CSF acidosis augments ventilation through cholinergic mechanisms

Ventilation is influenced by the acid-base status of the brain extracellular fluids (ECF). CO2 may affect ventilation independent of changes in H+. Whether the acidic condition directly alters neuronal firing or indirectly alters neuronal firing through changes in endogenous neurotransmitters remains unclear. In this work, ventriculocisternal perfusion (VCP) was used in anesthetized (pentobarbital sodium, 30 mg/kg) spontaneously breathing dogs to study the ventilatory effects of acetylcholine (ACh), eucapnic acidic (pH approximately 7.0) cerebrospinal fluid (CSF), and hypercapnic acidic (pH approximately 7.1) CSF in the absence and presence of atropine (ATR). Each animal served as its own control. Base line was defined during VCP with control mock CSF (pH approximately 7.4). With ATR (4.8 mM) there was an insignificant downward trend in minute ventilation (VE). ACh (6.6 mM) increased VE 53% (n = 12, P less than 0.01), eucapnic acidic CSF increased VE 41% (n = 12, P less than 0.01), and hypercapnic acidic CSF increased VE 47% (n = 6, P less than 0.01). These positive effects on ventilation were not seen in the presence of ATR. This suggests that acidic brain ECF activates ventilatory neurons through muscarinic cholinergic mechanisms. Higher concentrations of ACh increased ventilation in a concentration-dependent manner. Higher concentrations of ATR decreased ventilation progressively, resulting in apnea. The results suggest that ACh plays a significant role in the central augmentation of ventilation when the brain ECF is made acidic by either increasing CSF PCO2 or decreasing CSF bicarbonate.     

Effect of centrally administered gamma-aminobutyric acid on metabolic function

gamma-Aminobutyric acid (GABA) content of the brain increases during hypoxia and hypercapnia and GABA by itself is a central ventilatory depressant and may depress metabolism as well. Therefore the effect of centrally administered GABA by ventriculocisternal perfusion on O2 consumption (VO2) and CO2 production (VCO2) was studied in pentobarbital-anesthetized dogs. GABA (30 mM) in mock cerebrospinal fluid (CSF) was perfused for 15 min at the rate of 1.0 ml/min followed by perfusion with mock CSF alone. Body temperature, perfusion pressure, and CSF pH were kept constant. Minute ventilation (VE) was kept constant mechanically. Under these conditions, VO2, VCO2, alveolar ventilation (VA), and relative pulmonary dead space volume (VD/VT) were measured. During perfusion with 30 mM GABA, mean VO2 (+/- SE) decreased from 96.5 +/- 3.3 to 81.9 +/- 5.1 ml/min, VCO2 from 72.1 +/- 3.8 to 60.7 +/- 3.0 ml/min, and VA from 1.7 +/- 0.1 to 1.3 +/- 0.1 l/min. VD/VT increased from 0.55 +/- 0.02 to 0.65 +/- 0.01. Perfusion with mock CSF alone restored these parameters to initial levels within 15 min. We conclude that centrally administered GABA depresses VO2 and VCO2. This reduction in metabolic function is independent of the central modulatory effects of GABA on respiration.     

Central cardiorespiratory effects of glutamate in dogs

Metabolism of certain amino acid neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA) are closely linked in the brain to CO2 fixation and H+ metabolism. Additionally they may also affect central modulation of cardiorespiratory function. Therefore central cardiorespiratory effects of L-glutamate were determined in lightly anesthetized dogs using ventriculocisternal perfusion with artificial cerebrospinal fluid (CSF) (pH 7.25-7.28) containing 30 or 60 mM glutamate at a flow rate of 1.0 ml/min for 20 min followed by perfusion with artificial CSF alone. Tidal volume and minute ventilation increased with 60 mM glutamate, as did respiratory drive. These changes returned to normal with mock CSF perfusion. Glutamate (30 mM) had no significant effect on ventilation. At both concentrations, glutamate significantly increased mean femoral arterial pressure and mean pulmonary arterial pressure, which was accompanied by bradycardia. All these increases rapidly returned to normal with mock CSF perfusion. Cardiac output and pulmonary capillary wedge pressure did not change with glutamate perfusion. The results suggest that glutamate may have a significant central excitatory role in modulation of ventilatory drive as well as of hemodynamic functions.     

