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Effects of Hyperthermia on Ventilation and Metabolism During Hypoxia in Conscious Mice

Effects of Hyperthermia on Ventilation and Metabolism During Hypoxia in Conscious Mice

Japanese Journal of Physiology, 54, 53–59, 2004

Effects of on Ventilation and during in Conscious Mice

Michiko IWASE, Masahiko IZUMIZAKI, Mitsuko KANAMARU, and Ikuo HOMMA

2nd Department of Physiology, Showa University School of Medicine, Shinagawa-ku, Tokyo, 142–8555 Japan

Abstract: Hyperthermia and hypoxia influence at a higher level during hyperthermia than during ventilation and metabolism; however, their syner- normothermia throughout the 10 min experiment. gistic effects remain unanswered. We hypothe- V˙ O2 decreased during hypoxia at both BTs. Hy- sized that an enhancement of ventilation induced poxia increased the V˙ E–V˙ O2 ratio because of rel- by hyperthermia is competitive with hypoxic hy- atively high V˙ E with respect to the decreased pometabolism. We then examined the relation- V˙ O2, which means . At hypoxia ship of body , hypoxia, and respira- under hyperthermia, serious hyperventilation oc- tion in conscious mice, measuring minute ventila- curred with a further increase in V˙ E. The aug- tion (V˙ E), aerobic metabolism, and arterial blood mented ventilation may be due to the thermal gases. All parameters were measured at two dif- stimulus and a lowered thermoregulatory set ferent body (BTs), approximately point for hypoxia. Thus hyperthermia reduces 37°C (normothermia) and 39°C (hyperthermia), ventilation and metabolism to maintain normo- under both normoxia (room air ) and capnia; as a result, thermogenesis is reduced hypoxia (7% O2 inhalation). Under normoxia, V˙ E under normoxia. Hyperthermia augments hyper- and O2 consumption (V˙ O2) were lower at hyper- ventilation induced by hypoxia, leading to severe thermia than at normothermia, and the V˙ E–V˙ O2 hypoxic . Thermal stimuli may impair ratio remained constant. PaCO2 values were nor- the adjustment of ventilation and metabolism mal at both BTs under normoxia. Hypoxic gas in- when O2 is limited. [The Japanese Journal of halation increased V˙ E, which reached a peak in Physiology 54: 53–59, 2004] 2 min, then decreased at both BTs. V˙ E remained

Key words: hyperthermia, hypoxia, ventilation, aerobic metabolism, mice.

It has been reported that hyperthermia associated have also observed the BT-induced polypnea during with and may lead to and hypercapnic conditions in mice [7]. However, the ther- [1], and that elevated body temperature (BT) is mal effect on the ventilation under the of recorded after death in sudden infant death syndrome room air or hypoxic gas is uncertain in mice. [2]. Thus hyperthermia is an important risk factor for The effects of hyperthermia on ventilation under cardiorespiratory disorders. Here we are concerned hypoxia remain misunderstood in comparison with the with hyperthermia in respect to the control of ventila- effects of . In general, ventilation under tion and metabolism. acute hypoxia shows an initial augmentation and a Thermal effects on breathing patterns have been ex- subsequent decline, referred to as hypoxic depression, amined by artificially increasing BT under anesthesia. followed by hypometabolism [8, 9]. Hypoxic depres- The increased BT affects the rate-determining mecha- sion lowers cellular activity by reducing cell metabo- nism in the respiratory centers to increase the respira- lism and energy requirements, a survival mechanism tory frequency ( f ), even in a range below the panting for neurons and other cells. Furthermore, hypoxic hy- threshold in cats [3–5] and rabbits [6]; thus most pometabolism affects the thermoregulatory set point mammals show an increase of f under elevated BT. We [10], reduces thermogenesis, and lowers BT directly

Received on November 25, 2003; accepted on January 28, 2004 Correspondence should be addressed to: Michiko Iwase, 2nd Department of Physiology, Showa University School of Medicine, 1–5–8 Hatanodai, Shinagawa-ku, Tokyo, 142–8555 Japan. Tel: ϩ81–3–3784–8113, Fax: ϩ81–3–3784–0200, E-mail: [email protected]

