Effects of fasting on hypoxic ventilatory responses and the contribution of histamine H1 receptors in mice

We tested the hypothesis that fasting affects hypoxic ventilatory responses through metabolic changes via histamine H1 receptors. Wild-type (WT) and histamine H1 receptor knockout (H1RKO) mice were studied in fed and fasted states. In the fed WT, hypoxic-gas exposure elicited an increase and a subsequent decline in ventilation (hypoxic ventilatory decline or HVD). HVD was influenced by fasting in breathing pattern with metabolic rate. Fasting elicited hypoglycemia, a drop in R, and increases in free fatty acid and ketone bodies in the serum. In H1RKO, HVD was blunted in the fed state, but it appeared in the fasted state. There was a minimal drop in R following fasting and a low triglyceride concentration. Thus, fasting affects HVD through a change in energy mobilization from glucose to lipid metabolism. Histamine H1 receptors are involved in HVD during fed and fasted states, resulting in adaptation to the environmental conditions.     

Contribution of histamine type-1 receptor to metabolic and behavioral control of ventilation

Histaminergic neurons in the hypothalamus are well documented as being involved in the control of autonomic functions, such as the balance of energy metabolism and circadian rhythm. We tested the hypothesis that an activation of the histamine type-1 (H1) receptor is required for the control of ventilation during the course of a day in free-moving mice. Ventilation, aerobic metabolism, and electroencephalogram were measured by a whole-body-plethysmograph, a magnetic-type mass spectrometry system, and a telemetry system, respectively, in H1 receptor-knockout (H1RKO) and wild-type mice. Both genotypes showed daily oscillations in minute ventilation (V(E)) and oxygen consumption (VO(2)), with greater values during the dark period compared to the light period. In the latter, H1RKO mice showed increased V(E) and CO(2) excretion (VCO(2)) relative to wild-type mice, and V(E) was comparable to the VCO(2) increase. However, there was no change in VO(2) in H1RKO mice, suggesting that differences in VCO(2) between genotypes are responsible for differences in V(E) during the light period. During the dark period, VCO(2) was elevated in H1RKO mice compared with WT mice. Because there was no difference in V(E), the ratio of V(E) to VCO(2) was reduced in H1RKO mice. Electroencephalogram results suggested that this might be due to a depressed arousal state in H1RKO mice because the ratio of delta to theta band power spectrum densities was greater in H1RKO mice than in wild-type mice. We concluded that histamine modulates ventilation by affecting metabolism and arousal state via H1 receptors.     

Central histamine contributes to the inspiratory off-switch mechanism via H1 receptors in mice

Central histaminergic neurons are distributed in areas of the medulla and pons concerned with respiratory rhythm generation, but their effects on breathing pattern are unknown. We examined breathing pattern during hypercapnic responses in wild type (WT) and H1 receptor knockout (H1RKO) mice at 9-10 weeks of age before and after vagotomy. Minute ventilation increased with PaCO(2) increase equally in both genotypes; respiratory rate response was lower and tidal volume (V(T)) response higher in H1RKO mice than in WT mice. The V(T)-inspiratory time (T(I)) relation during hypercapnia was hyperbolic in both groups, with the curve in H1RKO mice shifted right-upward. After vagotomy, the V(T)-T(I) relation was a vertical line, which shifted right in H1RKO mice. We conclude that alterations of inspiratory off-switch and respiratory rhythm generation change breathing pattern without affecting central chemosensitivity in H1RKO. Histamine might affect breathing pattern centrally via H1 receptors.     

Increased hypoxic ventilatory response during 8 weeks at 3800 m altitude

Acclimatization to chronic hypoxia (CH) increases ventilation (V(I)) and the isocapnic hypoxic ventilatory response (HVR) over 2-14 days but hypoxic desensitization blunts the HVR after years of CH. We tested for hypoxic desensitization during the first 2 months of CH by studying five normal subjects at sea level (SL) and for 8 weeks at 3800 m (CH, PI(O(2)) approximately 90 Torr). We measured the isocapnic HVR (Delta V(I)/Delta Sa(O(2)) and tested for hypoxic ventilatory decline (HVD) by stepping Sa(O(2)) to 80% after 14 min at 90%. The HVR increased significantly after 2 days and remained significantly elevated for 8 weeks of CH. HVD was similar at SL and during 8 weeks of CH. Hence, hypoxic desensitization of the HVR does not occur after only 8 weeks of hypoxia and the increased HVR during this time does not involve changes in HVD.     

