Exaggerated respiratory chemosensitivity and association with SaO2 level at 3568 m in obesity

To investigate whether obesity is associated with alterations in respiratory chemosensitivity, we compared the ventilatory response to hypoxia (HVR) and hypercapnia (HCVR) in 9 obese men (BMI: 37.0+/-4.3 kg m(-2)) and 10 lean men (BMI: 25.8+/-4.8 kg m(-2)). HVR (DeltaVE, L min(-1) per DeltaSaO2, %) was measured by a progressive isocapnic hypoxia technique, and HCVR (DeltaVE/DeltaPETCO2, L min(-1)Torr(-1)) was measured by a progressive hypercapnic method. HCVR, was greater (p<0.001) in the obese men (2.68+/-0.78) than in the lean men (1.4+/-0.45) as was HVR (p<0.05) (1.26+/-0.65 versus 0.71+/-0.43, respectively). The difference (DeltaSaO2, 4.30+/-3.69 and 10.54+/-3.45 in the lean and obese men, respectively, p<0.01) between daytime (86+/-1 and 86+/-1%) and nighttime SaO2 (81+/-3 and 76+/-4%) at a simulated altitude of 3658 m was significantly (p<0.05) correlated with both HVR (r=0.51) and HCVR (r=0.48). These results suggest that chemosensitivity in mildly obese men is increased, not blunted. Furthermore, otherwise healthy, obese individuals have the potential for significant desaturation during sleep at high altitude possibly due to exaggerated sleep-disordered breathing.     

Cardioventilatory effects of acclimatization to aquatic hypoxia in channel catfish

The mechanisms responsible for altering cardioventilatory control in vertebrates in response to chronic hypoxia are not well understood but appear to be mediated through the oxygen-sensitive chemoreceptor pathway. Little is known about the effects of chronic hypoxia on cardioventilatory control in vertebrates other than mammals. The purpose of this study was to determine how cardioventilatory control and the pattern of response is altered in channel catfish (Ictalurus punctatus) by 1 week of moderate hypoxia. Fish were acclimatized for 7 days in either normoxia (P(O(2)) approximately 150 Torr) or hypoxia (P(O(2)) approximately 75 Torr). After acclimatization, cardioventilatory, blood-gas and acid/base variables were measured during normoxia (P(O(2)) 148+/-1 Torr) then at two levels of acute (5 min) hypoxia, (P(O(2)) 72.6+/-1 and 50.4+/-0.4 Torr). Ventilation was significantly greater in hypoxic acclimatized fish as was the ventilatory sensitivity to hypoxia (Delta ventilation/Delta P(O(2))). The increase in ventilation and hypoxic sensitivity was due to increases in opercular pressure amplitude, gill ventilation frequency did not change. Heart rate was greater in hypoxic acclimatized fish but decreased in both acclimatization groups in response to acute hypoxia. Heart rate sensitivity to hypoxia (Delta heart rate/Delta P(O(2))) was not affected by hypoxic acclimatization. The ventilatory effects of hypoxic acclimatization can be explained by increased sensitivity to oxygen but the effects on heart rate cannot.     

Difference in the effects of acetazolamide and ammonium chloride acidosis on ventilatory responses to CO2 and hypoxia in humans

