Effects on breathing in awake and sleeping goats of focal acidosis in the medullary raphe.

Our aim was to determine the effects of focal acidification in the raphe obscurus (RO) and raphe pallidus (RP) on ventilation and other physiological variables in both the awake and sleep states in adult goats. Through chronically implanted microtubules, 1) a focal acidosis was created by microdialysis of mock cerebrospinal fluid (mCSF), equilibrated with various levels of CO2, and 2) medullary extracellular fluid (ECF) pH was measured by using a custom-made pH electrode. Focal acidosis in the RO or RP, by dialyzing either 25 or 80% CO2 (mCSF pH approximately 6.8 or 6.3), increased (P < 0.05) inspiratory flow by 8 and 12%, respectively, while the animals were awake during the day, but not at night while they were awake or in non-rapid eye movement sleep. While the animals were awake during the day, there were also increases in heart rate and blood pressure (P < 0.05) but no significant change in metabolic rate or arterial Pco2. Dialysis with mCSF equilibrated with 25 or 80% CO2 reduced ECF pH by the same amount (25%) or three times more (80%) than when inspired CO2 was increased to 7%. During CO2 inhalation, the reduction in ECF pH was only 50% of the reduction in arterial pH. Finally, dialysis in vivo only decreased ECF pH by 19.1% of the change during dialysis in an in vitro system. We conclude that 1) the physiological responses to focal acidosis in the RO and RP are consistent with the existence of chemoreceptors in these nuclei, and 2) local pH buffering mechanisms act to minimize changes in brain pH during systemic induced acidosis and microdialysis focal acidosis and that these mechanisms could be as or more important to pH regulation than the small changes in inspiratory flow during a focal acidosis.     

Influence of chronic respiratory acid-base disorders on acute CO2 titration curve

We have recently shown that background presence of chronic metabolic acid-base disorder markedly alters in vivo acute CO2 titration curve. These studies were carried out to assess the influence of chronic respiratory acid-base disorders on response to acute hypercapnia and to explore whether the chronic level of plasma pH is the factor responsible for alterations in the CO2 titration curve. We compared whole-body responses to acute hypercapnia of dogs with preexisting chronic respiratory alkalosis (n = 8) with that of normal animals (n = 4) and animals with chronic respiratory acidosis (n = 13). Chronic respiratory alkalosis and acidosis, as well as the acute CO2 titrations, were produced in unanesthetized dogs within a large environmental chamber. For comparison with our data on chronic metabolic acidosis and alkalosis, plasma bicarbonate levels, which are secondarily altered in chronic respiratory acid-base disorders, were used as an index of chronic acid-base status of the animals. Results indicate that, as with chronic metabolic acid-base disorders, a larger increment in plasma bicarbonate occurs during acute hypercapnia when steady-state plasma bicarbonate is low (respiratory alkalosis) than when it is high (respiratory acidosis). Yet, in further analogy with the metabolic studies, plasma hydrogen ion concentration is better defended at higher plasma bicarbonate levels in accordance with mathematical relationships defined by the Henderson-Hasselbalch equation. Combined results demonstrate that the influence of chronic acid-base status on whole-body response to acute hypercapnia is independent of initial plasma pH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acid-base balance and plasma glutamine concentration in man

Plasma glutamine concentrations were measured in chronic metabolic acidosis and alkalosis in healthy male volunteers. Metabolic acidosis resulted in a significant drop in glutamine concentration while metabolic alkalosis significantly elevated glutamine levels. These changes in glutamine concentration correlated with both the bicarbonate and PCO2 levels. To determine whether bicarbonate or PCO2 levels influence the glutamine concentrations, respectively acidosis was induced by respiring 5% CO2. This resulted in a significant elevation in both PCO2 and glutamine while bicarbonate levels remained unchanged. The results demonstrate an effect of acid-base alterations upon plasma glutamine concentration mediated by PCO2.     

Different effects of simple anoxic lactic acidosis and simulated in vivo anoxic acidosis on turtle heart.