Ventilatory response to acute hypoxia in transgenic mice over-expressing erythropoietin: effect of acclimation to 3-week hypobaric hypoxia

We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.     

Multi-organ system model of O2 and CO2 transport during isocapnic and poikilocapnic hypoxia

A multi-organ systems model of O(2) and CO(2) transport is developed to analyze the control of ventilation and blood flow during hypoxia. Among the aspects of the control processes that this model addressed are possible mechanisms responsible for the second phase of the ventilatory hypoxic response to mild hypoxia, i.e., hypoxic ventilatory decline (HVD). Species mass transport processes are described by compartmental mass balances in brain, heart, skeletal muscle, and "other tissues" connected in parallel via the circulation. In pulmonary and systemic capillaries and in the vasculature connecting the systemic tissues, species transport processes are represented by a one-dimensional, convection-dispersion model. The effects of bicarbonate acid-base buffering, hemoglobin, and myoglobin on the transport processes are included. The model incorporates feedback control mechanisms through a cardiorespiratory control system in which peripheral and central chemoreceptors sense O(2) and CO(2) partial pressures. Model simulations of the ventilatory responses to isocapnic and poikilocapnic hypoxia show two phases with distinct dynamics. A fast phase is discernable immediately after switching from normoxic to hypoxic conditions, while a delayed slow phase (HVD) typically becomes manifested after several minutes. Model simulations allow quantitative evaluation of several proposed mechanisms to account for HVD. Under isocapnic hypoxia, simulations indicate that an increase in brain blood flow has no effect on HVD, but that HVD can be entirely described by central ventilatory depression (CVD). Under poikilocapnic hypoxia, the hypocapnia caused by hypoxic hyperventilation has no effect on HVD.     

Lack of involvement of μ1 opioid receptors in dermorphin-induced inhibition of hypoxic and hypercapnic ventilation in rat pups

The effects of dermorphin, a mu-selective opioid agonist, on respiratory responses to altered O(2) and CO(2) during postnatal development were investigated in conscious, unrestrained Wistar rats aged 2-21 days. Respiration was recorded by barometric plethysmography. Dermorphin (4 mg kg(-1)) was administered subcutaneously, and the ventilatory responses to hypoxia (11% O(2), 89% N(2)) in 2-21-day-old pups and hyperoxia (100% O(2)), and hypercapnia (8% CO(2), 92% O(2)) in 2-13-day-old pups were assessed in the presence and absence of the mu(1) receptor antagonist naloxonazine (10 mg kg(-1) s.c.) administered 1 day before testing. Six minutes of hypoxia increased ventilation in all age groups, largely via an increase in frequency. Dermorphin inhibited the ventilatory response to hypoxia, and this inhibition was insensitive to naloxonazine. After 5 min of hyperoxia, ventilation was the same as with air breathing except in the presence of dermorphin, when hyperoxic ventilation was depressed by a naloxonazine-insensitive decrease in frequency. Following this 5 min 100% O(2) exposure, pups were exposed to hypercapnia, and respiratory parameters were measured 5 min later. The ventilatory response to CO(2) was inhibited by dermorphin in a naloxonazine-insensitive manner. There was no evidence for endogenous mu(1) receptor modulation of the ventilatory responses to altered gases in rat pups of any age. Thus, mu opioid-induced inhibition of the hypoxic and hypercapnic responses in young rats does not occur via activation of mu(1) opioid receptors.     

