem outputs, we examined the effect of PBH on the tonic (tSCS) and inspiratory-synchronous (iSCS) components of preganglionic superior cervical sympathetic (SCS) nerve activity. Peak phrenic and SCS activity were measured in nine anesthetized, paralyzed, peripherally chemodenervated, vagotomized cats. PBH was produced by inhalation of 0.5% CO in 40% O2 while blood pressure and end-tidal CO2 were maintained constant. A progressive reduction in arterial O2 content from 14.3 +/- 0.6 to 4.5 +/- 0.3 vol% caused a 79 +/- 7% depression of peak phrenic activity and an 84 +/- 10% reduction of iSCS activity, but tSCS activity increased 42 +/- 21%. During CO2 rebreathing, iSCS activity increased in parallel with peak phrenic activity while tSCS activity was unchanged. The slopes of the CO2 responses of both phrenic (6.3 +/- 1.2%max/mmHg) and iSCS (4.6 +/- 0.8%max/mmHg) activity were unaffected by PBH. In four of nine hypocapnic and three of nine hypoxic studies, inspiratory activity in the SCS nerve was observed even after completely silencing the phrenic neurogram.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ventral medullary pH and ventilatory responses to hyperperfusion and hypoxia

The role of a sudden increase in brain perfusion on ventral medullary surface pH (Vm pH) and minute ventilation (VI) was assessed in anesthetized peripherally chemo denervated cats. Acute hypertension (AH), produced by rapid inflation of an aortic balloon, and hypoxemia, produced with either inhalation of 1% CO (COHx) or inhalation of a hypoxic gas (HHx), were used to increase brain blood flow. In the AH group, increasing arterial blood pressure (from 122 +/- 3 to 180 +/- 5 mmHg) caused a rapid (less than 5 s) increase in Vm pH in every trial (n = 18). Associated with the mean peak increases in Vm pH (0.003 +/- 0.0004 pH units) were significant decrease in tidal volume (7-9%). In the COHx group, 17% HbCO caused a significant increase in Vm pH (0.003 +/- 0.0005 pH unit) and diminution of VI (9%). Further increases in HbCO caused a progressive ventral medullary acidosis and greater reductions in VI. The results from the HHX group were qualitatively similar to the COHx group; there was a biphasic response of Vm pH, i.e., an initial increase in Vm pH (0.008 +/- 0.001) followed by a steady decrease in Vm pH, with reductions in VI associated with both phases. We conclude that hyperperfusion, per se, produces an increase in Vm pH and a reduction in VI equivalent in magnitude to that predicted from the CO2 stimulus-response curve; the alkalotic shift in Vm pH and concomitant diminution in VI associated with mild hypoxia is probably related to an increase in ventral medullary perfusion; and the ventilatory depression associated with the medullary acidosis of moderate brain hypoxia must be attributed to another mechanism.     

Chronic administration of sodium cyanate decreases O2 extraction ratio in dogs

It has been proposed that an increase in the affinity of hemoglobin for O2 may be beneficial in severe hypoxemia. To test this hypothesis, we compared the response to progressive hypoxemia in dogs with normal hemoglobin affinity (P50 = 32.4 +/- 0.7 Torr) to dogs with a left shift of the oxyhemoglobin dissociation curve (P50 = 21.9 +/- 0.5 Torr) induced by chronic oral administration of sodium cyanate. Animals were anesthetized, paralyzed, and mechanically ventilated. The inspired O2 fraction was progressively lowered by increasing the inspired fraction of N2. The lowest level of O2 transport required to maintain base-line O2 consumption (VO2) was 9.3 +/- 0.8 ml.min-1.kg-1 for control and 16.5 +/- 1.1 ml.min-1.kg-1 for the sodium cyanate-treated dogs (P less than 0.01). Other measured parameters at this level of O2 transport were, for experimental vs. control: arterial PO2 19.3 +/- 2.4 (SE) Torr vs. 21.8 +/- 1.6 Torr (NS); arterial O2 content 10.0 +/- 1.2 ml/dl vs. 4.9 +/- 0.4 ml/dl (P less than 0.01); mixed venous PO2 14.0 +/- 1.5 Torr vs. 13.8 +/- 1.0 Torr (NS); mixed venous O2 content 6.8 +/- 1.0 ml/dl vs. 2.3 +/- 0.2 ml/dl (P less than 0.01); and O2 extraction ratio 32.7 +/- 2.8% vs. 51.2 +/- 3.8% (P less than 0.01). We conclude that chronic administration of sodium cyanate appears to be detrimental to O2 transport, since the experimental dogs were unable to increase their O2 extraction ratios to the same level as control, thus requiring a higher level of O2 transport to maintain their base-line VO2 values.     

