Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response.

Recent data suggest that the increase in ventilation during hypoxia may be related to the release of the excitatory amino acid neurotransmitter glutamate centrally. To further investigate this, we studied the effects of MK-801, a selective noncompetitive N-methyl-D-aspartate receptor antagonist, on the hypoxic ventilatory response in lightly anesthetized spontaneously breathing intact dogs. The cardiopulmonary effects of sequential ventriculocisternal perfusion (VCP) at the rate of 1 ml/min with mock cerebrospinal fluid (CSF, control) and MK-801 (2 mM) were compared during normoxia and 8 min of hypoxic challenge with 12% O2. Minute ventilation (VE), tidal volume (VT), and respiratory frequency (f) were recorded continuously, and hemodynamic parameters [heart rate (HR), blood pressure (MAP), cardiac output (CO), pulmonary arterial pressure, and pulmonary capillary wedge pressure] were measured periodically. Each dog served as its own baseline control before and after each period of sequential VCP under the two different O2 conditions. During 15 min of normoxia, there were no significant changes in the cardiopulmonary parameters with mock CSF VCP, whereas with MK-801 VCP for 15 min, VE decreased by approximately 27%, both by reductions in VT and f (17 and 9.5%, respectively). HR, MAP, and CO were unchanged. During 8 min of hypoxia with mock CSF VCP, VE increased by 171% associated with increased VT and f (25 and 125%, respectively). HR, MAP, and CO were likewise augmented. In contrast, the hypoxic response during MK-801 VCP was characterized by an increased VE of 84%, mainly by a rise in f by 83%, whereas the VT response was abolished. The cardiovascular excitation was also inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoventilation in ponies after carotid body denervation.

Seven ponies were subjected to carotid body denervation (CD) and two ponies were sham operated (S). Measurement of arterial blood gases and arterial blood and cerebrospinal fluid (CSF) acid-base balance were made prior to and 1,2,4,9, and 17 wks after surgery in unanesthetized animals. Resting ventilation and ventilatory responsiveness to hypoxia and NaCN infusion were assessed prior to and 2,9, and 17 wks after surgery. Alveolar hypoventilation in the CD ponies was marked 1-2 wk after surgery when VE and VA were reduced 40% and 10%, respectively, from control and PaCO2 was 12-15 mmHg above control. However, the effect was not nearly as great 4, 9, and 17 wk after surgery when the PaCO2 stabilized at approximately 6 mmHg above control PaCO2. Arterial blood pH was normal in the hypercapnic CD ponies, but CSF pH remained acid relative to normal throughout the 17-wk period. Changes in ventilatory responsiveness to hypoxia and NaCN tended to parallel changes in resting ventilation. These findings suggest: 1) the carotid bodies are essential in ponies to maintain normal ventilation: 2) in CD ponies peripheral chemosensitivity is partially regained at some unestablished locus; and 3) pH compensating mechanisms in chronically hypercapnic ponies function relatively better in blood than in CSF.     

Ventilatory effects of impaired glial function in a brain stem chemoreceptor region in the conscious rat.

Glia are thought to regulate ion homeostasis, including extracellular pH; however, their role in modulating central CO2 chemosensitivity is unclear. Using a push-pull cannula in chronically instrumented and conscious rats, we administered a glial toxin, fluorocitrate (FC; 1 mM) into the retrotrapezoid nucleus (RTN), a putative chemosensitive site, during normocapnia and hypercapnia. FC exposure significantly increased expired minute ventilation (VE) to a value 38% above the control level during normocapnia. During hypercapnia, FC also significantly increased both breathing frequency and expired VE. During FC administration, maximal ventilation was achieved at approximately 4% CO2, compared with 8-10% CO2 during control hypercapnic trials. RTN perfusion of control solutions had little effect on any ventilatory measures (VE, tidal volume, or breathing frequency) during normocapnic or hypercapnic conditions. We conclude that unilateral impairment of glial function in the RTN of the conscious rat results in stimulation of respiratory output.     

Sodium salicylate centrally augments ventilation through cholinergic mechanisms.

