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The asthmatic athlete: metabolic and ventilatory responses during exercise with and without pre-exercise… Ienna, Tiziana Mona 1994

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THE ASTHMATIC ATHLETE: METABOLIC AND VENTILATORY RESPONSES DURING EXERCISE WITH AND WITHOUT PRE-EXERCISE MEDICATION By TIZIANA MONA IENNA  A THESIS SUBMrTTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES School of Human Kinetics  We accept this thesis as conforming to the required standard  TIlE UNiVERSiTY OF BRITISH COLUMBIA May 1994 © Tizana M. lenna, 1994  in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my In presenting this thesis  department  or  by  his  or  her  representatives.  It  is  understood  that  copying  or  publication of this thesis for financial gain shall not be allowed without my written permission.  (Signature)  Department  of  The University of British Columbia Vancouver, Canada Date  DE-6 (2/88)  L%  ABSTRACT To determine whether asthmatic athletes have normal physiological responses to exercise without pre-exercise medication, we studied 17 female and male asthmatic subjects, 9 highly trained ( Hi’) (age = 26.1 ± 5.7 yrs; ht = 173.6 ± 10.5 cm; wt = 66.4 ± 10.8 kg; VO2max 24.1 ± 3.1 yrs; ht  =  57.0 ± 4.9 ml.kg-’.min-’), and 8 moderately trained (MT) (age = 183.1 ± 11.8 cm; wt = 78.6 ± 15.3 kg; VO2max = 51.3 ± 4.8 ml•kg  min- ) with exercise-induced asthma (ETA) under 2 randomly assigned experimental 1 conditions: salbutamol ( S  )( 2 puffs = 200 jig) or placebo (PL) was administered via  metered-dose inhaler 15 minutes prior to exercise. The exercise task was 4 continuous 5 minute increments on an electronically braked cycle ergometer representing 25, 50, 75, and 90% of the subject’s VO2max. V0 , minute ventilation (VE), respiratory exchange 2 ratio (RER), % saturation (Sa02), and HR were continuously measured during exercise. A venous catheter was inserted in the subject’s antecubital vein to allow measurement of blood lactate (La) each minute throughout exercise and recovery. Post-medication, exercise, and recovery measurements of peak expiratory flow rates (PEFR) were made using a Mini-Wright flow meter. The data failed to show significance (p > 0.05) between treatment conditions at any stage of exercise with respect to 2 V0 VE, RER, HR, and Sa02. However, among , the HT group the mean HR for the 4 exercise conditions was significantly higher under placebo (151.7 (PL) vs. 147.2 (S): p = 0.01). No difference was found in La during exercise or in recovery. Pre-exercise PEFR was significantly higher (582(S) vs. 545 L.sec-’(PL): p =0.003 ) when pretreatment was salbutamol, but prior to treatment there was no difference between the two pre-exercise PEER’s. Mean PEER measures for the exercise and recovery conditions were significantly higher ( 600.1(S) vs. 569.6 (PL): p = 0.002) with the salbutamol treatment. Scheffe’s post-hoc comparisons indicated a II  significant difference in mean PEER measures with respect to the two treatments between low intensities (25 % and 50 %) and high intensities (75 % and 90 %) of exercise. There was no difference in the physiological response to exercise between groups based on training status. It was concluded that although salbutamol affects the PEER, these asthmatic athletes do not have altered metabolic or ventilatory responses during exercise.  m  TABLE OF CONTENTS  Abstract  ii  Table of Contents  iv  List of Tables  v  List of Figures  x  List of Abbreviations and Symbols  xii  Acknowledgements  xiv  Introduction  1  Methods  4 Subjects  4  Methacholine Challenge Test  5  Maximal Oxygen Uptake Test  6  Experimental Procedures  6  Lactate Analysis  8  Statistical Analysis  8  Results  10  Discussion  22  References  28  Appendix A- Review of Literature  34  Appendix B- Tables  53  Appendix C- Figures  90  iv  LIST OF TABLES  Table 1  Physical characteristics of the subjects (mean ± SD, range)  10  Table 2  V02, YE, HR, RER, and Sa02 of all subjects ( n  11  Table 3  , VE, HR, RER, and Sa02 of highly trained (n 2 V0  =  17), group data =  9), group  data Table 4.  12  , YE, HR, RER, and Sa02 of moderately trained (n=8) group 2 V0 data  Table 5.  12  Lactate (mmol.Fl) of all subjects, highly trained and moderately trained,  group data Table 6  13  PEFR (l.sec-1) of all subjects, highly trained and moderately trained, group data  Table 7  13  Age, height, weight, VO2max, and PC2O, individual data of subjects in the Highly trained group  Table 8  53  Age, height, weight, VO2max, and PC2O, individual data of subjects in the Moderately trained group  Table 9  , RER, PEFR, and Sa02 at 25 % VO2max with placebo, 2 YE, V0 individual subject data ( n  Table 10  =  17)  55  , RER, PEFR, and 5a02 at 25 % VO2max with salbutamol, 2 VE, V0 individual subject data ( n = 17)  Table 11  54  56  , RER, PEFR, and Sa02 at 50% VO2max with placebo, 2 YE, V0 individual subject data ( n = 17)  V  57  Table 12  , RER, PEFR, and Sa02 at 50 % VO2max with salbutamol, 2 VE, V0 individual subject data ( n = 17  Table 13  =  17)  =  17  )  =  17  )  64  65  , RER, PEER, and Sa02 at 75 % VO2max with salbutamol, 2 VE, V0 individual subject data for the HT group  Table 23  64  , RER, PEER, and Sa02 at 75 % VO2max with placebo, 2 VE, V0 individual subject data for the HT group  Table 22  63  , RER, PEER, and Sa02 at 50 % VO2max with salbutamol, 2 VE, V0 individual subject data for the HT group  Table 21  63  , RER, PEFR, and Sa02 at 50 % VO2max with placebo, 2 VE, V0 individual subject data for the HT group  Table 20  62  , RER, PEFR, and Sa02 at 25 % VO2max with salbutamol, 2 VE, V0 individual subject data for the HT group  Table 19  61  , RER, PEFR, and Sa0 2 2 at 25 % VO2max with placebo, VE, V0 individual subject data for the HT group  Table 18  60  , RER, PEFR, and Sa02 at 90 % VO2max with salbutamol, 2 VE, V0 individual subject data ( n  Table 17  59  , RER, PEFR, and Sa02 at 90% VO2max with placebo, 2 VE, V0 individual subject data ( n  Table 16  )  , RER, PEFR, and Sa02 at 75 % VO2max with salbutamol, 2 VE, V0 individual subject data ( n  Table 15  58  , RER, PEFR, and Sa02 at 75 % VO2max with placebo, 2 VE, V0 individual subject data ( n = 17  Table 14  )  65  , RER, PEER, and Sa02 at 90 % VO2max with placebo, 2 VE, V0 individual subject data for the HT group  vi  66  Table 24  , RER, PEFR, and Sa02 at 90 % VO2max with salbutamol, 2 VE, V0 individual subject data for the HT group  Table 25  VE, V02, RER, PEFR, and Sa02 at 25 % VO2max with placebo, individual subject data for the MT group  Table 26  =  17  )  71  Pre and post medication and recovery PEFR measures with salbutamol, individual subject data ( n = 17  Table 35  70  Pre and post medication and recovery PEFR measures with placebo, individual subject data ( n  Table 34  70  VE, V02, RER, PEFR, and Sa02 at 90 % VO2max with salbutamol, individual subject data for the MT group  Table 33  69  , RER, PEFR, and Sa02 at 90% VO2max with placebo, 2 VE, V0 individual subject data for the MT group  Table 32  69  , RER, PEFR, and Sa02 at 75 % VO2max with salbutamol, 2 VE, V0 individual subject data for the MT group  Table 31  68  , RER, PEFR, and Sa02 at 75 % VO2max with placebo, 2 VE, V0 individual subject data for the MT group  Table 30  68  VE, V02, RER, PEFR, and Sa02 at 50 % VO2max with salbutamol, individual subject data for the MT group  Table 29  67  VE, V02, RER, PEFR, and Sa02 at 50% VO2max with placebo, individual subject data for the MT group  Table 28  67  VE, V02, RER, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data for the MT group  Table 27  66  )  72  Pre and post medication and recovery PEER measures with placebo, individual subject data for the HT group  vII  73  Table 36  Pre and post medication and recovery PEFR measures with salbutamol, individual subject data for the HT group  Table 37  73  Pre and post medication and recovery PEFR measures with placebo, individual subject data for the MT group  Table 38  74  Pre and post medication and recovery PEFR measures with salbutamol, individual subject data for the MT group  Table 39  Blood lactates (mmoltl) at 25, 50, 75, and 90 % VO2max with placebo, individual subject data ( n = 17  Table 40  74  )  75  Blood lactates 1 (mmol.l measures at rest and recovery conditions ) with placebo, individual subject data ( n = 17  Table 41  =  17  )  77  Blood lactates (mmol•l) measures at rest and recovery conditions 1 with salbutamol, individual subject data ( n = 17  Table 43  76  Blood lactates ( mmol.1) at 25, 50,75, and 90 % VO2max with 1 salbutamol, individual subject data (n  Table 42  )  )  Blood lactates ( mmol l) at 25, 50, 75, and 90 % VO2max with placebo, individual subject data for the HT group  Table 44  80  Blood lactates (mmolt ) measures at rest and recovery conditions 1 with salbutamol, individual subject data for the HT group  Table 47  79  Blood lactates (mmol.[l) at 25, 50, 75, and 90 % VO2max with salbutamol,individual subject data for the HT group  Table 46  79  Blood lactates (mmoitl) measures at rest and recovery conditions with placebo, individual subject data for the lIT group  Table 45  78  80  Blood lactates 1 (mmol.P at 25, 50, 75, and 90 % VO2max with ) placebo,individual subject data for the MT group  vi’  81  Table 48  Blood lactates (mmol.l ) measures at rest and recovery conditions 1 with placebo, individual subject data for the MT group  Table 49  Blood lactates (mmol.1l) at 25, 50,75, and 90 % VO2max with salbutamol,individual subject data for the MT group  Table 50  82  The duration of exercise test with salbutamol and placebo, individual subject data (n = 17  Table 52  82  Blood lactates (mmol.1l) measures at rest and recovery conditions with salbutamol, individual subject data for the MT group  Table 51  81  )  83  The duration of exercise test with salbutamol and placebo, individual subject data for the HT and MT groups  84  Table 53  RMANOVA summary (N =17)  85  Table 54  RMANOVA summary for PEFR and Blood lacatate measurements  85  Table 55  RMANOVA summary for the lIT group  86  Table 56  RMANOVA summary for the MT group  87  Table 57  RMANOVA summary for subjects with a PC2O < 4.0 mg.ml 1  88  Table 58  Baseline spirometry for the lIT group  89  Table 59  Baseline spirometry for the MT group  89  ix  LIST OF FIGURES  Figure 1  Figure 2  Figure 3  Figure 4  Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12  PEFR (l•sec) measures under salbutamol and placebo conditions 1 at various exercise intensities and 3 to 15 minutes into recovery, all subject data ( n = 17 )  