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)     

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 acute exposure to high altitude on ventilatory drive and respiratory pattern

To assess changes in ventilatory regulation in terms of central drive and timing, on exposure to high altitude, and the effects of induced hyperoxia at high altitude, six healthy normal lowland subjects (mean age 19.5 +/- 1.64 yr) were studied at low altitude (518 m) and on the first 4 days at high altitude (3,940 m). The progressive increase in resting expired minute ventilation (VE; control mean 9.94 +/- 1.78 to 14.25 +/- 2.67 l/min on day 3, P less than 0.005) on exposure to high altitude was primarily due to a significant increase in respiratory frequency (f; control mean 15.6 +/- 3.5 breaths/min to 23.8 +/- 6.2 breaths/min on day 3, P less than 0.01) with no significant change in tidal volume (VT). The increase in f was due to significant decreases in both inspiratory (TI) and expiratory (TE) time per breath; the ratio of TI to TE increased significantly (control mean 0.40 +/- 0.08 to 0.57 +/- 0.14, P less than 0.025). Mouth occlusion pressure did not change significantly, nor did the ratio of VE to mouth occlusion pressure. The acute induction of hyperoxia for 10 min at high altitude did not significantly alter VE or the ventilatory pattern. These results indicate that acute exposure to high altitude in normal lowlanders causes an increase in VE primarily by an alteration in central breath timing, with no change in respiratory drive. The acute relief of high altitude hypoxia for 10 min has no effect on the increased VE or ventilatory pattern.     

Ventilatory responses to increased blood flow and decreased lung volume in awake dogs

The effect of decreased lung volume on ventilatory responses to arteriovenous fistula-induced increased cardiac output was studied in four chronic awake dogs. Lung volume decreases were imposed by application of continuous negative-pressure breathing of -10 cmH2O to the trachea. The animals were surgically prepared with chronic tracheostomy, indwelling carotid artery catheter, and bilateral arteriovenous femoral shunts. Control arteriovenous blood flow was 0.5 l/min, and test flow level was 2.0 l/min. Arterial blood CO2 tension (PaCO2) was continuously monitored using an indwelling Teflon membrane mass spectrometer catheter, and inhaled CO2 was given to maintain isocapnia throughout. Increased fistula flow alone led to a mean 52% increase in cardiac output (CO), whereas mean systemic arterial blood pressure (Psa) fell 4% (P less than 0.01). Negative-pressure breathing alone raised Psa by 3% (P less than 0.005) without a significant change in CO. Expired minute ventilation (VE) increased by 27% (P less than 0.005) from control in both of these conditions separately. Combined increased flow and negative pressure led to a 50% increase in CO and 56% increase in VE (P less than 0.0025) without any significant change in Psa. Effects of decreased lung volume and increased CO appeared to be additive with respect to ventilation and to occur under conditions of constant PaCO2 and Psa. Because both decreased lung volume and increased CO occur during normal exercise, these results suggest that mechanisms other than chemical regulation may play an important role in the control of breathing and contribute new insights into the isocapnic exercise hyperpnea phenomenon.     

Hyperoxia causes increased albumin permeability of cultured endothelial monolayers

The effect of phasic eye movement activity on ventilation during rapid-eye-movement (REM) sleep was studied in seven healthy young adults by use of the respiratory inductive plethysmograph. Mean ventilation (VE) and ventilatory components during REM sleep were not significantly different from that seen in either stages 1-2 or 3-4 sleep. The percent of rib cage contribution to ventilation in REM sleep, 29.3 +/- 5.1%, was reduced compared with 54.4 +/- 5.8% in stage 1-2 and 52.2 +/- 4.3% in stage 3-4 sleep (P less than 0.005). When one separated breaths by the degree of associated phasic eye movement activity, it became apparent that breathing during REM sleep is very heterogeneous. Increasing eye movement activity was associated with inhibition of ventilation with a reduction in VE from 5.1 +/- 0.3 to 3.8 +/- 0.3 l/min. Tidal volume and frequency both fell, whereas inspiratory duration was unchanged. Compartmental ventilation was also affected, with the fall in the rib cage contribution from 37.8 +/- 6.4 to 15.3 +/- 5.6%. Chest wall and abdominal movement became more asynchronous as phasic-eye-movement activity increased and frank paradoxical breathing was seen.     