Japanese Journal of Physiology Vol. 54, No. 1, 2004 53 M. IWASE et al. effecting central neural structures [11, 12]. Hypoxic measurements of ventilation and metabolism hypometabolism with decreased BT is therefore es- were performed under normothermia and 3 d later sential to life. Conversely, the artificial maintenance of under hyperthermia. BT during hypoxic exposure does not reverse hy- Measurement of lung ventilation. Each pometabolism. Instead, it creates an additional burden mouse was placed in a 250 ml glass chamber with on the cardiorespiratory system because BT is per- ether-dropped cotton and acutely anesthetized. Subse- ceived as a hyperthermic stimulus [13, 14]. We hy- quently, the mouse was placed in a double-chamber pothesize that hyperthermia interferes with the hy- ; a thermistor probe coated with petro- poxic ventilatory control accompanied by hypometab- latum jelly for the prevention of stress was inserted olism. into the rectum to monitor BT as previously described The purpose of this study is to evaluate the interac- [7, 15]. The mouse was acclimatized to the plethys- tion among BT, hypoxia, and , which clari- mograph chamber for at least 30 min and confirmed to fied the adjustment of ventilation for metabolism show quiet breathing and a recovery of rectal tempera- under hyperthermia and hypoxia in conscious mice. ture before measurements were begun. We therefore measured ventilation, aerobic metabo- To set a mouse to the double chamber plethysmo- lism, and arterial blood gases to examine respiratory graph system, mild anesthesia was needed. Lung ven- output, all at two different BTs, normothermia and hy- tilation and hypoxic ventilatory responses are affected perthermia, under normoxia and hypoxia in mice. by anesthesia, which may continue even after arousal. At this point we chose ether as an anesthetic because MATERIALS AND METHODS of the minimal time needed for the mouse to regain consciousness, even though to some degree ether af- Animals. Twenty-two inbred male C57BL/6 fects airway secretions. mice were used for 8 to 10 weeks in this study. The The airflow of the head chamber was measured animals were provided with food and water ad libi- with a pneumotachograph (TV-241T and TP-602T, tum, housed at a controlled temperature (24Ϯ1°C), Nihon Kohden). The mouse in the plethysmograph and exposed to a daily 12 : 12 h light–dark cycle. All first breathed room air, then gas consisting of 7% O2 experiments were conducted in an environmentally balanced with N2 for 10 min. Respiratory flow, BT, controlled room at 24Ϯ1°C. The data were randomly and percentage of inspiratory O2 were sampled every sampled from 10:00 to 18:00. The study protocol was 0.5 ms and processed through an analog to a digital approved by the Showa University Animal Experi- converter (MacLab, AD Instruments, NSW, Australia) ments Committee. under both conditions. The data were stored in a per- In the present study, ventilation, aerobic metabo- sonal computer and analyzed by a software package lism, and blood gas were measured in separate mice. (MacLab, AD Instruments). Ten consecutive breaths Moreover, anesthesia was varied among the groups of were analyzed under each condition in a steady state. mice measuring blood gas, ventilation, and metabo- The total breath duration (TT, s), VT, (ml BTPS), in- lism because long-term anesthesia was needed for the spiratory time (TI, s), and expiratory time (TE, s) were preparation of blood gas analysis. These methodologi- obtained by averaging the values; f (breaths/min) was cal limitations were primarily derived from specie determined as 60/TT. VT was calibrated by injecting sizes. Experiments were done at a sufficient interval 0.5 ml ambient air with a syringe through a small hole after anesthesia, and the mice were matched in age, in the head chamber. (V˙ E, ml body , BT, and other environmental conditions. BTPS) was determined as f ϫVT. VT and V˙ E were Control of BT. BT under conscious and normal normalized by 10 g body weight, and lung ventilation state was estimated in a body plethysmograph with no was measured at normothermia and hyperthermia in treatments 30 min after ether anesthesia, which was the same 5 mice. 37–37.5°C. This BT was regarded as normothermia, Measurement of aerobic metabolism. Each which in mice was not artificially controlled during mouse was placed in the body chamber of a plethys- hypoxia. For hyperthermia, the mice were warmed mograph, and a thermistor probe was inserted into the with a heat lamp from outside the body chamber of rectum in the same manner as that used for measuring the double-chamber plethysmograph mentioned lung ventilation. The mouse was acclimatized to the below. Rectal temperature was maintained at 39°C by chamber for 30 min before the measurement. The a controller (Animal Controller ATB-1100, Nihon Ko- head chamber of the plethysmograph continuously de- hden, Tokyo, Japan). Throughout the experiments; livered ambient air or the gas mixture at 750 ml/min. this temperature was regarded as hyperthermia. The Collected gases from the inflow and outflow of the