The effects of acetazolamide, a potent carbonic anhydrase inhibitor, and ammonium chloride (NH4Cl) on arterial blood gas tension, resting ventilation, and ventilatory responses to CO2 (HCVR) and hypoxia (HVR) were studied in healthy male subjects. Both drugs induced chronic metabolic acidosis with the reduction in plasma bicarbonate by a mean of 7.0 +/- 2.0 (S.D.) mM after acetazolamide and by 5.6 +/- 1.8 mM after NH4Cl. The ratio in the decrement of PaCO2 to that of plasma bicarbonate (delta PaCO2/delta [HCO3-]) was 1.51 in the former and 0.98 in the latter. Both drugs increased inspiratory minute ventilation (VI) predominantly due to increased tidal volume (VT) with acetazolamide and to increased respiratory frequency (f) with NH4Cl. In HCVR, the increments in CO2- ventilation slope and in ventilation at PETCO2 60 mmHg after drug administration were 0.77 +/- 0.51 l X min-1 X mmHg-1 and 20.0 +/- 11.2 l/min with acetazolamide and 0.59 +/- 0.40 l X min-1 X mmHg-1 and 8.0 +/- 2.8 l/min with NH4Cl, respectively. On the other hand, HVR both in terms of delta VI/delta SaO2 slope and of ventilation at SaO2 75% significantly increased after NH4Cl but not after acetazolamide administration. Thus, augmented VT and HCVR in the acetazolamide group and increased f and HVR in the NH4Cl group suggested that the central chemosensitive mechanism in the former and the peripheral chemosensitive mechanism in the latter may predominantly be responsible for the elevated ventilatory activities.     

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.     

Lack of gender difference in ventilatory chemoresponsiveness and post-hypoxic ventilatory decline

Altered chemoresponsiveness has been postulated to explain the gender difference in the incidence of sleep disordered breathing (SDB). The purpose of this investigation was to ascertain a gender difference in the effect of hypocapnic hypoxia on ventilation. Hypocapnic hypoxia was induced in stable NREM sleep for 3 min periods. In the first analysis, hypoxic ventilatory response in a steady state (SHVR) was defined as the amount of change in minute ventilation (VI) between mean room air (RA) and hypoxia divided by the change in Sa O2 between RA and hypoxia (DeltaVI/DeltaSa O2). The mean group SHVR values were 0.23+/-0.15 and 0.20+/-0.10 L/min per %SaO2, for men and women, respectively (P = ns). In the second analysis, we analyzed the decline in ventilatory parameters after the cessation of hypoxia. There was no difference in VI between the genders (men, 5.6+/-1.7 L/min vs. women, 4.9+/-1.9 L/min, P = ns). We conclude that the gender difference in SDB is not explained by a difference in the ventilatory response to hypocapnic hypoxia.     

Developmental plasticity of ventilatory control in zebrafish, Danio rerio

To determine whether development of ventilatory control in zebrafish (Danio rerio) exhibits plasticity, embryos were exposed to hypoxia, hyperoxia or hypercapnia for the first 7 days post-fertilization. Their acute reflex breathing responses to ventilatory stimuli (hypoxia, hypercapnia and external cyanide) were assessed when they had reached maturity (3 months or older). Zebrafish reared under hyperoxic conditions exhibited significantly higher breathing frequencies at rest (283+/-27min(-1) versus 212+/-16min(-1) in control fish); breathing frequency was unaffected in adult fish subjected to hyperoxia for 7 days. The respiratory responses of fish reared in hyperoxic water to acute hypoxia, hypercapnia or external cyanide were blunted (hypoxia, cyanide) or eliminated (hypercapnia). Adult fish exposed for 7 days to hyperoxia showed no change in acute responses to these stimuli. The respiratory responses to acute hypoxia, hypercapnia or external cyanide of fish reared under hypoxic or hypercapnic conditions were similar to those in fish reared under normal conditions. A subset of all fish examined exhibited episodic breathing; an analysis of breathing patterns demonstrated that fish reared under hypercapnic conditions had an increased tendency to display episodic breathing. The results of this study reveal that there is flexibility in the design and functioning of the embryonic or larval respiratory system in zebrafish.     

