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Clinical Science (1991)80,107-112

Effect of theophylline and dipyridamole on the respiratory response to isocapnic hypoxia in normal human subjects S. T. PARSONS, T. L. GRIFFITHS, J. M. L. CHRISTIE

AND

S. T. HOLGATE

Medicine 1, Southampton General Hospital, Southampton, U.K.

(Received 22 March/19 July 1990; accepted 9 August 1990)

SUMMARY 1. Twelve healthy young men took part in this investigation of the effect of oral theophylline and dipyridamole (two drugs known to affect the pharmacological effects of the purine nucleoside adenosine) on the respiratory response to isocapnic hypoxia. 2. The subjects underwent hypoxic rebreathing manoeuvres after 3-day pretreatments with each of the drugs for 12 h and were at least 2 h postprandial. For each inMinute ventilation, the maximum rate of isometric inspiratory pressure development at the mouth and the ratio of inspiratory duration to total breath duration were analysed breath-by-breath and regressions of these variables upon the haemoglobin oxygen saturation were performed. 3. The slopes and intercepts of the lines describing the relationships of minute ventilation and the maximum rate of isometric inspiratory pressure development at the mouth with haemoglobin oxygen saturation were unaffected by the study drugs, and no differences in the pattern of breathing were observed. 4. We conclude that oral administration of these drugs does not result in alteration of the response of the respiratory system to progressive isocapnic hypoxia. 5. This suggests that either adenosine has no physiological role in hypoxic respiratory control as measured, or that it has opposing peripheral chemoreceptor and central respiratory centre effects which could not be distinguished by the techniques used.

Key words: adenosine, dipyridamole, hypoxia, respiration, theophylline. Abbreviations: (dP/dt , , , ,)

maximum rate of isometric inspiratory pressure development at the mouth; Pco,, partial pressure of carbon dioxide; Sao,, haemoglobin Correspondence: Dr T. L. Griffiths, Medicine 1, Level D, Centre Block, Southampton General Hospital, Tremona Road, Southampton SO9 4XY, U.K.

oxygen saturation; T,/ TTOT, inspiratory duration to total breath duration ratio; minute ventilation.

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INTRODUCTION Respiratory stimulation by intravenous infusion of adenosine has been demonstrated in normal human subjects [l-31 and is thought to be produced by the action of adenosine on the peripheral chemoreceptors [2, 4, 51. However, it is unknown whether the effects reported represent a demonstration of a physiological action of adenosine in the carotid bodies or describe an effect unrelated to the activity of the endogenous nucleoside. A complicating factor is the reported central respiratory depressant effect of adenosine analogues demonstrated in animals which is antagonized by methylxanthines [6, 71. It is, therefore, of interest that the overall effect of exogenous adenosine in man is one of respiratory stimulation. This, presumably, indicates either a quantitatively greater peripheral effect or a barrier to the entry of adenosine into the central nervous system respiratory centre [8]. The mechanisms of carotid body function are poorly understood, but adenosine, being produced in hypoxia, could be important in the transduction of arterial hypoxaemia to afferent neural impulses. Hypoxia is sensed only at the carotid bodies in man [9-111 and so this study was designed to investigate the effect of drugs known to affect adenosine metabolism on the carotid body stimulation induced by isocapnic hypoxia. Theophylline is an antagonist of adenosine at cell-surface receptors which has been shown to attenuate the respiratory effects of infused adenosine [ 121. Dipyridamole blocks cellular uptake of adenosine, so increasing its extracellular and plasma concentrations [13], and has been shown to enhance the respiratory stimulation produced by intravenous adenosine boluses [14]. However, it does not cross the blood-brain barrier in humans [15]. By comparing the effects of these drugs and placebo on the ventilatory and respiratory drive responses to hypoxia, it was hoped to demonstrate the role of adenosine in hypoxic respiratory control.

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108 MATERIALS AND METHODS Subjects

Twelve healthy male volunteers participated in the study. None was taking any medication before the experiment and all abstained from xanthine-containing drinks for 12 h and were at least 2 h postprandial. For each individual, experiments were performed, where possible, at the same time of day and on the same day of the week. All gave written informed consent. The study was approved by the Southampton Joint Ethical Sub-committee. Details of the subjects are given in Table 1. Drugs

Subjects took placebo (vitamin C, 50 mg), theophylline (Nuelin SA; 175 or 250 mg tablets; Riker Laboratories, Loughborough, U.K.) or dipyridamole (Persantine; 100 mg tablets; Boehringer Ingelheim, Ingelheim, F.R.G.), 6-hourly for 3 days before each of the three sets of hypoxic studies. Tablets were enclosed in identical opaque rice-paper cachets and given in a double-blind, random-order fashion. The theophylline dose given to each subject and the measured steady-state plasma concentrations of theophylline and dipyridamole as assayed by h.p.l.c. are given in Table 1. Data from the three subjects with steady-state theophylline levels below 10 mg/l were not analysed.