54 Japanese Journal of Physiology Vol. 54, No. 1, 2004 Respiration at Hyperthermia and Hypoxia

Table 1. Effects of body temperature on respiratory variables during breathing of room air.

TI (s) TE (s) f (/min) V T (ml/10 g) V˙ E (ml/min/10 g)

Normothermia 0.13Ϯ0.007 0.17Ϯ0.01 198.70Ϯ8.18 0.087Ϯ0.003 17.33Ϯ1.22 Hyperthermia 0.13Ϯ0.002 0.23Ϯ0.01** 165.82Ϯ5.72* 0.080Ϯ0.002 13.36Ϯ0.72*

BT, body temperature; TI, inspiratory time; TE, expiratory time; f, respiratory frequency; V T, ; V˙ E, minute volume. Values are shown as meanϮSEM (nϭ5). * pϽ0.05 and ** pϽ0.01 vs. value at normothermia (Student’s t-test). head chamber were analyzed with an open-circuit sys- analysis of variance (ANOVA) was used to test for the tem by means of magnetic-type mass spectrometry separate effects of hypoxia and BT on respiratory (ARCO-1000, ARCO System Ltd., Chiba, Japan). variables and for any interaction between these two ef- Metabolic factors were measured while the mouse fects. The Student’s t-test was used to analyze the ef- breathed room air, and the hypoxic gas (7% O2 bal- fects of BT on respiratory variables and aerobic me- anced by N2) was delivered from a mixing chamber tabolism. The t-test was also used to analyze the ef- after an analysis of the O2 (Respina fects of BT and hypoxia on blood gas values with a IH26, San-ei, Tokyo, Japan). O2 consumption (V˙O2, ml commercially available software package (SPSS, STPD) and CO2 excretion (V˙CO2, ml STPD) were de- SPSS Japan Inc., Tokyo, Japan). A statistical signifi- termined and normalized by body weight in kilo- cance was accepted at pϽ0.05. grams. Consecutive data were collected throughout the experiment. Metabolism was examined at nor- RESULTS mothermia and hyperthermia in the same 5 mice. Blood gas analysis. Six mice under normoth- Effects of BT on ventilation during breathing ermia and another 6 mice under hyperthermia were of room air examined while breathing room air and a gas com- Respiratory values obtained during the breathing of posed of 7% O2, respectively. An arterial catheter room air at two BTs are shown in Table 1. At hyper- (BC-1P, Access Technology, IL, USA) for sampling thermia, f and V˙ E decreased significantly with pro- blood was inserted into the right carotid and longed TE in comparison to values at normothermia ligated under anesthesia (sodium pentobarbital, ( f, V˙ E: pϽ0.05; TE: pϽ0.01; Student’s t-test). VT and 25 mg/kg, i.p.). The inserted catheter tube was tun- TI were constant even though BT increased. neled under the neck skin to the back, which was stopped by a luer stub adapter with an injection cap Effects of hypoxic gas inhalation on ventila- (LSA-32, Access Technology, IL, USA). After tion at two different BTs surgery, the mouse was placed in a plastic box Hypoxic gas inhalation immediately increased f, (12ϫ9ϫ5 cm) and given room air for at least 4 h to re- VT, and V˙ E at both BTs, as shown in Fig. 1. All vari- cover from the anesthesia. Every mouse was checked ables reached a peak 2 min after the start of hypoxic for BT and warmed with a heat lamp according to gas inhalation at both BTs. There were significant ef- need. Arterial blood (120 ␮l) was drawn into a he- fects of 7% O2 inhalation on all variables ( f: pϽ0.01; parinized glass tube (MC0020, AVL Scientific Co., VT: pϽ0.001; V˙ E: pϽ0.05; 2-way ANOVA). However, GA, USA) from the catheter tube by removing the at hyperthermia, f and V˙ E were higher than values at stopper described above, then immediately subjected normothermia during hypoxic gas exposure. A signifi- to blood gas analysis (OPTI CCA, AVL Scientific cant BT effect was shown for f and V˙ E during 7% O2 Ϫ Co.) for pH, PaCO2, PaO2, and HCO3 . To compen- inhalation, but it was not detected for VT ( f: sate for the blood loss, 150 ␮l saline was infused pϽ0.001; V˙ E: pϽ0.05; 2-way ANOVA). At normoth- through an injection cap reconnected to the catheter. ermia, f, VT, and V˙ E gradually recovered to slightly One sample was taken while the mouse breathed room higher levels than baseline levels 10 min after the start air, and another was taken 10 min after a switch to hy- of inhalation. poxic gas. All blood samples were analyzed after au- tomatic stabilization in normothermia. Blood sampled V˙ O2 and V˙ CO2 measurements at 39°C was temperature compensated by formula ma- V˙O2, V˙CO2, and BT values measured during the nipulations installed in the analyzer. breathing of room air and 7% O2 at both normother- Statistical analysis. The data are shown as mia and hyperthermia are shown in Table 2. In hyper- meanϮSEM values. A two-way repeated-measure thermia, V˙O2 and V˙CO2 were both significantly lower

