"Individual differences in breathlessness during exercise, as"
5691 Journal of Physiology (1997), 499.3, pp.843-848 843 Individual differences in breathlessness during exercise, as related to ventilatory chemosensitivities in humans Nariko Takano, Satoru Inaishi and Yingzhen Zhang Physiology Laboratory, Department of School Health, Faculty of Education, Kanazawa University, Kanazawa 920-11, Japan 1. The present study attempted to test the hypothesis that breathlessness associated with exercise hyperpnoea is greater in subjects with greater activities of the central and peripheral chemoreceptors during exercise. The chemoreceptor activities were assessed by resting estimates of hypercapnic ventilatory response (AIE/APco,, HCVR) and hypoxic ventilatory response (AVE/-ASo2, HVR), respectively, where VE is minute ventilation and So2 is oxygen saturation. 2. Nine female and nine male subjects performed a 1 min incremental exercise test until exhaustion, during which breathlessness intensity (BS), assessed by a Borg category scale, and Vwere measured every minute. The maximum 02 uptake (Vo2 max) was also determined. 3. Using a stepwise multiple linear regression analysis, the relative contributions of not only VE, HCVR and HVR, but also t02,max and a predicted maximum voluntary ventilation (MVVp) of the individuals to BS, were examined. 4. The analysis showed that BS = 0g1IE + 4'9HVR - 0-03MVVP + 0 55 (r2 = 0-71), indicating that IE accounted for 44% of the variance of BS, HVR for 12% and MVVp for 15%. No significant relation of HCVR and P02 max to BS was found. 5. These results suggest a contribution of peripheral chemoreceptors to the generation of exertional breathlessness. Although its precise mechanism is not fully clarified, the hyperkalaemia with a resultant increase in ventilation (Nye, sensation of breathlessness has been considered to be 1994). The central chemoreceptors have been assumed to produced primarily by a centrally generated respiratory function during exercise, resulting in acid-base homeostasis motor command signal (Killian, Gandevia, Summers & through a fine tuning of the ventilatory response to Campbell, 1984; Adams, Lane, Shea, Cockcroft & Guz, increased CO2 production (Ward, 1994). 1985; Cherniack & Altose, 1987), with modulations by inhibitory afferent feedback from lung and chest wall Thus we hypothesized that the breathlessness associated mechanoreceptors (Chonan, Mulholland, Cherniack & Altose, with exercise hyperpnoea is greater in subjects with greater 1987) and excitatory afferent feedback from central and activities of the central and peripheral chemoreceptors peripheral chemoreceptors (Ward & Whipp, 1989; Chonan, during exercise. The present study was undertaken to test Mulholland, Leitner, Altose & Cherniack, 1990). Concerning this hypothesis. Activities of the central and peripheral the modulation by the chemoreceptors, it has been chemoreceptors during exercise were assessed by resting demonstrated that increases in the chemoreceptor activities estimates of hypercapnic ventilatory responsiveness (HCVR) with hypercapnia (Stark, Gambles & Lewis, 1981; Chonan and hypoxic ventilatory responsiveness (HVR), respectively. et al. 1990) or with hypoxia (Ward & Whipp, 1989) cause It has been reported that HCVR (Poon & Greene, 1985) and more intense breathlessness, while the ventilatory levels are HVR (Weil, Byrne-Quinn, Sodal, Kline, McCullough & kept the same as those before the changes in the blood-gas Filley, 1972; Martin, Weil, Sparks, McCullough & Grover, pressures. 1978; Regensteiner, Pickett, McCullough, Weil & Moore, 1988) increase with increasing exercise intensity, and the The peripheral chemoreceptors appear to be activated during exercise estimates of HVR depend on the resting estimates of exercise, as shown by their involvement in the regulation of HVR (Martin et al. 1978; Regensteiner et al. 1988; Igarashi, exercise hyperpnoea, such as 02-labile ventilatory drive up to Nishimura, Akiyama, Yamamoto, Miyamoto & Kawakami, 20% of exercise hyperpnoea, acceleration of the ventilatory 1994). The relative contributions of these chemosensitivities kinetics, respiratory compensation for lactic acidosis in heavy to the determination of the breathlessness intensity during exercise (Whipp, 1994), and reaction to exercise-induced exercise were examined using a multiple regression analysis. Downloaded from J Physiol (jp.physoc.org) by guest on December 23, 2009 844 N Takano, S. Inaishi and Y Zhang J Physiol. 