Influence of core temperature on autoresuscitation during repeated exposure to hypoxia in normal rat pups.

Failure to autoresuscitate by hypoxic gasping during prolonged sleep apnea has been suggested to play a role in sudden infant death. Furthermore, thermal stress brought about by a contribution of infection, overwrapping, or excessive environmental heating has been shown to be associated with an increased risk of sudden infant death, particularly in prone sleeping infants. The present experiments were carried out on newborn rat pups to investigate the influence of "forced" changes in core temperature on their time to last gasp during a single hypoxic exposure and on their ability to autoresuscitate during repeated exposure to hypoxia. On day 5 or 6 postpartum the pups were placed in a temperature-controlled chamber regulated to 33, 35, 37, 39, or 41 degrees C and exposed to a single period of hypoxia (97% N(2)-3% CO(2)) and their time to last gasp was determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnea was determined. Increases in core temperature brought about by changes in ambient temperature from 33 to 41 degrees C decreased the time to last gasp after a single hypoxic exposure and decreased the number of successful autoresuscitations after repeated hypoxic exposures. Thus our data support the hypothesis that forced changes in core temperature brought about by changes in ambient temperature influence protective responses in newborns that may prevent death during hypoxia, as may occur during single or repeated episodes of prolonged sleep apnea.     

Postnatal age influences the ability of rats to autoresuscitate from hypoxic-induced apnea

Failure to autoresuscitate from apnea by gasping has been suggested to have a role in sudden infant death. Little is known, however, about the factors that influence the ability of gasping to sustain life during acute hypoxia in the newborn. The present experiments were carried out on 105 rat pups to investigate the influence of postnatal age on the time to last gasp during a single hypoxic exposure and on the ability to autoresuscitate from primary apnea during repeated hypoxic exposures. On days 1-2, 5-6, 10-11, 15-16, and 19-20 postpartum, each pup was placed into a temperature-controlled chamber regulated to 37 +/- 1 degrees C and was exposed either to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2)-3% CO(2)), and the time to last gasp was determined, or repeated exposure to hypoxia was performed, and the ability to autoresuscitate from primary apnea was determined. Increases in postnatal age decreased the time to last gasp following a single hypoxic exposure and decreased the number of successful autoresuscitations following repeated hypoxic exposures. Thus our data provide evidence that postnatal age influences protective responses that may prevent death during hypoxia as may occur during episodes of prolonged sleep apnea.     

Influence of adenosine A(1)-receptor blockade and vagotomy on the gasping and heart rate response to hypoxia in rats during early postnatal maturation.

Failure to autoresuscitate from apnea has been suggested to play a role in sudden infant death. Little is known, however, about factors that influence the gasping and heart rate response to severe hypoxia that are fundamental to successful autoresuscitation in the newborn. The present experiments were carried out on 184 rat pups to investigate the influence of the parasympathetic nervous system, as well as adenosine, in mediating the profound bradycardia that occurs with the onset of hypoxic-induced primary apnea and in modulating hypoxic gasping. On days 1 to 2, days 5 to 6, and days 10 to 11 postpartum and following bilateral cervical vagotomy (VAG) or administration of a selective adenosine A(1) receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine; DPCPX), each pup was exposed to a single period of severe hypoxia produced by breathing an anoxic gas mixture (97% N(2)-3% CO(2)). Exposure to severe hypoxia resulted in an age-dependent decrease in heart rate (P < 0.001), accentuated with increasing postnatal age, that was attenuated in all age groups by DPCPX but not by VAG. Furthermore, DPCPX but not VAG decreased the time to last gasp but increased the total number of gasps in the 1- to 2-day-old and 5- to 6-day-old pups but not in the 10- to 11-day-old pups during exposure to severe hypoxia. Thus our data provide evidence that adenosine acting via adenosine A(1) receptors plays a role in modulating hypoxic gasping and in mediating the profound bradycardia that occurs coincident with hypoxic-induced primary apnea in rats during early postnatal life.     

Mechanisms underlying induced autoresuscitation failure in BALB/c and SWR mice.