Japanese Journal of Physiology Vol. 54, No. 1, 2004 55 M. IWASE et al.

Table 2. Aerobic metabolism in relation to body tem- perature.

Normothermia Hyperthermia

V˙ O2 (ml/kg/min) Room air 55.2Ϯ2.8 38.5Ϯ3.3††

7% O2 26.6Ϯ3.5*** 25.2Ϯ2.9***

V˙ CO2 (ml/kg/min) Room air 41.2Ϯ3.0 32.1Ϯ2.5† † 7% O2 18.6Ϯ1.5*** 26.3Ϯ0.9

BT (°C) Room air 37.3Ϯ0.1 39.0Ϯ0.1†† †† 7% O2 36.9Ϯ0.1 38.8Ϯ0.1

*** pϽ0.001 for the difference between room air and 7% O2. † pϽ0.05 and †† pϽ0.01 for the differences between nor- mothermia and hyperthermia (Student’s t-test). Values are shown as meanϮSEM (nϭ5).

Table 3. Arterial blood gas analysis.

Room air 7% O2

pH Normothermia 7.42Ϯ0.01 7.46Ϯ0.05 Hyperthermia 7.42Ϯ0.01 7.46Ϯ0.03

PaCO2 (mmHg) Normothermia 42.40Ϯ1.15 28.00Ϯ3.28 Hyperthermia 39.73Ϯ1.73 19.30Ϯ0.86*

PaO2 (mmHg) Normothermia 91.31Ϯ1.00 32.01Ϯ0.79 Hyperthermia 99.37Ϯ1.67** 36.28Ϯ1.06* Ϫ HCO3 (mmol/l) Normothermia 27.14Ϯ0.51 17.81Ϯ0.79 Hyperthermia 25.02Ϯ0.76* 13.35Ϯ1.21***