Ventilatory acclimatization to hypoxia is not dependent on cerebral hypocapnic alkalosis

We previously demonstrated that, in awake goats, 6 h of hypoxic carotid body perfusion during systemic normoxia produced time-dependent hyperventilation that is typical of ventilatory acclimatization to hypoxia (VAH). The hypocapnic alkalosis that occurred could have produced VAH by inducing cerebral vasoconstriction and brain lactic acidosis even though systemic arterial normoxia was maintained. In the present study we tested the hypothesis that hypocapnic alkalosis is a necessary component of VAH. Goats were prepared so that one carotid body could be perfused, from an extracorporeal circuit, with blood in which gas tensions could be controlled independently from the blood perfusing the systemic arterial system, including the brain. Using this preparation we carried out 4 h of hypoxic carotid body perfusion while maintaining systemic arterial (and brain) normoxia in awake goats. Expired minute ventilation (VE) was measured while CO2 was added to inspired air to maintain normocapnia. Carotid body PCO2 and PO2 were maintained near 40 Torr during the 4-h carotid body perfusion. Control mean VE was 8.65 +/- 0.48 l/min (mean +/- SE). With acute carotid body hypoxia (30 min) VE increased to 21.73 +/- 2.02 l/min (P less than 0.05); over the ensuing 3.5 h of carotid body hypoxia, VE progressively increased to 39.14 +/- 4.14 l/min (P less than 0.05). These data indicate that neither cerebral hypoxia nor hypocapnic alkalosis are required to produce VAH. After termination of the 4-h carotid body stimulation, hyperventilation was not maintained in these studies, i.e., there was no deacclimatization. This suggests that acclimatization and deacclimatization are produced by different mechanisms.     

TRH microdialysis into the RTN of the conscious rat increases breathing, metabolism, and temperature.

Thyrotropin-releasing hormone (TRH) injected into the retrotrapezoid nucleus (RTN) of anesthetized rats produces a large, prolonged stimulation of ventilatory output (C. L. Cream, A. Li, and E. E. Nattie. J. Appl. Physiol. 83: 792-799, 1997). Here we inject or dialyze TRH into the RTN of conscious rats. In 6 of 17 injections (200 nl, 3.1 +/- 1.7 mM), ventilation (VE) increased 31% by 10 min, with recovery by 60 min. With dialysis, each animal of one group (n = 5) received, in random order, 10 mM TRH, 10 mM TRHOH (a metabolite of TRH), and artificial cerebrospinal fluid (aCSF); each animal of a second group (n = 5) received aCSF and 1 mM TRH. TRHOH and aCSF had no sustained effects. TRH (1 mM) increased VE (32%, P < 0.02, by 10 min, with recovery by 60 min), O(2) consumption (VO(2); 19%, P < 0. 03), and body (rectal) temperature (T(re); 0.5 degrees C, P < 0.09). TRH (10 mM) increased VE (78%, P < 0.01, by 10 min, with no recovery at 60 min), VO(2) (48%, P < 0.01), and T(re) (1.0 degrees C, P < 0. 01). TRH also induced arousal. The tissue volume affected in dialysis, estimated by spread of dialyzed fluorescein (332.3 mol wt, mol wt of TRH = 362.4), was 1,580 +/- 256 nl for 10 mM (n = 5) and 590 +/- 128 nl for 1 mM (n = 5). We conclude that 1) the RTN is involved in the integration of VE, VO(2), T(re), and arousal and 2) TRH may establish the responsiveness of RTN neurons.     

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.     

Naloxone reduces decrease in ventilation induced by hypoxia in newborn infants

The mechanism responsible for the decrease in ventilation during breathing of low fractional concentration of inspired O2 in the newborn infant is poorly understood. The present study tested the hypothesis that endogenous opiates account for this ventilatory decrease. Eleven healthy newborn infants breathed 15% O2, balance N2 for 5 min following an injection of saline and following an injection of naloxone. Neither injection caused a change in minute ventilation (VE) or ventilatory pattern when the infants were breathing room air. However, the decreased ventilation during hypoxia following naloxone was significantly less than that following saline. VE dropped about 14% following saline but only about 4% following naloxone. However, the adult ventilatory response to hypoxemia, i.e., a relatively sustained increase in VE, was not attained. Naloxone had no influence on the occurrence of periodic breathing during hypoxemia. Thus in the healthy full-term newborn infant, endogenous opiates account only for a part of the decreased ventilation during hypoxemia.     