Pressure at the mouth was monitored continuously (Pressure Transducer; Ether Ltd, Stevenage, Herts, U.K.). The differentiated pressure signal, being the rate of change of pressure (dP/dt), was displayed on a pen recorder (MX4; Devices, Ormed Engineering, Welwyn Garden City, Herts, U.K.).The signal response of this system was linear from 0 to 60 cmH,O/s. As an index of respiratory motor drive, the peak rate of inspiratory pressure change, (dP/dt),,,, was entered into the computer manually for each breath. The haemoglobin oxygen saturation (Sao,) was measured continuously with an ear oximeter calibrated using an internal standardization cavity (47201A and 14383A; Hewlett Packard, Wokingham, Berks, U.K.). The Sao, corresponding to each breath was entered manually into the computer. The rebreathe continued until a minimum Sao, of 60-65% was reached. End-tidal Pco, was monitored using an infra-red medical gas analyser (LB-2; Beckman, Cardio Kinetics Ltd, Salford, U.K.) and maintained at pre-rebreathe levels by pumping variable volumes of gas through a Ca(OH),filled chamber. The largest deviation from pre-rebreathe end-tidal Pco, observed was an increase of 0.3 kPa. Two rebreathes were performed at least 30 min apart for each treatment. At the end of each experimental session venous blood was sampled to assay plasma drug concentrations. Analysis

Hypoxic rebreathing

The method used was based on that of Rebuck & Campbell [16]. After reaching a steady end-tidal partial pressure of carbon dioxide (Pco,)and a stable respiratory pattern breathing room air, subjects were connected to a rebreathing bag containing 6-8 litres of room air positioned in a rigid box connected to a bell spirometer (Expirograph; Godart, P. K. Morgan, Chatham, Kent, U.K.). Changes in bag volume were registered by a potentiometer fitted to the spirometer pully. After analogue to digital conversion the signal passed to a BBC microcomputer for derivation of breath-by-breath tidal volumes and inspiratory and expiratory durations. Gas volumes were corrected to BTPS.

Data were collected and analysed for breaths corresponding to an Sao, of between 95% and 65%. Breathby-breath minute ventilation ( was computed from each tidal volume and breath duration. The ratio of inspiratory duration to total breath duration ( T I /TToT ) was also derived from the spirometer signal. The computer produced plots of breath-by-breath (dP/dt),,, and T,/T,,, against Sao, for each rebreathe on each drug. The plots were well fitted by straight lines drawn using simple linear regression and characterized by their gradient and ordinate intercept at an Sao, of 75%. Mean values of these parameters were calculated for the two rebreathes on each drug, there being no statistically significant order effect discernible when the first and second

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Table 1. Details of the subjects studied ~~

Subject (no.) 1 2 3 4 5 6 7 8 9 10 11 12

Age (years) 22 22 22 22 22 22 21 21 21 20 22 22

Weight (kg) 70 71 78 67 70 89 67 75 77 68 60 70

Theophylline dose (mid6 h) 350 350 250 250 350 250 175 250 350 175 250 350

Plasma theophylline level

(ms/l) 15.9 5.8 11.3 15.3 11.8 14.9 7.8 14.7 15.7 19.9 12.9 8.5

Plasma dipyridamole level (mg/l) 0.64 1.10 0.45 0.37 0.08 0.88 0.35 0.45 1.23 0.30

Drug effects on respiratory control runs were compared using paired t-tests. The data were then analysed by using two-way analysis of variance. A P value of < 0.05 was regarded as significant.

RESULTS There were no statistically significant differences between the pre-rebreathe end-tidal Pco, observed with the different drugs (placebo 5.48 f0.20, theophylline 5.31 f0.15 and dipyridamole 5.37 f0.16 kPa, means fSEM). An example of an experimental pen recording is shown in Fig. 1. The Sao, trace shows the decline in saturation from 95% to 60% with a progressive increase in respiratory drive indicated by the deepening (dP/dt),,,. The mouth carbon dioxide trace shows the end-expiratory level remaining constant. Copies of the computer-drawn regressions of and (dP/dt),,, upon Sao, relating to this pen recording are shown in Fig. 2(a) nd Fig. 2(b), respectively. These plots consistently demonstrated the linearity of the relationships. The average gradients of the regression line of upon Sao, for each subject on placebo, dipyridamole and theophylline are shown in Fig. 3(b). Two-way analysis of variance showed no significant difference between drug treatments (F-ratio = 3.44; P> 0.05). Similarly, the mean I'Eat an Sao, of 75% for subjects taking each drug is shown in Fig. 3(a). Two-way analysis of variance again showed no statistically significant difference between drug treatments (F-ratio = 1.103; P> 0.35). Similar findings were made for the relationship between (dP/dt),,, and Sao,. There was no significant difference between drugs in terms of the slope of the regression placebo 0.55 f0.08 dipyridamole 0.59 k 0.09, and theophylline 0.52 f0.06 cmH,O s %Sao,-', means fSEM; F-ratio = 0.28;

