D A Bascom

Changes in arterial K+ and ventilation during exercise in normal subjects and subjects with McArdle's syndrome.

1. We have examined the relationship between ventilation (VE), lactate (La) and arterial plasma K+ concentrations [( K+]a) during incremental exercise in six normal subjects and in four subjects with McArdles syndrome (myophosphorylase deficiency) who do not become acidotic during exercise. 2. In normal subjects, [K+]a rose to ca 7 mM at the point of exhaustion. The time courses of the increases in VE, La and [K+]a were all similar during the exercise period. La reached its peak concentration during the recovery from exercise when both VE and [K+]a were returning to resting levels. 3. McArdles subjects, like normal subjects, had a non‐linear ventilatory response during incremental exercise. Their [K+]a was closely related to VE throughout exercise and recovery. 4. The arterial pH of McArdles subjects, rather than remaining constant, actually rose from the onset of exercise. 5. For a given level of exercise, the levels of VE and [K+]a were greater in the McArdles subjects than in normal subjects. 6. These findings are consistent with the idea that hyperkalaemia may contribute significantly to the drive to breathe, especially during heavy exercise.

Changes in peripheral chemoreflex sensitivity during sustained, isocapnic hypoxia.

One hypothesis concerning the origin of hypoxic ventilatory decline is that hypoxia acts centrally to depress peripheral chemoreflex loop activity. To investigate possible changes in peripheral chemoreflex loop activity during sustained, isocapnic hypoxia, the ventilatory responses to four one minute pulses of either extra hypoxia (45 Torr) or carbon dioxide (8 Torr above resting levels) were measured in man at minutes 2, 7, 12, and 17 of a 23 min isocapnic, hypoxic period (50 Torr). For hypoxia, the first pulse response (130%) was significantly greater (P less than 0.05) than the fourth response (74%). For CO2, pulse responses 2 and 3 (101 and 103%, respectively) were significantly greater (P less than 0.05) than the fourth response (91%). A central depression of peripheral chemoreflex loop activity should affect peripheral sensitivities to CO2 and hypoxia equally. Our results suggest that the peripheral sensitivity to hypoxia declined more than that to CO2, implying a peripheral chemoreceptor origin for hypoxic ventilatory decline.

An assessment of central-peripheral ventilatory chemoreflex interaction using acid and bicarbonate infusions in humans.

1. The object of this study was to investigate the effect of central chemoreceptor stimulation on the ventilatory responses to peripheral chemoreceptor stimulation. 2. The level of central chemoreceptor stimulation was varied by performing experiments at two different levels of end‐tidal CO2 pressure (PCO2). Variations in peripheral chemoreceptor stimulus were achieved by varying arterial pH (at constant end‐tidal PCO2) and by varying end‐tidal O2 pressure (PO2). 3. Two protocols were each performed on six human subjects. In one protocol ventilatory measurements were made during eucapnia, when the arterial pH was lowered from 7.4 to 7.3. The variation in pH was achieved by the progressive infusion of acid (0.1 M HCl). In the other protocol ventilatory measurements were made during hypercapnia, when the arterial pH was increased from 7.3 to 7.4. The variation in pH was achieved by the progressive infusion of 1.26% NaHCO3. In each protocol ventilatory responses were measured during euoxia (end‐tidal PO2, 100 Torr), hypoxia (end‐tidal PO2, 50 Torr) and hyperoxia (end‐tidal PO2, 300 Torr), with end‐tidal PCO2 held constant. 4. The increase in ventilatory sensitivity to arterial pH induced by hypoxia (50 Torr) was not significantly different between protocols (acid protocol, ‐104 +/‐ 31 l min‐1 (pH unit)‐1 vs. bicarbonate protocol, ‐60 +/‐ 44 l min‐1 (pH unit)‐1; mean +/‐ S.E.M.; not significant (n.s.)). The ventilatory sensitivity to hypoxia at an arterial pH of 7.35 was not significantly different between protocols (acid protocol, 14.7 +/‐ 3.3 l min‐1 vs. bicarbonate protocol, 15.6 +/‐ 2.4 l min‐1; mean +/‐ S.E.M.; n.s.). The results provide no evidence to suggest that peripheral chemoreflex ventilatory responses are modulated by central chemoreceptor stimulation.

An assessment of central-peripheral ventilatory chemoreflex interaction in humans.

The independence of the central and peripheral chemoreflexes has been tested in humans. Acute metabolic acidosis generated by a prior bout of brief, hard exercise was used to stimulate primarily the peripheral chemoreceptors, and respiratory acidosis generated by inhaled CO2 was used to stimulate both central and peripheral chemoreceptors. Seven healthy young men were studied. Ventilation and arterial pH, PCO2 and PO2 were recorded. Peripheral chemoreflex sensitivity to hypoxia during acute metabolic acidosis was repeatedly determined by measuring ventilation in euoxia (PETO2 = 100 Torr) and hypoxia (PETO2 = 50 Torr) as the subject recovered from exercise-induced acidosis. Peripheral chemoreflex sensitivity to hypoxia during CO2 inhalation was repeatedly determined by measuring ventilation in euoxia and hypoxia at two levels of hypercapnia (PETCO2 = 45 Torr and PETCO2 = 50 Torr). The ventilatory sensitivity to hypoxia at matched arterial pH values was not significantly different between conditions of high (CO2 inhalation) and low (metabolic acidosis) central chemoreceptor activity. We therefore conclude that interaction between central and peripheral chemoreflexes was non-significant in all subjects.