Several different stimuli, including hydrogen ions, may exert their effect on central ventilatory control through cholinergic mechanisms. Salicylates are known to be central respiratory stimulants. Therefore this study explored whether the ventilatory effect of sodium salicylate (SAL) is through cholinergic mechanisms. Ventriculocisternal perfusion was used in spontaneously breathing anesthetized (pentobarbital sodium, 30 mg/kg) mongrel dogs to study the effects of SAL (50 mM), atropine (ATR, 4.8 mM), and SAL-ATR on ventilation. After 15 min of perfusion with mock cerebrospinal fluid, each test agent was perfused for 15 min at a rate of 1 ml/min. Cardiovascular and ventilatory parameters were monitored. Values at 15 min of test agent perfusion were compared with values at 15 min of mock cerebrospinal fluid perfusion, with each animal used as its own control. Body temperature was kept between 37.5 and 39.0 degrees C. Perfusion with SAL increased minute ventilation (VE) by 54% (P less than 0.005) and respiratory frequency by 50% (P less than 0.005). Tidal volume was not changed, but mean inspiratory flow rate increased (P less than 0.05). Perfusion with ATR decreased VE by 22% (P less than 0.1), and perfusion with SAL-ATR decreased VE by 20% (P = 0.01). No significant cardiovascular changes were noted in any group. We conclude that SAL increases VE centrally, primarily by increasing respiratory frequency. Because ATR blocked this effect, cholinergic mechanisms are probably involved in the salicylates' central stimulation of ventilation.     

Somatostatin inhibits the ventilatory response to hypoxia in humans

The effects of a 90-min infusion of somatostatin (1 mg/h) on ventilation and the ventilatory responses to hypoxia and hypercapnia were studied in six normal adult males. Minute ventilation (VE) was measured with inductance plethysmography, arterial 02 saturation (SaO2) was measured with ear oximetry, and arterial PCO2 (Paco2) was estimated with a transcutaneous CO2 electrode. The steady-state ventilatory response to hypoxia (delta VE/delta SaO2) was measured in subjects breathing 10.5% O2 in an open circuit while isocapnia was maintained by the addition of CO2. The hypercapnic response (delta VE/delta PaCO2) was measured in subjects breathing first 5% and then 7.5% CO2 (in 52-55% O2). Somatostatin greatly attenuated the hypoxic response (control mean -790 ml x min-1.%SaO2 -1, somatostatin mean -120 ml x min-1.%SaO2 -1; P less than 0.01), caused a small fall in resting ventilation (mean % fall - 11%), but did not affect the hypercapnic response. In three of the subjects progressive ventilatory responses (using rebreathing techniques, dry gas meter, and end-tidal Pco2 analysis) and overall metabolism were measured. Somatostatin caused similar changes (mean fall in hypoxic response -73%; no change in hypercapnic response) and did not alter overall O2 consumption nor CO2 production. These results show an hitherto-unsuspected inhibitory potential of this neuropeptide on the control of breathing; the sparing of the hypercapnic response is suggestive of an action on the carotid body but does not exclude a central effect.     

Ventilatory control in hypercapnia and exercise: optimization hypothesis

A model of the respiratory control system incorporating both chemical and respiratory neuromechanical feedbacks is proposed to describe the steady-state ventilatory responses to CO2 inhalation and exercise. It is postulated that ventilatory output (VE) is set by the respiratory center to minimize a net operating cost representing the conflicting challenges of arterial chemical imbalance and respiratory-mechanical discomfort (intolerance of effort), given, respectively, by a quadratic function of arterial PCO2 and a logarithmic function of VE. In addition, the system is assumed to be mechanically limited at maximum VE (Vmax). The predicted responses in VE during moderate hypercapnia, exercise, and ventilatory loading closely mimic those normally observed, even though no separate signal unique to exercise is assumed. As a quantitative validation, the model yielded good fits to ventilatory response data obtained in eight healthy subjects during eucapnic and hypercapnic exercise; the predicted Vmax averaged approximately 77% of the maximum voluntary ventilation in all subjects. The results demonstrate the plausibility of the proposed optimization mechanism and suggest an important role for respiratory-mechanical factors in the control of VE.     