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D 0 . 7 6 ) or (dPldt),,, at an Sao, of 75% placebo 15.07 k 1.94, dipyridamole 16.24 f 2.09 and theophylline 15.26f 1.09 cmH,O/s, m e a n s f s ~ ~F-ratio=0.19; ; P> 0.82). Analysis of T,/T,, revealed no consistent change in the pattern of breathing during the rebreathe period recorded and the three treatments produced no change in the response of the breathing pattern to hypoxia.

DISCUSSION We have determined the respiratory response to isocapnic hypoxia in normal subjects and found a linear relationship between both and (dP/dt),,, and Sao,. The range of AVE/ASao, seen in placebo was within the range reported by Rebuck & Campbell [16], although with a narrower range probably resulting from our reporting the mean of two observations in each subject as opposed to reporting individual observations. We chose to record (dP/dt),,, as an index of respiratory drive as it reflects the strength of the initial inspiratory effort which depends on the respiratory centre motor output and respiratory muscle contractility. Its effectiveness as "a means of measuring respiratory drive in response to hypercapnia [ 17, 181 and muscular exercise [ 191 has been demonstrated. Although theoretically, changes in functional residual capacity might affect it [20], Matthews & Howell [17, 181 have shown that (dP/dt),,, is not affected by changes in airways resistance or mechanical loading of the chest as it is registered before the inspiratory valve opens and air flows. Burki et al. [21] have shown a close correlation between the ventilatory and (dP/dt , , ,) responses to isocapnic hypoxia. Thus,

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Fig. 1. Tracing of a chart recording showing the Sao, trace, (dP/dt) signal and carbon dioxide concentration measured at the mouth during a single isocapnic, hypoxic rebreathe. The end-tidal Pco, was held constant in the face of increased alveolar ventilation by allowing a controlled rise in the carbon dioxide level within the breathing circuit.

S. T. Parsons et al.

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Sao, ( O h ) Fig. 2. Copy of the computer-drawn regression of I',( a ) and (dP/dt),,. ( b )upon Sao, for the experiment shown in Fig. 1.The broken line shows the V, and (dP/dt),,,, at an Sao, of 75%.

when dealing with substances such as adenosine and theophylline which may alter airway calibre, at least in asthmatic subjects [22], (dP/dt),,, is useful in providing corroboration of the more conventional indices of the ventilatory response. In spite of this, we have been unable to demonstrate any effect of clinically relevant doses of dipyridamole or theophylline, drugs known to be active on the physiological effects of adenosine, on the ventilatory response to isocapnic hypoxia. It is unlikely that the lack of effect of theophylline was due to inadequate plasma concentrations as subjects with levels below 10 mg/l were excluded from analysis. Furthermore, when the data from those subjects with the highest theophylline or dipyridamole levels were compared either with their placebo runs, or with responses achieved in those with the lowest circulating drug levels, no drug-related pattern could be discerned. The tissue and plasma concentrations of dipyridamole necessary to inhibit cellular uptake of adenosine in the carotid bodies is unknown. Observations by German et al. [13] using the same dipyridamole regimen as in the present experiment showed that plasma adenosine concentrations were maximally raised after 48 h of dipyridamole treatment in humans and that an average plasma concentration of about 1 mg/l was associated with significant elevation of plasma adenosine concentrations. All but two of our subjects had dipyridamole concentrations below this level; however, only two had a value below the range reported by these authors. Whilst the plasma concentration of dipyridamole associated with increases in plasma adenosine concentrations is known, that required to raise extracellular adenosine levels within the carotid bodies is not. Cell-specific differences in sensitivity of adenosine transport to inhibition by dipyridamole

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Fig. 3. ( a ) shows the average ventilation at an Sao, of 75% for each subject (subject nos. are given) after treatment with placebo (mean 41.70 l/min, SEM 4.54), dipyridamole (mean 45.08 I/&, SEM 3.89) and theophylline (mean 39.57 l/min, SEM 2.50) (differences were not significant). ( b ) shows the gradient of the regression of V, upon Sao, for each subject after treatment with placebo (mean 1.36 1 min-' o/o Sao;', SEM 0.19), dipyridamole (mean 1.55 1min-'% Sao;', SEM 0.19) and theophylline (mean 1.21 1mir-' OO/ Sao; ',SEM 0.1 1)(differenceswere not significant).