16  PEFR (l•sec) measures under salbutamol and placebo conditions 1 at various exercise intensities and 3 to 15 minutes into recovery, HT groupdata(n=9)  17  PEFR (l.sec ) measures under salbutamol and placebo conditions 1 at various exercise intensities and 3 to 15 minutes into recovery, MT groupdata(n=8)  18  PEFR (l.secl) measures under salbutamol and placebo conditions at various exercise intensities and 3 to 15 minutes into recovery, 1 (n =6) group data PC2O <4.0mg. mF  19  Blood lactate ( mmol.1 ) at various exercise intensities and 1 to 10 1 minutes into recovery, all subject data ( n = 17 )  20  HR (bpm) responses at various exercise intensities, HT group data(n=9)  21  V0 (l.nthrl) responses at various exercise intensities (% VO2max), 2 all subject data ( n = 17)  90  ) responses at various exercise intensities (%VO2max), 4 V0 (l•min 2 HT subject data  91  V0 (l.miir 2 ) responses at various exercise intensities (% VO2max), 1 MT subject data  92  ) responses at various exercise intensities (% VO2max), 1 VE (Fmin all subject data ( n = 17)  93  ) responses at various exercise intensities (% VO2max), 1 VE (lmiir Hi’ subject data  94  ) responses at various exercise intensities (% VO2max), 4 VE (1.mlir HT subject data  95  x  Figure 13 Figure 14 Figure 15 Figure 16 Figure 17 Figure 18 Figure 19 Figure 20  HR (bpm) responses at various exercise intensities (% VO2max), allsubjectdata(n=17)  96  HR (bpm) responses at various exercise intensities (% VO2max), MT subject data  97  RER responses at various exercise intensities (% VO2max), aflsubjectdata(n=17)  98  RER responses at various exercise intensities (% VO2max), HT subject data  99  RER responses at various exercise intensities (% VO2max), MT subject data  100  Sa02 responses at various exercise intensities (% VO2max), all subject data ( n = 17 )  101  Sa02 responses at various exercise intensities (% VO2max), HT subject data  102  Sa02 responses at various exercise intensities (% VO2max), MT subject data  103  Figure 21  Blood lactate (mmol.li) at various exercise intensities (% VO2max), HT subject data 104  Figure 22  Blood lactate (mmol.1 ) at various exercise intensities (% VO2max), 1 MT subject data 105  xi  List of Abbreviations &Svmbols  (X  alpha  (A-a)D02  alveolar-arterial difference  (A-a)P02  alveolar-arterial partial pressure of oxygen  ANOVA  analysis of variance beta  Ca  calcium ion  cAMP  cyclic adenosine monophosphate  CNS  central nervous system  EIA  exercise-induced asthma  EIH  exercise-induced hypoxemia  EIh  exercise-induced hyperventilation  75 .. 25 FEF  mid-maximal expiratory flow  FEV1  forced expiratory volume in one second  FVC  forced vital capacity  HR  heart rate  HT  highly trained  bC  International Olympic Commission  La  blood lactate  MMEF  mid-maximal expiratory flow  MT  moderately trained  PEFR  Peak expiratory flow rate  xI1  Pa02  arterial partial pressure of oxygen  PaCO2  arterial partial pressure of carbon dioxide  PC20  concentration of agent that will provoke a 20 % fall in FEV1  pHa  arterial pH  RER  respiratory exchange ratio  RMANOVA  repeated-measures analysis of variance  Sa02  oxygen saturation of arterial hemoglobin  VA/Q  alveolar ventilation-perfusion ratio  VE  volume of air expired per minute  V02  rate of oxygen uptake  VO2max  maximal rate of oxygen uptake  xlii  Acknowledgements  I would like to express my thanks and appreciation to the subjects for their participation and cooperation in this study, and to several individuals who contributed to the evolution and successful completion of this thesis. First, my thanks to my thesis committee members Drs. Don McKenzie, Ken Coutts, and Pierce Wilcox for their help and guidance. I would like to give special thanks to my advisor, Don McKenzie for his endless encouragement and support, both emotional and fmancial. As well, his enthusiasm, expertise, and quality of research in the area of exercise physiology has been an invaluable contribution to the development of my own interests and research skills. I hope to continue these standards in my future endeavors. To Diana Jespersen, whose practical knowledge and skills in the lab were an invaluable contribution during my data collection period. Also, for her help and patience in teaching me how to use the equipment and solving any problems that arose. To Dr. Coutts for his expertise and knowledge in the lab, and problem solving ability made the completion of my thesis possible. Thanks also goes to Han J 00 Eom for all his statistical advice. To Angelo Belcastro for allowing me access to his lab and offering his equipment and expertise in the lactate analyses. To my lab-mates and fellow colleagues, Trevor and Sue who assisted me in subject recruitment and always provided a stimulating learning environment, and special thanks to Jim Potts for his kindness, support and encouragement throughout my graduate studies. I would also like to acknowledge Glaxo Canada Inc. for their financial support. Finally, to my dearest friends Annita and Gavin who I have learned a lot from and whose unconditional support and encouragement have helped me to explore my unique interests, talents, and potential. xiv  INTRODUCTION  Exercise-Induced Asthma (EIA) is a reversible airway disease that occurs in almost all individuals with asthma when challenged under appropriate exercise conditions. Among competitive athletes the prevalence of asthma is higher than one would expect; sixty-seven of the 597 (11.2%) athletes competing in the 1984 Olympic games suffered from EIA (67).  The type of exercise performed plays a major role in the severity of bronchoconstriction. Running outdoors is the most asthmogenic followed by treadmill running indoors, cycling, swimming, and walking (2). Intermittent activities such as soccer or baseball are better tolerated than continuous activities such as rowing or cross -country skiing. 5-8 minutes of exercise at an intensity of 60-80 % of predicted maximal oxygen consumption increase the chances of an attack; exercising any longer than this, may diminish the response (59). Exercising in environmental conditions where the air is warmed and humidified can provide a protective effect on the airways (19, 37). Similarly, warm-up exercises and regular aerobic conditioning can attenuate and decrease the incidence of EIA (31, 48). Although many preventative measures can be taken to modify the severity of asthma, pharmacological intervention is oftened required. Inhaled salbutamol (Ventolin®), a f2- agonist, is a commonly used medication in the prophylactic management of EIA (20, 28). Its powerful bronchodilating effect and 132 selectivity can virtually abolish bronchospasm when taken 10-15 minutes prior to exercise. The effects of salbutamol on physiological parameters such as pH, arterial gas tensions for oxygen (PaO2) and carbon dioxide (PaCO2), maximal oxygen consumption  1  (VO2max) and minute ventilation (VE max) during exercise have been shown to be minimal in untrained asthmatics (33, 56).  Few studies have looked at the physiological responses of asthmatics to exercise without the use of pre-exercise medication. Physiological parameters such as maximal heart rate (HR), VEmax, VO2max PaCO and Pa02 have all been shown to be within ,  ,  normal range in asthmatics when free of an attack; any abnormalities seen in these variables have been concluded to be due to the untrained state of the asthmatic subjects tested. For example, higher blood lactates have been reported in asthmatics by several authors (1, 5, 10, 53  ), but these individuals were untrained and their higher levels could  be more representative of their lower fitness level. Conversely, Anderson et al., (1) found asthmatics to have higher plasma lactate (LA) compared to non-asthmatics of similar fitness level exercising at the same oxygen consumption.  Oxyhemoglobin saturation (Sa0 ) and arterial oxygen tension (Pa0 2 ) in healthy 2 individuals stay relatively consistant throughout exercise, but approximately 50 % of highly trained (HT) athletes who are free of asthma, exhibit arterial hypoxemia and desaturation of hemoglobin at maximal exercise. This phenomenon known as exerciseinduced hypoxemia (Effi), defined as a reduction in Sa0 2 of 4% below resting values, is thought to be attributed to two causes: a lower alveolar P02 (PAO ) due to an inadequate 2 ventilatory response to exercise, and secondly, excessive widening of the alveolar-arterial 2 difference ((A-a)D02)) caused by veno-arterial shunt, ventilation/perfusion (VA/Q) P0 non-uniformity, and diffusion limitations (15, 55). HT athletes are capable of achieving extreme metabolic capacities (VO2max values greater than 5.0 lmin 1 and cardiac outputs as high as 30-35 lmin -1) through physiological adaptations of the cardiovascular 2  system and oxidative capacities of skeletal muscle. However, the pulmonary system is thought to be the least trainable organ system which may, in turn, limit exercise performance (16). In asthmatics, Anderson et al., (1) found in one subject a significant decrease in arterial oxygen tension during exercise. Therefore, the lIT asthmatic athlete, who may experience gas exchange limitations, and experience other abnormalities due to their asthma, may be compromised at maximal exercise. All of the studies addressing the metabolic and ventilatory response of asthmatics to exercise have been conducted on untrained asthmatic subjects. To date, no study has looked at these variables in HT asthmatics. Therefore, the purpose of this study is to examine the metabolic and ventilatory responses to submaximal and maximal exercise in highly trained asthmatic athletes with and without pre-exercise medication.  3  METHODS  Subjects  Seventeen subjects, 9 highly trained athletes ( 5 females, 4 males; age = 26.1 ± 5.7 yrs; ht.  =  173.6 ± 10.5 cm; wt.  66.5 ± 10.6 kg; V02 max = 57.2 ± 4.8 ml.kg 1 m in -1),  and 8 moderately trained athletes (1 female, 7 males; age = 24.1 ± 3.1 yrs; ht. 11.8 cm; wt.  =  =  183.1 ±  78.8 ± 15.5 kg; V02 max = 51.2± 4.8 nil•kg -i.min ), with EIA 1  participated in this study. Subjects in this study demonstrated mild to moderate airway responsiveness and all but three of the subjects had a history of asthma. Baseline spirometry indicated 6 of the 17 subjects had a 1 FEV of <80 %. The criteria for % inclusion in the study was a positive methacholine challenge test which was defmed as a decrease in Forced Expiratory Volume of 20% or greater in one second (FEVi ) at a methacholine concentration of 16.0 mg.mll or less (PC2O  16 mg•n*’). Subjects were  placed into one of the two groups depending on their fitness level; the highly trained group consisted of subjects who had achieved a V02 max and  min- for males 60 ml.kg 1  50 ml.kg -1 •min -1 for females; all other subjects were placed in the moderately  trained group, but had to achieve a minimum VO2max  45 mlkg  1 for males and mi  40 ml.kg -1 •min -1 for females. Prior to entering the study, informed consent was obtained. This study was approved by the Clinical Screening Committee for Experimental Involvement of Human Subjects.  