499.3 METHODS Incremental exercise test. After 2 min unloaded cycling on a bicycle ergometer, the subjects exercised at a 1 min incremental Subjects work load until exhaustion. The rate of increment of the load was Nine female subjects (aged 22 + 5 years (mean + S.D.); weight, 49 + 25 W min-' at the pedalling rate of 70 r.p.m. for the male subjects 5 kg; height, 158 + 5 cm) and nine male subjects (aged 24 + 4 years; and 15 W min-' at 50 r.p.m. for the female subjects. The subjects weight, 65 + 6 kg; height, 172 + 4 cm) volunteered for this study, adjusted the pedalling rates by watching a speedometer. At each after giving written, informed consent. They were all healthy non- incremental work load, BS was measured at 45 s of the 1 min smokers, and had taken part in recreational sports. All subjects period and VE was assessed by averaging the breath-by-breath data were unaware of the purpose of this study, but knew that it during the last half-minute of the 1 min period. Maximum 02 involved the measurement of breathlessness during exercise. The uptake (PO2,max) was determined as the average value of breath-by- experiment was carried out at least 3 h after the subject's last meal. breath data of V02 during the last 1 min of the exercise test and was Measurements normalized for body weight. The subjects breathed through a respiratory mask (dead space, Before the tests, the subjects underwent a training session in order 200 ml) to which a hot-wire flowmeter was fixed in order to measure to familiarize them with the use of the modified Borg category scale respiratory flow. Respiratory gas was continuously sampled for breathlessness scoring, while wearing the respiratory mask and (200 ml min-') from a nostril and introduced into a C02-02 gas exercising. analyser (MG-360, Minato Medical Co., Japan), with which the CO2 and 02 concentrations were analysed through an infrared Multiple linear regression analysis absorption and zirconium oxide reaction, respectively. Signals from We hypothesized that BS is related linearly and additively to PE the flowmeter and gas analyser were fed into a computer (RM-200, during exercise and to HVR, HCVR and other variables, if Respiromonitor, Minato Medical Co.) and processed breath by present, of the individual subjects, giving an equation such as breath to obtain pulmonary ventilation (VE), 02 uptake (VO2), CO2 y = a, x, + a2 X2 + . . . + a. x, + constant, where y is a dependent elimination (Vco) and end-tidal Po, and Pco2 Heart rate (HR) was variable (i.e. BS), x, to x. independent variables, and a, to a., monitored through an electrocardiogram. Arterial oxygen saturation respectively, regression coefficients. A stepwise multiple linear (802) was measured using a finger oximeter (Oximet, Minoruta regression analysis was applied to test the hypothesis. All the Camera Co., Osaka, Japan). independent variables were introduced first for the analysis, and then more suitable variables were chosen so that the F value of a The intensity of breathlessness during exercise (BS) was assessed final multiple regression model, and partial F values of the with the use of a modified Borg category scale (Borg, 1982). The independent variables chosen became maximum and significant at subjects were asked 'How severe is your discomfort when breathing?' a < 0 05 for the F distribution. Standardized regression coefficients ('Ikigurushisa ha donokurai ka?' in Japanese), and in response of the independent variables, which were defined as regression were required to point to a score on a scale that had eleven values coefficients standardized for the