Mechanisms underlying failure of autoresuscitation from hypoxic apnea were investigated. Failure was induced by repeated exposure to hypoxia. The influence of maturation was studied in adults, weanlings, and 10- and 5-day-old mice. Mice successful at autoresuscitation (BALB/c) as well as those prone to autoresuscitation failure (SWR weanlings) were studied. Hypoxic apnea was induced with 97% N2-3% CO2, and 21% O2 was given at its onset; electrocardiogram and ventilation were recorded. Hypoxic exposure was repeated if autoresuscitation (recovery of eupnea) occurred. Autoresuscitation failure (death) was induced in all mice. Young BALB/c mice tolerated more trials than older mice. SWR weanlings frequently failed to autoresuscitate on the initial exposure and tolerated fewer repeat trials overall than age-matched BALB/c mice. Induced autoresuscitation failure in all mice appeared to be unrelated to gasping regulation, because both gasp number and amplitude were similar during the failed trial and the previous successful trial. In most mice, failure was associated with absent recovery of heart rate during gasping. In BALB/c mice in particular, this persistent bradycardia was usually due to heart block, which occurred in 95% of failed trials. In addition, heart block occurred with increasing frequency on later successful trials, but conversion to sinus rhythm always preceded successful autoresuscitation. Heart block was also frequent in SWR mice and had similar consequences. BALB/c mice exposed to continuous anoxia survived longer than SWR mice, indicating increased endurance of components of the autoresuscitation mechanism not directly related to the ventilatory function of gasping (e.g., cardiovascular components).(ABSTRACT TRUNCATED AT 250 WORDS)     

Failure of autoresuscitation in weanling mice: significance of cardiac glycogen and heart rate regulation.

"Autoresuscitation" (AR) is the spontaneous recovery from hypoxic apnea by gasping. We examined aspects of heart function in two situations: 1) the maturationally acquired failure of AR that is characteristic of SWR, but not BALB/c, weanling mice and 2) AR failure in BALB/c mice induced by repeated exposures to anoxia. We determined maturational changes in heart and liver glycogen. Unlike liver glycogen levels, heart glycogen levels in SWR mice differed from those in BALB/c mice. They were consistently much lower throughout maturation and reached a nadir during the brief period when SWR weanling mice are vulnerable to AR failure. Also, rate of cardiac glycogen utilization in vulnerable SWR mice was lower than that of same-aged BALB/c mice and was nil during the latter one-half of the gasping stage when heart function is critical for AR success. Therefore, because glycogen utilization reflects cardiac work, heart failure could explain AR failure in SWR weanlings. Additionally, the increase in hypoxic heart rate that occurs with maturation is developmentally delayed in SWR mice, and this may contribute to their AR failure. Cardiac glycogen was not fully depleted in BALB/c mice during repeated anoxic exposures, indicating other reasons for AR failure. We view these findings as a potential model for the age-related peak in incidence of sudden infant death syndrome.     

Prior exposure to hypoxic-induced apnea impairs protective responses of newborn rats in an exposure-dependent fashion: influence of normoxic recovery time.

Experiments were carried out to determine whether prior exposure to hypoxic-induced apnea impairs protective responses of newborn rats. Ninety-five, 5- to 6-day-old rat pups were instrumented for respiratory measurements and placed prone in a metabolic chamber regulated to 37.0 degrees C. The time to first and last gasp as well as the number of gasps were determined on exposure to unrelenting hypoxia after each pup had experienced 0, 1, 2, 3, 4, 9, or 14 hypoxic-induced apnea/autoresuscitation cycles (HIA/AR) at 5-min intervals. Prior exposure to HIA/AR did not significantly alter the time to first gasp, but it decreased the time to last gasp after two HIA/AR and the number of gasps after three HIA/AR on exposure to unrelenting hypoxia. When the normoxic recovery time after 9 HIA/AR was varied from 5 to 120 min, the time to last gasp as well as the total number of gasps increased on exposure to unrelenting hypoxia but only at 120 min (i.e., the number of gasps was similar but the time to last gasp was still decreased compared with that observed in naive animals exposed to unrelenting hypoxia). Thus prior exposure to hypoxic-induced apnea as may occur during obstructive sleep apnea or positional asphyxia decreases the number and duration of potential autoresuscitation producing gasps on exposure to unrelenting hypoxia for a period of up to and exceeding 120 min, respectively. The mechanism by which prior exposure to hypoxic-induced apnea influences the duration and number of hypoxic-induced gasps is unknown.     

Mechanism of failure of recovery from hypoxic apnea by gasping in 17- to 23-day-old mice.

