C.N. Olievier

Relative contribution of central and peripheral chemoreceptors to the ventilatory response to CO2 during hyperoxia.

Using the technique of artificial ponto-medullary perfusion, the steady state ventilation during hyperoxia was measured in 15 anaesthetized cats as a function of the central PaCO2 (PaCO2) and peripheral PaCO2 (PapCO2). To a first approximation the ventilatory response was linearly related to both the central and peripheral arterial carbon dioxide pressures, viz. VE=SC . PacCO2 + Sp . PapCO2 - K where Sc and Sp represent the overall central and peripheral sensitivity to carbon dioxide. The mean ratio Sp/Sc was 0.48 (range 0.21 to 1.08). In carotid sinus denervated cats Sp was zero, while the values of Sc in these cats were in the range of Sc of cats with intact carotid sinus nerves. It is concluded that the peripse to CO2 under steady-state conditions. Chemodenervation experiments revealed that the carotid bodies play an essential role in this contribution.

Effects of brain stem hypoxaemia on the regulation of breathing

In 22 cats, anaesthetized with chloralose-urethane, the brain stem was artificially perfused with their own blood via a gas exchanger in which the central PaO2 and PaCO2 were imposed independently from the peripheral PaO2 and PaCO2 in the systemic arterial blood. The effects of brain stem hypoxaemia on ventilation and on the ventilatory responses to central and peripheral chemoreceptor stimulation were investigated. When the central PaO2 was lowered from 375 mm Hg to 100 and 50 mm Hg, keeping all other blood gas tensions constant, ventilation decreased on the average by 0.22 L X min-1 and 0.54 L X min-1, respectively. The increase in ventilation due to peripheral hypoxaemia and the sensitivities to central and peripheral CO2 (delta VE/delta PaCO2) were independent of the central PaO2, despite the depression of ventilation. The sensitivity to central CO2 was also not influenced when central hypoxaemia was combined with peripheral hypoxaemia. The linear VE-VT relation was not affected by central hypoxaemia. Our findings suggest that the functioning of respiratory neurons in the brain stem is unaltered during moderate central hypoxaemia.

Influence of peripheral O2 tension on the ventilatory response to CO2 in cats

The effects of peripheral hypoxia on ventilation were investigated in 18 cats anaesthetized with chloralose urethane. The ponto-medullary region of the brain was artificially perfused via a cannulated vertebral artery, using an extracorporeal circuit fed from a femoral artery. In this way the carbon dioxide tension (PacCO2) and the oxygen tension in the blood supplying the brainstem could be imposed independently from the peripheral PCO2 (PapCO2) and PO2 (PapO2) in the systemic circulation. In all experiments the brainstem was kept hyperoxic. The steady-state ventilation VE could be described by (formula; see text) where Sp and Sc represent the peripheral and central sensitivity to carbon dioxide and K is a constant. Sc and K were independent of the PapO2. In general, peripheral hypoxia increased and peripheral hyperoxia decreased Sp, compared to normoxia. It is concluded that: (1) there is no interaction in the ventilatory response between peripheral O2-CO2 and central CO2 stimuli; and (2) a positive interaction in the ventilatory response between peripheral hypoxia and CO2 originates from the arterial chemoreceptors.

Artificial perfusion of the ponto-medullary region of cats. A method for separation of central and peripheral effects of chemical stimulation of ventilation☆

A technique is described by which the ponto-medullary region of anaesthetized cats is artificially perfused with their own blood in which the blood gas tensions are varied independently from gas exchange in the lung. Blood from a femoral artery is fed into a foamer and defoamer. After alteration of the blood gas tensions in this equilibrator it is pumped via a cannulated vertebral artery into the medulla oblongata, pons and cerebellum. In this way two separately perfused areas are obtained in which the blood gas tensions can be changed independently. The peripheral chemoreceptors are supplied with blood of the systemic circulation while the central chemoreceptors and respiratory integrating centres are artificially perfused. With this technique the contribution of the peripheral and central chemoreceptors to the total ventilation and their interaction can be assessed. In addition the method is also suitable for studying the effects of drugs on the central regulation of respiration and circulation.