We compared responses of turtle heart at 20 degrees C to an anoxic lactic acidosis solution (LA) containing 35 mM lactic acid in an otherwise normal turtle Ringers equilibrated with 3% CO2/97% N2 at pH 7.0) to a solution simulating in vivo anoxic acidosis (VA), with elevated concentrations of lactate, Ca2+, Mg2+, and K+, and decreased Cl-, equilibrated with 10.8% CO2/89.2% N2 at pH 7.0. We examined mechanical properties on cardiac muscle strips and determined intracellular pH (pHi) and high energy phosphates on perfused hearts using 31P-NMR. Maximum active force (Fmax) and the maximum rate of force development (dF/dtmax) of muscle strips were significantly higher during VA than during LA superfusion. An elevation of Ca2+ alone (to 6 mM) in LA significantly increased both Fmax and dF/dtmax but the effects diminished toward the end of the exposure; however, hypercapnic anoxic lactic acidosis (addition of 20 mM HCO3- to LA, equilibrated with 10.8% CO2/89.2% N2, pH 7.0) did not significantly affect Fmax or dF/dtmax. During VA perfusion, pHi (6.73 +/- 0.01) was significantly higher than that during LA perfusion (pHi 6.69 +/- 0.013), but the difference is probably too small to have physiological significance. ATP, creatine phosphate, and inorganic phosphate were not significantly different in the two anoxic solutions. We conclude that the reduction of cardiac mechanical function in vivo is minimized by the integrated effects of changes of ionic concentrations, but the observed changes in Ca2+ and pHi cannot fully explain the effect.     

Mechanisms of respiratory response to isoproterenol in glomectomized cats

Effects of intravenous isoproterenol (2-3 micrograms) on arterial pressure, end-tidal CO2 partial pressure (PCO2), medullary extracellular fluid (ECF) pH, and phrenic activity were studied in 13 anesthetized paralyzed cats whose vagi and carotid sinus nerves were cut. The cats were servo-ventilated to keep PCO2 relatively constant. Injections of Ringer solution were without effect. Isoproterenol caused arterial pressure to fall, a transient small (1 Torr) increase of PCO2, increased venous CO2 return to the lungs, a medullary ECF acidosis, and a stimulation of respiration that continued to be elevated after arterial pressure, PCO2, and medullary ECF pH had returned to control. We show that the ECF acidosis is minimally due to the hypotension and to the small transient rise of PCO2. We also show that the respiratory response cannot be explained solely by the ECF acidosis. We conclude that, in addition to its known stimulation of peripheral chemoreceptors, isoproterenol causes medullary ECF to become acidic probably due to metabolic effects on neural tissue and has a separate direct stimulating effect on neurons in the brain.     

Acetazolamide teratogenesis: association of maternal respiratory acidosis and ectrodactyly in C57BL/6J mice

Exposure of C57BL/6J mice to CO2 during a critical period of gestation results in predominantly right-sided, postaxial, forelimb ectrodactyly in the offspring. The incidence and severity of CO2-induced limb malformations has been shown to be dependent on the concentration of inspired CO2, the developmental age of the embryo at exposure and the duration of CO2 exposure. Offspring of acetazolamide-treated C57BL/6J mice also display this highly specific form of ectrodactyly (Green et al., '73). Since the drug has been shown to elevate tissue CO2 tension (Mithoefer and Davis, '58), the teratogenic effect of acetazolamide may be related to induction of a hypercapnic embryonic environment.     

Effect of air breathing on acid-base and ion regulation after exhaustive exercise and during low pH exposure in the bowfin, Amia calva.

To explore a potential conflict between air breathing and acid-base regulation in the bowfin (Amia calva), we examined how individuals with access to air differed from fish without air access in their response to acidosis. After exhaustive exercise, bowfin with access to air recovered significantly more slowly from the acidosis than fish without air access. While arterial blood pH (pH(a)) of fish without air access recovered to resting levels by 8 h, pH(a) was still significantly depressed in fish having access to air. In addition, Pco(2) was slightly more elevated in fish having air access than those without it. Fish with access to air still had a significant metabolic acid load after 8-h recovery, while those without air access completely cleared the load within 4 h. These results suggest that bowfin with access to air were breathing air and, consequently, were less able to excrete CO(2) and H(+) and experienced a delayed recovery. In contrast, during exposure to low pH, air breathing seemed to have a protective effect on acid-base status in bowfin. During exposure to low pH water, bowfin with access to air developed a much milder acidosis than bowfin without air access. The more severe acidosis in fish without air access was caused by an increased rate of lactic acid production. It appears that enhanced O(2) delivery allowed air-breathing bowfin to avoid acidosis-induced anaerobic metabolism and lactic acid production. In addition, during low pH exposure, plasma Na(+) and Cl(-) concentrations of fish without air access fell slightly more rapidly than those in fish with air access, indicating that the branchial ventilatory changes associated with air breathing limited, to some degree, ion losses associated with low pH exposure.     