Combined effects of female hormones and metabolic rate on ventilatory drives in women

Increased resting ventilation (VE) and hypoxic and hypercapnic ventilatory responses occur during pregnancy in association with elevations in female hormones and metabolic rate. To determine whether increases in progestin, estrogen, and metabolic rate produced a rise in VE and hypoxic ventilatory response (HVR) similar in magnitude to that observed at full-term pregnancy, we studied 12 postmenopausal women after 1 wk of treatment with placebo, progestin (20 mg tid medroxyprogesterone acetate), estrogen (1.25 mg bid conjugated equine estrogens), and combined progestin and estrogen. Progestin alone or with estrogen raised VE at rest and decreased end-tidal PCO2 (PETCO2) by 3.9 +/- 0.8 and 3.3 +/- 0.6 Torr, respectively (both P less than 0.05), accounting for approximately one-fourth of the rise in VE and three-fourths of the PETCO2 reduction seen at full-term pregnancy. The addition of mild exercise sufficient to raise metabolic rate by 33-36% produced the remaining three-fourths of the rise in VE but no further decline in PETCO2. Combined progestin and estrogen raised HVR and hypercapnic ventilatory response more consistently than progestin alone and could account for one-half of the increase in HVR seen at full-term pregnancy. Mild exercise alone did not raise HVR, but when exercise was combined with progestin and estrogen administration, HVR rose by amounts equal to that seen at full-term pregnancy. We concluded that female hormones together with mild elevation in metabolic rate were likely responsible for the pregnancy-associated increases in VE and HVR.     

Influence of body size and gender on control of ventilation

Hypoxic (HVR) and hypercapnic (HCVR) ventilatory responses are influenced by both metabolic activity and hormonal factors. By studying 67 subjects of both sexes, including those at the extremes of stature, we examined the influence of gender, CO2 production (VCO2), O2 consumption (VO2), body surface area (BSA), and vital capacity (VC) on resting ventilation (VE), HVR, and HCVR. We measured resting VE, VO2, and VCO2 and then performed isocapnic progressive hypoxic and hypercapnic ventilatory responses. The effect of stature was reflected in higher VE and metabolic rate (both P less than 0.001) in tall men compared with short men that was ablated by correction for BSA. Perhaps because their heights vary less than those of the men, tall women were not statistically distinguishable from short women in any of these measured parameters. Tall men tended to have greater hypoxic chemosensitivity than short men but this was not significantly different (P = 0.07). Gender affected the control of ventilation in a number of ways. Men had higher VE (P less than 0.05) and metabolic rate (P less than 0.001) than women. Even after correction for BSA men still had higher metabolic rates. Women had higher VE/VCO2 than men (P less than 0.05) and lower resting end-tidal Pco2 (PETCO2) values (P less than 0.05). Both A, the shape parameter of the hyperbolic HVR curve, and HVR determined from mouth occlusion pressure (AP) were greater in women than in men, although only AP reached statistical significance. However, corrections of A for BSA (P less than 0.05), VCO2 (P less than 0.01), and VC (P less than 0.001) amplified these differences.(ABSTRACT TRUNCATED AT 250 WORDS)     

L-NAME differentially alters ventilatory behavior in Sprague-Dawley and Brown Norway rats.

Nitric oxide (NO) is a regulating factor in respiration. The question was whether NO synthase (NOS) blockade would affect posthypoxic ventilatory behavior similarly in two rat strains with known differences in steady-state hypoxic and hypercapnic responses and in posthypoxic ventilatory behavior. Ventilatory behavior [respiratory frequency (f) and minute ventilation (VE)] was measured by body plethysmography on unanesthetized, unrestrained adult male Sprague-Dawley (SD; n = 8) and Brown Norway rats (BN; n = 8) at baseline and 1 min after rapid transition to 100% O(2) after 5 min of isocapnic hypoxia (10% O(2)-3% CO(2)-balance N(2)). Testing was performed 30 min after intraperitoneal injection of either saline (vehicle) or 100 mg/kg of N(G)-nitro-L-arginine methyl ester (L-NAME). Resting f and VE increased after L-NAME in both strains, more markedly in SD compared with BN (77 vs. 47% for f, and 42 vs. 16% for VE, respectively; P < 0.05). With vehicle, posthypoxic f and VE decline (Dejours phenomenon) was present only in BN and was absent in SD. With L-NAME, the Dejours phenomena were still present in BN but also were apparent in SD (f: 95.3 vs. 134.4 beats/min at baseline; VE: 66.3 vs. 88.8 ml/min at baseline; P < 0.05). Thus NOS blockade results in a strain-specific alteration in resting ventilation and uncovers the Dejours phenomenon in the SD strain.     

