Low-dose acetazolamide reduces CO(2)-O(2) stimulus interaction within the peripheral chemoreceptors in the anaesthetised cat.

1. Using the technique of end-tidal CO(2) forcing, we measured the effect of the carbonic anhydrase inhibitor acetazolamide (4 mg kg(-1), I.V.) on the CO(2) sensitivities of the peripheral and central chemoreflex loops both during hyperoxia and hypoxia in 10 cats anaesthetised with alpha-chloralose-urethane. 2. In the control situation, going from hyperoxia (arterial P(O2) (P(a,O2)) 47.40 +/- 3.62 kPa, mean +/- S.D.) into moderate hypoxia (P(a,O2) 8.02 +/- 0.30 kPa) led to an almost doubling of the peripheral CO(2) sensitivity (S(P)): a rise from 0.09 +/- 0.07 to 0.16 +/- 0.06 l min(-1) kPa(-1). After acetazolamide, however, lowering the P(a,O2) from 46.95 +/- 5.19 to 8.02 +/- 0.66 kPa did not result in a rise in S(P), indicating the absence of a CO(2)-O(2) stimulus interaction. 3. In hypoxia, acetazolamide reduced S(P) from 0.16 +/- 0.06 to 0.07 +/- 0.05 l min(-1) kPa(-1). In hyperoxia, however, the effect on S(P) was much smaller (an insignificant reduction from 0.09 +/- 0.07 to 0.06 +/- 0.05 l min(-1) kPa(-1)). 4. Acetazolamide reduced both the hyperoxic and hypoxic sensitivities (S(C)) of the central chemoreflex loop: from 0.45 +/- 0.16 to 0.27 +/- 0.13 l min(-1) kPa(-1) and from 0.40 +/- 0.16 to 0.26 +/- 0.13 l min(-1) kPa(-1), respectively. In hyperoxia, the apnoeic threshold B (X-intercept of the ventilatory CO(2) response curve) decreased from 2.91 +/- 0.57 to 0.78 +/- 1.9 kPa (P = 0.005). In hypoxia, B decreased from 1.59 +/- 1.22 to -0.70 +/- 2.99 kPa (P = 0.03). 5. Because acetazolamide abolished the CO(2)-O(2) interaction, i.e. the expected increase in S(P) when going from hyperoxia into hypoxia, we conclude that the agent has a direct inhibitory effect on the carotid bodies. The exact mechanism by which the agent exerts this effect will remain unclear until more detailed information becomes available on the identity of the carbonic anhydrase iso-enzymes within the carotid bodies and their precise subcellular distribution.

The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing.

Inhibitors of nitric oxide synthase (NOS) have analgesic properties and reduce opioid tolerance and dependency. To investigate a possible interaction of NOS inhibitors with the respiratory depressant action of morphine, we determined the effects of the neuronal NOS inhibitor 7-nitroindazole (7-NI) on the ventilatory carbon dioxide response curve; subsequently, we studied the effects of additional morphine application. Finally, using naloxone, we investigated a possible interaction (at the opioid receptor) between the effects of 7-NI and morphine. The effects of 7-NI 50 mg kg-1 i.p., morphine 0.1 mg kg-1 i.v. and naloxone 0.1 mg kg-1 i.v. were studied using dynamic end-tidal carbon dioxide forcing in eight cats under alpha-choralose-urethane anaesthesia. Data analysis was performed using a two-compartment model comprising a fast peripheral and a slow central component characterized by carbon dioxide sensitivities and a single offset B (apnoeic threshold). 7-NI decreased the mean apnoeic threshold from 4.27 (SD 0.87) to 2.59 (1.71) kPa. Peripheral and central carbon dioxide sensitivities were reduced from 0.56 (0.22) to 0.26 (0.09) litre min-1 kPa-1 and from 0.09 (0.05) to 0.04 (0.03) litre min-1 kPa-1, respectively. Morphine increased the apnoeic threshold by 0.5 kPa and reduced carbon dioxide sensitivity by a further 35%. Naloxone reversed the ventilatory effects of morphine but not those induced by 7-NI. We conclude that the respiratory effects of 7-NI and morphine are mediated independently and that the effects of 7-NI do not result from interaction with opioid receptors.