Short-latency ventilatory responses to sudden withdrawal of hypoxia at normal and raised body temperature in man

Approximately isopnoeic conditions (VE=40 l/min) were achieved by the inhalation of asphyxial gas mixtures (PA,O2 60 torr, PA,CO2 40-45 torr) in normothermia after a rise in rectal temperature of 1.6 degrees C had been induced by a heated flying suit. Arterial chemoreceptor drive was transiently reduced by either isocapnic removal of hypoxia (type (1) tests: two breaths of CO2 in O2) or simultaneous withdrawal of both hypercapnia and hypoxia (type (2) tests: two breaths of O2). 8-13 tests of each type were performed at both temperature conditions in 6 expts. on 4 healthy human subjects. Expired volume, total breath duration and inspiratory time were recorded, and minute ventilation and expiratory time subsequently computed breath by breath. In hyperthermia the steady-state ventilation of 40 l/min (at a relatively higher respiratory frequency and a correspondingly lower tidal volume) was achieved at a PA,CO2 which was 5 torr lower than in normothermia. Ventilation decreased significantly in all tests. Tested with a 3-way analysis of variance significant differences between the ventilatory responses at the two temperature conditions, and between the two test types were found. The rate of change of ventilation was greater in hyperthermia than in normothermia, and also greater in type (2) tests than in type (1) tests. Since isopnoeic conditions existed prior to the tests, this implies that the arterial chemoreceptor contribution to the total ventilatory drive is increased in hyperthermia. In type (2) tests a significant lengthening of expiratory time was observed in the first test breath. This finding confirms the effect in man of changes in airway PCO2 on lung stretch receptor discharge.     

Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg(-1) I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 +/- 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2 in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 +/- 0.66 vs. 4.07 +/- 1.03 l x min(-1) (mmHg CO2)(-1), P < 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 +/- 0.92 vs. 1.33 +/- 0.46 l x min(-1) (mmHg CO2)(-1), P < 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.     

Effects of five nights of normobaric hypoxia on the ventilatory responses to acute hypoxia and hypercapnia

This study examined the effects of five nights of normobaric hypoxia on ventilatory responses to acute isocapnic hypoxia (AHVR) and hyperoxic hypercapnia (AHCVR). Twelve male subjects (26.6 +/- 4.1 years, standard deviation (S.D.)) slept 8-9 h per day overnight for 5 consecutive days at a simulated altitude of 4,300 m (FiO2= approximately 13.8%). Using the technique of dynamic end-tidal forcing, the AHVR and AHCVR were assessed twice prior to, immediately after, and 5 days following the hypoxic exposure. Immediately following the exposure, AHVR was increased by 1.6 +/- 1.3 L min(-1) %(-1) (P<0.01) when compared with control values. Likewise, after the exposure, ventilation in hyperoxia was increased (P<0.001) and was associated with both an increase in the slope (1.5 +/- 1.4 L min(-1) Torr(-1); P<0.05) and decrease in the intercept (-2.7 +/- 4.3 Torr; P<0.05) of the AHCVR. These results show that five nights of hypoxia can elicit similar perturbations, in both AHVR and AHCVR, as have been reported during more chronic altitude exposures.     

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.     

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.     

Respiratory frequency response to progressive isocapnic hypoxia.

1. Ventilatory, tidal volume and frequency responses to progressive isocapnic hypoxia have been measured in twenty-nine healthy subjects by a rebreathing technique. 2. A strong correlation was found between ventilatory response to hypoxia (deltaVI/DELTASaO2) and frequency response to hypoxia (deltaf/deltaSaO2) (r=0-82, P less than 0-001). There was a lesser correlation between deltaV1/deltaSaO2 and tidal volume response (deltaVT/deltaSaO2) (r=0-50, P less than 0-01). These findings suggest that the wide range of ventilatory response to hypoxia among subjects is mainly determined by differences in frequency response and contrast with previous findings in studies of the response to progressive hypercapnia. 3. The breathing pattern during progressive hypoxia and hypercapnia was compared in ten subjects. Ventilation/tidal volume plots were constructed and patterns of response were further analysed in terms of inspiratory duration (TI), expiratory duration (TE) and mean inspiratory flow rate (VI). 4. Increments in ventilation during hypoxia were achieved with a greater respiratory frequency and a smaller tidal volume than during hypercapnia in eight of the ten subjects studied. In two subjects no difference in breathing pattern during hypoxia and hypercapnia was observed. 5. Changes in respiratory frequency during progressive hypoxia were achieved in all subjects by a progressive shortening of TI and TE. By contrast, TI remained constant during hypercapnia until VT had increased to 3-5 times the eupnoeic value; during hypercapnia the increase in frequency was achieved mainly by a progressive shortening of TE. 6. It is concluded that different mechanisms may be involved in altering respiratory frequency when ventilation is driven progressively by these different chemical stimuli.     