Lack of involvement of mu(1) opioid receptors in dermorphin-induced inhibition of hypoxic and hypercapnic ventilation in rat pups

The effects of dermorphin, a mu-selective opioid agonist, on respiratory responses to altered O(2) and CO(2) during postnatal development were investigated in conscious, unrestrained Wistar rats aged 2-21 days. Respiration was recorded by barometric plethysmography. Dermorphin (4 mg kg(-1)) was administered subcutaneously, and the ventilatory responses to hypoxia (11% O(2), 89% N(2)) in 2-21-day-old pups and hyperoxia (100% O(2)), and hypercapnia (8% CO(2), 92% O(2)) in 2-13-day-old pups were assessed in the presence and absence of the mu(1) receptor antagonist naloxonazine (10 mg kg(-1) s.c.) administered 1 day before testing. Six minutes of hypoxia increased ventilation in all age groups, largely via an increase in frequency. Dermorphin inhibited the ventilatory response to hypoxia, and this inhibition was insensitive to naloxonazine. After 5 min of hyperoxia, ventilation was the same as with air breathing except in the presence of dermorphin, when hyperoxic ventilation was depressed by a naloxonazine-insensitive decrease in frequency. Following this 5 min 100% O(2) exposure, pups were exposed to hypercapnia, and respiratory parameters were measured 5 min later. The ventilatory response to CO(2) was inhibited by dermorphin in a naloxonazine-insensitive manner. There was no evidence for endogenous mu(1) receptor modulation of the ventilatory responses to altered gases in rat pups of any age. Thus, mu opioid-induced inhibition of the hypoxic and hypercapnic responses in young rats does not occur via activation of mu(1) opioid receptors.     

Activation of NMDA receptors prevents excessive metabolic decrease in hypoxic rat pups

We tested the hypothesis that glutamate NMDA receptors may help maintain metabolic rate and body temperature during acute or chronic hypoxic exposure in newborn rats. We recorded ventilation, metabolism ((.)V(O(2)) -- ((.)V(CO(2)) and rectal temperature, under normoxia, acute hypoxia (30 min -- 12% O(2)), or following 10 days of chronic hypoxia, in 10 days old male and female rats, receiving saline i.p. injection or the NMDA receptor antagonist MK-801. Acute hypoxia decreased rectal temperature and metabolism, and increased ventilation, and (.)V(E)/((.)V(O(2) and (.)V(E)/((.)V(CO(2) to the same extent in males and females. MK-801 injection amplified the metabolic decrease under acute (in males and females) and chronic (in males) hypoxia, prevented the increase of minute ventilation, while (.)V(E)/((.)V(O(2) or (.)V(E)/((.)V(CO(2)remained constant. Hence, NMDA glutamate receptors help to maintain metabolic rate, minute ventilation and body temperature at a determined level in acute (males and females) and chronic hypoxia (males only).     

Interaction between defects in ventilatory and thermoregulatory control in mice lacking 5-HT neurons

We have previously shown that mice with near-complete absence of 5-HT neurons (Lmx1bf/f/p) display a blunted hypercapnic ventilatory response (HCVR) and impaired cold-induced thermogenesis, but have normal baseline ventilation (), core body temperature (TCore) and hypoxic ventilatory responses (HVR) at warm ambient temperatures (TAmb; 30 degrees C). These results suggest that 5-HT neurons are an important site for integration of ventilatory, metabolic and temperature control. To better define this integrative role, we now determine how a moderate cold stress (TAmb of 25 degrees C) influences ventilatory control in adult Lmx1bf/f/p mice. During whole animal plethysmographic recordings at 25 degreesC, baseline , metabolic rate , and TCore of Lmx1bf/f/p mice were reduced (P < 0.001) compared to wild type (WT) mice. Additionally, the HCVR was reduced in Lmx1bf/f/p mice during normoxic (-33.1%) and hyperoxic (-40.9%) hypercapnia. However, in Lmx1bf/f/p mice was equal to that in WT mice while breathing 10% CO2, indicating that non-5-HT neurons may play a dominant role during extreme hypercapnia. Additionally, ventilation was decreased during hypoxia in Lmx1bf/f/p mice compared to WT mice at 25 degrees C due to decreased TCore. These data suggest that a moderate cold stress in Lmx1bf/f/p mice leads to further dysfunction in ventilatory control resulting from failure to adequately maintain TCore. We conclude that 5-HT neurons contribute to the hypercapnic ventilatory response under physiologic, more than during extreme levels of CO2, and that mild cold stress further compromises ventilatory control in Lmx1bf/f/p mice as a result of defective thermogenesis.     