The role of peripheral chemoreceptor activity on the respiratory responses to hypoxia and hypercapnia in anaesthetised rabbits with induced hypothyroidism

The purpose of this study was to investigate the role of peripheral chemoreceptor activity on the hypoxic and hypercapnic ventilatory drives in rabbits with induced hypothyroidism. Experiments were carried out in control and hypothyroid rabbits. Hypothyroidism was induced by an administration of an iodide-blocker, methimazole in food (75 mg/100 g food) for ten weeks. At the end of the tenth week, triiodothyronine (T3) and thyroxine (T4) levels significantly decreased (P<0.001) while thyroid stimulating hormone (TSH) increased (P<0.001). Tidal volume (VT), respiratory frequency (f/min), ventilation minute volume (VE) and systemic arterial blood pressure (BP) were recorded during the breathing of the normoxic, hypoxic (8% O2-92% N2) and hypercapnic (6% CO2-Air) gas mixtures, in the anaesthetised rabbits of both groups. At the end of each experimental phase, PaO2, PaCO2, and pHa were measured. The same experimental procedure was repeated after peripheral chemoreceptor denervation in both groups. VT significantly decreased in some of the rabbits with hypothyroidism during the breathing of the hypoxic gas mixture (nonresponsive subgroup) (P<0.05). After chemodenervation, a decrease in VT was observed in this nonresponsive subgroup during normoxia (P<0.05). The percent decrease in VT in nonresponsive subgroup of hypothyroid rabbits after chemodenervation was lower than that of the chemodenervated control animals (P<0.01). When these rabbits with hypothyroidism were allowed to breath the hypercapnic gas mixtures, increases in VT and VE were not significant. In conclusion, although there is a decrease in peripheral chemoreceptor activity in hypothyroidism, it does not seem to be the only cause of decrease in ventilatory drive during hypoxia and hypercapnia.     

Adrenergic and cholinergic interaction in central ventilatory control

The ventrolateral medulla, which functions as integrator of cardiorespiratory control, contains cholinergic and adrenergic neurons. Exogenously administered cholinergic and adrenergic agents affect both ventilation and circulation. It is not clear whether these agents act in an independent or coordinate manner. beta-Adrenergic and alpha 2-adrenergic agents stimulate and depress the cardiorespiratory system, respectively. beta-Adrenergic and alpha 2-adrenergic agents stimulate and depress the production of adenosine 3',5'-cyclic monophosphate (cAMP), respectively. Increased intracellular cAMP may facilitate the release of acetylcholine (ACh). This work seeks to answer the following questions: 1) Are the cardiorespiratory effects of adrenergic agents secondary to possible changes in ACh release? 2) Does cAMP production have an intermediate role? By means of ventriculocisternal perfusion in anesthetized (pentobarbital sodium, 30 mg/kg) spontaneously breathing dogs, isoproterenol (ISO) increased ventilation (VE) 75% (P less than 0.05); heart rate and cardiac output were also increased (P less than 0.05). Esmolol (a beta-antagonist) blocked both the cardiovascular and ventilatory effects of ISO. Atropine (a cholinergic antagonist) blocked the ventilatory effects of ISO, but the circulatory changes persisted. Forskolin (a direct activator of adenylate cyclase) increased VE 51% (P less than 0.05), and its effect was also blocked by atropine. Clonidine decreased VE 42% (P less than 0.05); heart rate and cardiac output were also decreased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of altered CSF [H+] on ventilatory responses to exercise in the awake goat