4  Methacholine Challenge Test  This procedure was used to assess the bronchial reactivity of each subject. Before the inhalation test, a baseline FEVi was measured using a Medical Graphics Metabolic Cart with 1070 Pulmonary Function Software. Aerosols were administered using a Wright nebulizer attached to a face mask calibrated to deliver the aerosols at ,  . Aerosols were inhaled for periods of 2 minutes followed by 30 1 a rate of 0.13 mlmin and 90 second FEVi determinations. After a baseline FEV1 was established with saline,  methacholine was inhaled in doubling concentrations (.125, .25, .5, 1.0, 2.0,4.0, 8.0, and 16.0 mg•m1 ) every 5 minutes (34). FEVi was measured every 30 and 90 seconds after 1 each concentration until a fall in FEV 1 of 20 % (PC20), compared to the saline control was achieved. The percentage fall in FEV 1 was calculated from the lowest FEV 1 after each methacholine inhalation and the PC20 was determined by using the following equation; PC20 = antilog [log Ci + (logC2 log Cn(20-Ri)] R2-Ri -  where:  A PC2O  Ci = second last concentration (<20% FEV fa11) 1 C2 = last concentration (>20 % FEV1 fall) Ri = % fall FEV1 after Ci R2 = % fall FEV1 after C2  16 mgm1 1 was chosen as indicative of asthma for this study (41).  Prescribed inhaled bronchodilators were withheld for 12 hours prior to the test, however, subjects on inhaled steroids were allowed to continue taking their medication in regular doses.  5  Maximal Oxygen Uptake test  Prior to this test subjects were permitted to take their pre-exercise asthmatic medication. The maximal oxygen uptake test was performed on an electronically braked Mijnhardt KEM 3 cycle ergometer ramped continuously at 30 wattsmin -1 until the subject reached volitional fatigue. Oxygen uptake (V0 ), carbon dioxide (VCO 2 ), and 2 minute ventilation (VE) were continuously sampled with a Metabolic Measurement Cart (Beckman LB-2 C02 Analyzer, and Ametek Oxygen Analyzer S-3A/1), which calculated and reported 15 second averages. Heart rate (KR) was monitored continuously with a Polar Vantage XL7M heart rate monitor set to record HR’s in 15 second intervals. A regression equation using workload and oxygen uptake was generated for each subject; from this data the workloads in watts were determined to elicit 25, 50, 75, and 90 % of the subject’s V02 max. Attainment of VO2max was determined when at least three of the following four criteria were met: (1) a plateau of oxygen consumption with increasing workloads, (2) a respiratory exchange ratio> 1.10, (3) 90 % of predicted maximal HR was achieved, or (4) volitional fatigue.  Experimental Procedures  Subjects performed two randomized exercise tests one week apart, one using pre exercise salbutamol and the other a pre-exercise placebo. All bronchodilator drugs were withheld for 12 hours prior to each session, while subjects on corticosteroids were allowed to continue taking their medication. Fifteen minutes prior to testing subjects received two puffs from a coded metered-dose inhaler containing either salbutamol (200  6  jig) or the placebo given in a double blind fashion. Before the start of exercise a 20 gauge venous catheter (kept patent with normal saline and heparin, 1000 units/500m1) was inserted in the subject’s antecubital vein and a pre-exercise blood sample (— 0.5 ml) was withdrawn. Pre and post-medication Peak Expiratory Flow Rates (PEFR) were -  measured using a Mini-Wright flow meter. The exercise protocol consisted of a 20 minute cycle on an electronically braked cycle ergometer divided into 4 continuous five minute increments. The workloads, predetermined from the VO2max test, were set to elicit 25, 50,75, and 90 % of the subject’s VO2max. Respiratory gas exchange variables, V02,VCO2, VE, and RER, were continuously measured with a Metabolic Cart (Beckman LB-2 CO2 Analyzer, and Ametek Oxygen Analyzer S-3A/1). The means of the four consecutive 15 second averages in the third minute of each increment were reported. Sa02 was measured with a Hewlett Packard (47201A) oximeter attached to the subject’s ear and secured by a head band. To improve perfusion of blood to the ear, the helix of the ear was rubbed with Finalgon (Boehringer Ingelheim), a vasodilator cream, The ear oximeter, interfaced to an IBM compatible computer, reported SaO2 in 15 second averages. For the purpose of this study only 1 minute averages of V02,VE, HR, RER, and Sa02 were calculated 3 minutes into each stage of exercise. In the fourth minute of each exercise task the subjects momentarily removed the mouth piece (measuring respiratory gases) and forcibly expired into the peak flow meter this was followed by a ,  blood sample. PEFR measurements were made 3, 5, 10, and 15 minutes of recovery and blood samples were taken 1, 3, 5, and 10 minutes after the cessation of exercise.  7  Lactate Analysis  The initial 0.5 ml of blood drawn from the subject was added to 2 ml of chilled perchloric acid (10%). After vortexing, the samples were placed in an ice bath for at least 5 minutes. These samples were centrifuged at 2500 rpm for 10 minutes and the 0  supernatant was collected and split into duplicates before being stored at -70 C. The lactate concentrations were measured using a modification of an enzymatic assay commercially available from Sigma Diagnostics®. The samples were allowed to thaw to room temperature before proceeding. The pH of the samples was neutralized by adding  500pL of the sample to l5OiiL of Tris-OH buffer (pH). After mixing, 20pL of the buffered sample was added to lml of the lactate reagent. Samples were incubated for 15 minutes which allowed for colour development. The absorbance of each sample was measured at 540 nm with a UV-160 Spectrophotometer, and the blank, consisting of the lactate reagent alone, and the samples were compared to lOpL of a Lactate Standard Solution (4.44 m•mo1 1 lactic acid (40 mg.dLl)).  Statistical Analysis  The independent variables were the treatment factor which had two levels; Salbutamol and Placebo, and the exercise condition which had 4 levels for the dependent variables; V0 , VE, fiR, RER, Sa02; 8 and 9 levels for PEFR and LA, respectively. The 2 4 levels of the exercise condition consisted of 25 % 50 %, 75 %, and 90 % of the ,  subject’s VO2max and the 9 levels included the resting condition, the 4 exercise conditions, and 1, 3, 5, and 10 minutes into recovery for the dependent variable LA. The  8  8 levels for the dependent variable PEFR included the four exercise conditions and 3, 5, 10, and 15 minutes into recovery. All subject comparisons between the 2 treatments for the 7 dependent variables were made by a repeated measures analysis of variance (ANOVA). V0 , VE, FIR, RER, 2 and Sa02 were statistically analysed with a 2 (Treatment factor) X 4 (Exercise condition) ANOVA with repeated measures on both factors. PEFR and blood lactates were analysed with a 2 X 8 and 2 X 9 repeated measures ANOVA, respectively. Between and within-group comparisons were also performed by a repeated measures ANOVA to determine any differences between the male and female subjects, males in the FIT group from males in the MT group, and the highly trained from the moderately trained group. A post-medication rise in PEFR was expected after the administration of salbutamol, so independent t-tests were conducted on pre- and postmedication measures with a level of significance (a) set at p < 0.01. Post hoc comparisons using Tukeys HSD and Scheffe’s method were performed on significant main effects and significant interaction effects, respectively. The level of significance (a) was set at a p <0.05 for all of the analyses of variance comparisons. All statistical analyses were performed using Systat software ( 5.0 version, Systat, Inc.)  9  RESULTS  Mean values for the physical characteristics of the highly trained and moderately  trained subjects are presented in Table 1.  Table 1.  Physical Characteristics (mean ± SD range) ,  Subjects  Highly trained  Moderately trained  SEX  5 females, 4 males  1 female, 7 males  AGE  (years)  26.1 ± 5.7 (19-35)  24 .1 ± 3.1 (21-31)  HEIGHT  (cm)  174.0± 10.5 (162-190)  183.1± 11.8 (161-200)  WEIGHT  (Kg)  66.4 ± 10.8 (51-85)  78.6 ± 15.3 (49-94)  VO2max  (m1Kgmin)  57.0 ± 4.9 (50-63)  51.3 ± 4.8 (4557)*  PC2O  (mg.ml)  7.2 ±5.8 (0.7-15.8)  7.6 ± 5.0 (0.8-15.9)  P  AU subjects passed the baseline criteria of a positive methacholine(PC2O  <  0.05  16.0 mg.mll)  1 for the highly trained group and 7.6 ± 5.0 mg with a mean PC20 of 7.2 ± 5.8 mg•mP 1 for the moderately trained group. There was a statistically significant difference in m1 mean VO2max values between the highly trained and moderately trained groups (57.0 ± 4.9 vs. 51.3 ± 4.8; p =  =  0.002) and male and female subjects  ( 55.5 ± 6.0 vs. 52.3 ± 4.4; p  0.007). Although the duration of the experimental test varied for each subject, there  was no statistical difference in duration of the exercise protocol between the placebo and salbutamol.  10  Analysis of variance performed on all subjects revealed no significant difference in the pretreatment with either salbutamol or placebo at any stage of exercise with respect to V02, VE, HR, RER, Sa02, and LA. The group means and standard deviations are shown in Tables 2 and 5.  Table 2.  V02, VE, FIR, RER, andSaO2 of all subjects ( n = 17), group data Salbutamol  Variables  Placebo  25%  50%  75%  90%  25%  50%  75%  90%  V021/min  1.17±.23  1.98±.39  3.09±.63  3.70±.81  1.16±26  2.03±.49  3.14±.65  3.74±.76  yE btps  313 ± 5.6  51.8 ± 9.0  92.9 ± 19.6  131.8 ± 30.  