Medroxyprogesterone acetate with acetazolamide stimulates breathing in cats.

Both medroxyprogesterone acetate (MPA) and acetazolamide (ACET) increase ventilation. Combined administration of these agents could result in an additional improvement of blood gases, for example in patients with chronic obstructive pulmonary diseases. The aim of this study in anaesthetized female (ovariohysterectomized, pre-treated with 17-beta-estradiol) cats was to compare the effects on the CO2 response curve of MPA alone (4 microg kg(-1), i.v.) with those after MPA followed by ACET (4 mg kg(-1) i.v.). We performed dynamic end-tidal CO2 forcing and analysed the data with a two-compartment model comprising a fast peripheral and slow central compartment, characterized by CO2 sensitivities (Sp and Sc, respectively) and a single offset (the apnoeic threshold B). MPA reduced Sp from 0.22 +/- 0.09 (mean +/- S.D.) to 0.13 +/- 0.06 L min(-1) kPa(-1) (P < 0.01) and Sc from 1.01 +/- 0.38 to 0.88 +/- 0.32 L min(-1) kPa(-1) (P < 0.01). B decreased from 4.02 +/- 0.27 to 3.64 +/- 0.42 kPa (P < 0.01). Subsequent administration of ACET reduced Sp and Sc further to 0.09 +/- 0.06 and to 0.70 +/- 0.49 L min(-1) kPa(-1) (P < 0.01), respectively. The apnoeic threshold decreased further to 2.46 +/- 1.50 kPa (P < 0.01). Because both treatments reduced ventilatory CO2 sensitivity, we conclude that a simulating effect on ventilation is due to a decrease in the apnoeic threshold. Combined administration of MPA and ACET may lead to larger increases in ventilation than treatment with either drugs alone.

Influences of morphine on the ventilatory response to isocapnic hypoxia.

BACKGROUND: The ventilatory response to hypoxia is composed of the stimulatory activity from peripheral chemoreceptors and a depressant effect from within the central nervous system. Morphine induces respiratory depression by affecting the peripheral and central carbon dioxide chemoreflex loops. There are only few reports on its effect on the hypoxic response. Thus the authors assessed the effect of morphine on the isocapnic ventilatory response to hypoxia in eight cats anesthetized with alpha-chloralose-urethan and on the ventilatory carbon dioxide sensitivities of the central and peripheral chemoreflex loops. METHODS: The steady-state ventilatory responses to six levels of end-tidal oxygen tension (PO2) ranging from 375 to 45 mmHg were measured at constant end-tidal carbon dioxide tension (P[ET]CO2, 41 mmHg) before and after intravenous administration of morphine hydrochloride (0.15 mg/kg). Each oxygen response was fitted to an exponential function characterized by the hypoxic sensitivity and a shape parameter. The hypercapnic ventilatory responses, determined before and after administration of morphine hydrochloride, were separated into a slow central and a fast peripheral component characterized by a carbon dioxide sensitivity and a single offset B (apneic threshold). RESULTS: At constant P(ET)CO2, morphine decreased ventilation during hyperoxia from 1,260 +/- 140 ml/min to 530 +/- 110 ml/ min (P < 0.01). The hypoxic sensitivity and shape parameter did not differ from control. The ventilatory response to carbon dioxide was displaced to higher P(ET)CO2 levels, and the apneic threshold increased by 6 mmHg (P < 0.01). The central and peripheral carbon dioxide sensitivities decreased by about 30% (P < 0.01). Their ratio (peripheral carbon dioxide sensitivity:central carbon dioxide sensitivity) did not differ for the treatments (control = 0.165 +/- 0.105; morphine = 0.161 +/- 0.084). CONCLUSIONS: Morphine depresses ventilation at hyperoxia but does not depress the steady-state increase in ventilation due to hypoxia. The authors speculate that morphine reduces the central depressant effect of hypoxia and the peripheral carbon dioxide sensitivity at hyperoxia.