Acid-base effects of altering plasma protein concentration in human blood in vitro

We altered the concentration of plasma proteins in human blood in vitro by adding solutions with [Na+], [K+], and [Cl-] resembling those in normal blood plasma, either protein-free or with a high concentration of human albumin. After equilibrating the samples with a gas containing 5% CO2-12% O2-83% N2 at 37 degrees C, we measured pH, PCO2, and PO2; in separated plasma, we determined the concentrations of total plasma proteins and albumin and of the completely dissociated electrolytes (strong cations Na+, K+, Mg2+ and anions Cl-, citrate3-). With PCO2 nearly constant (mean = 35.5 Torr; coefficient of variation = 0.02), lowering plasma protein concentration produced a metabolic alkalosis, whereas increasing plasma albumin concentration gave rise to a metabolic acidosis. These acid-base disturbances occurred independently of a minor variation in the balance between the sums of strong cations and anions. We quantified the dependence of several acid-base variables in plasma on albumin (or total protein) concentration. Normal plasma proteins are weak nonvolatile acids. Although their concentration is not regulated as part of acid-base homeostasis, hypoproteinemia and hyperalbuminemia per se produce alkalosis and acidosis, respectively.     

Acute renal response to rapid onset respiratory acidosis

Renal strong ion compensation to chronic respiratory acidosis has been established, but the nature of the response to acute respiratory acidosis is not well defined. We hypothesized that the response to acute respiratory acidosis in sheep is a rapid increase in the difference in renal fractional excretions of chloride and sodium (Fe(Cl) - Fe(Na)). Inspired CO(2) concentrations were increased for 1 h to significantly alter P(a)CO(2) and pH(a) from 32 ± 1 mm Hg and 7.52 ± 0.02 to 74 ± 2 mm Hg and 7.22 ± 0.02, respectively. Fe(Cl) - Fe(Na) increased significantly from 0.372 ± 0.206 to 1.240 ± 0.217% and returned to baseline at 2 h when P(a)CO(2) and pH(a) were 37 ± 0.6 mm Hg and 7.49 ± 0.01, respectively. Arterial pH and Fe(Cl) - Fe(Na) were significantly correlated. We conclude that the kidney responds rapidly to acute respiratory acidosis, within 30 min of onset, by differential reabsorption of sodium and chloride.     

Intracellular pH in hibernation and respiratory acidosis in the European hamster

Intracellular pH was determined (DMO method) in European hamsters, in the spontaneously-occurring respiratory acidosis of hibernation, in hypercapnia due to breathing 12% CO2 in air in euthermy in spring, and in euthermicnormocapnic controls. From euthermy to hibernation, the temperature coefficient of pH was lowest in blood plasma and brain, intermediate in striated muscles (thigh muscles and diaphragm), and highest in heart and liver (Fig. 1). Correspondingly, the estimated dissociation ratio of the protein imidazole buffer groups, alpha Im, decreased markedly in plasma and brain, denoting an acid titration, but varied little in liver and heart. Striated muscles were intermediate (Fig. 2). Like in other mammals, intracellular responses to short-term euthermic respiratory acidosis were characterized by a partial metabolic compensation in the brain and a small metabolic acidification in striated muscles. In hibernation, a powerful metabolic compensation took place in liver and heart, nearly restoring alpha Im, but none occurred in brain (Figs. 3 to 5). The existence of an intracellular acidosis in brain and striated muscles during hibernation is in keeping with an inhibitory role of acidosis, whereas the homeostasis of intracellular alpha Im in liver and heart would subserve the eurythermal functioning of metabolic regulations in these organs, like in most organs of ectotherms.     