The mechanism of failure of autoresuscitation from hypoxic apnea in 17- to 23-day-old (weanling) Swiss Webster related/J mice was investigated by recording electrocardiogram (ECG) and ventilation in adult, weanling, and 11-day-old mice. Hypoxic apnea was induced with 97% N2-3% CO2. O2 (21% or 50% O2) or 97% N2-3% CO2 was given at the onset of apnea. The ECG showed no arrhythmias predictive of failure of autoresuscitation. The first indication of failure was a progressive fall in gasp volume ("run down"). This pattern also occurred in animals given continuous 97% N2-3% CO2 and was significantly different from that in mice that survived. Gasping duration in 97% N2 was longer in weanlings than adults but shorter than in 11 day olds. Respiratory and heart rate recovery were more rapid in adults than in weanlings. Although recovery in high O2 was more rapid, the survival rate was not increased. The lack of effect of high O2 on survival and the virtually identical pattern of gasping in mice dying in 97% N2 and air leads us to conclude that in mice that fail to autoresuscitate little or no O2 reaches the medullary respiratory centers. We speculate that this may be due to increased vulnerability of cardiac muscle to anoxia in 17- to 23-day-old mice, resulting in early and severe heart failure.     

Gasping Generation in Developing Swiss–Webster Mice In Vitro and In Vivo

During hypoxia the respiratory network produces gasping in vivo and in vitro. To understand the mechanisms involved in such response and to validate in vitro findings, correlative studies are necessary. During perinatal age gasping generation is robust and then declines during postnatal development, possibly due to changes in either the rhythm generator (the pre-Bötzinger complex, PBC) and/or its motor outputs. We tested this hypothesis by recording respiratory response to hypoxia in vivo and in vitro during postnatal development. We found that postnatal age influences: (1) The hypoxia-induced pattern change in the PBC bursts, (2) The coupling between the PBC and the XII nucleus during prolonged hypoxia and (3) The ability of mice to gasp and autoresuscitate from hypoxic conditions. We conclude that the inability of mice to gasp during late postnatal development might be determined by a progressive uncoupling between the respiratory rhythm generator and its motor outputs in hypoxia.     

Gasping and autoresuscitation in the developing rat: effect of antecedent intermittent hypoxia.

Gasping is a critically important mechanism for autoresuscitation and survival during extreme tissue hypoxia. Evidence of antecedent hypoxia in sudden infant death syndrome suggests that intermittently occurring hypoxic episodes may modify gasping and autoresuscitation. To examine this issue, an intermittent hypoxia (IH) profile consisting of alternating room air and 10% O(2)-balance N(2) every 90 s was applied to pregnant Sprague-Dawley rats (IHRA; n = 50) and to pups after a normal pregnancy (RAIH; n = 50) as well as to control pups (RARA; n = 50). At postnatal day 5, pups were exposed to 95% N(2)-5% CO(2), and gasping and the ability to autoresuscitate were assessed. Compared with RARA, IHRA- and RAIH-exposed pups had a reduced number of gasps, decreased overall gasp duration, and were less likely to autoresuscitate on introduction of room air to the breathing mixture during the last phase of gasping (P < 0.001 vs. RARA). We conclude that both prenatal and early postnatal IH adversely affect gasping and related survival mechanisms.     

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.     

Effects of increase in body temperature on the breathing pattern in premature infants

This study was designed to determine the effects of a mild increase in body temperature within the physiological range (0.8 degrees C) in healthy premature infants. Seven unsedated premature infants (38.4 wk +/- 1.5 postconceptional age) were monitored polygraphically during "morning naps" in an incubator under two different environmental temperatures: (1) normothermia with the incubator temperature set at 25 degrees C and the rectal temperature equal to 36.9 degrees C +/- 0.1; (2) hyperthermia with the incubator temperature set at 35 degrees C and the rectal temperature equal to 37.7 degrees C +/- 0.15. Respiratory frequency and heart rate, respiratory events, i.e., central and obstructive apnea, and periodic breathing with and without apneic oscillations were tabulated. Results for respiratory events were expressed as (1) indices of the total number of respiratory events, and of specific respiratory events per hour of total, quiet and active sleep times; (2) duration of total and specific respiratory events expressed as a percentage of total sleep, quiet and active sleep times. Respiratory frequency and heart rate were significantly increased by hyperthermia (P less than 0.05). Hyperthermia did not significantly modify the indices or the duration of central and obstructive apnea. But the indices and the duration of periodic breathing with and without apneic oscillations were significantly increased by hyperthermia during active sleep (P less than 0.05) but not during quiet sleep. The present study shows that a mild increase in body temperature within the physiological range in premature infants enhances the instability of the breathing pattern during active sleep.     