Drug effects on respiratory control have been observed. For example, concentrations of 2.5-5.0 mg/l are required to inhibit erythrocyte adenosine uptake in whole blood [23], but only 0.1 mg/l is required to inhibit platelet adenosine transport in plasma by 50% [24]. In this context it is not possible to say whether or not the dose of dipyridamole given in this experiment would have significantly altered the carotid body extracellular adenosine concentration in our subjects. However, we are able to draw conclusions as to the effects of the conventional therapeutic dose of the drug. Intravenous theophylline and caffeine have been shown to attenuate the ventilatory stimulation caused by intravenous adenosine [ 12, 251. Dipyridamole, conversely, has been shown to potentiate respiratory stimulation by adenosine when given orally at a dose of 300 mg/day for 7 days [14]. These effects are believed to be due to an interaction at the peripheral chemoreceptors. In man, the respiratory stimulation seen in intact subjects [ 1-41 is not observed in the absence of normal carotid body function [5]. Maxwell et af. [26] have shown potentiation of the hypoxic ventilatory response but not the hypercapnic response by infused adenosine in man; however, all these observations do not necessarily reflect a physiological role for adenosine in carotid body function. Indeed, it is not known whether adenosine is produced in increased amounts in the hypoxic carotid bodies. Interpretation of our results is complicated by reports of a probable physiological central respiratory depressant effect of adenosine. These demonstrate its production in the hypoxic brain [8].Furthermore, in neonatal rabbits [29] and in glomectomized adult cats [30], the respiratory depressant effect of hypoxia normally seen is attenuated by theophylline and, in the rabbit preparation, is potentiated by dipyridamole, suggesting a physiological, central respiratory depressant effect of adenosine. A similar effect of aminophylline on the ventilatory fall seen during sustained hypoxia in man has also been observed [311. Thus one interpretation of our results could be that the lack of an effect of theophylline was due to inhibition of mutually antagonistic peripheral and central adenosinerelated mechanisms. In this model, dipyridamole, which does not enter the brain [15], may either not have been effective in raising carotid body adenosine levels (and so have been without effect), or the elevation of plasma adenosine it produced may have had equal and opposite effects peripherally and centrally. The latter possibility is unattractive as intravenous adenosine is an effective respiratory stimulant in humans. An alternative interpretation is that if carotid body cellular uptake of adenosine was inhibited by dipyridamole and this drug does not enter the central nervous system [15], the lack of effect of either dipyridamole or theophylline on the ventilatory response to hypoxia could suggest that endogenous adenosine does not play an important physiological role in hypoxic respiratory control in adult humans as tested in this experiment. Further research is needed to determine which interpretation is correct. Another interesting aspect of our results is the finding that oral theophylline in conventionally therapeutic doses

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does not enhance the ventilatory response to hypoxia. The effect of methylxanthines (usually given as parented aminophylline) on respiratory control has been the subject of a number of studies. Our finding that resting endtidal Pco, was not significantly changed by theophylline is similar to that of Lakshminarayan et af. [32] and concordant with other studies reporting little change in resting ventilation [33-351. However, Sanders er af. [36] have shown a dose-dependent reduction in resting arterial Pco, after both oral and intravenous aminophylline. The reason for these discrepancies is not clear but may lie in the preparation of subjects for experimentation. Aminophylline is widely held to be a respiratory stimulant but again its effect on the ventilatory response to isocapnic hypoxia is not clear. Lakshminarayan et af. [32] reported an enhancement of the ventilatory response to hypoxia after acute intravenous administration of aminophylline. In contrast, Sanders et af. [36] found no change in hypoxic responsiveness measured at resting end-tidal Pco, after either oral or intravenous aminophylline treatment. Adjustment of the Pco, to pre-aminophylline levels did result in an enhancement of hypoxic responsiveness when assessed with intravenous aminophylline administration. Thus, it may be that the mode of administration of methylxanthines may dictate their effect on hypoxic responsiveness. This may be related to the finding of an increase in respiratory muscle contractility brought about by intravenous aminophylline [37] or other acute xanthine effects. CONCLUSIONS (1) When given orally in clinically relevant doses, neither theophylline nor dipyridamole affect the ventilatory response to isocapnic hypoxia. (2) These findings are consistent with two different interpretations, namely that endogenous adenosine has no role in the ventilatory response to progressive isocapnic hypoxia; or that oral theophylline has equal and opposite effects on peripheral and central respiratory control under these circumstances. (3) Further research is required to determine whether adenosine plays a physiological role in carotid body function.