31.6 ± 4.8  52.9 ± 10.8  HRbpm  104.5± 10.0 134.4± 11.8 169.0±9.5  93.8 ± 20.8 135.7 ± 32.2  183.9±7.3 103.7± 10.9 135.6± 12.9 171.6± 10.1 186.7±6.5  RER  0.80 ± .06  0.88 ± .08  0.99 ± .08  1.05 ± .09  0.81 ± .06  0.87 ± .06  0.99 ± .06  1.05 ± .07  Sa02  96.9±1.4  96.7±1.0  95.8±0.8  94.6±1.5  96.9±0.6  96.5±0.7  95.5±0.9  94.7±1.5  Pre-exercise PEFR was signfficantly higher (582 vs. 545 l•sec: p = 0.003) when the 1 pretreatment condition was salbutamol, but prior to treatment there was no difference between the two PEFR’s. PEFR increased significantly over the course of exercise for all subjects, and averaged over the exercise and recovery conditions was significantly higher with the salbutamol treatment (600.1 vs. 569.6: p = 0.002) than the placebo. The significant drug by exercise condition interaction (p = 0.00 1) indicates, with respect to the 2 treatments, a different pattern of change in PEFR measures over exercise and the recovery conditions. Post hoc pairwise comparisons using Scheffe’s test revealed a significant difference between PEFR measures at low intensities (25 % and 50 %) with high intensities (75% and 90 %) of exercise and differences in the first two recovery  11  conditions ( 3 and 5 mm.) with the last two (10 and 15 mm.). There was a larger  difference in the two treatments at lower intensities and not at the higher intensities of exercise and a greater difference 10-15 minutes as opposed to 3-5 minutes of recovery (Figure 1). Comparisons made between the lIT and MT groups indicated no significant difference at any stage of the experimental protocol between the two groups with respect , VE, HR, RER, Sa02, and LA (Tables 3-6). 2 to V0 Table 3.  , VE, HR, RER, and Sa02 of highly trained (n= 9), group data 2 V0 Salbutamol  Variables  25%  V02 L/mm 1.08 ± 0.21  50%  Placebo  75%  90%  25%  50%  75%  90%  1.91 ± 0.38 2.98 ± 0.61 3.48 ± 0.66 1.06 ± 0.26 2.00 ± 0.59 3.08 ± 0.71 3.57 ± 0.77 51.0 ± 8.7 95.3 ± 21. 132.5 ± 30.  29.8 ± 4.3 52.5 ± 11.9 98.5 ± 222 139.4 ± 35.  VEbips  30.2 ± 6.1  HRbpm  104.1 ± 8.9 133.8 ± 11. 168.4 ± 10. 182.4 ± 8.2 104.3 ± 7.9 139.8 ± 11. 175.8 ± 9.3 186.7 ± 7.6  RER  0.79 ± 0.05 0.87 ± 0.06 1.00 ± 0.06 1.05 ± 0.08 0.81 ± 0.06 0.86 ± 0.06 1.00 ± 0.06 1.05 ± 0.08  Sa02  97.1 ± 1.7  Table 4.  96.6 ± 1.3  95.7 ± 1.0  93.9 ± 1.2 97.0 ± 0.7 964 ± 0.8  94.2 ± 0.9  VO2,VE, HR, RER, and Sa02 of moderately trained (n = 8), group data Salbutamol  Variables  95.2 ± 0.8  25%  50%  Placebo  75%  90%  25%  50%  75%  90%  V02 L/mm 1.27 ± 0.21 2.06 ± 0.41 3.21 ± 0.67 3.96 ± 0.92 1.28 ± 0.21 2.08 ± 0.39 3.21 ± 0.61 3.91 ± 0.75 52.6 ± 9.8 90.2 ± 18.5 130.9 ± 32.3 33.6 ± 4.8 53.3 ± 10.1 88.5 ± 19.2 131.5 ± 30.1  VEbtps  32.6 ± 5.0  HR bpm  104.9 ± 11.7 135.2 ± 13.2 169.7 ± 9.3 185.7 ± 6.2 103.0 ± 14. 130.9 ± 14.( 166.9 ± 92 186.7 ± 5.6  RER  0.82 ± 0.07 0.89 ± 0.09 0.98 ± 0.10 1.04 ± 0.10 0.80 ± 0.06 0.88 ± 0.06 0.97 ± 0.06 1.05 ± 0.07  Sa02  96.5 ± 1.0  96.6 ± 0.5  95.8 ± 0.7  94.7 ± 1.0  12  97.1 ± 0.8  96.8 ± 0.5  95.9 ±0.9  95.1 ± 1.6  However, among the Hi’ group the mean HR averaged over the 4 exercise conditions was significantly higher under the placebo condition (147.2 (S) vs. 151.7 (PL) bpm: p = 0.01). The significant drug by exercise condition interaction (p = 0.002) demonstrates a greater change in HR under the placebo treatment than the salbutamol for the same level of exercise (Figure 6). A Tukey’s post hoc analysis indicated significance between the two treatments only at a workload of 75 % VO2max (168.4 (S) vs. 176.8 (PL) bpm: p < 0.05).  Table 5.  Lactate ( mmol•l) of all subjects, highly trained and moderately 1 trained, group data  n=17 LACTATE (mmol•1 ) 1 CONDITION Salbutamol Placebo  HT-Salb.  HT-Placebo MT- Salb.  REST  0.8 ± 0.5  0.9 ± 0.3  0.9 ± 0.6  1.0 ± 0.3  0.8 ± 0.5  0.8 ± 0.4  25 % VO2max  1.1 ± 0.8  1.2 ± 0.6  1.0 ± 0.8  1.1 ± 0.4  1.3 ± 0.9  1.3 ± 0.7  50 % VO2max  1.5 ± 0.6  1.6 ± 0.7  1.6 ± 0.7  1.5 ± 0.4  1.4 ± 0.5  1.7 ± 0.9  75 % VOmax  5.7 ± 2.4  5.4 ± 2.2  6.0 ± 2.6  6.4 ± 1.9  5.3 ± 2.3  4.3 ± 2.0  90 % VO2max  10.3 ± 3.9  11.1 ± 4.0 10.6 ± 4.4  12.5 ± 4.2  10.0 ± 3.4  9.6 ± 3.4  1 mill Post Ex.  11.1 ± 4.0  112 ± 3.7 11.6 ± 4.9  12.5 ± 3.5  10.5 ± 2.9  9.7 ± 3.5  3 mm Post Ex.  10.7 ± 3.7  10.7 ± 3.6 11.7 ± 4.7  11.4 ± 3.2  9.6 ± 2.3  9.8 ± 4.1  5 mm Post Ex.  9.8 ± 4.1  10.4 ± 3.6 10.6 ± 5.8  10.8 ± 3.8  92 ± 2.8  9.9 ± 3.6  10 mm Post Ex.  8.2 ± 4.2  8.3 ± 3.6  9.1 ± 3.3  7.7 ± 3.2  7.4 ± 3.9  n=9  8.8 ± 5.1  n=8 MT- PL  Analysis of subjects within the HT group revealed significantly higher mean PEFR values (569.3 vs. 539.3: p  =  0.009) with the pretreatment of salbutamol (Figure 2)  However, among the MT group no difference was found in PEFR at any stage of exercise or recovery between the two experimental conditions (Figure 3). The means and standard  13  deviations for PEFR measures for all groups are presented in Table 6 and illustrated in graphical format in Figures 1-4. Between-group analysis of variance revealed no significant difference in mean PEFR values between the two groups based on training status Table 6.  PEFR ( lsec1 ) of all subjects, highly trained and moderately trained, group data  1 n=17 PEFRI•sec CONDITION  n=9  Salbutamol  Placebo  HT-Salb.  n8 HT-Placebo  MT- SaIb.  MT- PL  PRE-MED  563.8 ± 102.1 555.9 ± 96.1  528.9 ± 103.8 527.0 ± 92.4 603.0 ± 90.6  POST-MED  581.8 ± 100.4 545 ± 94.8  551.6 ± 98.6  25 % VO2max  595.0 ± 98.2 550.6 ± 101.7 565.0 ± 92.8  513.3 ± 88.9 628.8 ± 98.8  50 % VO2max  605.9 ± 96.4  536.1 ± 97.9 640.0 ± 98.6 603.1 ± 103.9  75 % VO2max  618.5 ± 101.1 602.9 ± 103.0 589.4 ± 93.0  571.7 ± 105.8 651.3 ± 105.6 638.1 ± 93.7  90 % VO2max  622.9 ± 108.3 612.9 ± 101.9 591.1 ± 99.5  572.8 ± 87.5 658.8 ± 112.9 658.1 ± 102.9  3mm Post Ex.  605.6 ± 1032 572.9 ± 108.2 572.8 ± 100.4 550.6 ± 105.4 642.5 ± 99.4  598.1 ± 112.7  5mm Post Ex.  583.5 ± 92.0  562.1 ± 103.1 561.7 ± 89.7  540.0 ± 95.6 608.1 ± 94.0  586.9 ± 111.8  10mm Post Ex.  582.4 ± 91.0  546.5 ± 103.1 556.1 ± 86.3  521.1 ± 92.9 611.9 ± 92.3  575.0 ± 112.6  15mm Post Ex.  587.1 ± 103.3 540.9 ± 97.5 560.6 ± 97.5  567.7 ± 103.5 575.6 ± 88.7  522.8 ± 88.9  588.5 ± 95.1  615.8 ± 97.0 570.0 ± 100.8 592.5 ± 103.9  526.1 ± 97.5 616.9 ± 107.8 557.5 ± 101.2  Comparing male and female subjects, males had significantly higher mean V02 (2.79 vs. 1.97 l• mm  -1:  p = 0.000), VE ( 84.2 vs 65.91: p = 0.008) values, but there were  no differences in HR, RER, Sa02, and blood lactate. Male subjects did have statistically higher PEFR values than female subjects. Comparisons made between males in the HT group with males in the MT group revealed no differences with respect to any of the variables measured.  14  Statistical analysis performed on data of those subjects with a PC2O <4.0 mg•ml1 (n =6) showed no significant main drug effect with respect to HR, V02, VE, RER, Sa02, or lactate. Although not significantly different (p  =  0.058), V0 2 was higher when  pretreatment was the placebo. PEFR (559.3 vs. 506.5: p = 0.03 ) averaged over the exercise and recovery conditions for this group was significantly higher with salbutamol (Figure 4). Post hoc comparisons were performed on the significant drug by exercise condition interaction (p = 0.047). Figure 1. illustrates the larger differences in PEFR measures under the two treatments at the lower intensities as compared to little difference at higher intensities. For all subject groups tested, the greatest mean difference in PEFR measures between the two treatments was seen in the more severe asthmatic subjects 1015 minutes post-exercise.  15  PEFR (1 •sec  Figure 1.  1)  measures under salbutamol and placebo conditions  at various exercise intensities (% VO2max) and 3 to 15 minutes into recovery, all subjects data ( n = 17)  640 620 600 0  0  Salbutamol  •  Placebo  *  a,  580 LI Ui 0  540  520 POST-MED.25%  50% 75% Exercise  90%  3mm  5mm 10mm Recovery  15mm  Mean values plotted; open circles, salbutamol; closed circles, placebo. The overall mean PEFR measures were statistically higher with salbutamol: p  =  0.002. Post-  medication PEFR values were statistically higher with salbutamol (* p < 0.05).  16  Figure 2.  PEFR (1.sec-i) measures at various exercise intensities (% V0 2 max) and 3 to 15 minutes into recovery, Hi’ group data ( n =9)  600 580  560  0  Salbutamol  •  Placebo  *  [40. 520  500 i.i.i.i...i.i.i... POST-MED25 % 50 % 75 % 90 % 3 mm 10 mm 15 mm 5 mm Exercise Recovery  Values are means; open circles, salbutamol; closed circles, placebo. The overall mean PEFR measures were statistically higher with salbutamol: p  =  0.009. Post-  medication PEFR measures were statistically higher with salbutamol(  17  *  p < 0.05).  PEER (1.sec-l) measures at various exercise intensities  Figure 3.  (%VO2max (n =8)  ), and 3 to 15 minutes into recovery, MT group data  680 660  °  Salbutamol  •  Placebo  640 620 600• 580 560 1•1•  -  POST MED  25 %  I•  50 %  75 %  Exercise  I•  90 %  3 mm  I•I•  5 mm io miii 15 miii Recovery  Values are means; open circles, salbutamol; closed circles, placebo : p = 0.078.  18  PEER (l.secl) measures at various exercise intensities(% VO max), 2 and 3 to 15 minutes into recovery, PC2O < 4.0 mgm11 (n =6) group data.  Figure 4.  —0---  SALBUTAMOL  ! 52O  5oo. 480 4. 440  I  post-med 25%  50% 75% Exercise  90%  3 mm  5 mm 10 mm 15 mm Recovery  Values are means; open circles, salbutamol; closed circles, placebo. The overall PEER measures were statistically higher with salbutamol: p 0.03 Post medication PEER measures were statistically higher with salbutamol(* p < 0.05) -  19  Figure 5.  Blood lactate (mmol•l  1)  at various exercise intensities  (% VO2max) and 1 to 10 minutes into recovery, all subject data (n=17).  16 14  E  12  0  E 10 E  —0— •  Salbutamol Placebo  €0  C.)  0 REST  25%  50%  75%  Exercise  90%  1mm  5mm 3mm Recovery  10mm  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = 0.688.  20  Figure 6.  HR (bpm) responses at various exercise intensities (% VO2max), HT group data (n = 9).  210 *  190 170 1500— •  130  Salbutamol Placebo  11090  I  25%  I  50% 75% Exercise (% V02 max)  90%  Values are means ± SD; open circles, salbutamol; closed circles, placebo. The overall mean HR measures were statistically higher with placebo: p = 0.01. Post hoc analysis on significant main effect revealed higher HR under the placebo condition only at 75 % VO2max ( * p < 0.05).  