The influence of indomethacin on the ventilatory response to CO2 in newborn anaesthetized piglets.

1. Indomethacin, a cyclo-oxygenase inhibitor, decreases baseline values of cerebral blood flow, attenuates the cerebrovascular sensitivity to CO2 and stimulates ventilation in newborn piglets. 2. In twelve newborn anaesthetized piglets we investigated the influence of indomethacin on the ventilatory response to CO2 using the dynamic end-tidal forcing technique by applying square-wave changes in end-tidal CO2 tension of 1.5-2.0 kPa at constant end-tidal PO2 of 15 kPa. 3. Each response, measured on a breath-to-breath basis, is separated into a fast peripheral and a slow central component with each component characterized by a CO2 sensitivity, a time constant, a time delay and an apnoeic threshold. 4. The results showed that indomethacin increases the central CO2 sensitivity from 232 +/- 38 to 292 +/- 43 ml min-1 kPa-1 (mean +/- S.E.M.). Neither the peripheral CO2 sensitivity nor the apnoeic threshold changed. 5. The central on-transient and off-transient time constants increased from 50.0 +/- 7.4 and 81.0 +/- 9.6 s, respectively, to 69.1 +/- 9.8 and 139.9 +/- 13.4 s after indomethacin. 6. Using a physiological model we argue that the respiratory effects of indomethacin are due to effects on cerebral blood flow.

Effects of morphine and physostigmine on the ventilatory response to carbon dioxide.

BACKGROUND: It has been reported that physostigmine antagonizes morphine-induced respiratory depression, but it is not known whether this is due to a central chemoreceptor effect, an effect on the peripheral chemoreflex loop, or both. We therefore assessed the effect of morphine and physostigmine on the normoxic hypercapnic ventilatory response mediated by the central and peripheral chemoreceptors in ten alpha-chloralose-urethan-anesthetized cats. METHODS: The breath-by-breath ventilatory responses to stepwise changes in end-tidal CO2 tension were determined before (control), after administration of morphine hydrochloride (0.15 mg.kg-1) and during intravenous infusion of physostigmine salicylate (bolus of 0.05 mg.kg-1 followed by 0.025 mg.kg-1.h-1). Each response was separated into a central and a peripheral chemoreflex characterized by CO2 sensitivity (Sc and Sp), time constant, time delay, and apneic threshold (a single off-set B). RESULTS: Morphine increased B and decreased Sc and Sp (P < 0.01), but not the ratio Sp/Sc. Subsequent infusion of physostigmine decreased B (P < 0.01), without further change of Sp and Sc. Premedication with physostigmine decreased B, Sp and Sc (P < 0.01) vs. control, but not Sp/Sc. Subsequent administration of morphine decreased Sp and Sc further but increased B (P < 0.01), while Sp/Sc remained constant. CONCLUSIONS: Because morphine diminishes the Sc and Sp of the chemoreflex loop to the same extent this depressant effect is presumably due to an action on the respiratory integrating centers rather than on the peripheral and central chemoreceptors as such and is not antagonized by physostigmine. We argue that the increase in B may be due to changes in the amount of acetylcholine available in the brain and can be antagonized by physostigmine.

Ventilatory interaction between hypoxia and hypercapnia in piglets shortly after birth.