The effect of hyperglycemia on the tumor response to irradiation given alone or in combination with hyperthermia

The effect of hyperglycemia (elevated blood glucose level) on the response of a murine tumor to irradiation given alone or in combination with hyperthermia was studied. Tumors were early generation isotransplants of a spontaneous C3H/Sed mouse fibrosarcoma, FSa-II. Single-cell suspensions were transplanted into the foot, and irradiation was given when each tumor reached an average diameter of 7 mm. Following irradiation, the tumor growth time to reach 1000 mm3 was studied and the dose-response curve between the tumor growth time and radiation dose was fitted. Preadministration of glucose increased the size of the hypoxic and chronically hypoxic cell fractions without altering the slope of the dose-response curve where the chronically hypoxic cell fraction is determined as the fraction of cells which were not oxygenated under hyperbaric oxygen conditions. Hyperthermia given prior to irradiation enhanced the tumor response to irradiation, but simultaneously increased the size of the hypoxic and chronically hypoxic cell fractions. Similar results were observed following hyperthermia given after irradiation. When hyperthermia at 43.5 degrees C was given 24 h before irradiation, the size of the hypoxic cell fraction increased with increasing treatment time, while a substantial decrease in the chronically hypoxic cell fraction was observed. Administration of glucose 60 min before hyperthermia further increased the size of the hypoxic cell fraction. Possible mechanisms explaining why glucose administration increases the hypoxic cell fractions are discussed.     

Hering-Breuer reflex in conscious newborn rats: effects of changes in ambient temperature during hypoxia.

In a previous study in conscious normoxic newborn rats, we found that the strength of the Hering-Breuer reflex (HB reflex) was greater (188%) at high (36 degrees C) than at low (24 degrees C) ambient temperature (T(a); D. Merazzi and J. P. Mortola. Pediatr. Res. 45: 370-376, 1999). We now asked what the effect would be of changes in T(a) during hypoxia. Rat pups at 3-4 days of age were studied in a double-chamber airflow plethysmograph. The HB reflex was induced by negative body surface pressures of 5 or 10 cmH(2)O and quantified from the inhibition of breathing during maintained lung inflation. Rats were first studied at T(a) = 32 degrees C in normoxia, followed by hypoxia (10% O(2) breathing). During hypoxia, oxygen consumption (VO(2)) averaged 47%, and HB reflex 115%, of the corresponding normoxic values, confirming that in the newborn, differently from the adult, hypoxia does not decrease the strength of the HB reflex. As hypoxia was maintained, lowering T(a) to 24 degrees C or increasing it to 36 degrees C, on average, had no significant effects on VO(2) and the HB reflex. However, with 5-cmH(2)O inflations, the HB reflex during the combined hypoxia and hyperthermia was significantly stronger than in normoxia. We conclude that in conscious newborn rats during normoxia the T(a) sensitivity of the HB reflex is largely mediated by the effects of T(a) on thermogenesis and VO(2); in hypoxia, because thermogenesis is depressed and VO(2) varies little with T(a), the HB reflex is T(a) independent. The observation that the reflex response to lung inflations during hypoxic hyperthermia can be greater than in normoxia may be of importance in the pathophysiology of apneas during the neonatal period.     

Perinatal nicotine exposure impairs ability of newborn rats to autoresuscitate from apnea during hypoxia

Failure toautoresuscitate by hypoxic gasping during prolonged sleep apnea hasbeen suggested to play a role in sudden infant death. Furthermore,maternal smoking has been repeatedly shown to be a risk factor forsudden infant death. The present experiments were carried out onnewborn rat pups to investigate the influence of perinatal exposure tonicotine (the primary pharmacological and addictive agent in tobacco)on their time to last gasp during a single hypoxic exposure and ontheir ability to autoresuscitate during repeated exposure to hypoxia.Pregnant rats received either nicotine (6 mg · kg¹ · 24 h¹) or vehiclecontinuously from day 6 of gestationto days 5 or 6 postpartum via an osmotic minipump.On days 5 or6 postpartum, pups were exposed eitherto a single period of hypoxia (97%N₂-3% CO₂) and their time to last gaspwas determined, or they were exposed repeatedly to hypoxia and theirability to autoresuscitate from primary apnea was determined. Perinatalexposure to nicotine did not alter the time to last gasp, but it didimpair the ability of pups to autoresuscitate from primary apnea. Aftervehicle, the pups were able to autoresuscitate from 18 ± 1 (SD)periods of hypoxia, whereas, after nicotine, the pups were able toautoresuscitate from only 12 ± 2 periods(P < 0.001) of hypoxia. Thus ourdata provide evidence that perinatal exposure to nicotine impairs the ability of newborn rats to autoresuscitate from primary apnea duringrepeated exposure to hypoxia, such as may occur during episodes ofprolonged sleep apnea.