Ventilatory responses to isocapnic and poikilocapnic hypoxia in humans

We examined the hypoxic ventilatory response (HVR) including breathing frequency (f(R)) and tidal volume (V(T)) responses during 20 min of step isocapnic (IH) and poikilocapnic (PH) hypoxia (45 Torr). We hypothesized an index related to [Formula: see text] (pHPR) may be more robust during PH. Peak HVR was suppressed during PH (P<0.001), and mediated by V(T) during PH and both V(T) and f(R) during IH. The relative magnitude of HVD remained similar between conditions indicating a suppressive role of hypocapnia in development of the HVR unrelated to the degree of subsequent HVD, implying a primarily O(2) dependant mechanism. Post-hypoxic frequency decline was observed following both IH (3.4+/-3.7 bpm, P<0.05) and PH (3.6+/-3.1 bpm, P<0.01), despite no f(R) response during exposure to PH. Use of pHPR improved the signal to noise ratio during PH, though failed to detect the peak ventilatory response, and therefore may not be appropriate when describing peak responses.     

Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice

Acetylcholine (ACh) acting through muscarinic receptors is thought to be involved in the control of breathing, notably in central and peripheral chemosensory afferents and in regulations related to sleep-wake states. By using whole-body plethysmography, we compared baseline breathing at rest and ventilatory responses to acute exposure (5 min) to moderate hypoxia (10% O(2)) and hypercapnia (3 and 5% CO(2)) in mice lacking either the M(1) or the M(3) muscarinic receptor, and in wild-type matched controls. M(1) knockout mice showed normal minute ventilation (V(E)) but elevated tidal volume (V(T)) at rest, and normal chemosensory ventilatory responses to hypoxia and hypercapnia. M(3) knockout mice had elevated V(E) and V(T) at rest, a reduced V(T) response slope to hypercapnia, and blunted V(E) and frequency responses to hypoxia. The results suggest that M(1) and M(3) muscarinic receptors play significant roles in the regulation of tidal volume at rest and that the afferent pathway originating from peripheral chemoreceptors involves M(3) receptors.     

Ventilation- and carotid chemoreceptor discharge-response to hypoxia during induced hypothermia in halothane anesthetized rat

It has been hypothesized that respiratory "gain" to hypoxic stimulus is not depressed in hypothermic animals though ventilation and that metabolic O(2) demand (Vo(2)) decreases with reduction in body temperature. The present study addressed this hypothesis by quantitative analysis of ventilatory and carotid chemoreceptor responsiveness to hypoxia during induced hypothermia in halothane anesthetized and spontaneously breathing rats. Rectal temperature was lowered from 37 degrees C (normothermia) to 30 and 25 degrees C by cooling body surface at comparable anesthetic depth without inducing shivering. Ventilation (V(E)), V(O2), PaO(2) and carotid chemoreceptor afferent discharges were measured during hyperoxic and hypoxic gas breathing. PaO(2) values at the same Fi(O2) (range 0. 35-0.08) decreased progressively as rectal temperature decreased. Both the V(E)/V(O2)- and chemoreceptor discharge-response curves shifted toward a lower PaO(2) range with a slight increase in the response slopes during hypothermia. The results indicated that the sensitivity of carotid chemoreceptor and ventilatory responses to hypoxia did not decrease at reduced body temperature. It is concluded that carotid chemoreceptor mediated regulation of ventilation is tightly coupled to changes in PaO(2 )range in halothane anesthetized rats during induced hypothermia.     