In 12 piglets aged 0-1.5 days we assessed the relative contribution of the peripheral and central chemoreceptors in mediating the ventilatory response to CO2 at three levels of arterial O2 tension using the dynamic end-tidal forcing technique. With this technique the ventilatory response is separated into a peripheral and a central component using a two-compartment model. Each component is described by a CO2 sensitivity, a time constant, a transport time and a single apnoeic threshold. The results showed that the sensitivity of the peripheral chemoreceptors significantly (P < 0.01) increased from 25.0 +/- 23.6 ml.min-1.kPa-1.kg-1 (mean +/- SD) during normoxia (PaO2 = 12.8 +/- 0.3 kPa) to 42.5 +/- 29.4 ml.min-1.kPa-1.kg-1 during moderate hypoxia (PaO2 = 8.8 +/- 0.4 kPa) and to 80.2 +/- 44.4 ml.min-1.kPa-1.kg-1 at severe hypoxia (PaO2 = 5.1 +/- 0.3 kPa). There was no significant effect of the level of PaO2 on the other parameters. The results were compared with those obtained in a previous study in piglets aged 2-11 days. It showed that the interaction strength at the level of the peripheral chemoreceptors, defined as the negative ratio of the change in the peripheral CO2 sensitivity to the changes in PaO2 was greater in the younger piglets. From these results we conclude that in the newborn piglet the positive ventilatory interaction between hypoxia and hypercapnia at the level of the peripheral chemoreceptors is already developed shortly after birth and becomes smaller during development.

Hypercapnia induces c-fos expression in neurons of retrotrapezoid nucleus in cats.

To investigate which neurons in the medulla oblongata produced the nuclear protein FOS during stimulation of respiration by hypercapnia, we subjected six anaesthetized cats to 10% CO2 in air for one hour. Four animals inhaled room air. Coronal sections from the medulla oblongata were processed for FOS immunohistochemistry. Only the retrotrapezoid nucleus (RTN) of the animals exposed to CO2 contained a large population of labelled neurons. This indicates that RTN neurons are strongly activated during hypercapnia.

Maturation of the ventilatory response to CO2 in the newborn piglet.

In 12 piglets aged 0 to 1.5 d, we assessed the contribution of the peripheral and central chemoreceptors in mediating the ventilatory response to CO2 and the apneic threshold during normoxia (arterial O2 tension, 13 kPa) using the dynamic end-tidal forcing technique. With this technique, the ventilatory response is separated into a peripheral and a central component using a two-compartment model. Each component is described by a CO2 sensitivity, a time constant, a transport delay time, and an apneic threshold. The means of the estimated parameters per piglet were compared with those obtained in a previous study in piglets aged 2 to 11 d (Wolsink JG, Berkenbosch A, DeGoede J, Olievier CN: J Physiol (Lond) 456:39-48, 1992). The ratio of the peripheral CO2 sensitivity to the total CO2 sensitivity was found to be significantly lower in the younger group of piglets (0.14 +/- 0.10 versus 0.29 +/- 0.10), whereas the apneic threshold was significantly higher (2.52 +/- 1.12 kPa versus 1.06 +/- 1.46 kPa). We conclude that the peripheral chemoreceptors are responsive to CO2 shortly after birth. However, the ventilatory response to CO2 maturates in the first few days after birth by an increase in the relative contribution of the peripheral chemoreceptors to the total ventilatory response and a decreasing apneic threshold.

Effects of eseroline on the ventilatory response to CO2.

The effect of eseroline on the normoxic hypercapnic ventilatory response was assessed in nine alpha-chloralose-urethane-anaesthetized cats. The ventilatory responses to step changes in end-tidal PCO2 were determined before (control), during i.v. infusion of eseroline (bolus of 1.2 mg.kg-1 followed by 0.65 mg.kg-1 x h-1) and 1 h after the end of the infusion. Each response was separated into central and peripheral chemoreflexes, characterized by CO2 sensitivity, time constant, time delay and apnoeic threshold. We found that eseroline depressed ventilation by affecting both tidal volume and breathing frequency. The ventilatory response to CO2 was depressed due to a decrease in the CO2 sensitivity of peripheral chemoreceptors from 0.20 to 0.12 l.min-1 x kPa-1 and in the CO2 sensitivity of central chemoreceptors from 1.04 to 0.50 l.min-1 x kPa-1 (P < 0.01). However, the ratio of these sensitivities was not changed, like the apnoeic threshold. The depressant effect was reversed by naloxone. We conclude that the depressant effect of eseroline on ventilatory response to CO2 is mainly due to an action on the respiratory integrating centres in the brainstem rather than on the CO2 sensitivity of peripheral and central chemoreceptors.

The effects of hypoxia on the ventilatory response to sudden changes in CO2 in newborn piglets.