     

The process of cardiorespiratory autoresuscitation in intact newborn rats

To examine the process of spontaneous autoresuscitation and the recovery of the hypoxic ventilatory response (HVR) after prolonged anoxia, we monitored respiratory frequency (f, by body plethysmography) and heart rate (HR, by ECG) in intact newborn rats (n = 12, day 2-4) before, during, and after 100% N2 exposure. The rat before anoxia showed signs of HVR: f changes at acute hypoxia (10% O2) and hyperoxia (100% O2). During anoxia, the spontaneous respiratory movement "gasping" appeared for 21 min (mean). At O2 restoration (with 100% O2), gasping stopped and no respiratory flow was detected for 1 min. One rat failed to autoresuscitate and had heart arrhythmia during the transient apnea, but 11 rats recovered respiration after the HR acceleration. Despite the successful autoresuscitation, the rats did not show HVR at 10 min into the recovery period and the recovery of HVR required more than 30 min. The results indicate that O2 inhalation is useful to trigger autoresuscitation even when the rat has already been in a state of profound hypoxic depression, but the rat becomes transiently insensitive to HVR after autoresuscitation. We estimate that reform of the respiratory control system in newborn rats is not yet firmly established to track HVR early in the recovery phase after prolonged anoxia.     

Ionotropic excitatory amino acid receptors in pre-Botzinger complex play a modulatory role in hypoxia-induced gasping in vivo.

Activation of ionotropic excitatory amino acid (EAA) receptors in pre-B?tzinger complex (pre-B?tC) not only influences the eupneic pattern of phrenic motor output but also modifies hypoxia-induced gasping in vivo by increasing gasp frequency. Although ionotropic EAA receptor activation in this region appears to be required for the generation of eupneic breathing, it remains to be determined whether similar activation is necessary for the production and/or expression of hypoxia-induced gasping. Therefore, we examined the effects of severe brain hypoxia before and after blockade of ionotropic EAA receptors in the pre-B?tC in eight chloralose-anesthetized, deafferented, mechanically ventilated cats. In each experiment, before blockade of ionotropic EAA receptors in the pre-B?tC, severe brain hypoxia (6% O2 in a balance of N2 for 3-6 min) produced gasping. Although bilateral microinjection of the broad-spectrum ionotropic EAA receptor antagonist kynurenic acid (20-100 mM; 40 nl) into the pre-B?tC eliminated basal phrenic nerve discharge, severe brain hypoxia still produced gasping. Under these conditions, however, the onset latency to gasping was increased (P < 0.05), the number of gasps was reduced for the same duration of hypoxic gas exposure (P < 0.05), the duration of gasps was prolonged (P < 0.05), and the duration between gasps was increased (P < 0.05). These findings demonstrate that hypoxia-induced gasping in vivo does not require activation of ionotropic EAA receptors in the pre-B?tC, but ionotropic EAA receptor activation in this region may modify the expression of the hypoxia-induced response. The present findings also provide additional support for the pre-B?tC as the primary locus of respiratory rhythm generation.     

Seasonal changes in the preferred body temperature, cardiovascular, and respiratory responses to hypoxia in the toad, Bufo paracnemis

Estivation is accompanied by a reduction of oxygen consumption in amphibians during drought. We tested the hypothesis that, during the dry season, the toad Bufo paracnemis selects a lower preferred body temperature (T(b)), and would be less sensitive to hypoxia, than during its active period. Therefore, during winter (dry season in S?o Paulo state, Brazil) and summer, we measured the effects of hypoxia (7% inspired O(2)) on preferred T(b). Additionally, pulmonary ventilation, heart rate, blood pressure, and oxygen consumption were also measured in toads at 15 and 25 degrees C. Blood gases were measured at 25 degrees C. Oxygen consumption was significantly higher during summer in toads at 25 degrees C. Under normoxia, preferred T(b) was higher during summer than during winter, and hypoxia caused a drop in preferred T(b) during both seasons. In both seasons, toads at 15 degrees C showed reduced pulmonary ventilation, heart rate, and blood pressure, and hypoxia had no effect. At 25 degrees C during summer only, hypoxia caused an increase in ventilation. Season had no effect on blood gases. We conclude that B. paracnemis displays an endogenous seasonal pattern of thermoregulation and control of ventilation. The decreased preferred T(b) and the physiological responses to hypoxia may be beneficial to toads encountering drought and when food is not available.     