What is the ultimate goal in acid-base regulation?

It is common to see chapters on acid-base physiology state that the goal of acid-base regulatory mechanisms is to maintain the pH of arterial plasma and not arterial Pco(2) (Pa(CO(2))) or plasma HCO(3). A hypothetical situation in which the Pa(CO(2)) of arterial plasma is 80 mmHg and the plasma HCO(3) concentration is 48 mM is presented and analyzed to get over this misconception. As per the modified Henderson equation, the pH of arterial plasma would be 7.4; however, we explain that this may be associated with intracellular acidosis due to intracellular hypercapnia and that derangement of homeostasis is evident from the occurrence of respiratory depression and, eventually, coma in the patient described. This suggests that the ultimate goal of acid-base regulatory mechanisms is not just the maintenance of the pH of arterial plasma but the maintenance of the steady-state pH of intracellular fluid as well.     

Effects on breathing of focal acidosis at multiple medullary raphe sites in awake goats.

To gain insight into why there are chemoreceptors at widespread sites in the brain, mircrotubules were chronically implanted at two or three sites in the medullary raphe nuclei of adult goats (n = 7). After >2 wk, microdialysis (MD) probes were inserted into the microtubules to create focal acidosis (FA) in the awake state using mock cerebral spinal fluid (mCSF) equilibrated with 6.4% (pH = 7.3), 50% (pH = 6.5), or 80% CO(2) (pH = 6.3), where MD with 50 and 80% CO(2) reduces tissue pH by 0.1 and 0.18 pH unit, respectively. There were no changes in all measured variables with MD with 6.4% at single or multiple raphe sites (P > 0.05). During FA at single raphe sites, only 80% CO(2) elicited physiological changes as inspiratory flow was 16.9% above (P < 0.05) control. However, FA with 50 and 80% CO(2) at multiple sites increased (P < 0.05) inspiratory flow by 18.4 and 30.1%, respectively, where 80% CO(2) also increased (P < 0.05) tidal volume, heart rate, CO(2) production, and O(2) consumption. FA with 80% CO(2) at multiple raphe sites also led to hyperventilation (-2 mmHg), indicating that FA had effects on breathing independent of an increased metabolic rate. We believe these findings suggest that the large ventilatory response to a global respiratory brain acidosis reflects the cumulative effect of stimulation at widespread chemoreceptor sites rather than a large stimulation at a single site. Additionally, focal acidification of raphe chemoreceptors appears to activate an established thermogenic response needed to offset the increased heat loss associated with the CO(2) hyperpnea.     

Carbon dioxide and pH effects on temperature-sensitive and -insensitive hypothalamic neurons.

The preoptic-anterior hypothalamus (POAH) controls body temperature, and thermoregulatory responses are impaired during hypercapnia. If increased CO(2) or its accompanying acidosis inhibits warm-sensitive POAH neurons, this could provide an explanation for thermoregulatory impairment during hypercapnia. To test this possibility, extracellular electrophysiological recordings determined the effects of CO(2) and pH on the firing rates of both temperature-sensitive and -insensitive neurons in hypothalamic tissue slices from 89 male Sprague-Dawley rats. Firing rate activity was recorded in 121 hypothalamic neurons before, during, and after changing the CO(2) concentration aerating the tissue slice chamber or changing the pH of the solution bathing the tissue slices. Increasing the aeration CO(2) concentration from 5% (control) to 10% (hypercapnic) had no effect on most (i.e., 69%) POAH temperature-insensitive neurons; however, this hypercapnia inhibited the majority (i.e., 59%) of warm-sensitive neurons. CO(2) affected similar proportions of (non-POAH) neurons in other hypothalamic regions. These CO(2) effects appear to be due to changes in pH since the CO(2)-affected neurons responded similarly to isocapnic acidosis (i.e., normal CO(2) and decreased pH) but were not responsive to isohydric hypercapnia (i.e., increased CO(2) and normal pH). These findings may offer a neural explanation for some heat-related illnesses (e.g., exertional heat stroke) where impaired heat loss is associated with acidosis.     

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.     