units of the variables and ranging from 0 (not at all breathless) to 10 (maximally breathless), calculated as an8.D.x /8.D.Y (where S.D. iS standard deviation), were accompanied by adjectival descriptions, as shown in Fig. 1. The considered to indicate the relative contribution of the independent subjects were required to avoid rating the magnitude of breath and variables to BS. non-respiratory sensations such as headache or leg fatigue. Tests Three tests were given to the subjects in the following order. RESULTS Transient hypoxic test for HVR assessment. This was based on Figure 1 shows VE-BS relationships during incremental the method of Shaw, Schonfeld & Whitcomb (1982). A reservoir bag exercise in all subjects, indicating progressive increases in containing pure N2 was connected to an inspiratory port of a BS with increasing PE. BS at given levels of V, varied greatly J-valve, which was fixed to a hot-wire flowmeter. After VE and HR among the subjects, partly due to individual differences in reached steady state during air breathing, the inspired gas was the exercise ventilatory response. Therefore, BS was plotted switched to N2 and three to eight breaths of N2 were imposed on against TE/MVVp (%), as shown in Fig. 2, where MVVp the subjects, followed by air breathing. Subsequent hypoxic was a predicted maximum voluntary ventilation and was transients with a different number of N2 breaths were resumed calculated using Nishidas formula (Nishida et al. 1986). after end-tidal Po2, 802 and HR returned to the air-breathing levels. The individual variations in PE-BS and TE/MVVp-BS Peak VE (actually calculated as the mean value of the two highest consecutive VE) and the lowest S02 that occurred within 10-20 s relationships were assessed in terms of the coefficient of following the last breath of N2 were obtained in each hypoxic variance (c.v., mean/s.D., as a percentage) of VE levels, at transient, and then using the data from all the six hypoxic which BS was 5. The cv. was 44 % in the PE-BS relationship transients a linear regression of peak VE against the lowest S02 was and 27% in the IE/MVVp-BS relationship, indicating a analysed for each subject by a least-squares method. The slope of 39 % reduction of the individual variation of BS with the regression line, A1E/-ASO2, was designated as HVR. normalization of PE for MVVp and hence a dependency of C02 rebreathing test for HCVR assessment. This was based on BS on MVVp. Thus MVVp was adopted as an independent the method of Read (1967). After VE and HR reached steady state variable in the multiple regression analysis. In addition, during air breathing, the subjects rebreathed a 7% CO2-93% 02 gas contained in a reservoir bag for 4 min, during which end-tidal V°2,max was taken into consideration as another independent variable, since Adams, Chronos, Lane & Guz (1986) have PCo2 and VE were measured. A regression line of the end-tidal reported a significant correlation between physical fitness of PC02-VE relationship was calculated and the slope (AVE/APcO2) was subjects and the breathlessness intensity during exercise. defined as HCVR. Consequently, five independent variables that were assumed Downloaded from J Physiol (jp.physoc.org) by guest on December 23, 2009 J Physiol. 499.3 Breathlessness during exercise 845 BS (units) Maximal 10 Very, very severe 8 Very severe 6 Severe Somewhat severe 4 [ Moderate Slight 2 Very slight Not at all 0 0 40 80 120 160 VE (I min-1) Figure 1. V.-BS relationship during incremental exercise in individual subjects The thin lines represent females, and thick lines represent males. 10 r 8 6 cn C m 4 2 0 I 0 20 40 60 80 100 VE/ MVVP (%) Figure 2. V./MVVp-BS relationship during incremental exercise in individual subjects For explanation, see Fig. 1. Downloaded from J Physiol (jp.physoc.org) by guest on December 23, 2009 846 N Takano, S. Inaishi and Y Zhang J Physiol. 