Effects of dopamine and domperidone on ventilation during isocapnic hypoxia in humans

In order to investigate the role of dopamine in the ventilatory response to sustained, isocapnic hypoxia six subjects were studied three times in each of three pharmacological conditions: (1) in the absence of any drug administration, (2) during i.v. infusion of dopamine (3 micrograms.kg-1.min-1), and (3) after pretreatment with domperidone. Otherwise the experimental protocol was identical on each day and consisted of holding the subjects end-tidal PO2 at 100 Torr for 10 min, then 50 Torr for 20 min and finally at 100 Torr again for 5 min. End-tidal PCO2 was held constant 2-3 Torr above normal throughout the experiment. Domperidone increased, and dopamine decreased the magnitudes of both the fast on- and off-responses, but neither drug affected the magnitude of the hypoxic ventilatory decline (HVD). The results of this study suggests: (1) that a peripheral dopaminergic mechanism is not involved in the genesis of HVD, and (2) the peripheral chemoreflex may be modulated peripherally to produce HVD.

Effects of different levels of end-tidal PO2 on ventilation during isocapnia in humans

The purpose of this investigation was to examine how the ventilatory decline observed during sustained, eucapnic hypoxia (HVD) is affected by different levels of hypoxia. Six subjects were each studied 3-6 times at each of 5 different levels of isocapnic hypoxia (end-tidal PO2 equal to 45, 50, 55, 65 and 75 Torr) in random order. The following variables were linearly related to saturation: (1) the rapid increase in ventilation at the onset of hypoxia; (2) the decline in ventilation over the period of hypoxia; and (3) the undershoot in ventilation below the pre-hypoxic control values at the relief of hypoxia. The rapid decrease in ventilation at the relief of hypoxia, however, was not linearly related to saturation. The mean time to peak ventilation was 2.13 +/- 0.07 min (+/- SE) at the onset of hypoxia, which was significantly longer (P less than 0.05) than the time to minimum ventilation at the relief of hypoxia of 1.23 +/- 0.18 min. The recovery from the undershoot in ventilation was 95% +/- 3% complete after 5 min, whereas the recovery in sensitivity to hypoxia was only 35% +/- 13% complete after 5 min of euoxia.

Ventilatory chemoreflexes at rest following a brief period of heavy exercise in man.

1. Ventilatory chemoreflex responses have been studied at rest during the recovery from a brief period of heavy exercise. 2. Six young, healthy male subjects each undertook four experimental studies. In each study measurements were made at rest during recovery from an exhaustive 1‐2 min sprint on a bicycle ergometer with a workload of 400 W. Three levels of end‐tidal O2 pressure (Po2) were employed. Continuous ventilatory measurements were made during euoxia (end‐tidal Po2, 100 Torr), hypoxia (end‐tidal Po2, 50 Torr) and hyperoxia (end‐tidal Po2, 300 Torr). Arterialized venous blood samples were drawn during each of the measurement periods for the estimation of arterial pH. In two of the studies, end‐tidal CO2 pressure (Pco2) was maintained throughout at 1‐2 Torr above the eucapnic level that existed prior to exercise (isocapnic post‐exercise protocol, IPE). In the other two studies, end‐tidal Pco2 was allowed to vary (poikilocapnic post‐exercise protocol, PPE). Data from a previously published study on the same subjects involving an infusion of hydrochloric acid were used to provide control data with a varying level of metabolic acidosis, but with no prior exercise. 3. Ventilation‐pH slopes in the IPE protocol were no different from control. Ventilation‐pH slopes in the PPE protocol were significantly lower than in the IPE and control protocols (P < 0.05, ANOVA). This difference may be due to the progressive change in end‐tidal Pco2 in the PPE protocol compared with the constant end‐tidal Pco2 in the IPE and control protocols. 4. An arterial pH value of 7.35 was attained 30.4 +/‐ 2.7 min (mean +/‐ S.E.M.) after the end of exercise in the IPE protocol and 17.1 +/‐ 1.4 min after the end of exercise in the PPE protocol. 5. Hypoxic sensitivities at an arterial pH of 7.35 were not significantly different between the IPE, PPE and control protocols (ANOVA). 6. Euoxic ventilation at an arterial pH 7.35 was significantly greater than control for the IPE protocol (P < 0.001, Students paired t test) and no different from control for the PPE protocol. 7. The results suggest that 30 min after heavy exercise, ventilation remains stimulated by processes other than the post‐exercise metabolic acidosis, and that changes in peripheral chemoreflex sensitivity to hypoxia and acid are not implicated in this.

Effects of Varying End-Tidal PO2 on Hypoxic Ventilatory Decline in Humans

It is well-established that at a given end-tidal PCO2, Pet CO2, the magnitude of the acute ventilatory response to hypoxia increases in proportion to the degree of hypoxia, and also that if the hypoxic exposure is prolonged, ventilation falls over 20–30 min, this decline being known as hypoxic ventilatory decline or HVD1. Most studies have thus far concentrated on an individual’s response to only one level of hypoxia. The purpose of this study was to examine the ventilatory response at five different levels of Pet O2.