We investigated the effects of selective large changes in the acid-base environment of medullary chemoreceptors on the control of exercise hyperpnea in unanesthetized goats. Four intact and two carotid body-denervated goats underwent cisternal perfusion with mock cerebrospinal fluid (CSF) of markedly varying [HCO-3] (CSF [H+] = 21-95 neq/l; pH 7.68-7.02) until a new steady state of alveolar hypo- or hyperventilation was reached [arterial PCO2 (PaCO2) = 31-54 Torr]. Perfusion continued as the goats completed two levels of steady-state treadmill walking [2 to 4-fold increase in CO2 production (VCO2)]. With normal acid-base status in CSF, goats usually hyperventilated slightly from rest through exercise (-3 Torr PaCO2, rest to VCO2 = 1.1 l/min). Changing CSF perfusate [H+] changed the level of resting PaCO2 (+6 and -4 Torr), but with few exceptions, the regulation of PaCO2 during exercise (delta PaCO2/delta VCO2) remained similar regardless of the new ventilatory steady state imposed by changing CSF [H+]. Thus the gain (slope) of the ventilatory response to exercise (ratio of change in alveolar ventilation to change in VCO2) must have increased approximately 15% with decreased resting PaCO2 (acidic CSF) and decreased approximately 9% with increased resting PaCO2 (alkaline CSF). A similar effect of CSF [H+] on resting PaCO2 and on delta PaCO2/VCO2 during exercise also occurred in two carotid body-denervated goats. Our results show that alteration of the gain of the ventilatory response to exercise occurs on acute alterations in resting PaCO2 set point (via changing CSF [H+]) and that the primary stimuli to exercise hyperpnea can operate independently of central or peripheral chemoreception.     

Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep

Although the influence of altitude acclimatization on respiration has been carefully studied, the associated changes in hypoxic and hypercapnic ventilatory responses are the subject of controversy with neither response being previously evaluated during sleep at altitude. Therefore, six healthy males were studied at sea level and on nights 1, 4, and 7 after arrival at altitude (14,110 ft). During wakefulness, ventilation and the ventilatory responses to hypoxia and hypercapnia were determined on each occasion. During both non-rapid-eye-movement and rapid-eye-movement sleep, ventilation, ventilatory pattern, and the hypercapnic ventilatory response (measured at ambient arterial O2 saturation) were determined. There were four primary observations from this study: 1) the hypoxic ventilatory response, although similar to sea level values on arrival at altitude, increased steadily with acclimatization up to 7 days; 2) the slope of the hypercapnic ventilatory response increased on initial exposure to a hypoxic environment (altitude) but did not increase further with acclimatization, although the position of this response shifted steadily to the left (lower PCO2 values); 3) the sleep-induced decrements in both ventilation and hypercapnic responsiveness at altitude were equivalent to those observed at sea level with similar acclimatization occurring during wakefulness and sleep; and 4) the quantity of periodic breathing during sleep at altitude was highly variable and tended to occur more frequently in individuals with higher ventilatory responses to both hypoxia and hypercapnia.     

Morning attenuation in cerebrovascular CO2 reactivity in healthy humans is associated with a lowered cerebral oxygenation and an augmented ventilatory response to CO2.

We hypothesized that, in healthy subjects without pharmacological intervention, an overnight reduction in cerebrovascular CO(2) reactivity would be associated with an elevated hypercapnic ventilatory [ventilation (VE)] responsiveness and a reduction in cerebral oxygenation. In 20 healthy male individuals with no sleep-related disorders, continuous recordings of blood velocity in the middle cerebral artery, arterial blood pressure, VE, end-tidal gases, and frontal cortical oxygenation using near infrared spectroscopy were monitored during hypercapnia (inspired CO(2), 5%), hypoxia [arterial O(2) saturation (Sa(O(2))) approximately 84%], and during a 20-s breath hold to investigate the related responses to hypercapnia, hypoxia, and apnea, respectively. Measurements were conducted in the evening (6-8 PM) and in the early morning (6-8 AM). From evening to morning, the cerebrovascular reactivity to hypercapnia was reduced (5.3 +/- 0.6 vs. 4.6 +/- 1.1%/Torr; P < 0.05) and was associated with a reduced increase in cerebral oxygenation (r = 0.39; P < 0.05) and an elevated morning hypercapnic VE response (r = 0.54; P < 0.05). While there were no overnight changes in cerebrovascular reactivity or VE response to hypoxia, there was greater cerebral desaturation for a given Sa(O(2)) in the morning (AM, -0.45 +/- 0.14 vs. PM, -0.35 +/- 0.14%/Sa(O(2)); P < 0.05). Following the 20-s breath hold, in the morning, there was a smaller surge middle cerebral artery velocity and cerebral oxygenation (P < 0.05 vs. PM). These data indicate that normal diurnal changes in the cerebrovascular response to CO(2) influence the hypercapnic ventilatory response as well as the level of cerebral oxygenation during changes in arterial Pco(2); this may be a contributing factor for diurnal changes in breathing stability and the high incidence of stroke in the morning.     