21  DISCUSSION  The findings of the present study have demonstrated that highly trained and moderately trained asthmatics have normal physiological responses during submaximal and maximal exercise. There was no difference between the pretreatment of salbutamol or placebo during all stages of exercise with respect to V02, VE, HR, and Sa02, thus suggesting no impairment in oxygen delivery to the exercising muscles in the asthmatic subjects that were tested. Packe et al., (53) found similar results in these variables when they compared untrained asthmatics and non-asthmatics exercising on a treadmill at 85 % VO2max. Ingeman-Hansen et a!., (33) also found no difference between inhaled salbutamol and saline control for the variables VE, V0 , HR, PaCO2 measured in 5 2 asthmatics during a 6 minute graded bicycle exercise test. Recently, Pa02, PaCO , and 2 pH were compared between asthmatics and non-asthmatics during steady state exercise and were found to have similar responses; however, VE was significantly lower in the asthmatic than in the non-asthmatic. In this latter study the subjects were not highly trained and did not exercise to maximum (21). Recent studies have shown that approximately 50 % of HT endurance athletes develop a significant reduction (<91 %) in arterial hemoglobin saturation (Sa02) during intense exercise ( VO max  90 % ) (15,54). This has been shown to have an adverse  effect on maximal oxygen consumption  (— 1% drop in VO2max for every % fall in Sa02)  (15, 55) and total work output when mild (90%) and more severe (87 %) saturation levels were induced (39). Therefore, the maximal performance capacity of the HT athlete’s can be limited. Although, no study to date has looked at EIH in asthmatics, it is possible the HT asthmatic athlete, who may experience gas exchange limitations and experience other abnormalities due to asthma, may be even more limited at maximal exercise.  22  Deal and coworkers (14) demonstrated the impact that changes in VE have on the rate of respiratory heat loss (RHL). They suggested that the degree of RHL was directly related to the severity of the post-exercise bronchoconstriction. McFadden found that the rate and magnitude of bronchial rewarming affected the severity of bronchospasm (25, 45).  In other words, the greater the VE, the greater the RHL, which in turn increases the severity of exercise-induced bronchoconstriction. Hi’ athletes have high minute ventilations at maximal exercise, this may cause a large RHL which, may in turn, increase airway resistance and the work of breathing. In HT asthmatics, the combination of a higher incidence of EIH and high minute ventilations may be limiting performance at exercise intensities  75 % VOmax. In this study there was no difference in Sa02 at  intensities of 75 or 90 % VO2max between the placebo or salbutamol conditions and none of the subjects had any evidence of respiratory obstruction at the higher workloads as demonstrated by a significant rise in PEFR. Furthermore, none of the FiT subjects desaturated (< 91%) at maximal exercise. Interestingly, however, the lowest drop in Sa02 (91.5 %) in the HT group occurred in the most severe asthmatic tested (PC2O = 0.7 mg•mt ) 1 . Difference in protocols and fitness level may explain the discrepancy seen in our results with respect to the incidence of Effi. Our subjects in the HT group were well  trained, but their mean VO2max is lower than other studies reporting higher incidences of EIH (15, 55). Also, the exercise protocols used in the studies reporting higher  incidences were shorter in duration and ramped as compared with the stepwise progressive incremental exercise used in our study. Previous studies have demonstrated a greater rise in blood lactate in asthmatics compared to non-asthmatics exercising at the same oxygen consumption (1, 5, 10). Although we did not compare our asthmatic subjects with normal subjects we found no significant difference between the two experimental conditions. The rise in blood lactate 23  over the course of exercise was similar to that reported in non-asthmatic trained individuals (62, 65). A moderate increase in lactate concentration from rest to intensities of 50 % V0 2 max was followed by an exponential increase as the exercise continued to maximal levels (Figure 5). In this study, there was no statistical difference in LA concentrations at submaxunal exercise (25 %, and 50 %) between the HT and MT groups. However, within the HT group higher LA values were measured under the placebo compared to the salbutamol condition at 90 % VO2max (12.5 (PL) vs. 10.6 ( S)). Furthermore, at the higher exercise intensities, comparisons between the HT and MT groups demonstrated higher LA values for the HT group for both treatment conditions (HT=12.5 (PL) vs. MT=9.6(PL); HT=10.6(S) vs. MT= 9.9(S) mmol•[ ), but this was not 1 statistically significant.. The capacity of the lactic acid system can be greatly developed depending on the type of training ; for example, one competitive rower in the HT group, had LA levels as high as 19.0 mmol•l 1 at 90 % VO2max, but this would be expected for the type of training this sport demands. LA concentration of muscle and blood in individuals without asthma return to near resting levels within 30-60 minutes into recovery ( 30). In the present study subjects were not allowed to warm down, therefore reducing the rate of LA clearance; however, blood lactate samples taken up to 10 minutes post-exercise demonstrated a similar rate of clearance in the moderately and highly trained asthmatic subjects as reported in normal individuals (30).  The asthmatics in this study demonstrated the typical pattern of response to exercise indicated by changes in pulmonary function. During exercise, bronchodilation occurred as indicated by a rise in PEFR measures followed by a fall in PEFR after exercise, reaching the lowest levels at 10-15 minutes after the cessation of exercise. Bronchodilation is a normal physiological response to exercise due to a decrease in vagal  24  tone, catecholamine release, and the slow release of an inhibitory prostaglandin (60). Under both the salbutamol and placebo conditions, PEFR increased significantly over the course of exercise, but these were only different from each other in the first two stages of exercise. Salbutamol proved to be an effective bronchodilator as the pre-exercise PEFR measure after inhalation of salbutamol was significantly higher ( 3.1% for all 17 subjects  and a 6.6 % rise in the more severe asthmatic group (PC20 < 4.0 mg•m1 ) ) than the pre 4 exercise salbutamol or placebo condition, and provided protection throughout the exercise and recovery period (see Figure 4). Meeuwisse et aL, (49) also showed a similar rise (4.5 %) after the administration of salbutamol, but in highly trained nonasthmatic subjects. A rise in circulating catecholamine levels during exercise has been demonstrated in normal and asthmatic subjects ( 9). In this study, at higher intensities of exercise (>75 % VO2max), the rise in PEFR under the placebo condition was no different from measures under the salbutamol condition, thus suggesting that the asthmatic subjects had a sufficient concentration of circulating adrenaline, enough to prevent any bronchoconstriction from occurring during exercise. Some studies have suggested that asthmatics have a blunted sympathoadrenal system, which is responsible for the post-exercise bronchoconstriction (6, 64). Although catecholamine concentrations were not measured in this study, this does not appear to be the case in the asthmatics tested. Fifteen minutes after stopping exercise, the mean PEFR for all subjects fell 12 % under the placebo and 6 % with salbutamol. The duration, intensity, and type of exercise  are determinants of the severity of the exercise-induced bronchospasm; this may explain why a greater fall in PEFR was not seen under the placebo condition as compared to other studies reporting larger falls in PEFR (1, 35, 56). The exercise protocol of 20 minutes in duration on a cycle ergometer would account for this, as running has been shown to be more asthmogenic than cycling and a duration of 6-8 minutes at 60-85 %  25  VO2max has been found to cause the greatest post exercise bronchoconstriction.(4, 59). Beyond this time the severity of the response is reduced and asthmatics have been observed to “run through” their asthma (19). Also, the first 10 minutes of the experimental test consisted of a slow increase in workloads of intensities of 25 and 50 % VO2max; this submaximal warm-up could provide protection against EIA by facilitating the release of catecholamines. A recent study demonstrated a continuous warm-up of 15 minutes at 60 % VO2max can significantly minimize EIA in moderately trained asthmatics (48). Thus, a more progressive, short duration exercise protocol may have produced a greater physiological response in the asthmatics tested. A logical concern is whether the severity of one’s asthma is a determinant of disturbances in performance-related variables such as VE, V0 , Sa02, RER, and LA. In 2 the present study we chose a PC2O of< 16 mg.mi 1 of methacholine as indicative of current asthma. Cockroft et al., (13) used a cut off point of 8 mg/mi and below to be a sensitive indicator of asthma and concluded concentrations between 8 and 16 mg.m1 1 to be a” gray area” or borderline hyper-responsiveness. Malo et a!., (41) suggested PC2O < 16 mg•mP 1 as an acceptable concentration based on his findings that 8 % of a population would show a reaction in the asthmatic or abnormal range. The mean values for both the HT and MT groups were below 8 mg.ml 1 in the present study. Also, data analysis performed on the more severe asthmatic subjects (PC20 <4.0 mgm11 ) revealed no significant difference in VE, V0 , RER, Sa02, and LA between the two experimental 2 conditions. However, mean PEFR measures averaged over the exercise and recovery conditions were significantly higher with the pretreatment of salbutamol. Therefore, the severity of asthma does not appear to have a greater disturbance on physiological parameters during exercise.  26  Of the 17 asthmatic subjects tested, 12 of the subjects felt the experimental test with the placebo to be more difficult than with the salbutamol, while 5 subjects found no difficulty in breathing in either of the exercise tests. 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Airway cooling and rewarming: The second reaction sequence in exercise-induced asthma. J. Clin. Invest. 90 (Sep): 699-704, 1992.  29  26.  Godfrey, S. Exercise-induced asthma-clinical, physiological, and therapeutic implications. J. Allergy Clin. Immunol. 56(l):l-17, 1975.  27.  Godfrey, S. and P. Konig. Inhibition of exercise-induced asthma by different pharmacological pathways. Thorax. 31: 137-142, 1976.  28.  Godfrey, S. Worldwide experience with albuterol (salbutamol). Ann. Allergy. 47: 423-426, 1981.  29.  Godfrey S. Bronchial challenge by exercise or hyperventilation. In: Spector SL, ed. Provocative challenge procedures: background and methodology. Mount Kisko, NY: Futura Publishing Co, 1989: 365-94.  30.  Gollnick, P. D., W. M. Bayly, and D. R. Hodgson. Exercise intensity, training, diet, and lactate concentration in muscle and blood. Med. Sd. Sports Exerc. 