Role of plasma adenosine in breathing responses to hypoxia in fetal sheep.

The importance of plasma adenosine in hypoxic inhibition of breathing movements was determined in chronically catheterized fetal sheep (greater than 0.8 term). Preductal arterial blood for adenosine measurements was withdrawn using a double lumen catheter to mix blood entering the catheter with a solution to stop adenosine metabolism. In 6 fetuses, isocapnic hypoxia (delta PaO2 congruent to -10 Torr) increased the average plasma adenosine concentration from 1.1 +/- 0.2 (SEM) to 2.0 to +/- 0.4 microM. During hypoxia, plasma levels of adenosine were inversely related to preductal arterial O2 content (CaO2) with values ranging between 1.6 and 4.0 microM when CaO2 was less than 3 ml/dl. Hypoxia also significantly reduced the incidence of fetal breathing and rapid eye movements. In other experiments, adenosine (0.36 +/- 0.03 mg/min/kg) was infused for one hour into the inferior vena cava of 5 fetuses. During this infusion, mean plasma concentration of adenosine was 2.8 +/- 0.3 microM, a value about 2.5 times the control average. Adenosine also significantly reduced the incidence of low voltage electrocortical activity, rapid eye movements and breathing activity. We conclude that hypoxic inhibition of fetal breathing most likely arises from an increase in central adenosine production, although during severe O2 deprivation (CaO2 less than 3 ml/dl) blood-borne adenosine could also contribute.     

Dichloroacetate blocks endogenous opioid effects during inspiratory flow-resistive loading.

Inspiratory flow-resistive loading (IRL) in unanesthetized goats causes central elaboration of endogenous opioids, which is accompanied by inhibition of several respiratory muscles. The peripheral stimulus responsible for mediating this phenomenon is unknown. We hypothesized that lactic acid mediates release of endogenous opioids during IRL. Unanesthetized goats were pretreated with either saline or dichloroacetate (DCA; 50 mg/kg iv), a blocker of lactic acid formation, and subjected to IRL (50 cmH2O.l-1.s) for 120 min followed by naloxone (NLX; 0.3 mg/kg iv). Electromyographic activities of the diaphragm (EMGdi), external oblique (EMGeo), and external intercostal (EMGei) were measured and expressed as a percentage of activity at an end-tidal CO2 of 8%. DCA blocked the NLX-induced augmentation of all EMGs observed after 120 min of IRL as follows (means +/- SE): delta EMGdi from 20.8 +/- 5.6% (saline) to 1.2 +/- 2.7% (DCA), delta EMGeo from 116.6 +/- 30.9% (saline) to 5.3 +/- 11.4% (DCA), and delta EMGei from 43.8 +/- 11.3% (saline) to -4.5 +/- 5.6% (DCA) (all P less than 0.05, DCA vs. saline). We conclude that lactic acid produced by the contracting respiratory muscles is the stimulus responsible for endogenous opioid pathway activation during IRL.     

Extracellular potassium homeostasis in the cat medulla during progressive brain hypoxia

Brain extracellular potassium [( K+]ec) in the ventral respiratory group of the medulla and the phrenic neurogram were recorded in anesthetized vagotomized peripherally chemodenervated ventilated cats during progressive isocapnic carbon monoxide (CO) hypoxia. During hypoxia, the phrenic neurogram was progressively depressed and became silent when arterial O2 content (CaO2) was reduced by 62 +/- 3% (SE). Gasping was seen in the phrenic neurogram when CaO2 was reduced by 78 +/- 1%. Medullary [K+]ec, an indicator of energy production failure due to O2 insufficiency, was 3.2 +/- 0.4 mM before hypoxia and was statistically unchanged at the onset of phrenic apnea during CO hypoxia (4 +/- 0.7 mM). By the onset of gasping, [K+]ec had increased to 6.1 +/- 1 mM, a value that tended to be different from control (P less than 0.1). After initiation of gasping, the rate of rise of [K+]ec increased, and [K+]ec reached a maximum value of 14.3 +/- 2.7 mM before hypoxia was terminated. With reoxygenation, [K+]ec returned to control levels within 20 min. On the basis of these results, we have drawn two major conclusions. 1) Hypoxic depression to the point of phrenic apnea does not appear to be caused by medullary energy insufficiency as measured by loss of [K+]ec homeostasis. 2) The rapid rise in [K+]ec in the medulla that characterizes severe hypoxia is closely associated with the onset of gasping in the phrenic neurogram, suggesting that gasping may serve as a marker for loss of medullary ionic homeostasis and thus onset of medullary energy insufficiency during hypoxia.     