The contribution of the peripheral chemoreceptors to the ventilatory response to CO2 in anaesthetized cats during hyperoxia

Abstract Experiments were performed on nine adult cats anaesthetized with chloralose and urethane. The ventilatory response to CO2 during hyperoxia (FlO2) was determined before and after denervation of the peripheral chemoreceptors. We observed flattening of the upper part of the CO2 response curve occurring at lower levels of V e after vagotomy. The part of the V e vs. PaCO2 curve could be described by a linear relation with slope S and intercept B at zero ventilation. In four cats both the slope and B value remained essentially the same after vagotomy. After subsequent sinus neurotomy a reduction in S in the range of 32–46% (mean 41%) was observed with no systematic change in B. In five cats the sequence of the denervation procedures was reversed. After carotid chemodenervation the slope decreased in the range of 23–54% (mean 41%) with no systematic change in B. When subsequent vagotomy was performed the changes in slope were negligible, except for one experiment where a further reduction in slope of 15% was observed. The arterial blood pressure and the stability of the respiratory variables tended to be more affected when both vagotomy and sinus neurotomy were performed. It is concluded from the slope reductions that in the presence of hyperoxia the contribution of the carotid chemoreceptors to the respiratory response to CO2 amounts to about 40%, and that the relative contribution of the aortic bodies to the ventilation is negligible.

Sites of action of halothane on respiratory pattern and ventilatory response to CO2 in cats.

To assess the major sites of action of halothane on the control of breathing, the ventilatory response to CO2 was studied in 11 cats and partitioned into tidal volume and frequency response. In these cats artificial perfusion of the ponto-medullary region was applied. In essence, this technique allows one to deliver to the brainstem blood-gas tensions and anesthetic concentrations at predetermined levels which are independent from those in the systemic circulation; thus the central and peripheral effects of halothane and CO2 can be determined separately.In cats exposed both centrally and peripherally to halothane (1.0–1.6%) tachypnea was observed which disappeared when the blood perfusing the brainstem was purged of halothane. From these results it follows that the tachypnea is exclusively due to an action of halothane on structures in the brainstem. In these cats the extrapolated PaCO2 at zero ventilation was significantly lower during general halothane anesthesia than during light chloralose-urethane anesthesia (P < 0.05). In cats lightly anesthetized with chloraloseurethane, halothane (0.5–1.5%) was either administered centrally or peripherally. In these experiments teh “overall” ventilatory CO2 sensitivity of both the peripheral and central chemorereflex pathways decreased significantly (P < 0.01). However, the ratio between these two sensitivities remained the same (P > 0.5). The extrapolated PaCO2 at zero ventilation was not affected by halothane provided its concentration was below 1% (P > 0.7). From these results we conclude that the depressant effect of halothane on ventilation originates centrally as well as peripherally. Furthermore, from the findings that the ratio of the CO2 sensitivities and the extrapolated PaCO2 at zero ventilation remained constant, the authors argue that halothane acts on the processing part of the neural respiratory drive (integrating centers) rather than on the neural activity of the peripheral and central chemoreceptors per se. The peripheral effect is mainly on the neuromechanical link between integrating centers and respiratory movements.

Influence of the CSF bicarbonate concentration on the ventilatory response to CO2 in relation to the location of the central chemoreceptors

In anaesthetized cats, in which the cerebrospinal fluid bicarbonate concentration was varied by a ventriculocisternal perfusion technique, the ventilatory response to CO2 during hyperoxia could be satisfactorily described by VE = S(PCSFCO2 -B). Both the slope S and the intercept B were positively and linearly related to the CSF bicarbonate concentration. Assuming that the PCSFCO2 is equal to the PCO2 in extracellular fluid, it can be shown that VE is a linear, but not a unique function of the [H+] at the site of the chemoreceptors; the slope of this relation varies with the bicarbonate concentration at that site, possibly due to chemical complex formation between HCO-3 and Ca2+ or Mg2+. Changes in the B-value were related to the location of the central chemoreceptors with the models of Pappenheimer and Berndt aand their coworkers. It was found that changes in the CSF bicarbonate concentration are reflected for 60 per cent at the site of the central chemoreceptors, and that this was independent of the cerebral perfusion. Using Berndts model a distance between CSF and central chemoreceptors of approximately 100 micron was found; this calculated distance is relatively insensitive to relationship (logarithmic or not) between ventilation and H+ concentration and to changes in cerebral perfusion, owing to the approximate nature of the diffusion model.