1. The ventilatory response to square-wave challenges in end-tidal partial pressure of CO2 (PCO2) was investigated at three levels of arterial PO2 (Pa,O2) in nineteen anaesthetized 2- to 11-day-old piglets. 2. The ventilatory responses, measured on a breath-to-breath basis, were separated into a peripheral and a central component using a two-compartment model. Both components were described by a CO2 sensitivity, a time constant, a time delay and a single offset. 3. Fifty-six responses were analysed against a background of normoxaemia (Pa,O2 = 12.70 +/- 0.72 kPa, mean +/- S.D.), fifty-three against a background of moderate hypoxaemia (Pa,O2 = 8.63 +/- 0.34 kPa) and fifty-one against a background of severe hypoxaemia (Pa,O2 = 4.98 +/- 0.30 kPa). 4. The sensitivity of the peripheral chemoreceptors in mediating the response to CO2 increased from 38.3 +/- 17.0 ml min-1 kPa-1 kg-1 during normoxaemia to 48.8 +/- 15.3 ml min-1 kPa-1 kg-1 during moderate hypoxaemia and to 72.9 +/- 24.0 ml min-1 kPa-1 kg-1 at severe hypoxaemia. 5. As compared with the central CO2 sensitivity during moderate hypoxaemia and normoxaemia (104.0 +/- 39.0 and 100.8 +/- 41.6 ml min-1 kPa-1 kg-1, respectively) it decreased to 85.9 +/- 54.1 ml min-1 kPa-1 kg-1 at severe hypoxaemia. 6. We conclude that in newborn piglets there is a positive interaction between hypoxia and hypercapnia at the level of the peripheral chemoreceptors while severe hypoxaemia reduced the CO2 sensitivity centrally.

Effect on ventilation of papaverine administered to the brain stem of the anaesthetized cat.

1. To investigate whether cerebral vasodilatation by itself contributes to the decrease in ventilation as found during brain stem hypoxia the role of cerebral vasodilatation on minute ventilation was investigated in twelve cats anaesthetized with alpha-chloralose-urethane. 2. Cerebral vasodilatation in the medulla oblongata was produced by adding papaverine to the blood perfusing the brain stem. 3. Papaverine at concentrations of 10-35 micrograms per millilitre of blood had an appreciable depressant effect on ventilation. At a concentration of 14.3 micrograms ml-1 the depression in ventilation averaged 0.7 +/- 0.1 l min-1. 4. The ventilatory response to stepwise changes in papaverine concentration could be adequately described with a single exponential function with a time delay. 5. The time constant of the ventilatory response following a step increase in papaverine concentration (134 +/- 15 s) was longer than that of the step decrease (105 +/- 10 s) in concentration (P = 0.034). The time delays of the ventilatory response (88 +/- 21 s and 53 +/- 8 s respectively) were not significantly different (P = 0.126). 6. The ventilatory response to stimulation of the peripheral chemoreceptors by hypoxia and of the central chemoreceptors by hypercapnia was not impaired by papaverine. 7. The results support the hypothesis that cerebral vasodilatation by itself contributes to the decrease in ventilation by brain stem hypoxia.

Ventilatory sensitivities of peripheral and central chemoreceptors of young piglets to inhalation of CO2 in air.

In 20 piglets aged 2-12 d (mean 6.8 d) and anesthetized with alpha-chloralose-urethane, we investigated the contribution of the peripheral and central chemoreceptors to the ventilatory response to inhalation of CO2 in air. For this purpose we used the dynamic end-tidal forcing technique, applying square-wave changes in end-tidal CO2 tension of 1.5-2.0 kPa at a constant end-tidal O2 tension of 15 kPa. Each response, measured on a breath-to-breath basis, was separated into a fast peripheral and a slow central component by fitting the sum of two exponentials to the measured ventilation. Each component was characterized by a CO2 sensitivity, a time constant, a time delay, and an apneic threshold. The results showed that in 2- to 12-d-old piglets the peripheral chemoreceptors are responsive to CO2 during air breathing. The contribution of the peripheral chemoreceptors in mediating the response to CO2 averaged 30 +/- 10%. Within this age range we could not demonstrate a significant correlation of the parameters characterizing the dynamic ventilatory response to CO2 with postnatal age.