18(3): 334-340, 1986.  31.  Haas, F., S. Pasierski, N. Levine, M. Bishop, K. Axen, H. Pineda and A. Haas. 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Prevention with and without the use of medications for exercise induced asthma. Med. Sci. Sports andEx. 18(3):331-333, 1986.  38.  Kivity, S., Y. B. Aharon, A. Man, and M. Topilsky. The effect of caffeine on exercise-induced bronchoconstriction. Chest 97 (5): 1083-1085, 1990.  39.  Koskolou, M. D. andD. C. Mckenzie. Arterial hypoxemia and performance during intense exercise. Eur. J. ofAppl. Physiol. 68:, 1994. 30  40.  Lin, C. C., Jen-Liang Wu, Wen-Chu Huang and Ching-Yuang Lin. A bronchial response comparison of exercise and methacholine in asthmatic subjects. J. Asthma. 28(1): 31-40, 1990.  41.  Malo, Jean-Luc, L. Pineau, A. Cartier, and R. R. Martin. Reference values of the provocative concentrations of methacholine that causes 6 % and 20 % changes in forced expiratory volume in one second in a normal population. Am. Rev. Respir. Dis. 128:8-11,1983.  42.  McCarthy, P. Wheezing and breezing through exercise-induced asthma. Phys. Sportsmed. 17 (7): 125-130, 1989.  43.  McFadden, E. R. and R. H. Ingram. Exercise-induced asthma. N. Engi. J. Med. 301(14): 763-769, 1979.  44.  McFadden, E. R. Exercise performance in the asthmatic. Am. Rev. Respir. Dis. 129: Suppi S84-S87, 1984.  45.  McFadden, E. R. Hypothesis: exercise-induced asthma as a vascular phenomenon. The Lancet. 335:880-882, 1990.  46.  McKenzie, D. C., E. C. Rhodes, D. R. Stirling, 3. P. Wiley, D. W. Dunwoody, I. B. Filsinger and A. Stevens. Salbutamol and treadmill performance in non-atopic athletes. Med. Sci. Sports Exerc. 15(6): 520-522, 1983.  47.  McKenzie, D. C. The asthmatic athlete: a brief review. Clin. J. Sport Med. 1:110114, 1991.  48.  McKenzie, D. C., S. L. McLuckie,. The protective effects of continuous and interval exercise in athletes with EIA. Med. Sci. Sport Ex.erc., In press, 1994.  49.  Meeuwisse, W. H., S. R. Hopkins, J. Roads, and D. C. McKenzie. The effects of Salbutamol on performance in elite non-asthmatic athletes. Med. Sci. Sports & Exercise. 24(10): 1161-1 166, 1992.  50.  Meltzer, D. L. and J. P. Kemp. Beta2-Agonist: phannacology and recent developments. J. Asthma. 28(3): 179-186, 1991.  51.  Morton, A. R. C. A. Scott, and K. D. Fitch. The effects of Theophylline on the physical performance and work capacity of well-trained athletes. J. ofAllergy & Clinical Immunology 83: 55-60, 1989.  52.  Morton, A. R., and K. D. Fitch. Asthmatic Drugs and Competitive Sport: An Update. Sports Medicine 14(4): 228-242, 1992.  ,  31  53.  Packe, G. E., 3. Wiggins, B. M. Singh, M. Nattrass, A. D. Wright and R. M. Cayton. Blood fuel metabolites in asthma during and after progressive submaximal exercise. Clin. Sd. 73: 81-86, 1987.  54.  Page, C. P. Beta Agonists and the Asthma Paradox: Review article. J. of Asthma. 30 (3), 155-164, 1993.  55.  Powers, S. K., S. Dodd, 3. Lawler, G. Landry, M. Kirtley, T. McKnight, and S. Grinton. Incidence of exercise induced hypoxemia in elite endurance athletes at sea level. Eur. J. Appi. Physiol. 58: 298-302, 1988.  56.  Schmidt, A., B. Diamant, A. Bundgaard and P. L. Madsen. Ergogenic effect of inhaled B2-Agonist in asthmatics. mt. J. Sports Med. 9: 338-340, 1988.  57.  Schoeffel, R. B., Anderson, S. D. and R. E. C. Altounyan. Bronchial hyperreactivity in response to inhalation of ultrasonically nebulized solutions of distilled water and saline. Br. Med. J. 283: 1285-1287, 1982.  58.  Shapiro, G. G., J. P. Kemp, R. DeJong and M. Chapko. Effects of albuterol and procaterol on exercise-induced asthma. Ann. Allergy. 65:273-276, 1990.  59.  Silverman, M. and S. D. Anderson. Standardization of exercise tests in asthmatic children. Arc. Dis. Child. 47: 882-889, 1972.  60.  Spector, Sheldon L. Update on exercise-induced asthma. Annals ofAllergy. 71 Dec.): 571-577, 1993.  61.  Sport Medicine Council of Canada and Sport Canada. Banned and restricted doping classes and methods. Government of Canada, Fitness and Ameteur Sport, 1989.  62.  Stanley, W. C., R. A. Neese, J. A. Wisneski, and E. W. Gertz. Lactate kinetics during submaximal exercise in humans: Studies with isotopic tracers. J Cardiopulmonary Rehabil 9: 331-340, 1988.  63.  Strauss, R. H., E. R. Mcfadden, R. H. Ingram, E. C. Deal and J. J. Jaeger. Influence of heat and humidity on the airway obstruction induced by exercise in asthma. J. Clin. mv. 61:433-440, 1978.  64.  Warren, 3. B., R. 3. Keynes, M. 3. Brown, D. A. Jenner and M. W. McNicol. Blunted sympathoadrenal responses to exercise in asthmatic subjects. Br. J. Dis. Chest. 76: 147-150, 1982.  65.  Wasserman, K., W. L. Beaver, and B. J. Whipp. Mechanism and patterns of blood lactate increase during exercise in man. Med. Sci. Sport Exerc. 18 (3): 344-352, 1986.  32  66.  Weinberger, S. E.. Principles of pulmonary medicine. 1986 W. B. Saunders Company, Toronto.  67.  Voy, R. 0. The U.S. Olympic Committee experience with exercise-induced bronchospasm, 1984. Med. Sci. Sports Exerc. 18(3): 328-330, 1986.  33  APPENDIX A Review of Literature -  EXERCISE INDUCED ASTHMA  i) ii) iii) iv) v)  Introduction Clinical Presentation Diagnosis Pulmonary function tests Pathogenesis a) Hypernea, Hypocapnea, and Lactic acidosis b) Heat and Water Loss theory  vi) vii)  Prevention Treatment a) 3-Adrenergic receptor physiology b) Salbutamol (f2 Adenergic agonsist) c) Other Pharmacological Agents  viii)  Circulatory, Ventilatory, and Metabolic Responses to Exercise  34  REVIEW OF LITERATURE  EXERCISE-INDUCED ASTHMA  i)  Introduction  Exercise-Induced Asthma (EIA) is defined as a reversible airway narrowing precipitated by physical activity. Exercise can be a potent stimulus for producing bronchoconstriction within minutes after exercise in most individuals with asthma. However, with the proper medication and management, asthmatics are encouraged to participate in sports. In fact, the prevalence of asthma among competitive athletes is higher than one would expect; 11.2% of athletes competing in the 1984 Olympic games suffered from EIA (67). The attack of bronchoconstriction, classically displayed by signs of chest tightness, shortness of breath, wheezing, and coughing, is most apparent 5-15 minutes after exercise (2). Clinically, this airflow obstruction is represented by a decrease in flow rate which can be measured by simple spirometry, Forced Expiratory Volume in 1 second (FEVi) or Peak Expiratory Flow Rate (PEFR).  While the precise mechanism of EIA is still unclear, it is generally accepted that cooling and drying of the airways associated with high ventilation represent the initiating stimuli for the post-exercise bronchoconstriction (3, 14, 63). This popular theory has been criticised and a new hypothesis suggesting EIA to be a vascular phenomenon has  35  been proposed (45). It has also been suggested that because exercise can cause airway narrowing in the absence of irritants or antigens, perhaps metabolic changes associated with exercise could trigger bronchoconstriction (5).  ii)  Clinical Presentation: The classical signs of an acute asthmatic attack are chest tightness, shortness of  breath, coughing, and/or wheezing. However, some individuals with EIA may only complain of one of these symptoms, eg., breathlessness or coughing may be apparent during or shortly after moderate to strenuous exercise. Approximately 90 % individuals with asthma and 35-40% of those with allergic rhinitis/hay fever experience EIA(42). Exercising at a intensity of 65-85 % for 6-8 minutes produces maximal bronchoconstriction; above this intensity or duration diminishes the EIA response (59). The common physiological response of an individual with EIA to exercise is mild bronchodilation, usually persisting throughout exercise, followed by bronchoconstriction in recovery. This increase in airway resistance peaks 8-15 minutes after exercise has ceased and normal pulmonary function returns in 30- 60 minutes.  iii)  Diagnosis:  In diagnosing individuals with EIA, bronchial provocation tests with methacholine or histamine, or an exercise challenge can be used to measure the degree of bronchial hyperactivity in subjects. Bronchial provocation challenges with  36  pharmacological agents such as methacholine or histamine are performed by measuring changes in lung function followed by inhalation of the agent, increasing in doubling concentrations (60).  The most popular method of administering phannacological  provocation tests is the continuous tidal volume breathing method from a nebulizer. The most commonly used index of bronchial reactivity is the PC2O, the concentration of 1 to 20% below the control level. methacholine/histamine which provokes a fall in FEV Histamine is thought to trigger airway constriction through stimulation of sensory receptors and direct action on bronchial smooth muscle (29).  On the other hand,  methacholine acts on cholinergic muscarinic receptors on airway smooth muscle, and in asthmatic airways, smaller doses of methacholine are needed to cause a bronchial response (40).  A standardized exercise challenge test described by Silverman & Anderson (59) consists of a 6-8 minutes of steady state exercise on the treadmill or cycle ergometer at 90% of the subjects predicted maximal HR. A 15 -20 % decrease in FEVi is considered to be a positive exercise challenge test (34, 40). Several authors have compared these tests and found the pharmacological challenge with methacholine to be better than the histamine or the exercise challenge in distinguishing the asthmatics from the controls (11, 40).  37  iv)  Pulmonary Function Tests:  In asthmatics, the typical pattern of change in pulmonary function during exercise is a slight decrease in airway resistance which is measured by an increase in PEFR and FEVi, compared to normal subjects (26,47). This appears to be due to the release of catecholamines (24). However, within minutes after exercise, airway resistance increases markedly with peak bronchospasm between 5-15 minutes (10) and recovers to baseline levels within 30 to 40 minutes (2, 36). The response to exercise can be determined by several indexes of pulmonary function: FEV , PEFR, and FEF 25-75% (MMEF). A 1 change in large and small airway resistance is quantified by the ratio FEVi/FVC. A fall in FEV 1 of 20-30% is considered to be mild to moderate obstruction while a fall greater than 30% is considered severe (36). Forced expiratory flow between 25 and 75% (FEF 25-75% or maximal mid expiratory flow rate (MMEF) ) of volume expired during Forced Vital Capacity (FVC) is a sensitive measure of airflow obstruction in the smaller airways (36,47). Peak expiratory flow rate (PEFR) measured by a Wright Flow Meter is the most commonly used method of determining airway resistance in the small and large airways because of its portability and convenience, but  more variable results have been shown using this method  compared to FEV 1 (66). Both FEV 1 and PEFR are effort dependent measures and are therefore not the most sensitive measure compared to the effort independent measure MMEF.  