The VO2 response to submaximal ramp cycle exercise: Influence of ramp slope and training status

The aim of the study was to test whether ramp slope and training status interact in the oxygen uptake (VO2) response during submaximal ramp exercise. Eight cyclists (VO2 peak=67.8+/-3.7 ml min(-1)kg(-1)) and eight physically active students (PA students) (VO2 peak=49.1+/-4.3 ml min(-1)kg(-1)) performed several ramp protocols, respectively, 25 and 40 W min(-1) for the cyclists and 10, 25 and 40 W min(-1) for the PA students. Vo(2) was plotted as a function of time and work rate up to the gas exchange threshold (GET). Faster ramp elicited a significantly shorter mean response time (MRT) in both groups, and MRT was significantly longer for each ramp protocol in the PA students (126+/-32s, 76+/-15s and 50+/-6s for ramp 10, ramp 25 and ramp 40, respectively) compared to the cyclists (61+/-9s and 40+/-11s for ramp 25 and ramp 40, respectively). Ramp 40 showed less steep Delta VO2/Delta W than ramp 25 in both groups (p<0.01) and Delta VO2/Delta W was less steep for each ramp protocol in PA students (p<0.01) (9.82+/-0.30 ml min(-1)W(-1) and 9.33+/-0.45 ml min(-1)W(-1) for ramp 25 and ramp 40, respectively) compared to cyclists (10.31+/-0.40 ml min(-1)W(-1) and 10.05+/-0.48 ml min(-1)W(-1) for ramp 25 and ramp 40, respectively). In the PA students, Delta VO2/Delta W did not differ between ramp 10 and ramp 25. Statistical analysis showed no interaction effects between ramp slope and training status for MRT (p=0.62) and Delta VO2/Delta W (p=0.35).     

Enhanced chemosensitivity after intermittent hypoxic exposure does not affect exercise ventilation at sea level

The purpose of the present study was to test the hypothesis that the ventilatory response to exercise at sea level may increase after intermittent hypoxic exposure for 1 week, accompanied by an increase in hypoxic or hypercapnic ventilatory chemosensitivity. One group of eight subjects (hypoxic group) were decompressed in a chamber to 432 torr (where 1 torr=1.0 mmHg, simulating an altitude of 4,500 m) over a period of 30 min and maintained at that pressure for 1 h daily for 7 days. Oxygen uptake and pulmonary ventilation (V_E) were determined at 40%, 70%, and 100% of maximal oxygen uptake at sea level before (Pre) and after (Post) 1 week of daily exposures to hypoxia. The hypoxic ventilatory response (HVR) was determined using the isocapnic progressive hypoxic method as an index of ventilatory chemosensitivity to hypoxia, and the hypercapnic ventilatory response (HCVRSB) was measured by means of the single-breath carbon dioxide method as an index of peripheral ventilatory chemosensitivity to hypercapnia. The same parameters were measured in another group of six subjects (control group). In the hypoxic group, resting HVR increased significantly (P<0.05) after intermittent hypoxia and HCVRSB increased at Post, but the change was not statistically significant (P=0.07). In contrast, no changes in HVR and HCVRSB were found in the control group. There were no changes in either V_E or the ventilatory equivalent for oxygen during maximal and submaximal exercise at sea level throughout the experimental period in either group. These results suggest that the changes in resting hypoxic and peripheral hypercapnic chemosensitivities following short-term intermittent hypoxia have little effect on exercise ventilation at sea level. Electronic Publication     