Dynamic response of the peripheral chemoreflex loop to changes in end-tidal O2.

We studied the peripheral ventilatory response dynamics to changes in end-tidal O2 tension (PETO2) in 13 cats anesthetized with alpha-chloralose-urethan. The arterial O2 tension in the medulla oblongata was kept constant using the technique of artificial perfusion of the brain stem. At constant end-tidal CO2 tension, 72 ventilatory on-responses due to stepwise changes in PETO2 from hyperoxia (45-55 kPa) to hypoxia (4.7-9.0 kPa) and 62 ventilatory off-responses due to changes from hypoxia to hyperoxia were assessed. We fitted two exponential functions with the same time delay to the breath-by-breath ventilation and found a fast and a slow component in 85% of the ventilatory on-responses and in 76% of the off-responses. The time constant of the fast component of the ventilatory on-response was 1.6 +/- 1.5 (SD) s, and that of the off-response was 2.4 +/- 1.3 s; the gain of the on-response was smaller than that of the off-response (P = 0.020). For the slow component, the time constant of the on-response (72.6 +/- 36.4 s) was larger (P = 0.028) than that of the off-response (43.7 +/- 28.3 s), whereas the gain of the on-response exceeded that of the off-response (P = 0.031). We conclude that the ventilatory response of the peripheral chemoreflex loop to stepwise changes in PETO2 contains a fast and a slow component.

Dynamics of the ventilatory response to central hypoxia in cats.

The dynamics of the effect of central hypoxia on ventilation were investigated by the technique of artificial perfusion of the brain stem in alpha-chloralose-urethan-anesthetized cats. A two-channel roller pump and a four-way valve allowed switching the gas exchanger into and out of the extracorporeal circuit which controlled the brain stem perfusion. When isocapnic hypoxia (arterial PO2 range 18-59 Torr) was limited to the brain stem, a decline in ventilation was consistently found. In 12 cats 47 steps into and 48 steps out of central hypoxia were made. The ventilatory response was fitted using least squares with a model that consisted of a latency followed by a single-exponential function. The latencies for the steps into and out of hypoxia were not significantly different (P = 0.14) and were 32.3 +/- 4.0 and 25.1 +/- 3.6 (SE) s, respectively. The time constant for the steps into hypoxia (149.7 +/- 8.5 s) was significantly longer (P = 0.0002) than for the steps out of hypoxia (105.5 +/- 10.1 s). The time constants for the increase and decrease in ventilation after step changes in the central arterial PCO2 found in a previous study (J. Appl. Physiol. 66: 2168-2172, 1989) were not significantly different (P greater than 0.2) from the corresponding time constants in this study (for 7 cats common to both studies). Theories of the mechanisms behind hypoxic ventilatory decline need to account for the long latency, the similarity between the time constants for the ventilatory response to O2 and CO2, and the differences between the time constants for increasing and decreasing ventilation.

Almitrine and the peripheral ventilatory response to CO2 in hyperoxia and hypoxia.

The effects of almitrine bismesylate (initial intravenous dose 0.6 mg.kg-1 followed by continuous infusion of 0.4 mg.kg-1.h-1) on the ventilatory response to CO2 during hyperoxia and hypoxia were determined in 6 anaesthetized cats with the use of the dynamic end-tidal CO2 forcing technique. It was found that almitrine almost doubled the peripheral ventilatory sensitivity to CO2 during hyperoxia (mean PETO2 45.6 kPa) and also during mild hypoxia (mean PETO2 8.7 kPa). The apnoeic threshold (B) was in both cases shifted to substantially lower values than those of the control measurements. No significant effects of almitrine were found on the central ventilatory sensitivity to CO2 either during hyperoxia or during hypoxia. It is argued that the decrease of the apnoeic threshold may be due to an inhibitory effect of almitrine on the carotid body dopaminergic activity, and that the increase of the sensitivity to CO2 stems from a "hypoxia mimetic" mechanism.