Flow-volume curves illustrate in greater detail the specific airway conductance or flow at different lung volumes. Obstruction in the upper expiratory phase is apparent when the curve appears “scooped” or “curved” rather than a smooth continuous line as  38  seen in normal loops. However, the flow-volume ioop can be abnormal even when the FEVi/FVC ratio is normal, thus implying the greater sensitivity of this test (66).  v)  Pathogenesis:  For some time, asthma and EIA were thought to be two separate conditions. It is now known that exercise is just another stimulus in provoking an asthmatic attack. Although the exact etiology of EIA is still unclear, several theories have been proposed. Earlier studies have speculated hyperventilation, hypocapnia, and acidosis to be causally related to ETA (6, 10, 32, 43). The more widely accepted theory today is that water and heat loss from the respiratory mucosa represents the initiating stimulus for the postexercise bronchoconstriction (3, 14, 63). This is based on earlier investigations which have consistently demonstrated that asthmatics exercising in warm, humid environments are less likely to experience an attack than while exercising in cool, dry environments (2).  Recently, a new hypothesis by Mcfadden (45) suggests that ETA is a vascular phenomenon. This theory is built on the fact that asthmatics have a hyperplastic capillary bed in their airways that is highly sensitive to thennal stimuli.  a) HYPERPNEA, HYPOCAPNEA, AND LACTIC ACIDOSIS  Hyperventilation associated with exercise and consequent hypocapnia have been suggested as possible causes of ETA based on earlier studies demonstrating that voluntary hyperventilation at rest can increase airway resistance in asthmatics (10, 32). Fisher et  39  a!., (18) demonstrated by breathing an 8% CO 2 gas mixture during vigorous physical activity, significantly reduced post-exercise bronchoconstriction. On the other hand, Chan-Yeung et al., (10) noted that the combination of hyper-ventilation and breathing 2 actually increased airway resistance, measured by a greater decline in FEV CO 1 compared to breathing room air. This author concluded that “EIA” is probably exerciseinduced hyperventilation “(EIh)”. Although the mechanism of EIh is probably different from EIA, people who suffer from EIA generally develop a bronchial response to voluntary hyperventilation. Some differences have been found between EIA and EIh; voluntary hyperventilation does not release catecholamines, so the bronchodilation normally seen in asthmatics during exercise does not occur during the period of hypernea and therefore a faster onset of bronchoconstriction occurs (29, 60). Also, with exercise a diminished responsiveness to exercise performed within 2 hours after the initial exertion has been seen in some asthmatics; this refractory period may not occur with voluntary hypernea (29, 60).  Higher blood lactate levels have been reported in asthmatics working at the same oxygen consumption as non-asthmatics with similar fitness levels (1). This lactic acidosis has been suggested to play a role in EIA based on the theory that high hydrogen ion concentrations may cause the release of mediators from mast cells (43). However, the administration of bicarbonate, which buffers the excess H ions, did not appear to reduce post-exercise bronchospasm (43). Therefore, no substantial evidence in the literature confirms these earlier hypotheses that hypocapnea, hyperventilation, or acidosis are causally related to EIA.  40  b) HEAT AND WATER LOSS THEORY  Chen and Horton (12) demonstrated the importance of water loss and/or heat loss by demonstrating that asthmatics who breathe fully saturated air at 37 degrees Celsius during exercise prevent EIA. More recent studies by McFadden and co-workers (43, 63), who have looked at the effects of environmental conditions on exercise-induced bronchoconstriction, have helped to clarify some of the earlier controversies regarding etiology. Strauss and McFadden (63) demonstrated a greater bronchospastic response while breathing cold air during exercise, and a blunted response when breathing inspired air at 37 degrees celsius and fully saturated (BTPS). These findings suggest that this rapid rewanning of the airways significantly reduces EIA (63). Deal and co-workers (14) developed the heat-flux hypothesis using the following equation to determine heat loss:  RHL=VE(HC[Ti-TeJ+Hv[Wi-We])  where HC  =  0  heat capacity of air (3.04 x 10 Kcal•L 1  of inspired and expired air, respectively in water ( 5.8 Kcal.g ), and Wi and We 1  =  0  C, Hv  =  ), Ti and Te are temperature 1 C  latent heat of evaporization for  water content of the inspired and expired air at  0•L in air -1). This equation demonstrates that high 2 the mouth, respectively (mg H minute ventilations will have a greater heat loss and a consequently greater airway obstruction (14). These authors also showed that voluntary hyperventilation while breathing cold air produced an increase in airway resistance, suggesting that the stimulus of EIA was heat loss from the respiratory mucosa and not exercise. A weak link in the respiratory heat loss (RHL) theory comes from the fact that inspiring air as warm as 80  41  degrees causes no less of a bronchoconstriction than while breathing air at body temperature.  Anderson and coworkers have emphasized the effects of drying of the airways to be a more important stimulus of EIA than cooling (3, 63). They suggested that the increase in osmolarity of the respiratory mucosa due to water loss was a possible stimulus of EIA (4). This is based on Schoeffel’s findings which demonstrated that the inhalation of hyper- and hypo-tonic solutions could elicit bronchoconstriction in resting asthmatics  (57). This increase in osmolarity was speculated to stimulate the release of mediators from lung mast cells, thus causing airway narrowing. This is thought to either act on smooth muscle or on cells in the respiratory mucosa by stimulating epithelial irritant receptors and/or disrupting epithelial junctions (4).  Despite the evidence for the  cooling/drying hypothesis, some subjects can still develop EIA while breathing warm humid air; thus implying that H20 and RFIL cannot be the sole trigger factors by themselves (8).  Gilbert and McFadden (24) have challenged the osmolarity theory, and have presented a new hypothesis suggesting that exercise-induced asthma is a vascular phenomenon. These investigators demonstrated little change in surface osmolarity when the intrathoracic thermal fluxes were measured during hypemea. This indicates that the respiratory tract has a protective mechanism that prevents drying of the airways (24). McFadden (45) proposed a new hypothesis that suggests cooling of the airways after exercise is followed by rapid warming and the development of mucosal hyperemia and edema, thus causing the airway narrowing. Recently Gilbert and McFadden tested this theory and found both airway cooling and rapid rewarming after isocapnic  42  hyperventilation played a key role in the production of bronchial narrowing (25) Although they were not able to determine how rapid bronchial rewarming causes the obstruction, they suggested the development of mucosal hyperemia and edema to be a possible explanation. If this theory is correct, the degree of hyperemia would depend on the rate of bronchial rewarming. Slow rewarming (ie. the subject warms down) has been found to abolish the effects of hyperventilation or hyperpnea during exercise, whereas rapid rewarming increases obstruction (45). It has also been shown that airways of asthmatics rewarm twice as fast in the first minute of recovery than normal individuals (24). Because hyperemia increases local heat in the bronchial circulation, the main heat source in the central airways, supports the hypothesis that EIA could be due to the heatsensitive airway microcirculation responding to the fall that accompanies hyperpnea. However, rewarming may not be the trigger because asthmatics who are able to “run through” their asthma fail to develop bronchoconstriction after prolonged exercise, but still rewarm their airways (29).  vi)  Prevention:  EIA can be prevented in many asthmatic athletes who choose not to use medication. Different types of activities are less asthmogenic; for example, exercise  performed in warm humid environments, such as swimming, are less likely to provoke an attack than outdoor cold weather activities such as running, cycling, rowing, cross country skiing, and hockey. The duration of exercise is another determinant of the severity of EIA; for example, sports involving intermittent running such as basketball, football, rugby, and baseball are better tolerated by the asthmatic athlete than continuous  43  running activities (2, 36). The intensity of exercise can also affect the severity of exercise-induced bronchospasm; the greatest degree of exercise-induced airway obstruction tends to occur most frequently in asthmatics exercising between 60 and 85 % of maximal oxygen consumption for 6-8 minutes (59). However, at greater exercise intensities the degree of post-exercise bronchoconstriction appears unaltered and exercising longer than this generally diminishes the response (1, 19, 47). Performing a continuous warm-up 15 minutes in duration at an intensity of 60 % of maximal oxygen consumption prior to exercise significantly protects the airways of asthmatics from bronchoconstriction (48). The improvement in fitness level through aerobic training has been shown to reduce the severity, frequency, and duration of attacks (22, 31). Other techniques useful in minimizing EIA occurance are making a conscious effort to prevent exaggerated hyperventilation by breathing slower and deeper and using nasal breathing, which warms and cleans the air (37).  