499.3 Table 1. Variabilities of four independent variables in eighteen subjects Independent variable Mean + S.D. Range HVR (1 min' (-%)-') 0-37 + 015 016-0O64 HCVR (1 min-' mmHg-') 2-71 + 1-74 093-7-27 MVVp (1 min-') 127 + 35 82-165 02,max (ml min-' kg-') 42X5 + 6'0 32'8-57-3 to affect BS, i.e. VE during exercise and HVR, HCVR, to greater activities of the chemoreceptors during exercise. MVVp and V02,max of the subjects, were included in a To test the hypothesis, a multiple linear regression analysis multiple linear regression analysis, by which the interaction with five independent variables of not only HVR and HCVR of these variables to determination of BS was analysed. but also MVVp and V2omax of the subjects and VE during Variabilities between the subjects of the latter four exercise was used. The values of HVR and HCVR in our independent variables are shown in Table 1. subjects (Table 1) were within the ranges of the previously reported values for HVR (Edelman, Epstein, Lahiri & As shown in Table 2, the multiple regression analysis gave the result that BS during exercise was related positively to Cherniack, 1973; Shaw et al. 1982) and HCVR (Irsigler, 1976), measured using virtually identical tests as in this VE and HVR, but inversely to MVVp. Neither HCVR nor study. 70,,max was related to BS. The analysis demonstrated that the intensity of breath- Consequently, the multiple linear regression equation was: lessness during exercise could be explained by a multiple BS = 0'lVf + 4-9HVR 003MVVp + 0 55, which explained - regression model with three independent variables of VE 71 % of the variance. The equation indicates that BS during exercise, HVR and MVVp of the subjects. The model increased linearly with increasing VE during exercise, and explained 71 % of the variance, and indicated that the that this regression line on a VE-BS graph was located more breathlessness intensity increases linearly with increasing to the left (upward) in the subjects with higher HVR and more to the right in those with higher MVVp. Based on the PE, and the VE-associated breathlessness is augmented by HVR and reduced by MVVp of the subjects. In other words, results of r2 and standardized regression coefficients, it was estimated that on average, VE accounted for 44% of BS subjects with higher levels of HVR perceive greater intensities of breathlessness at given levels of VE and those (0X71 x 0X91 x 100/(0 91 + 0'24 + 0'32)), HVR for 12% with higher levels of MVVp perceive lower intensities of and MVVp for 15%. Needless to say, as VE increased, the breathlessness. contribution of VE increased, while that of the other two variables decreased. Breathlessness during exercise and I7 Proportional increases in exertional breathlessness to VE have been observed by various investigators (e.g. Adams DISCUSSION et al. 1986; Leblanc, Bowie, Summers, Jones & Killian, The working hypothesis of this study was that subjects with 1986; Chonan et al. 1990; Lane, Adams & Guz, 1990). The higher HVR and/or HCVR perceive more intense breath- multiple regression model revealed that compared with lessness associated with exercise hyperpnoea, probably due HVR and MVVp, VE was a more predominant determinant Table 2. Multiple linear regression equation for determining the breathlessness intensity during exercise Independent Regression Standard regression Partial variable coefficient coefficient F value a VE 0098 0912 413-6 < 001 HVR 4-884 0244 32-3 <0-01 HCVR n.s. n.s. n.s. n.s. MVVP -0027 -0-316 47-4 < 0-01 VO,2max Constant n.s. 0554 n.s. n.s. 07 n.s. n.s. Multiple regression model r2 = 7 (F= 142'5, a < 0 01). The equation is given as BS = aVE + bHVR + 710 cHCVR + dMVVp + elk 2,max + constant, in which a to e are regression coefficients. r2 is the coefficient of d determination of the model. n.s., not significant. Downloaded from J Physiol (jp.physoc.org) by guest on December 23, 2009 J Physiol. 