ACKNOWLEDGMENTS

We are indebted to Dr J. Heath for help with computing. We also thank Boehringer Ingelheim for analysis of plasma dipyridamole levels. The Clinical Lectureship of T.L.G. was funded by Janssen Pharmaceutical Limited.

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adenosine in conscious man. Evidence for chemoreceptor activation. Circ. Res. 1987;61,779-86.

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3. Fuller, R.W., Maxwell, D.L., Conradson, T.-B.G., Dixon, C.M.S. & Barnes, P.J. Circulatory and respiratory effects of infused adenosine in conscious man. Br. J. Clin. Pharmacol. 1987; 24,309-17. 4. Watt. A.H.. Reid., P.G.. Steohens. M.R. & Routledge, P.A. Adenosine’induced respiratory stimulation in man dapends on site of infusion. Evidence for an action on the carotid body? Br. J. Clin. Pharmacol. 1987; 23,486-90. 5 . Griffiths, T.L., Warren, S.J., Chant, A.D.B. & Holgate, S.T. Ventilatory effects of hypoxia and adenosine infusion in patients after bilateral carotid endarterectomy. Clin. Sci. 1990; 78,25-31. 6. Wessberg, P., Hedner, J., Hedner, T., Person, B. & Jonason, J. Adenosine mechanisms in the regulation of breathing in the rat. Eur. J. Pharmacol. 1985; 106,58-68. 7. Eldridge, EL., Millhorn, D.E. & Kiley, J.P. Antagonism by theophylline of respiratory inhibition by adenosine. J. Appl. Physiol. 1985; 59, 1428-33. 8. Berne, R.M., Rubio, R. & Curnish, R.R. Release of adenosine from the ischaemic brain: effect on cerebral vascular resistance and incorporation into cerebral adenine nucleotides. Circ. Res. 1974; 35,262-7 1. 9. Lugliani, R., Whipp, B.J., Seard, C. & Wasserman, K. Effect of bilateral carotid-body resection on ventilatory control at rest and during exercise in man. N. Engl. J. Med. 1971; 285, 1105-1 1. 10. Swanson, G.D., Whipp, B.J., Kaufman, R.D., Aqleh, K.A., Winter, B. & Belville, J.W. The effect of hypercapnia on hypoxic ventilatory drive in normal and carotid body resected man. J. Appl. Physiol. 1978; 45,971-7. 1 1 . Honda, Y., Watanabe, S., Hashizume, I. et al. Hypoxic chemosensitivity in asthmatic patients two decades after carotid body resection. J. Appl. Physiol. 1979; 46,632-8. 12. Maxwell, D.L., Fuller, R.W., Conradson, T.-B. et al. Contrasting effects of two xanthines, theophylline and enprofylline, on the cardio-respiratory stimulation of infused adenosine in man. Acta Physiol. Scand. 1987; 131,459-65. 13. German, D.C., Kredich, N.M. & Bjornsson, T.D. Oral dipyridamole increases plasma adenosine levels in human beings. Clin. Pharmacol. Ther. 1989; 45,80-4. 14. Watt, A.H. & Routledge, P.A. Dipyridamole modulation of heart rate and ventilatory changes produced by intravenous adenosine boluses in man. Br. J. Clin. Pharmacol. 1987; 23, P632-3. 15. Sollevi, A., Link, H. & Fredholm, B.B. Dipyridamole treatment doubles the plasma adenosine level in patients with minor stroke. Thromb. Hemostas. 1983; 50,20. 16. Rebuck, A.S. & Campbell, E.J.M. A clinical method for assessing the ventilatory response to hypoxia. Am. Rev. Respir. Dis. 1974; 109, 345-50. 17. Matthews, A.W. & Howell, J.B.L. The rate of isometric inspiratory pressure development as a measure of responsiveness to carbon dioxide in man. Clin. Sci. 1975; 49, 57-68. 18. Matthews, A.W. & Howell, J.B.L. Assessment of responsiveness to carbon dioxide in patients with chronic airways obstruction by rate of isometric inspiratory pressure development. Clin. Sci. 1976; 50, 199-205. I

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Effect of theophylline and dipyridamole on the respiratory response to isocapnic hypoxia in normal human subjects.

1. Twelve healthy young men took part in this investigation of the effect of oral theophylline and dipyridamole (two drugs known to affect the pharmac...
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