Intermittent hypoxia reduces cerebrovascular sensitivity to isocapnic hypoxia in humans

The purpose of this study was to determine the changes in human cerebrovascular function associated with intermittent poikilocapnic hypoxia (IH). Healthy men (n=8; 24+/-1 years) were exposed to IH for 10 days (12% O(2) for 5min followed by 5min of normoxia for 1h). During the hypoxic exposures, oxyhemoglobin saturation (SaO(2)) was 85% and the end-tidal partial pressure of CO(2) was permitted to fall as a result of hypoxic hyperventilation. Pre- and post-IH intervention subjects underwent a progressive isocapnic hypoxic test where ventilation, blood pressure, heart rate, and cerebral blood flow velocity (middle cerebral artery, transcranial Doppler) were measured to determine the ventilatory, cardiovascular and cerebrovascular sensitivities to isocapnic hypoxia. When compared to the pre-IH trial, cerebrovascular sensitivity to hypoxia significantly decreased (pre-IH=0.28+/-0.15; post-IH=0.16+/-0.14cms(-1)%SaO(2)(-1); P<0.05). No changes in ventilatory, blood pressure or heart rate sensitivity were observed (P>0.05). We have previously shown that the ability to oxygenate cerebral tissue measured using spatially resolved near infrared spectroscopy is significantly reduced following IH in healthy humans. Our collective findings indicate that intermittent hypoxia can blunt cerebrovascular regulation. Thus, it appears that intermittent hypoxia has direct cerebrovascular effects that can occur in the absence of changes to the ventilatory and neurovascular control systems.     

Effect of hypoxia on ventilatory and arousal responses to CO2 during NREM sleep with and without flurazepam in young adults

We examined the ventilatory response to CO2 at two levels of oxygenation during wakefulness and sleep in healthy young adults before and after the ingestion of a single dose of 30 mg flurazepam. Progressive hypercapnia was produced at two levels of arterial O2 saturation (greater than 99 and 87%) by having subjects re-breathe from a tight-fitting face mask and a reservoir bag containing gas mixtures with two different O2 concentrations. Ventilation was measured with an inductive plethysmograph. O2 saturation was measured with an ear oximeter. Sleep was monitored using standard techniques by recording the electroencephalogram, eye movements, and chin electromyogram. During wakefulness, hypoxia increased the slope of the ventilatory response to CO2 and shifted the response slightly to the left. NREM sleep lowered the slope of the CO2 response under both hyperoxic and hypoxic conditions. The slope of the hyperoxic CO2 response curve was not affected by flurazepam during wakefulness or sleep. After administration of flurazepam to the subjects, the shift of the CO2 response curve to the left produced by hypoxia (additive effect) during NREM sleep was slightly less as compared to control, but hypoxia still increased the slope of the CO2 ventilatory response. During hypoxic hypercapnia, the PCO2 at arousal from sleep was significantly lower than during hyperoxic hypercapnia, but the level of ventilation at arousal during hypercapnia was similar in the control condition and after flurazepam. We conclude that (a) both natural and flurazepam-induced sleep depress ventilatory responses to hyperoxic and hypoxic hypercapnia and alter, in a complex fashion, the effects of hypoxia and hypercapnia on ventilation; and (b) hypoxia and hypercapnia interact as arousal stimuli in both natural and flurazepam-induced sleep.     