Circadian pattern of ventilation during prolonged hypoxia in conscious rats

In mammals, metabolic rate is well known to present a circadian oscillation. Because metabolism is a major determinant of the magnitude of the hypoxic ventilatory response, we hypothesized that the level of this response would follow a circadian pattern. To this end, we measured pulmonary ventilation (VE), oxygen consumption (V(O(2))), body temperature (Tb) and activity simultaneously and continuously in conscious adult rats by non-invasive methods. Measurements were made in a 12:12-h light (L):dark (D) cycle for 3 days in air, and then for 4 days in 10.5% normobaric hypoxia (HX). In normoxia, all variables oscillated, with the highest values in D. In HX, the circadian Tb and V(O(2)) oscillations were blunted, due to a decrease in their D values. The hypoxic VE response (% increase in VE from the corresponding air value) was greater in L than in D. This L-D difference was proportionate to that of the V(O(2)) response such that the hyperventilatory response (% increase in VE/V(O(2))) was similar throughout the day. The VE/V(O(2)) response was also similar between L and D when it was compared for the same level of activity; in this case, however, there was no L-D difference in the VE or V(O(2)) response. We conclude that the circadian oscillation in the hypoxic VE response was related to the time-of-day changes in the effect of HX on V(O(2)), and that, in the rat, the presence of a circadian clock does not compromise the hyperventilatory response to HX, as this response presents no time-of-day variation.     

Chemoreflex control of ventilation is altered during wakefulness in humans with OSA

We hypothesized that patients with obstructive sleep apnea (OSA) have a different awake ventilatory response to carbon dioxide above and below eupnea compared with normal. Eight male subjects with OSA and control subjects matched for gender, race, age, height and weight voluntarily hyperventilated during wakefulness to reduce the partial pressure of carbon dioxide (PET(CO2)) below 25 mmHg. Subjects were then switched into a rebreathing bag containing a normocapnic (42 mmHg) hypoxic [partial pressure of end tidal oxygen (PET(O2))=50 mmHg (H50)] or hyperoxic [PET(O2)=140 mmHg (H140)] gas mixture. During the trial PET(CO2) increased while PET(O2) was maintained at a constant level. The point at which ventilation and PET(CO2) increased linearly was considered to be the carbon dioxide ventilatory recruitment threshold (VRT(CO2)). Measurements of ventilation and its components (i.e. tidal volume and breathing frequency) were made below this threshold and the slope of the minute ventilation; tidal volume or breathing frequency response above the threshold was determined. Four trials for a given oxygen level were completed. The PET(CO2) that demarcated the VRT(CO2) was increased (H(50)=43.43+/-0.92 vs. 41.05+/-0.67; H(140)=47.65+/-0.80 vs. 45.28+/-0.75), as were measures of ventilation below the threshold (H(50)=18.50+/-2.11 vs. 13.44+/-1.43; H(140)=19.66+/-2.71 vs. 10.83+/-1.24) in the OSA subjects compared with control. In contrast the OSA and control subjects did not respond differently to changes in PET(CO2) above the threshold. We conclude that the PET(CO2) that delineates the VRT(CO2) and ventilation below this threshold is elevated in subjects with OSA.     

Progesterone increases hypoxic ventilatory response and reduces apneas in newborn rats

We hypothesized that progesterone may enhance the hypoxic ventilatory response and reduce the occurrence of apneas in newborn male rats. We studied 10-day-old rats chronically exposed to progesterone (Prog) or vehicle through the milk of lactating mothers. Respiratory and metabolic recordings were performed using whole body plethysmography under normoxia and during hypoxic exposure (10% O(2)--30 min). While progesterone did not alter baseline breathing and metabolic rate, it increased hypoxic ventilatory response particularly by limiting the magnitude of the ventilatory roll-off during the second phase of the hypoxic ventilatory response (i.e. following 5 min of exposure). In parallel, progesterone lowered the number of spontaneous apneas and drastically reduced the occurrence of post-sigh apneas during hypoxic exposure by limiting the time of the post-sigh expiratory pause. Following domperidone injection (used to block peripheral D2 dopamine receptor), minute ventilation increased in Veh pups and the number of spontaneous apneas decreased. These responses were not observed in Prog pups, suggesting that progesterone reduces peripheral dopaminergic inhibition on breathing. We conclude that progesterone is a potent stimulant of hypoxic ventilatory response in newborn rats and effectively reduces the occurrence of apneas.     