Effects of acute hypobaric hypoxia on acid-base status of fowl blood

Arterial blood Po/, Pco2, lactate levels and Cl- ion concentration as well as pH were measured on the time course in chickens (Gallus domesticus) as they settled in normoxic conditions and during exposure to acute hypobaric hypoxia (Pb = 450 Torr). Hypoxia provoked at first a CO2 increased output from blood and a brief stage of deep metabolic acidosis during which lactate levels suddenly increased. This acidosis was then compensated producing a return to the initial pH and a decrease in [HCO3-] + [CO3(2-)] after 60 min. Subsequently respiratory alkalosis associated with an increase in [HCO-3] + [CO3(2-)], a decrease in cl- ion concentration and a small decrease in lactate levels were observed. Prolonged exposure to hypoxia (16 h) resulted in a new return to the initial pH, a decrease in concentration of [HCO3-] + [CO3(2-)] and a high lactate level. The hematocrit value, the Hb concentration, and the plasma Na+, K+, Ca++ and Mg++ ion concentration did not change significantly.     

Adaptation to respiratory acidosis in the turtle bladder

The effect of in vivo respiratory acidosis for 4 and 48 hr was examined in the turtle bladder by placing turtles in hypercapnic chambers. Blood pH was significantly lowered and pCO2 was significantly elevated over control values both 4 and 48 hr, while blood bicarbonate was only increased after 48 hr. In vitro rates for H+ secretion determined by the reverse short-circuit current were significantly greater in bladders from 48 hr of respiratory acidosis than those of controls (27.3 +/- 2.7 vs 20.6 +/- 1.7 microA, P less than 0.05). In vitro rates for HCO3- secretion determined by pH stat were not altered. Fluorescence microscopy was used to study cell morphology. The number of carbonic anhydrase cells (corrected for the total number of cells) as determined by four different fluorescence stains (6-carboxyfluorescein, rhodamine 123, acridine orange, and 3,3'-diethyloxacarbocyaninine iodide) was increased both after 4 and 48 hr of respiratory acidosis. However, the number of HCO3(-)-secreting (beta subtype) carbonic anhydrase cells, determined by a probe for the anion exchanger, NBD-taurine, was not increased. In vitro 1% CO2 for 4 hr also resulted in an increase in H+ secretion and in the number of 6-carboxyfluorescein-positive cells, both of which could be blocked with SITS pretreatment. We conclude that CO2 changes the mucosal cells more toward the carbonic anhydrase phenotype, and that if NBD-taurine accurately identifies the beta cells, that the adaptation produces or recruits more alpha-carbonic anhydrase cells.     

Effects of naloxone on the breathing, electrocortical, heart rate, glucose and cortisol responses to hypoxia in the sheep fetus

Continuous infusions of naloxone HC1 (0.5 mg/kg or 3.8 mg/kg) or saline were given intravenously to fetal sheep at 119 to 137 days of gestation during a one hour period of air administration and a one hour period of hypoxia induced by having ewes breathe 9% O2, 3% CO2 and 88% N2. Fetal carotid PaO2 fell to 13.0 +/- 0.5 mmHg during hypoxia with no change in pH. During hypoxia, plasma cortisol concentration increased significantly more in naloxone-infused fetuses than controls. Ewes, whose fetuses received naloxone, showed a significant increase in cortisol during hypoxia whereas no increase was observed in controls. There were no significant differences between saline and naloxone-infused fetuses during hypoxia in fetal breathing incidence, amplitude, frequency, number of deep inspiratory efforts per hour, heart rate, electrocortical activity or in the rise in plasma glucose caused by hypoxia. Results suggest that endogenous opiates may have a role in modulating cortisol production in the ewe and fetus during hypoxia but do not have a role in mediating the decrease in incidence of breathing activity or rise in plasma glucose. During air administration, naloxone significantly increased fetal breath amplitude, fetal and maternal plasma glucose, fetal heart rate, and the number of electrocortical changes per hour. This suggests endogenous opiates may have a more important role in the normoxic pregnant ewe and fetus.     