Modulation of respiratory responses to carotid sinus nerve stimulation by brain hypoxia.

This study examines the effect of progressive isocapnic CO hypoxemia on respiratory afterdischarge and the phrenic neurogram response to supramaximal carotid sinus nerve (CSN) stimulation. Twelve anesthetized, vagotomized, peripherally chemodenervated, ventilated cats with blood pressure controlled were studied. During isocapnic hypoxemia, the amplitude of the phrenic neurogram was progressively depressed. In contrast, the increase in peak phrenic amplitude produced by CSN stimulation was unchanged, suggesting that the central respiratory response to CSN stimulation is unaffected by progressive hypoxemia. The time constant of respiratory afterdischarge (tau) was calculated from best-fit plots of phrenic amplitude vs. time after cessation of CSN stimulation. Under control conditions the value of tau was 57.7 +/- 3 (SE) s (n = 12). During progressive isocapnic hypoxemia, tau decreased as a linear function of arterial O2 content (CaO2) such that a 40% reduction of CaO2 resulted in a 48% reduction in tau. This reduction of respiratory afterdischarge may contribute to the genesis of periodic breathing during hypoxia.     

Aminophylline effects on ventilatory response to hypoxia and hyperoxia in normal adults

In 10 normal young adults, ventilation was evaluated with and without pretreatment with aminophylline, an adenosine blocker, while they breathed pure O2 1) after breathing room air and 2) after 25 min of isocapnic hypoxia (arterial O2 saturation 80%). With and without aminophylline, 5 min of hyperoxia significantly increased inspiratory minute ventilation (VI) from the normoxic base line. In control experiments, with hypoxia, VI initially increased and then declined to levels that were slightly above the normoxic base line. Pretreatment with aminophylline significantly attenuated the hypoxic ventilatory decline. During transitions to pure O2 (cessation of carotid bodies' output), VI and breathing patterns were analyzed breath by breath with a moving-average technique, searching for nadirs before and after hyperoxia. On placebo days, at the end of hypoxia, hyperoxia produced nadirs that were significantly lower than those observed with room-air breathing and also significantly lower than when hyperoxia followed normoxia, averaging, respectively, 6.41 +/- 0.52, 8.07 +/- 0.32, and 8.04 +/- 0.39 (SE) l/min. This hypoxic depression was due to significant decrease in tidal volume and prolongation of expiratory time. Aminophylline partly prevented these alterations in breathing pattern; significant posthypoxic ventilatory depression was not observed. We conclude that aminophylline attenuated hypoxic central depression of ventilation, although it does not affect hyperoxic steady-state hyperventilation. Adenosine may play a modulatory role in hypoxic but not in hyperoxic ventilation.     

The ergogenic effect of recombinant human erythropoietin on VO2max depends on the severity of arterial hypoxemia

Treatment with recombinant human erythropoietin (rhEpo) induces a rise in blood oxygen-carrying capacity (CaO(2)) that unequivocally enhances maximal oxygen uptake (VO(2)max) during exercise in normoxia, but not when exercise is carried out in severe acute hypoxia. This implies that there should be a threshold altitude at which VO(2)max is less dependent on CaO(2). To ascertain which are the mechanisms explaining the interactions between hypoxia, CaO(2) and VO(2)max we measured systemic and leg O(2) transport and utilization during incremental exercise to exhaustion in normoxia and with different degrees of acute hypoxia in eight rhEpo-treated subjects. Following prolonged rhEpo treatment, the gain in systemic VO(2)max observed in normoxia (6-7%) persisted during mild hypoxia (8% at inspired O(2) fraction (F(I)O(2)) of 0.173) and was even larger during moderate hypoxia (14-17% at F(I)O(2) = 0.153-0.134). When hypoxia was further augmented to F(I)O(2) = 0.115, there was no rhEpo-induced enhancement of systemic VO(2)max or peak leg VO(2). The mechanism highlighted by our data is that besides its strong influence on CaO(2), rhEpo was found to enhance leg VO(2)max in normoxia through a preferential redistribution of cardiac output toward the exercising legs, whereas this advantageous effect disappeared during severe hypoxia, leaving augmented CaO(2) alone insufficient for improving peak leg O(2) delivery and VO(2). Finally, that VO(2)max was largely dependent on CaO(2) during moderate hypoxia but became abruptly CaO(2)-independent by slightly increasing the severity of hypoxia could be an indirect evidence of the appearance of central fatigue.     

Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias

O2-carrying fluids based on hemoglobin (Hb) are in various stages of clinical trials to determine their suitability as O2-carrying plasma expanders. Polymerized Hb solutions are characterized by their vasoactivity, low O2 affinity, oncotic effect, prolonged shelf life, and stability. Physiological responses to facilitated O2 transport after exchange transfusion with polymerized bovine Hb (PBH) were studied in the hamster window chamber model during acute moderate anemia to determine how PBH affects microvascular perfusion and tissue oxygenation. The anemic state [29% hematocrit (Hct)] was induced by hemodilution with a plasma expander (70 kDa dextran). After hemodilution, animals were randomly assigned to different exchange transfusion groups. Study groups were based on the concentration of PBH used, namely: PBH at 13 g Hb/dl [PBH13], PBH diluted to 8 (PBH8) or 4 (PBH4) g Hb/dl in albumin solution at matching colloidal osmotic pressure (COP), and no PBH (only albumin solution) at matching COP (PBH0). Measurement of systemic parameters, microvascular hemodynamics, capillary perfusion, and intravascular and tissue O2 levels was performed at 18% Hct. Restitution of O2-carrying capacity with PBH13 increased arterial pressure and triggered vasoconstriction, low perfusion, and high peripheral resistance. PBH4 and PBH0 exhibited lower arterial pressures compared with PBH13. Exchange transfused animals with PBH8 and PBH4 better maintained perfusion and functional capillary density than PBH13. Blood gas parameters and acid-base balance were recovered proportional to microvascular perfusion. Arterial O2 tensions were improved with PBH4 and PBH8 by preventing O2 precapillary release and increasing O2 reserve. Further studies to establish PBH optimal dosage, efficacy, safety, and its effect on outcome are indicated before Hb-based O2-carrying blood substitutes are implemented in routine practice.     

Effect of progressive exercise on lung fluid balance in sheep

The purpose of this study is to determine the roles of cardiac output and microvascular pressure on changes in lung fluid balance during exercise in awake sheep. We studied seven sheep during progressive treadmill exercise to exhaustion (10% grade), six sheep during prolonged constant-rate exercise for 45-60 min, and five sheep during hypoxia (fraction of inspired O2 = 0.12) and hypoxic exercise. We made continuous measurements of pulmonary arterial, left atrial, and systemic arterial pressures, lung lymph flow, and cardiac output. Exercise more than doubled cardiac output and increased pulmonary arterial pressures from 19.2 +/- 1 to 34.8 +/- 3.5 (SE) cmH2O. Lung lymph flow increased rapidly fivefold during progressive exercise and returned immediately to base-line levels when exercise was stopped. Lymph-to-plasma protein concentration ratios decreased slightly but steadily. Lymph flows correlated closely with changes in cardiac output and with calculated microvascular pressures. The drop in lymph-to-plasma protein ratio during exercise suggests that microvascular pressure rises during exercise, perhaps due to increased pulmonary venous pressure. Lymph flow and protein content were unaffected by hypoxia, and hypoxia did not alter the lymph changes seen during normoxic exercise. Lung lymph flow did not immediately return to base line after prolonged exercise, suggesting hydration of the lung interstitium.     