Combinatorial roles for histamine H1-H2 and H3-H4 receptors in autoimmune inflammatory disease of the central nervous system

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H(1)-H(4). We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H(1) R and H(2) R are propathogenic, while H(3) R and H(4) R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H(1) H(2) RKO and H(3) H(4) RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H(1) H(2) RKO mice developed a less severe clinical disease course, whereas the disease course of H(3) H(4) RKO mice was more severe. H(1) H(2) RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H(3) H(4) RKO mice. Additionally, splenocytes from immunized H(1) H(2) RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.     

Ventilatory responses during and following exposure to a hypoxic challenge in conscious mice deficient or null in S-nitrosoglutathione reductase

Exposure to a hypoxic challenge increases ventilation in wild-type (WT) mice that diminish during the challenge (roll-off) whereas return to room air causes an increase in ventilation (short-term facilitation, STF). Since plasma and tissue levels of ventilatory excitant S-nitrosothiols such as S-nitrosoglutathione (GSNO) increase during hypoxia, this study examined whether (1) the initial increase in ventilation is due to generation of GSNO, (2) roll-off is due to increased activity of the GSNO degrading enzyme, GSNO reductase (GSNOR), and (3) STF is limited by GSNOR activity. Initial ventilatory responses to hypoxic challenge (10% O₂, 90% N₂) were similar in WT, GSNO+/? and GSNO?/? mice. These responses diminished markedly during hypoxic challenge in WT mice whereas there was minimal roll-off in GSNOR+/? and GSNOR?/? mice. Finally, STF was greater in GSNOR+/? and GSNOR?/? mice than in WT mice (especially females). This study suggests that GSNOR degradation of GSNO is a vital step in the expression of ventilatory roll-off and that GSNOR suppresses STF.     

Differential sensitivity to hypoxic inhibition of respiratory processes in the anesthetized rat

To estimate the sensitivity to hypoxic inhibition of various regulatory processes for respiration, changes in breathing pattern during hypoxic ventilatory depression (HVD) were analyzed in the halothane-anesthetized spontaneously breathing rat using a "progressive isocapnic hypoxia test." In the carotid sinus nerve (CSN) intact rats, ventilatory augmentation was followed by depression due to reduction in respiratory frequency (f) at end-tidal PO2 (PETO2) levels below 50-60 mmHg despite increased afferent activities from the carotid chemoreceptors. After CSN section, ventilation was progressively depressed at PETO2 lower than normoxic level with simultaneous decreases of f and tidal volume. An increase in CO2 stimulus or the prevention of arterial hypotension during hypoxia by infusing a vasoconstrictor agent (phenylephrine) inhibited the occurrence of ventilatory depression in both the CSN intact and denervated animals. In all cases studied, the reduction in f resulted mainly from the prolongation of expiratory time (TE). The results suggest that in the anesthetized rat the effect of respiratory stimulation from carotid chemoreceptor afferents becomes inadequate to offset the prolongation of TE due to the central hypoxia at lower PETO2, and that the neural process for regulating TE is the major site of deterioration during central hypoxic inhibition. Roles of CO2 stimulus and systemic circulatory conditions in the generation of HVD were also discussed.     

M(1)/M(3) and M(2)/M(4) muscarinic receptor double-knockout mice present distinct respiratory phenotypes

We investigated the role of muscarinic acetylcholine receptors in the control of breathing. Baseline breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O(2)) and hypercapnia (3% and 5% CO(2)), measured by whole-body plethysmography in partially restrained animals, were compared in mice lacking either M(1) and M(3) or M(2) and M(4) muscarinic receptors, and in wild-type matched controls. M(1/3)R double-knockout mice showed at rest an elevated ventilation (V (E)) due to a large (57%) increase in tidal volume (V(T)). Chemosensory ventilatory responses were unaltered. M(2/4)R double-knockout mice were agitated and showed elevated V (E) and breathing frequency (f(R)) at rest when partially restrained, but unaltered V (E) and low f(R) when recorded unrestrained. Chemosensory ventilatory responses were unaltered. The results suggest that M(1) and M(3) receptors are involved in the control of tidal volume, while M(2) and M(4) receptors may be involved in the control of breathing frequency at rest and response to stress.