Ventilatory response to sustained hypoxia in carotid body denervated rats

Hypoxia stimulates ventilation, but when it is sustained, a decline in the ventilatory response is seen. The mechanism responsible for this decline lies within the CNS, but still remains unknown. In this study, we attempted to elucidate the possible role of hypoxia-induced depression of respiratory neurons by comparing the ventilatory response to hypoxia in intact rats and those with denervated carotid bodies. A whole-body plethysmograph was used to measure tidal volume, frequency of breathing and minute ventilation (VE) in awake and anesthetized intact rats and rats after carotid body denervation during exposure to hypoxia (FIO2 0.1). Fifteen-minute hypoxia induced an initial increase of VE in intact rats (to 248% of control ventilation in awake and to 227% in anesthetized rats) followed by a consistent decline (to 207% and 196% of control VE, respectively). Rats with denervated carotid bodies responded with a smaller increase in VE (to 134% in awake and 114% in anesthetized animals), but without a secondary decline (145% and 129% of control VE in the 15th min of hypoxia). These results suggest that afferentation from the carotid bodies and/or the substantial increase in ventilation are crucial for the biphasicity of the ventilatory response to sustained hypoxia and that a central hypoxic depression cannot fully explain the secondary decline in VE.     

Background ventilatory stimulus as a determinant of load compensation

Compensation for inspiratory flow-resistive loading was compared during progressive hypercapnia and incremental exercise to determine the effect of changing the background ventilatory stimulus and to assess the influence of the interindividual variability of the unloaded CO2 response on evaluation of load compensation in normal subjects. During progressive hypercapnia, ventilatory response was incompletely defended with loading (mean unloaded delta VE/delta PCO2 = 3.02 +/- 2.29, loaded = 1.60 +/- 0.67 1.min-1.Torr-1 CO2, where VE is minute ventilation and PCO2 is CO2 partial pressure; P less than 0.01). Furthermore the degree of defense of ventilation with loading was inversely correlated with the magnitude of the unloaded CO2 response. During exercise, loading produced no depression in ventilatory response (mean delta VE/delta VCO2 unloaded = 20.5 +/- 1.9, loaded = 19.2 +/- 2.5 l.min-1.l-1.min-1 CO2 where VCO is CO2 production; P = NS), and no relationship was demonstrated between degree of defense of the exercise ventilatory response and the unloaded CO2 response. Differences in load compensation during CO2 rebreathing and exercise suggest the presence of independent ventilatory control mechanisms in these states. The type of background ventilatory stimulus should therefore be considered in load compensation assessment.     

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.     

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.     

Effect of elastic loading on ventilatory pattern during progressive exercise

Ventilatory responses to progressive exercise, with and without an inspiratory elastic load (14.0 cmH2O/l), were measured in eight healthy subjects. Mean values for unloaded ventilatory responses were 24.41 +/- 1.35 (SE) l/l CO2 and 22.17 +/- 1.07 l/l O2 and for loaded responses were 24.15 +/- 1.93 l/l CO2 and 20.41 +/- 1.66 l/l O2 (P greater than 0.10, loaded vs. unloaded). At levels of exercise up to 80% of maximum O2 consumption (VO2max), minute ventilation (VE) during inspiratory elastic loading was associated with smaller tidal volume (mean change = 0.74 +/- 0.06 ml; P less than 0.05) and higher breathing frequency (mean increase = 10.2 +/- 0.98 breaths/min; P less than 0.05). At levels of exercise greater than 80% of VO2max and at exhaustion, VE was decreased significantly by the elastic load (P less than 0.05). Increases in respiratory rate at these levels of exercise were inadequate to maintain VE at control levels. The reduction in VE at exhaustion was accompanied by significant decreases in O2 consumption and CO2 production. The changes in ventilatory pattern during extrinsic elastic loading support the notion that, in patients with fibrotic lung disease, mechanical factors may play a role in determining ventilatory pattern.     

Effect of alpha adrenergic blockade on brain blood flow and ventilation during hypoxia in newborn piglets.