Oxygen consumption and force development in turtle and trout cardiac muscle during acidosis and high extracellular potassium

Relative to species such as rainbow trout, freshwater turtle shows a high tolerance to challenges involving acidosis and increases in extracellular K+. Therefore, the effects of acidosis or high K+ on twitch force and oxygen consumption were examined in ventricular ring preparations from these two species. The oxygen consumption associated with force development was estimated by net oxygen consumption (oxygen consumption during twitch force development minus that during rest). For turtle, elevation of CO2 from 2% (pH 7.7) to 12% (pH 6.9) in the gas equilibrating the muscle bath decreased twitch force by 20% without any effects on oxygen consumption. Decreasing pH from 7.7 to 6.9 with 22 mM lactic acid had similar effects. For trout, CO2-induced acidosis decreased twitch force by approximately 60%. Furthermore, force development became energetically less efficient as it fell disproportionately more than net oxygen consumption. This was not observed for lactic acidosis. For trout but not for turtle, acidosis resulted in an increase in oxygen consumption during rest. An increase in extracellular K+ from 2.5 mM to 10 mM depressed force and oxygen consumption proportionately for both species. Adrenaline (10 microM) increased twitch force for both species and oxygen consumption for trout; it attenuated the effects of high extracellular K+. Neither adrenaline nor high K+ influenced the ratio of force to net oxygen consumption. As opposed to high extracellular K+, acidosis appears to increase the energetic cost of contractility, particularly for the trout heart.     

Effect of NH4Cl acidosis on the function of renin-angiotensin-aldosterone system in newborn infants.

The present study was undertaken to assess the influence of acute metabolic acidosis on the activity of renin-angiotensin-aldosterone system and renal function in a group of seven one-week-old neonates with mean birth weight of 2164 g (range: 1300-3750 g) and mean gestational age of 34 weeks (range: 28-40 weeks) undergoing oral NH4Cl load. NH4Cl was given in a dose of 2.8 mEq/kg to evaluate renal acidification. Prior to and following NH4Cl administration blood acid-base parameters, plasma urinary electrolytes, creatinine and aldosterone concentration as well as plasma renin activity, glomerular filtration rate, urine flow rate and net acid secretion were measured. NH4Cl administration significantly depressed blood pH (P < 0.05), total CO2 content (P < 0.01) and base excess (P < 0.01) and resulted in a significant elevation of plasma potassium concentration (P < 0.05). Furthermore, NH4Cl ingestion significantly increased urine flow rate, sodium, chloride and net acid excretion. In response to NH4Cl acidosis no consistent change in plasma renin activity and plasma aldosterone concentration could be detected. There was, however, an about 50% increase in urinary aldosterone excretion from the control value of 4.1 +/- 1.2 micrograms/day to 6.8 +/- 2.3 micrograms/day (P < 0.05) after NH4Cl administration. These data suggest that the responsiveness of neonatal adrenals to stimulation by metabolic acidosis is blunted, acidosis therefore, may play a minor role in the neonatal hyperfunction of renin-angiotensin-aldosterone system.     

Time-course of blood acid-base state during arousal from hibernation in the European hamster

1. Arterial blood was sampled at 15 min-intervals in European hamsters Cricetus cricetus fitted with indwelling catheters, from deep hibernation to full arousal. Temperature-corrected pH and PCO2, respectively pH* and P*CO2, were directly measured at 37 degrees C. 2. Deep hibernation corresponded to a respiratory acidosis: pH* = 7.01 +/- 0.01 (mean +/- SE), P*CO2 = 160 +/- 4 Torr (n = 9 animals). 3. Three periods could be distinguished in the arousal: (i) a period of hyperventilation (28 +/- 5 min), in which P*CO2 was reduced to 79 +/- 4 Torr, while cheek pouch temperature increased only by 0.9 +/- 0.2 degrees C; (ii) a period of metabolic acidification by lactate accumulation (84 +/- 6 min), corresponding to the period of peak thermogenesis; (iii) a progressive return to euthermic conditions (104 +/- 10 min), by simultaneous respiratory and metabolic alkalinization. 4. Over 60% of the blood CO2 stores accumulated at the beginning of the hibernation bout were released by hyperventilation during the first period, prior to the full development of thermogenesis. This is in agreement with the hypothesis of an inhibitory role of the respiratory acidosis in hibernation.