499.3 Breathlessness during exercise 847 of the breathlessness intensity during exercise. Although Such an augmented breathlessness was not confirmed in the the model did not clarify sensory mechanisms mediating the study of Lane et al. (1990), in which increases in the VE-associated breathlessness, the perception of respiratory breathlessness intensity during incremental exercise were muscle effort mediated by the motor command signals found to be similar in normoxic and hypoxic conditions. In appears to be involved (Killian et al. 1984; Leblanc et al. their study the breathlessness sensation was defined as 'an 1986). uncomfortable need to breathe'. Inconsistent results between the two studies may be due to the adoption of different Breathlessness during exercise and MVVp experimental protocols and definitions of breathlessness. A dyspnoea index defined as VE/MVVP (Wright & Filley, 1951) has been available to patients for assessing the Breathlessness during exercise and HCVR attainability of dyspnoea to an intolerable level during The present finding of a lack of significant correlation exercise, implying that attainability is dependent on between BS and HCVR suggests less involvement of the maximum breathing capacities of the patients. Dependency central chemoreceptors in determination of the breath- of the breathlessness intensity on MVVp was also lessness intensity during exercise. This seems to be in line observed in our healthy subjects, such as those with lower with the studies of Ward & Whipp (1989) and Lane et al. MVVp perceiving greater intensities of exertional breath- (1990), which demonstrated that stimulation of the central lessness. Adams et al. (1986) have attributed 50% of the chemoreceptors by CO2 inhalation during exercise exerted individual difference in exertional discomfort at a VE of no influence on the breathlessness intensity, while VE was 50 1 min-' to MVVp of individuals. In the present study, isopnoeic compared with normocapnic exercise. the multiple regression model indicated that at a given Breathlessness during exercise and physical fitness level of VE, MVVP explained, on average, 41% (0.71 x 0-32 x 100/(0 32 + 0 24)) of the individual difference Adams et al. (1986) have reported an inverse correlation of the breathlessness intensity, this result being compatible between the breathlessness intensity at a VE of 501 min-' with that of Adams et al. (1986). during exercise and physical fitness of the individuals, which was evaluated by the heart rate response during Breathlessness during exercise and HVR exercise. If a correlation analysis with a single independent The multiple regression model indicated that HVR of the variable of o02,max is applied to the present results, a similar subjects acted to increase the sensation of breathlessness result to that of Adams et al. (1986) is obtained, such as an during exercise, and at a given level of VE it accounted for inverse correlation between BS at a VE of 50 1 min-' and 31% (0-71 x 0-24 x 100/(0 32 + 0 24)) of the breathlessness V02,max in the individuals (r=-0-77, n=18, P<0-01). intensity. HVR was assessed under resting conditions, on That is the case in BS at VE of 30, 40 and 60 1 min-m the assumption that it is indicative of not only HVR during (r= -061 to -0 73, P< 0 05). The multiple regression exercise but also the magnitude of the peripheral chemo- analysis, in which the interaction of the five independent receptor activity during exercise. Martin et al. (1978) have variables (VE, HVR, HCVR, MVVp and 72, max) to BS was demonstrated that in light exercise the °2 drive estimated analysed, however, showed no significant contribution of by the Dejours' 02 test varied from 5 to 45% of total VE °2,max to BS determination (Table 2). In our subject group among subjects and was correlated with the resting estimate (n = 18), a significant correlation between V02,max was seen of HVR. However, the entire magnitude of the peripheral in HCVR (r= 0 50), HVR (r= -0 58), and MVVp chemoreceptor activity might not be assessable by HVR and (r = 0 60). The inverse correlation between %2Vmax and HVR 02 drive, even if they were measured during exercise, since leads us to speculate that an effect of VO2 maX giving rise to a during exercise the chemoreceptors are likely to be activated lower intensity of breathlessness during