Effects of antioxidants on contracting spinotrapezius muscle microvascular oxygenation and blood flow in aged rats

Aged rats exhibit a decreased muscle microvascular O(2) partial pressure (Pmv(O(2))) at rest and during contractions compared with young rats. Age-related reductions in nitric oxide bioavailability due, in part, to elevated reactive O(2) species, constrain muscle blood flow (Qm). Antioxidants may restore nitric oxide bioavailability, Qm, and ameliorate the reduced Pmv(O(2)). We tested the hypothesis that antioxidants would elevate Qm and, therefore, Pmv(O(2)) in aged rats. Spinotrapezius muscle Pmv(O(2)) and Qm were measured, and oxygen consumption (Vm(O(2))) was estimated in anesthetized male Fisher 344 x Brown Norway hybrid rats at rest and during 1-Hz contractions, before and after antioxidant intravenous infusion (76 mg/kg vitamin C and 52 mg/kg tempol). Before infusion, contractions evoked a biphasic Pmv(O(2)) that fell from 30.6 +/- 0.9 Torr to a nadir of 16.8 +/- 1.2 Torr with an "undershoot" of 2.8 +/- 0.7 Torr below the subsequent steady-state (19.7 +/- 1.2 Torr). The principal effect of antioxidants was to elevate baseline Pmv(O(2)) from 30.6 +/- 0.9 to 35.7 +/- 0.8 Torr (P < 0.05) and reduce or abolish the undershoot (P < 0.05). Antioxidants reduced Qm and Vm(O(2)) during contractions (P < 0.05), while decreasing force production 16.5% (P < 0.05) and elevating the force production-to-Vm(O(2)) ratio (0.92 +/- 0.03 to 1.06 +/- 0.6, P < 0.05). Thus antioxidants increased Pmv(O(2)) by altering the balance between muscle O(2) delivery and Vm(O(2)) at rest and during contractions. It is likely that this effect arose from antioxidants reducing myocyte redox below the level optimal for contractile performance and directly (decreased tension) or indirectly (altered balance of vasoactive mediators) influencing O(2) delivery and Vm(O(2)).     

Effect of hypoxia on permeability of pulmonary endothelium of canine visceral pleura

To determine if hypoxia increases the permeability of the pulmonary capillaries of the visceral pleura, water and protein movement across visceral pleura of isolated blood-perfused lungs ventilated with 20% O2-5% CO2 or 0% O2-5% CO2 was analyzed in terms of a two-compartment model of fluid exchange. Lungs from mongrel dogs were enclosed in a water-impermeable membrane, thereby creating an artificial visceral pleural space (VPS); fluid flux was determined as the filtration or reabsorption of water and protein in the VPS. Hypoxic vasoconstriction was prevented by adding verapamil to the perfusate. Hydrostatic pressures were continuously monitored and samples of perfusate and pleural fluid were obtained for protein determinations. Pulmonary capillary pressure was varied between 5 and 20 Torr by changing venous pressure while the protein concentration gradient was varied from 0.5 to 6.6 g/dl by introducing different solutions of plasma mixed with saline into the VPS. The hydraulic conductivity (Lp) increased from 4.25 +/- 0.74 to 9.18 +/- 0.67 X 10(-7) ml X s-1 X mmHg-1 X cm-2 and the diffusional permeability (Pd) of protein increased from 1.29 +/- 0.28 to 4.06 +/- 0.44 X 10(-6) cm/s under hypoxic conditions (P less than 0.05). Inhibition of xanthine oxidase by the addition of allopurinol (10 mg/kg body wt) to the perfusate prevented the increase in Lp and Pd observed under hypoxic conditions. We conclude that free radicals generated via xanthine oxidase may be responsible for the increased permeability observed during severe hypoxia.     

Increased chemoreceptor output and ventilatory response to sustained hypoxia

In adult humans the ventilatory response to sustained hypoxia (VRSH) is biphasic, characterized by an initial brisk increase, due to peripheral chemoreceptor (PC) stimulation, followed by a decline attributed to central depressant action of hypoxia. To study the effects of selective stimulation of PC on the ventilatory response pattern to hypoxia, the VRSH was evaluated after pretreatment with almitrine (A), a PC stimulant. Eight subjects were pretreated with A (75 mg po) or placebo (P) on 2 days in a single-blind manner. Two hours after drug administration, they breathed, in succession, room air (10 min), O2 (5 min), room air (5 min), hypoxia [25 min, arterial O2 saturation (SaO2) = 80%], O2 (5 min), and room air (5 min). End-tidal CO2 was kept constant at the normoxic base-line values. Inspiratory minute ventilation (VI) and breathing patterns were measured over the last 2 min of each period and during minutes 3-5 of hypoxia, and nadirs in VI were assessed just before and after O2 exposure. Independent of the day, the VRSH was biphasic. With P and A pretreatment, early hypoxia increased VI 4.6 +/- 1 and 14.2 +/- 1 (SE) l/min, respectively, from values obtained during the preceding room-air period. On A day the hypoxic ventilatory decline was significantly larger than that on P day, and on both days the decline was a constant fraction of the acute hypoxic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of alkalosis on maximum oxygen uptake in rats acclimated to simulated altitude.