* pϽ0.05, ** pϽ0.01, *** pϽ0.001 for the differences be- tween normothermia and hyperthermia (Student’s t-test). Values are shown as meanϮSEM (nϭ6). Fig. 1. Effects of hypoxia on (a) respiratory frequency (f ), (b) tidal volume (V T), and (c) minute ventilation (V˙ E) Blood gases at normothermia (open circles) and hyperthermia The results of arterial blood gas analysis are shown (closed circles). Abscissa indicates time after the start of in Table 3. During the breathing of room air, pH and inhalation of 7% O2 gas in min; zero represents room air PaCO did not vary between normothermia and hyper- breathing. Data are shown as meanϮSEM. Significant main 2 thermia, showing normocapnia; however, PaO2 was effects of hypoxia were found for all variables under both Ϫ BT (* pϽ0.05; ** pϽ0.01; *** pϽ0.001; 2 way-ANOVA). Sig- higher and HCO3 was lower at hyperthermia than at Ͻ Ͻ nificant BT effect was found for f and V˙ E during 7% O2 gas normothermia (p 0.01 and p 0.05, respectively; inhalation (␸ pϽ0.05; ␸␸␸ pϽ0.001; 2 way-ANOVA). Student’s t-test). Hypoxic gas inhalation decreased Ϫ PaO2, PaCO2, and HCO3 at both BTs, but pH did not than values at normothermia (pϽ0.01 and pϽ0.05, vary. In particular, hypoxic gas inhalation significantly Ϫ respectively; Student’s t-test) under the breathing of decreased PaCO2 and HCO3 at hyperthermia com- Ͻ room air. During the inhalation of 7% O2, V˙O2 at hy- pared to normothermia (p 0.05, Student’s t-test). perthermia was similar to that at normothermia, but ˙ ˙ V˙CO2 was significantly higher at hyperthermia than at Relations between VE and VO2 and between normothermia (pϽ0.05, Student’s t-test). V˙ E and PaCO2 During the breathing of room air, V˙O2 at hyperther-

56 Japanese Journal of Physiology Vol. 54, No. 1, 2004 Respiration at Hyperthermia and Hypoxia ventilation in proportion to the reduction in metabo- lism, maintaining normal PaCO2. During hypoxia, in contrast, hyperthermia increased ventilation more than normothermia with hypoxic hypometabolism, leading to serious hyperventilation. Thermal stress in the pres- ence of hypoxic stress impaired an adjustment of ven- tilation and metabolism. The effects of hyperthermia on ventilation have been investigated in many species. The particular ef- fect is rapid and shallow breathing (referred to as ther- mal polypnea or panting) for heat loss with no major disturbance to alveolar ventilation [16, 17]. Very se- vere heat stress, however, reverses the breathing pat- tern from “rapid and shallow” to “deep and slow.” An example is hyperventilation with severe respiratory al- kalosis in oxen and sheep [18, 19]. It has also been re- ported that BT raised to 40.5–41.5°C produces no sig- nificant respiratory change in conscious rats [20]. In our mice, which are different from these animals, the breathing pattern associated with increased BT was slow without changes in VT; as a result, V˙ E decreased. Furthermore, the decrease of ventilation was accom- panied by a decrease of metabolism. Previous studies in oxen, sheep, and rats, unfortunately, did not esti- Fig. 2. V˙ E plotted against (a) V˙ O2 and (b) PaCO2 at nor- mothermia (squares) and hyperthermia (circles). A 7% mate the metabolism. In general, small animals and gas exposure (filled symbols) and the breathing of room air newborns show a high metabolic rate, which is attrib- (open symbols) are indicated. The dotted line shows the uted to higher thermogenic requirements [21, 22]. In ˙ ˙ Ϯ constant VE–VO2 ratio. Data are shown as mean SEM. the mouse, which is a small animal, the metabolic re- quirements of thermogenesis may be high under nor- mia was lower than at normothermia, and V˙ E was mothermia, which is reduced under the increased BT; lower at hyperthermia in proportion to V˙O2; the V˙ E to therefore, the V˙ E is optimized proportionately. The V˙O2 ratio remained constant, as indicated in Fig. 2a. constant V˙ E–V˙O2 ratio and normal PaCO2 show an ad- Ten min after the start of hypoxia at normothermia, equate adaptation to the altered thermal condition. V˙ E declined. However, V˙ E was relatively high with re- Our paper previously showed that the thermal ef- spect to the decreased V˙O2; therefore the V˙ E to V˙O2 fects of ventilation in mice inspired high CO2 [7, 15]. ratio under hypoxia was higher than that under nor- Hyperthermia increased f and decreased VT to adjust moxia. Thus the mice were hyperventilated during hy- V˙ E, which was different from the present results at the poxia. At hyperthermia, the V˙ E to V˙O2 ratio under hy- breathing of room air. At the breathing of high CO2, poxia was higher than at normothermia. metabolism might not be reduced by hyperthermia be- The relation between V˙ E and PaCO2 is shown in cause V˙ E was not changed between two different BTs. Fig. 2b. At hyperthermia, V˙ E decreased, but PaCO2 re- CO2 affects the central to augment f, mained at a normal level during the breathing of room VT, and V˙ E, which is dominant compared with other air. However, PaCO2 decreased both at normothermia inputs from the higher center. The augmentation of and at hyperthermia during hypoxia. The combined breathing induced by CO2 itself enhances heat loss effects of hyperthermia and hypoxia significantly de- [23]; furthermore, the thermal effect on breathing pat- creased PaCO2. tern follows up with polypnea. Thus under increased BT, the mice showed two different thermoregulatory DISCUSSION controls, an increase of heat loss under and a decrease of thermogenesis under normocapnia, The present study shows the effects of hyperthermia as shown in the present study. on ventilatory and of metabolic responses during nor- The effects of hypoxia on breathing in conscious moxia and acute hypoxia in conscious adult mice. mice were consistent with other awake and anes- Under normoxic conditions, hyperthermia reduced thetized animals [8, 9]. A 7% O2 gas inhalation