Dynamics of ventilatory response to step changes in PCO2 of blood perfusing the brain stem.

The technique of artificial brain stem perfusion was used to assess the ventilatory response to step changes in PCO2 of the blood perfusing the brain stem of the cat. A two-channel roller pump and a four-way valve allow switching the gas exchanger into and out of the extracorporeal circuit, which controlled the perfusion to the brain stem. Seven alpha-chloralose-urethan-anesthetized cats were studied, and 25 steps of increasing and 23 steps of decreasing PCO2 were analyzed. A model consisting of a single-exponential function with time delay best described the ventilatory response. The time delays 11.7 +/- 8.1 and 6.4 +/- 6.8 (SD) s (obtained from mean values per cat) for the step into and out of hypercapnia, respectively, were not significantly different (P = 0.10) and were of the order of the transit time of the tubing from valve to brain stem. The steady-state CO2 sensitivities obtained from the on- and off-responses were also not significantly different (P = 0.10). The time constants 87 +/- 25 and 150 +/- 51 s, respectively, were significantly different (P = 0.0002). We conclude that the central chemoreflex is adequately modeled by a single component with a different time constant for on- and off-responses.

Dynamic response of peripheral chemoreflex loop to changes in end-tidal CO2.

The dynamic ventilatory response of the peripheral chemoreflex loop after isoxic step changes in end-tidal PCO2 (PETCO2) (range 5-30 Torr) was studied in 12 alpha-chloralose-urethan-anesthetized cats. The technique of artificial brain stem perfusion allowed the response to be observed in isolation from the central chemoreflex loop. The data were fitted by an exponential with time delay. During normoxia the mean time constant and time delay (with SD) were 8.6 +/- 7.3 and 3.3 +/- 0.9 s, respectively (9 cats, 56 runs). During hypoxia [arterial PO2 (PaO2) approximately 60 Torr] these values were 6.0 +/- 4.5 and 2.9 +/- 0.9 s (6 cats, 38 runs). In 17 of the 94 runs an augmented breath occurred in the first three breaths after the stepwise increase in PETCO2. For these augmented breaths, tidal volume, inspiratory time, and expiratory time were not different from the next augmented breath occurring in the same run in the steady state. Neither a rate-sensitive component nor a central neural mechanism (central afterdischarge), with the property of maintaining an increased but slowly declining respiratory activity for some minutes after cessation of the PETCO2 challenge, was found. We conclude that the description of the ventilatory response of the peripheral chemoreflex loop to step changes in PETCO2 with a single exponential and time delay is adequate.

Effects of the dopamine antagonists haloperidol and domperidone on the normoxic ventilatory response to CO2 in cats.

We investigated the effects of the dopamine antagonists haloperidol and domperidone on the ventilatory response following square-wave changes in end-tidal CO2 during normoxia in chloralose-urethane anaesthetized cats. In 7 cats these responses were measured before (control, 28 runs) and after the administration of 1 mg/kg haloperidol i.v. (26 runs) and in 8 other cats before (39 runs) and after 0.5 mg/kg domperidone i.v. (34 runs). Each response was separated into a slow central and a fast peripheral part by fitting two exponential functions to the measured ventilation. These functions have as parameters a CO2 sensitivity, a time constant, a time delay and an apnoeic threshold B (extrapolated PETCO2 of the steady-state response curve at zero ventilation). Haloperidol significantly diminished the peripheral (Sp) and the central (Sc) ventilatory sensitivity to CO2 and the B-value (P less than 0.001). The ratio Sp/Sc, the time constants and the time delays were not significantly changed. Domperidone only diminished the B-value significantly (P less than 0.001). Since domperidone does not readily cross the blood-brain barrier, its effect was a CO2 independent increase of the ventilation mediated by the peripheral chemoreceptors. Haloperidol exhibited, besides the peripheral stimulatory effect a depressant central effect due to an action on the central integrative structures, resulting in a proportional decrease of Sp and Sc.