exercise might be by not only hypoxic but also non-hypoxic stimuli, such as exerted secondary to a reduction of HVR. Regarding a increased arterial [K+] and [H+] (Nye, 1994; Whipp, 1994), reduction of HVR with increasing physical fitness, some under which abolition of carotid body activity by hyperoxia investigators have argued for this (Byrne-Quinn, Weil, appears to be incomplete (Rausch, Whipp, Wasserman & Sodal, Filley & Grover, 1971; Scoggin, Doekel, Kryger, Huszczuk, 1991). With these reservations and based on the Zwillich & Weil, 1978) but others have argued against it study of Ward & Whipp (1989), it is suggested that the (Godfrey, Edwards, Copland & Gross, 1971; Martin et al. peripheral chemoreceptor activities during exercise increased 1978; Mahler, Moritz & Loke, 1982). A longitudinal study more markedly in those with higher HVR, resulting in more with long-term exercise training may elucidate the inter- intense breathlessness. relation between changes in exertional breathlessness, Ward & Whipp (1989) observed that during moderate physical fitness and the peripheral chemosensitivity. exercise with hypoxia, subjects perceived more intense In conclusion, it was examined how the peripheral and breathlessness than during exercise with hyperoxia; in both central chemosensitivities (HVR and HCVR, respectively) exercise conditions VE was kept isopnoeic and the sensation of the subjects were involved in determination of the BS of breathlessness was qualified as the difficulty in breathing. associated with VE during exercise. The interrelations of not It was suggested that an increased activity of the carotid only VE, HVR and HCVR, but also MVVp and V02 max to BS bodies is likely to augment the sensation of breathlessness. were tested using a multiple linear regression analysis. It Downloaded from J Physiol (jp.physoc.org) by guest on December 23, 2009 848 N Takano, S. Inaishi and Y Zhang J Physiol. 499.3 showed that BS = 01VE + 4-9HVR - 003MVVP + 0 55 AIARTIN, B. J., WEIL, J. V., SPARKS, K. E., MCCULLOUGH, R. E. & (r2 = 0-71), indicating that VE accounted for 44% of the GROVER, R. F. (1978). Exercise ventilation correlates positively with ventilatory chemoresponsiveness. Journal of Applied Physiology variance of BS, HVR for 12% and MVVP for 15%. No 45, 557-564. significant relation of HCVR and V02 max to BS was found. NISHIDA, O., KAMBE, M., Y'OSHIMI, T., SHIGENOBU, T., MIASAKI, S., These results suggest an involvement of peripheral chemo- SEWAKE, N., ARITA, K., OGOSHI, AM. & NISHIMOTO, Y. (1986). receptors, but less involvement of central chemoreceptors in Pulmonary function in healthy subjects and its prediction (in Japanese). Rinshou Byouri 24, 833-836. the generation of exertional breathlessness. NYE, P. C. G. (1994). Identification of peripheral chemoreceptor stimuli. Mledicine and Science in Sports and Exercise 26, 311-318. POON, C. S. & GREENE, J. G. (1985). Control of exercise hyperpnea during hypercapnia in humans. Journal of Applied Physiology 59, ADAMS, L., CHRONOS, N., LANE, R. & Guz, A. (1986). The 792-797. measurement of breathlessness induced in normal subjects: individual differences. Clintical Science 70, 131-140. RAUSCH, S. AM., WHIPP, B. J., WASSERMAN, K. & HuszczUK, A. (1991). Role of the carotid bodies in the respiratory compensation ADAMS, L., LANE, R., SHEA, S. A., COCKCROFT, A. & Guz, A. (1985). for the metabolic acidosis of exercise in humans. Journal of Breathlessness during diffierent forms of ventilatory stimulation: a Physiology 444, 567-578. study of mechanisms in normal subjects and respiratory patients. Clinical Science 69, 663-672. READ, D. J. C. (1967). A clinical method for assessing the ventilatory response to carbon dioxide. Australian An nals of MIedicine 16, BORG, G. (1982). Psychophysical bases of perceived exertion. Mledicinie 20-32. anid Science int Sports and Exercise 14, 377-381. REGENSTEINER, J. G., PICKETT, C. K., AICCULLOUGH, R. E., WEIL, BYRNE-QUINN, E., WEIL, J. V., SODAL, I. E., FILLEY, G. F. & J. V. & MOORE, L. G. (1988). Possible gender differences in the effect GROVER, R. F. (1971). Ventilatory control in the athlete. Journal of of exercise on hvpoxic ventilatory response. Respiration 53, Applied Physiology 30, 91-98. 