Lack of histamine type-1 receptors impairs the thermal response of respiration during hypoxia in mice (Mus musculus)

Thermoregulation and the hypoxic ventilatory response are modulated by histamine type-1 (H1) receptors in the brain. In this study, we tested the hypothesis that activation of H1 receptors is required for the thermal control of ventilation during normoxia and hypoxia, using conscious male wild-type and H1 receptor-knockout (H1RKO) mice (Mus musculus). Under normoxic conditions, hyperthermia (39 degrees C) decreased minute ventilation (V (E)) and oxygen consumption [Formula: see text] in both genotypes, suggesting that H1 receptors are not involved in thermal ventilatory control during normoxia. Pa(CO2) was unchanged in both hyperthermia and normothermia, suggesting that the thermal decrease in V (E) is optimized by metabolic demand. Acute hypoxic gas exposure (7% O(2)+3% CO(2) in N(2)) increased, and then decreased, V (E) in wild-type mice; this increase was augmented and sustained by hyperthermia. Hypoxic gas exposure reduced [Formula: see text] and [Formula: see text] in wild-type mice at both body temperatures; the reduced [Formula: see text] during combined hyperthermia and hypoxia was higher than during normothermia and hypoxia. In H1RKO mice, hyperthermia did not augment the V (E) response to hypoxia, and did not affect [Formula: see text] and [Formula: see text] during hypoxia. In conclusion, histamine participates in the thermal increase of ventilation during hypoxia by activating H1 receptors.     

The effects of hyperthermia and hypoxia on ventilation during low-intensity steady-state exercise

This study assessed whether the elevated sensitivity of ventilation to hypoxia during exercise is accounted for by an elevation of esophageal temperature (T(es)). Eleven males volunteered for two exercise sessions on an underwater, head-out cycle ergometer at a steady-state rate of oxygen consumption (V(.)(O(2))) of approximately 0.87 l/min (SD 0.07). In one exercise session, 31.5 degrees C (SD 1.4) water held T(es) at a normothermic level of approximately 37.1 degrees C, and in the other exercise session, water at 38.2 degrees C (SD 0.1) maintained a hyperthermic T(es) of approximately 38.5 degrees C. After a 30-min rest and 20-min warm-up, exercising participants inhaled air for 10 min [Euoxia 1 (E1)], an isocapnic hypoxic gas mixture with 12% O(2) in N(2) (H1) for the next 10 min and air again [Euoxia 2 (E2)] for the last 10 min. A significant increase in V(.)(E) during all hyperthermia conditions (0.01< P < 0.048) was evident; however, during hyperthermic hypoxia, there was a disproportionate and significant (P = 0.017) increase in V(.)(E) relative to normothermic hypoxia. This was the main explanation for a significant esophageal temperature and gas type interaction (P = 0.012) for V(.)(E). Significant effects of hyperthermia, isocapnic hypoxia, and their positive interaction remained evident after removing the influence of (V(.)(O(2))) on V(.)(E). Serum lactate and potassium concentrations, as well as hemoglobin oxygen saturation, were each not significantly different between normothermic and hyperthermic-hypoxic conditions. In conclusion, the elevated sensitivity of exercise ventilation to hypoxia during exertion appears to be modulated by elevations in esophageal temperature, potentially because of a temperature-mediated stimulation of the peripheral chemoreceptors.     

Effect of nitric oxide synthase inhibition on regional blood flow during hyperthermia

The loss of compensatory splanchnic vasoconstriction during hyperthermia was assessed in rats after administration of either 0, 10, 30, or 100mg/kg N(w)-nitro-L-arginine methyl ester,L-NAME. Rectal temperature (T(re)), heart rate (HR), mean arterial blood pressure (MAP), breathing frequency (BF), and renal, mesenteric and caudal blood flows (Q(R), Q(M) and Q(C)) were measured until irreversible cardiovascular collapse occurred. HR, MAP and BF increased as T(re) rose to 42 degrees C, then fell as circulatory collapse occurred. As dose increased T(re) at collapse decreased. Q(M) decreased until a T(re) of 41.5-42 degrees C and then increased. Q(R) and Q(C) were unaffected by either hyperthermia orL-NAME. Inhibition of NO synthase did not prevent the circulatory collapse of heatstroke; the higher doses ofL-NAME may have exacerbated the onset of circulatory failure.