Dynamic Ventilatory Response to Acute Isocapnic Hypoxia in Septuagenarians

This study compared the ventilatory response to 20 min of acute isocapnic hypoxia (end-tidal P(O(2)), 50 mmHg) using the technique of dynamic end-tidal forcing in young (Y) and old (O) men. Two groups of non-smoking male subjects (mean +/- s.d. age: Y, 29.8 +/- 6.9 years; O, 73.4 +/- 2.8 years) with similar body size, normal age-predicted spirometry, and normal moderate levels of physical activity were studied. Compared with baseline ventilation in euoxia (10.79 +/- 1.99 and 11.88 +/- 0.91 l min-1) both groups responded to the abrupt onset of isocapnic hypoxia with peak ventilatory responses of 22.58 +/- 2.60 and 24.56 +/- 2.54 l min-1 for Y and O, respectively (not significant, n.s.). Both groups demonstrated a significant increment in neuromuscular drive (i.e. tidal volume (V(T))/inspiratory time (T(I)); 0.46 +/- 0.06 to 0.91 +/- 0.15 and 0.48 +/- 0.06 to 0.91 +/- 0.12 l s-1 for Y and O, respectively) with a small (but also significant) change in central timing (T(I)/total ventilation time (T(tot)); 0.38 +/- 0.02 to 0.41 +/- 0.02 and 0.42 +/- 0.02 to 0.45 +/- 0.02 for Y and O, respectively). Oxygen sensitivity was assessed using Weil's equation, and gave a hyperbolic factor (A) of 282 +/- 75 and 317 +/- 72, and using the linear equation: change in expiratory minute volume (DeltaV.(E))/change in arterial O(2) saturation (DeltaS(a,O(2))) which gave -1.17 +/- 0.57 and -1.17 +/- 0.42 l min-1 %-1 (n.s.) for Y and O, respectively. After 20 min of sustained isocapnic hypoxia, ventilation declined to 14.29 +/- 1.92 and 16.85 +/- 2.34 l min-1 for Y and O, respectively (n.s.). The acute response to hypoxia was characterised by similar time constants (16.0 +/- 5.4 and 18.5 +/- 6.7 s) and time delays (4.8 +/- 2.1 and 4.6 +/- 1.9 s) for Y and O, respectively. Thus, the dynamic ventilatory response to acute isocapnic hypoxia is maintained into the eighth decade in a group of habitually active elderly men. Experimental Physiology (2001) 86.1, 117-126.     

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.     

Exercise intensity-dependent contribution of beta-adrenergic receptor-mediated vasodilatation in hypoxic humans

We previously reported that hypoxia-mediated reductions in alpha-adrenoceptor sensitivity do not explain the augmented vasodilatation during hypoxic exercise, suggesting an enhanced vasodilator signal. We hypothesized that beta-adrenoceptor activation contributes to augmented hypoxic exercise vasodilatation. Fourteen subjects (age: 29 +/- 2 years) breathed hypoxic gas to titrate arterial O(2) saturation (pulse oximetry) to 80%, while remaining normocapnic via a rebreath system. Brachial artery and antecubital vein catheters were placed in the exercising arm. Under normoxic and hypoxic conditions, baseline and incremental forearm exercise (10% and 20% of maximum) was performed during control (saline), alpha-adrenoceptor inhibition (phentolamine), and combined alpha- and beta-adrenoceptor inhibition (phentolomine/propranolol). Forearm blood flow (FBF), heart rate, blood pressure, minute ventilation, and end-tidal CO(2) were determined. Hypoxia increased heart rate (P < 0.05) and minute ventilation (P < 0.05) at rest and exercise under all drug infusions, whereas mean arterial pressure was unchanged. Arterial adrenaline (P < 0.05) and venous noradrenaline (P < 0.05) were higher with hypoxia during all drug infusions. The change (Delta) in FBF during 10% hypoxic exercise was greater with phentolamine (Delta306 +/- 43 ml min(-1)) vs. saline (Delta169 +/- 30 ml min(-1)) or combined phentolamine/propranolol (Delta213 +/- 25 ml min(-1); P < 0.05 for both). During 20% hypoxic exercise, DeltaFBF was greater with phentalomine (Delta466 +/- 57 ml min(-1); P < 0.05) vs. saline (Delta346 +/- 40 ml min(-1)) but was similar to combined phentolamine/propranolol (Delta450 +/- 43 ml min(-1)). Thus, in the absence of overlying vasoconstriction, the contribution of beta-adrenergic mechanisms to the augmented hypoxic vasodilatation is dependent on exercise intensity.