158-165. CHERNIACK, N. S. & ALTOSE, A. D. (1987). Mechanisms of dyspnea. SCOGGIN, C. H., DOEKEL, R. D., KRYGER, MI. H., ZWILLICH, C. W. & Clinics in C/lest Medicine 8, 207-214. WEIL, J. V. (1978). Familial aspects of decreased hypoxic drive in CHONAN, T., MULHOLLAND, AM. B., CHERNIACK, N. S. & ALTOSE, M. D. endurance athletes. Journal of Applied Physiology 44, 464-468. (1987). Effects of voluntary constraining of thoracic displacement SHAW, R. A., SCHONFELD, S. A. & W HITCOMB, AI. E. (1982). during hypercapnia. Journal of Applied Physiology 63, 1822-1828. Progressive and transient hypoxic ventilatory drive tests in healthy CHONAN, T., MULHOLLAND, AM. B., LEITNER, J., ALTOSE, AM. D. & subjects. Americant Review of Respiratory Disease 126, 37-40. CHERNIACK, N. S. (1990). Sensation of dyspnea during hypercapnia, STARK, R. D., GAMBLES, S. A. & LEWIS, J. A. (1981). Methods to exercise, and voluntary hyperventilation. Journal of Applied assess breathlessness in healthy subjects: a critical evaluation and Physiology 68, 2100-2106. application to analyse the acute effects of diazepam and EDELMAN, N. H., EPSTEIN, P. E., LAHIRI, S. & CHERNIACK, N. S. promethazine on breathlessness induced by exercise or by exposure (1973). Ventilatory responses to transient hypoxia and hypercapnea to raised levels of carbon dioxide. Clinical Scienice 61, 429-439. in man. Respiration Physiology 17, 302-314. \VARD, S. A. (1994). Peripheral and central chemoreceptor control of GODFREY, S., EDWARDS, R. H. T., COPLAND, G. MI. & GROSS, P. L. ventilation during exercise in humans. Canadian Journal of Applied (1971). Chemosensitivity in normal subjects, athletes, and patients Physiology 19, 305-333. with chronic airway obstruction. Journal of Applied Physiology 30, WVARD, S. A. & WHIPP, B. J. (1989). Effects of peripheral and central 193-199. chemoreflex activation on the isopnoeic rating of breathing in IGARASHI, T., NISHIMURA, M., AKIYAMA, Y., YAMAMOTO, M., exercising humans. Journal of Physiology 411, 27-43. MIYAMOTO, K. & KAWAKAMI, Y. (1994). Effect of aminophylline on WEIL, J. V., BYRNE-QUINN, E., SODAL, I. E., KLINE, J. S., plasma [K'] and hypoxic ventilatory response during mild exercise MICCULLOUGH, R. E. & FILLEY, G. F. (1972). Augmentation of in men. Journtal of Applied Physiology 77, 1763-1768. chemosensitivity during mild exercise in normal man. Journal of IRSIGLER, G. B. (1976). Carbon dioxide response lines in young adults: Applied Physiology 33, 813-819. The limits of the normal response. A nerican Review of Respiratory \VHiPP, B. J. (1994). Peripheral chemoreceptor control of exercise Disease 114, 529-536. hyperpnea in humans. Medicine and Science in Sports antd Exercise KILLIAN, K. J., GANDEVIA, S. C., SUMMERS, E. & CAMPBELL, E. J. M. 26, 337-347. (1984). Effect of increased lung volume on perception of WVRIGHT, G. WV. & FILLEY, G. F. (1951). Pulmonary fibrosis and breathlessness, effort, and tension. Journial of Applied Physiology respiratory function. A merican Journal of Mledicine 10, 642-661. 57, 686-691. LANE, R., ADAMS, L. & Guz, A. (1990). The effects of hypoxia and hypercapnia on perceived breathlessness during exercise in humans. Acknowledgements Journal of Physiology 428, 579-593. The authors acknowledge financial support of the Ono Sports LEBLANC, P., BOwIE, D. AM., SUMMERS, E., JONES, N. L. & Foundation for this research. KILLIAN, K. J. (1 986). Breathlessness and exercise in patients with Author's email address cardiorespirator clisease. A merica7n Review of Respiratory Disease 133, 21-25. N. Takano: email@example.com a-u.ac.jp AIAHLER, D. A., AIORITZ, E. D. & LOKE, J. (1982). Ventilatory responses at rest and during exercise in marathon runners. Journial Received 22 April 1996; accepted 21 Noviember 1996. of Applied Physiology 52, 388-392. Downloaded from J Physiol (jp.physoc.org) by guest on December 23, 2009