Effects of adenosine on ventilatory responses to hypoxia and hypercapnia in humans

Adenosine infusion (100 micrograms X kg-1 X min-1) in humans stimulates ventilation but also causes abdominal and chest discomfort. To exclude the effects of symptoms and to differentiate between a central and peripheral site of action, we measured the effect of adenosine infused at a level (70-80 micrograms X kg-1 X min-1) below the threshold for symptoms. Resting ventilation (VE) and progressive ventilatory responses to isocapnic hypoxia and hyperoxic hypercapnia were measured in six normal men. Compared with a control saline infusion given single blind on the same day, adenosine stimulated VE [mean increase: 1.3 +/- 0.8 (SD) l/min; P less than 0.02], lowered resting end-tidal PCO2 (PETCO2) (mean fall: -3.9 +/- 0.9 Torr), and increased heart rate (mean increase: 16.1 +/- 8.1 beats/min) without changing systemic blood pressure. Adenosine increased the hypoxic ventilatory response (control: -0.68 +/- 0.4 l X min-1 X %SaO2-1, where %SaO2 is percent of arterial O2 saturation; adenosine: -2.40 +/- 1.2 l X min-1 X %SaO2-1; P less than 0.01) measured at a mean PETCO2 of 38.3 +/- 0.6 Torr but did not alter the hypercapnic response. This differential effect suggests that adenosine may stimulate ventilation by a peripheral rather than a central action and therefore may be involved in the mechanism of peripheral chemoreception.     

Ventral medullary extracellular fluid pH and PCO2 during hypoxemia

We designed experiments to study changes in ventral medullary extracellular fluid (ECF) PCO2 and pH during hypoxemia. Measurements were made in chloralose-urethan-anesthetized spontaneously breathing cats (n = 12) with peripherial chemodenervation. Steady-state measurements were made during normoxemia [arterial PO2 (PaO2) = 106 Torr], hypoxemia (PaO2 = 46 Torr), and recovery (PaO2 = 105 Torr), with relatively constant arterial PCO2 (approximately 44 Torr). Mean values of ventilation were 945, 683, and 1,037 ml/min during normoxemia, hypoxemia, and recovery from hypoxemia, respectively. Ventilatory depression occurred in each cat during hypoxemia. Mean values of medullary ECF PCO2 were 57.7 +/- 7.2 (SD), 59.4 +/- 9.7, and 57.4 +/- 7.2 Torr during normoxemia, hypoxemia, and recovery to normoxemia, respectively; respective values for ECF [H+] were 60.9 +/- 8.0, 64.4 +/- 11.6, and 62.9 +/- 9.2 neq/l. Mean values of calculated ECF [HCO3-] were 22.8 +/- 3.0, 21.7 +/- 3.3, and 21.4 +/- 3.1 meq/l during normoxemia, hypoxemia, and recovery, respectively. Changes in medullary ECF PCO2 and [H+] were not statistically significant. Therefore hypoxemia caused ventilatory depression independent of changes in ECF acid-base variables. Furthermore, on return to normoxemia, ventilation rose considerably, still independent of changes in ECF PCO2, [H+], and [HCO3-].     

Acetazolamide reduces exercise capacity and increases leg fatigue under hypoxic conditions.

Acetazolamide (Acz) is used at altitude to prevent acute mountain sickness, but its effect on exercise capacity under hypoxic conditions is uncertain. Nine healthy men completed this double-blind, randomized, crossover study. All subjects underwent incremental exercise to exhaustion with an inspired O(2) fraction of 0.13, hypoxic ventilatory responses, and hypercapnic ventilatory responses after Acz (500 mg twice daily for 5 doses) and placebo. Maximum power of 203 +/- 38 (SD) W on Acz was less than the placebo value of 225 +/- 40 W (P < 0.01). At peak exercise, arterialized capillary pH was lower and Po(2) higher on Acz (P < 0.01). Ventilation was 118.6 +/- 20.0 l/min at the maximal power on Acz and 102.4 +/- 20.7 l/min at the same power on placebo (P < 0.02), and Borg score for leg fatigue was increased on Acz (P < 0.02), with no difference in Borg score for dyspnea. Hypercapnic ventilatory response on Acz was greater (P < 0.02), whereas hypoxic ventilatory response was unchanged. During hypoxic exercise, Acz reduced exercise capacity associated with increased perception of leg fatigue. Despite increased ventilation, dyspnea was not increased.     