Effect of temperature on the ventilation response curve to carbon dioxide in anaesthetized cats

Effects of body temperature on the ventilatory control system were studied in 17 anaesthetized cats. At different body temperatures (stabilized within 0.1 degrees C) CO2 response curves were measured in each cat. In with chloralose-urethan anaesthetized cats it was found that in the body temperature range of 34-40 degrees C, in which neither shivering nor panting occurred, no statistically significant trend with temperature was found in the slope (S) and the extrapolated intercept on the PaCO2-axis (B) of the linear CO2 response curve during hyperoxia as well as hypoxia. In two with pentobarbital anaesthetized cats similar results were obtained. The resting ventilation (at FICO2 = 0) did not change significantly, while the resting PaCO2 during hyperoxia showed a trend to increase with temperature just reaching the level of significance (P less than 0.05). Breathing frequency increased significantly with temperature (P less than 0.0005). When body temperature was elevated above 41 degrees C both the slope (S) and the intercept of the CO2 response curve (B) decreased. In three cats ventriculo-cisternal perfusion was performed and no apparent influence of body temperature was found on the relation between the PCSFCO2 and PETCO2 and on the VE-PCSFCO2 response curves. These findings show that body temperature has no important modifying effect on the ventilatory response to CO2 in anaesthetized cats in the temperature range of 34-40 degrees C.

Effects of CO2 and H+ on the ventilatory response to peripheral chemoreceptors stimulation

To determine whether the stimulatory effect of CO2 on the peripheral chemoreceptors is due to molecular CO2, H+ or both we measured steady-state ventilation (Ve) during normoxia in 9 and during hypoxia in 5 chloralose-urethane anaesthetized cats using the artificial brain stem perfusion technique. This technique allows one to manipulate independently the PaCO2, PaO2 and the pHa of the blood in the systemic circulation (peripheral) and the blood perfusing the brain stem (central). Keeping the central conditions constant the H+ and CO2 concentrations in the systemic circulation were changed by i.v. infusion of 0.3 M HCl or 0.6 M NaHCO3 and by giving the animal different CO2 mixtures to inhale. The peripheral H+ concentration ([H+]p) range covered was from 27 to 103 nmol X 1(-1); the peripheral arterial CO2 tension (PaPCO2) ranged from 2.3 kPa to 8.4 kPa. Fitting the data with the function VE = a[H+]p + bPaPCO2 + c revealed that the coefficient b was not significantly different from zero at the 0.05 level during normoxia and hypoxia. The mean value (+/- SEM) found for the coefficient a was 33.0 +/- 3.6 at normoxia and 36.0 +/- 15.4 ml X min-1 X nM-1 at hypoxia. We conclude that the steady-state ventilatory response due to the stimulation of the peripheral chemoreceptors with CO2 is mediated by H+. The effects of molecular CO2 are negligible.

In vivo measurement of carbon dioxide tension with a miniature electrode.

A commercially available catheter type electrode with whichPCO2 can be continuously measured in vivo and in vitro gave progressively less accurate results the longer the measuring period was extended. This proved to be due to temperature effects and a change in sensitivity with time. A correction procedure for these effects was developed which was based on two observations. 1. The relationship between temperature and the logarithm of the sensitivity of the electrodeamplifier combination was linear and virtually identical for 9 electrodes: 8% change in sensitivity for a deviation of 1° C from the temperature during calibration. 2. The change in sensitivity due to drift of the electrode output is approximately a logarithmic function of time: 1 h after calibration all electrodes exhibited a decreased sensitivity, varying between 0.3 and 16.7%. The drift effect can be dealt with by repeated calibrations, preferably at 11/2 h intervals.The adequacy of the correction procedure was assessed in in vivo measurements in cats and dogs. The meanPCO2 difference between the in vivo measurement, corrected for temperature and drift, and samples analyzed with a conventional electrode, was 0.005 kPa (0.04 mm Hg) with a standard deviation of 0.187 kPa (1.39 mm Hg).