Japanese Journal of Physiology Vol. 54, No. 1, 2004 57 M. IWASE et al. caused initial augmentation followed by the inhibition during in mice, which relates to the in- of ventilation and severe hypoxia in which PaO2 was crease in cerebral metabolic rate [28]. That is, hyper- 32.01Ϯ0.79 mmHg under normothermia. Ten min thermia and limited O2 availability as a result of hy- after the start of inhalation, V˙ E and V˙O2 were de- poxia may exacerbate O2 delivery to the mitochondria creased, but the V˙ E was higher than the appropriate in the brain and peripheral tissues. The brain, sus- level for V˙O2, increasing the V˙ E–V˙O2 ratio. Hypoxic tained by vigorous V˙O2, is very sensitive to thermal hypometabolism is known to be more apparent when hypoxia. The continuous hypoxic hypocapnia can in- V˙O2 is high [11]. This condition is found to be greater duce apnea accompanied with brain hypoxia, which in small species and less prominent or possibly absent may cause . Hyperthermia would appear to in adults of larger species [24]. It is observed in new- interrupt the and metabolism. born animals that hyperventilation during acute hy- In conclusion, hyperthermia under normoxia de- poxia is mostly achieved by a drop in V˙O2, regardless creases ventilation in proportion to reduced metabo- of the magnitude of the V˙ E response [22, 25–27]. In lism, therefore maintaining normocapnia in conscious our adult mice, hyperventilation during hypoxia is mice. Hyperthermia under hypoxia causes hyperventi- maintained via a weak and a decreased lation induced by hyperpnea in respect to the de- V˙O2, which is similar with other small species or new- creased V˙O2, leading to hypoxic hypocapnia. Hyper- born animals described earlier. thermia impairs the adjustment of ventilation and me- Hyperthermia under hypoxia facilitates ventilation tabolism when O2 is limited. compared with it being under normothermia; whereas V˙O2 is comparable. Hyperthermia at normoxia reduces This work was supported in part by a Showa University both V˙ E and V˙O2 along the line for the same V˙ E–V˙O2 Grant-in-Aid for Innovative Collaborative Research Projects ratio as shown in Fig. 2a; however, hyperthermia and a Special Research Grant-in-Aid for the Development of Characteristic Education from the Japanese Ministry of ˙ E ˙O under hypoxia reduces neither V nor V 2. Hypoxic Education, Culture, Sports, Science and Technology. hypometabolism is known to lower a thermoregula- tory set point to decrease shivering thermogenesis [10–12]. Under a lowered set point, increased BT is REFERENCES assumed to be higher than the actual BT. That is, mice may perceive thermal stimuli more severely during 1. Eshel G, Safar P, Sassano J, and Stezoski W: Hyper- thermia-induced in dogs and monkeys. hypoxia than during normoxia, leading to an increase 20: 129–143, 1990 of the V˙ E and a continuance of the V˙O2, which may be 2. Stanton AN: Sudden infant death. 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