Is the hyperpnea of muscular contractions critically dependent on spinal afferents?

We studied the role of spinal afferent pathways in the hyperpnea of electrically induced muscle contractions (ExE). The ventilatory (VE) and arterial CO2 partial pressure (PaCO2) responses were measured at rest and during two levels of ExE in awake human paraplegic subjects with clinically complete lesions of the spinal cord (range T4-T11). We hypothesized that if peripheral neural drive is critical to a normal ventilatory response, then ExE in the absence of intact pathways should cause a lower ventilatory response resulting in hypercapnia at the onset of ExE. ExE was induced by stimulation of the quadriceps and hamstring muscles that approximately doubled the resting level of CO2 production (VCO2). PaCO2 during work transitions and in the latter stages of ExE did not differ significantly from that at rest. Arterial pH progressively declined over time during ExE (P less than 0.01) as a result of increased lactate concentration (P less than 0.01). The linear relationship between VE and VCO2 was similar to that found for normal human subjects during ExE (P = 0.73). These data suggest that VE and presumably alveolar ventilation (VA) can be appropriately matched to VCO2 during low-intensity muscle contractions of the lower extremities in the absence of intact spinal afferent pathways. Moreover, since it is unlikely that postulated "central command" mechanisms were initiated during ExE in these paraplegic subjects, the data provide support for our previous conclusion that central command is not obligatory for matching VA to VCO2 (J. Appl. Physiol. 64: 218-225, 1988).     

Interaction of hypoxic and hypercapnic stimuli on breathing pattern in the newborn rat

We aimed to investigate whether newborn rats respond to acute hypoxia with a biphasic pattern as other newborn species, the characteristics of their ventilatory response to hypercapnia, and the ventilatory response to combined hypoxic and hypercapnic stimuli. First, we established that newborn unanesthetized rats (2-4 days old) exposed to 10% O2 respond as other species. Their ventilation (VE), measured by flow plethysmography, immediately increased by 30%, then dropped and remained around normoxic values within 5 min. The drop was due to a decrease in tidal volume, while frequency remained elevated. Hence, alveolar ventilation was about 10% below normoxic value. At the same time O2 consumption, measured manometrically, dropped (-23%), possibly indicating a mechanism to protect vital organs. Ten percent CO2 in O2 breathing determined a substantial increase in VE (+47%), indicating that the respiratory pump is capable of a marked sustained hyperventilation. When CO2 was added to the hypoxic mixture, VE increased by about 85%, significantly more than without the concurrent hypoxic stimulus. Thus, even during the drop in VE of the biphasic response to hypoxia, the respiratory control system can respond with excitation to a further increase in chemical drive. Analysis of the breathing patterns suggests that in the newborn rat in hypoxia the inspiratory drive is decreased but the inspiratory on-switch mechanism is stimulated, hypercapnia increases ventilation mainly through an increase in respiratory drive, and moderate asphyxia induces the most powerful ventilatory response by combining the stimulatory action of hypercapnia and hypoxia.     

Ventilatory response to hypercapnia during head-down tilt

The effect of hypercapnic ventilatory response was examined in anaesthetized spontaneously breathing rats by using rebreathing techniques both at supine and -30 degrees head-down tilt positions. No significant differences were found in the minute ventilation response between the supine and head-down positions during hypercapnic stimulations. In contrast, we found that hypercapnia-stimulated breathing affected the relationship between deltaPoes and deltaP(ET), CO2. This study demonstrates that higher peak deltaPoes was developed in order to maintain the same ventilation in the supine and head-tilt position. The higher deltaPoes/deltaP(ET), CO2 head-down ratio than the supine was a result of increased airflow impedance of the total respiratory system while head-down. It is concluded that ventilation at head-down is regulated in such a way as to maintain the pH and Paco, despite mechanical loading imposed by the environment. Hence, during hypercapnic stimulation the ventilatory response in head-down position is shaped by interaction of chemical drives and mechanical afferent information arising.