The objective of the present experiments was to determine whether prevention or moderation of exercise acidosis would influence arterial blood oxygenation and exercise capacity in hypoxia. The effect of administration of 0.3 M NaHCO3 (3 ml/100 g) on maximum O2 uptake (VO2max) and arterial blood oxygenation was determined in rats acclimated to simulated altitude (370-380 Torr barometric pressure) for 3 wk (HxBic) and in normoxic littermates (NxBic). Controls were simulated-altitude (HxNaCl) and normoxic rats (NxNaCl) given 0.3 M NaCl. Inspiratory PO2 during treadmill exercise was approximately 70 Torr for hypoxic rats and 140-145 Torr for normoxic rats. VO2max was 18% higher in HxBic than in HxNaCl (62.8 + 1.6 vs. 53.1 + 1.0 ml STPD.min-1.kg-1, respectively, P less than 0.05) and only 8% higher in NxBic than in NxNaCl (74.0 + 1.1 vs. 68.7 + 1.5 ml STPD.min-1.kg-1, respectively, P less than 0.05). Exercise in HxNaCl resulted in a decrease in arterial O2 concentration (CaO2), which was largely due to a pH-induced decrease in O2 saturation of arterial blood, and occurred despite an increase in arterial PO2. NaHCO3 moderated the acidosis of exercise and largely attenuated the decrease in CaO2. The effects of acidosis and bicarbonate on CaO2 were much less evident in the normoxic controls. There was an almost linear relationship between VO2max and the corresponding CaO2 for all four groups, suggesting that the effect of NaHCO3 on VO2max may be related to moderation of the decrease in CaO2.     

Effects of moderate hypoxia on fetal electrocortical activity, eye movements, and breathing activity in sheep

Isocapnic hypoxaemia (delta PaO2 = -8.0 +/- 0.5 mmHg; delta CaO2 = -2.86 +/- 0.20 ml/dl) was produced in fetal sheep by having the ewe breathe for one hour a gas mixture (v/v) of 10.5% O2 and 1.5% CO2 in N2. Mean fetal heart rate, blood pressure, and incidence of low voltage electrocortical activity were not affected. However, the incidence of rapid-eye-movements and breathing activity was reduced by about 40%. Breathing movements during hypoxaemia had a mean inspiratory time, breath interval, and tracheal pressure amplitude which did not differ significantly from those during control experiments in which the ewe breathed air from the plastic bag. These observations suggest that hypoxia decreases the incidence of breathing movements but does not affect the amplitude or pattern of breathing activity and that it may reduce the incidence of eye movements and breathing activity through a common mechanism.     

Relationship of CSF pH, O2, and CO2 responses in metabolic acidosis and alkalosis in humans

The effect of induced metabolic acidosis (48 h of NH4Cl ingestion, BE - 10.6 +/- 1.1) and alkalosis (43 h of NaHCO3- ingestion BE 8.8 +/- 1.6) on arterial and lumber CSF pH, Pco2, and HCO3- and ventilatory responses to CO2 and to hypoxia was assessed in five healthy men. In acidosis lumbar CSF pH rose 0.033 +/- 0.02 (P less than 0.05). In alkalosis CSF pH was unchanged. Ventilatory response lines to CO2 at high O2 were displaced to the left in acidosis (9.0 +/- 1.4 Torr) and to the right in alkalosis (4.5 +/- 1.5 Torr) with no change in slope. The ventilatory response to hypoxia (delta V40) was increased in acidosis (P less than 0.05) and it was decreased in four subjects in alkalosis (P, not significant). We conclude that the altered ventilatory drives of steady-state metabolic imbalance are mediated by peripheral chemoreceptors, and in acidosis the medullary respiratory chemoreceptor drive is decreased.