The influence of cardiovascular changes on ventilation has been demonstrated in adult animals and humans (Jones, French, Weissman & Wasserman, 1981; Wasserman, Whipp & Castagna 1974). It has been suggested that neonatal hypoxic ventilatory depression may be related to some of the hemodynamic changes that occur during hypoxia (Brown & Lawson, 1988; Darnall, 1985; Suguihara, Bancalari, Bancalari, Hehre & Gerhardt, 1986). To test the possible relationship between the cardiovascular and ventilatory response to hypoxia in the newborn, eleven sedated spontaneously breathing piglets (age: 5.9 +/- 1.6 days; weight: 1795 +/- 317 g; SD) were studied before and after alpha adrenergic blockade with phenoxybenzamine. Minute ventilation (VE) was measured with a pneumotachograph, cardiac output (CO) by thermodilution and total and regional brain blood flow (BBF) with radiolabeled microspheres. Measurements were performed while the animals were breathing room air and after 10 min of hypoxia induced by breathing 10% O2. Hypoxia was again induced one hour after infusion of phenoxybenzamine (6 mg/kg over 30 min). After 10 min of hypoxia, in the absence of phenoxybenzamine, the animals responded with marked increases in VE (P less than 0.001), CO (P less than 0.001), BBF, and brain stem blood flow (BSBF) (P less than 0.02). However, the normal hemodynamic response to hypoxia was eliminated after alpha adrenergic blockade. There were significant decreases in systemic arterial blood pressure, CO, and BBF during hypoxia after phenoxybenzamine infusion; nevertheless, VE increased significantly (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Lactate and ventilatory thresholds: disparity in time course of adaptations to training

We tested the hypothesis that the lactate threshold (Tlac) during incremental exercise could be increased significantly during the first 3 wk of endurance training without any concomitant change in the ventilatory threshold (Tvent). Tvent is defined as O2 uptake (VO2) at which ventilatory equivalent for O2 [expired ventilation per VO2 (VE/VO2)] increased without a simultaneous increase in the ventilatory equivalent for CO2 (VE/VCO2). Weekly measurements of ventilatory gas exchange and blood lactate responses during incremental and steady-rate exercise were performed on six subjects (4 male; 2 female) who exercised 6 days/wk, 30 min/session at 70-80% of pretraining VO2max for 3 wk. Pretraining Tlac and Tvent were not significantly different. After 3 wk of training, significant increases (P less than 0.05) occurred for mean (+/- SE) VO2max (392 +/- 103 ml/min) and Tlac (482 +/- 135 ml/min). Tvent did not change during the 3 wk of training, despite significant (P less than 0.05) reductions in VE responses to both incremental and steady-rate exercise. Thus ventilatory adaptations to exercise during the first 3 wk of exercise training were not accompanied by a detectable alteration in the ventilatory "threshold" during a 1-min incremental exercise protocol. The mean absolute difference between pairs of Tlac and Tvent posttraining was 499 ml/min. Despite the significant training-induced dissociation between Tlac and Tvent a high correlation between the two parameters was obtained posttraining (r = 0.86, P less than 0.05). These results indicate a coincidental rather than causal relationship.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diphasic ventilatory response to hypoxia in newborn lambs

The ventilatory response of newborn lambs to hypoxemia was evaluated in two groups of seven awake lambs studied at 2 and 7 days of life. Minute ventilation (VE) and airway occlusion pressure (P0.1) were monitored as the animals were exposed in sequence to room air, 12% O2 (15 min), 7% O2 (15 min), and room air. On 12 and 7% O2, 2-day-old lambs experienced a brisk hyperventilation followed by a VE depression, previously described in newborns of other species (diphasic response). The 7-day-old lambs had a clear diphasic VE response only on 7% O2 breathing. In the 2-day-old lambs, at the time of the relative VE depression to 12% O2, the respiratory centers showed a persisting responsiveness to further hypoxia; switching to 7% O2 caused a brisk increase in VE and P0.1 of 70 and 130%, respectively, which was followed again by a VE depression. The magnitude of the immediate VE response to hypoxia, taken as an index of the chemoreceptor strength, was inversely related to the magnitude of the VE depression (R = 0.81, P less than 0.001). It was concluded that 1) lambs as well as other neonates have an age-related diphasic VE response to hypoxia; 2) at the time of the VE depression, the respiratory centers maintain their responsiveness to further acute hypoxia; and 3) the weakness of the chemoreceptors in the newborn is a major determinant of the diphasic response.