vii)  Treatment  Although preventative measures can be taken for EIA, some asthmatic athletes require pharmacological intervention to overcome their asthma while exercising. The most effective drugs for preventing EIA are the i2 adrenergic agonists: salbutamol, terbutaline, fenoterol, or salmetorol. Salbutamol is the drug of choice by asthmatic athletes because of its powerful bronchodilator effects, 2 selectivity, and its use is permitted by the International Olympic Committee (IOC) (67).  Other classes of  medication used are sodium cromoglycate, methyl xanthines, corticosteroids, and bella donna alkaloids.  44  a)  f  -  Adrenergic receptor physiology  The n-receptors, stimulated by the sympathetic limb of the autonomic nervous system, can be divided into two groups, f i and P2. 3  1 receptors i 3  are more potently  stimulated by norepinephrine and are responsible for the chronotropic and inotropic effects of the heart, decrease in intestinal motility, and lipolysis, while P2 receptors mediate bronchodilation of airway smooth muscle, cause uterus, bladder, intestinal relaxation, and dilation of arteries supplying smooth muscle. P2-receptors can be found in many different cell types within the lung; including smooth muscle of all airways from the trachea down to the terminal bronchioles. Activation of these receptors by 3 agonists causes relaxation of central and peripheral airways. In addition to relaxation of smooth muscle,  agonists also reduce the release of mediators from mast cells, and may reduce  mucosal edema. Those drugs activating  Pt receptors cause a number of outcomes that  are unacceptable for use in international sport competitions. Therefore, drugs which have a greater selectivity for P2-receptors with minimal effects on  i-receptors are  preferred because of fewer cardiovascular side effects and their use has been sanctioned by the International Olympic Commission (IOC) (52). The cascade of events is initiated by the stimulation of P2 receptors by a P2 adrenoreceptor agonist (ie. catecholamines); this activates the enzyme adenylate cyclase, causing the formation of a second messenger, cyclic AMP (cAMP). Intracellular cAMP activates protein kinase A, which in the case of bronchial smooth muscle, causes a reduction of Ca dependent coupling of actin and myosin, resulting in smooth muscle relaxation. It has been suggested that the increase in bronchial reactivity seen in asthmatics is most likely caused by a decrease in the -adrenergic response (50).  45  b) 132 Adrenergic agonist (Salbutamol)  Salbutamol is one of the first generations of 132 adrenergic agonists developed for -  treating asthma. Inhaled Salbutamol given 15 minutes prior to exercise is very effective in preventing the post-exercise fall in PEFR (27, 58). Subjects given a placebo will show a 40% drop in peak flow and only a 10% drop with salbutamol, which is within normal limits. This drug has full bronchodilator effects for up to 3 hours with partial activity up until 6 hours (58). Inhalation of 12 agonists is the more preferred method of delivery over oral, sublingual, or parental (intravenous or intramuscular) routes because of its rapid onset of action, direct route to the respiratory tract, and fewer side effects. However, some subjects have experienced tremors, which are caused by direct stimulation of 132 adrenoreceptors in skeletal muscle (50). There is a growing concern of the overuse of sympathomimetic drugs based on a number of studies demonstrating the regular use of 132 agonists can lead to an increase in bronchial hyperresponsiveness (54). The use of salbutamol has been permitted by I.O.C. based on the assumption that this 13-agonist has no ergogenic effect in the asthmatic athlete. Studies that have looked at this drug in asthmatics and non-asthmatics as a possible performance enhancer, have reported conflicting results (7, 46, 49, 56). Bedi et al., (7) found salbutamol to increase sprint time in normal subjects, while others have reported no ergogenic benefit in nonasthmatics (46,49). Schmidt et al., (56) also found this drug to have no effect on exercise performance in asthmatics, thus encouraging its use by the asthmatic athlete to minimize EIA in competitive events. More recently Meeuwisse et al., (49) conducted a similar study to Bedi et al., (7) on elite non-asthmatic cyclists and found salbutamol to have no performance enhancing effect when given in therapeutic doses.  46  c) Other Pharmacological Agents  Sodium Cromoglycate is a safe and effective drug for the prophylactic management of asthma. In the treatment of EIA sodium cromoglycate can be used in combination with other drug classes and has been shown to be effective in preventing EIA when given before the start of exercise, but has little effect once EIA has been induced. Its mode of action was once thought to be a mast cell stabiliser but appears to have effects on other systems. There are no cardiovascular effects or performance enhancing qualities, therefore, sodium cromoglycate is allowed in international sporting competition (20, 52).  Methyl Xanthenes; one of the most extensively ingested drug of this group is caffeine. It has been shown to cause relaxation of bronchial smooth muscle and can significantly prevent EIA in high doses (7 mg/Kg) (38).  Caffeine is banned in  competition if serum concentrations exceeds 12 mg.L 1 (61). Theophylline, a methylated xanthene, is not as effective of a bronchodilation in the management of asthma as 132 agonists, but are used effectively by individuals who do not tolerate 132 stimulants. Theophylline is comparable to sodium cromoglycate in inhibiting EIA. However, there are a number of side effects including tacchycardia, mild CNS stimulation, diarrhea, headache, and nausea which are not compatible for use by an athlete during competition  (51). Oral and intravenous glucocorticosteroids play a valuable role in the management of severe chronic and acute asthma. The use of systemic corticosteroids have been banned from international sport competitions due to their potential to enhance performance. Inhaled glucocorticosteroids on the other hand, have been found to have ,  47  no ergogenic effects, but like oral glucocorticosteroids stabilize asthma, and have little ,  effect on EIA if administered just prior to exercise. Taken on a regular basis, inhaled glucocorticosteroids reduce inflammatory cell filtrate, bronchial hyperreactivity, and improve the effectiveness of pre-exercise f32 agonist in reducing the severity of EIA (52).  Belladonna Alkaloids are anticholinergic agents that play a role in the management of asthma.  Ipratropium bromide is an example of this class and is  administered via aerosol or by a nebulised solution. As a bronchodilator ipratropium bromide is used by individuals who do not respond well to 3 agonists or given in combination with  agonists and/ or sodium cromoglycate to give better protection than  using either drug alone. Side effects are rare with this drug, however some asthmatics complain of dryness of the throat. It is doubtful whether anticholinergic agents play a role in preventing EIA or whether these drugs will enhance performance ( 20).  48  Circulatory, Ventilatory, and Metabolic Responses to Exercise  vii)  Few studies have examined the physiological responses of asthmatics during exercise. In the data available, asthmatics have generally responded similarly to normal subjects when free from an attack (44). Any differences in these variables have been concluded to be due to the sedentary state of the asthmatics tested; for example, higher blood lactate levels in asthmatics have been reported by several authors (1,5,10,53). These individuals were inactive, so these higher levels could be more representative of their lower fitness level. On the other hand, Anderson et al., (1) found unusually high levels of lactate in asthmatics working at the same oxygen consumption as similarly trained non-asthmatics. It is not clear whether this response is due to the presence of asthma.  If so, this greater degree of metabolic acidosis may affect the optimal  performance of these athletes with EIA.  During the initial phase of exercise, many asthmatics develop mild bronchodilation, which is thought to be due to the release of catecholamines (26, 29). This bronchodilation usually persists throughout the duration of exercise, but may gradually decrease as indicated by a fall in PEFR.  However, within minutes of  completing exercise, there is a profound drop in PEFR (or FEVi) due to bronchoconstriction. The failure of normal catecholamine release during exercise may be responsible for this post-exercise airway narrowing seen in individuals with EIA. Much debate exists in the literature as to whether asthmatics actually have an altered catecholamine response to exercise. Some investigators have found significantly lower plasma adrenaline and noradrenaline levels in asthmatics when compared to matched  49  control subjects (6, 64), while other studies have not (9). This inconsistency may lie in the different protocols used. The former studies measured catecholamine levels at the end of exercise, whereas in the latter study blood samples were obtained throughout the exercise period. The alveolar to arterial P02 [A-a D02] is a good indicator of the adequacy of pulmonary gas exchange. In normal subjects (A-a)D02 decreases during moderate exercise, due to an improvement of perfusion  (Q) at the lung apices, but increases during  higher intensities of exercise. Katz et al., (35) found the distribution of ventilationperfusion (VA/Q) over the lung became more uneven during a progressive exercise performance in asthmatic children. Changes that develop in gas tension in asthmatics during exercise have been shown to be variable. Some authors have found no change in arterial oxygen tension (21), while others have reported a significant rise in Pa02 from resting levels in asthmatics performing progressive exercise (1, 35). After exercise, a fall in Pa02 has been observed to develop concomitantly with bronchoconstriction. This hypoxemia may be a result of inequalities in the VA/Q relationship due to airway narrowing(1). Arterial PCO2 was found to be variable in asthmatics during exercise (1, 21), while unchanged in others (35). Following exercise, hypercapnia may develop in asthmatics due to marked bronchoconstriction, but this does not occur in normal individuals.  2 of normal subjects stay relatively Arterial oxygen (Pa02) and arterial PCO consistant throughout exercise, although some HT athletes (VO2max  >  1 68 ml.kg.miw  who are free of asthma, exhibit arterial hypoxemia at maximal exercise.  This  phenomenon in HT athletes is called exercise-induced hypoxemia (EIH), and may suggest that the lungs are the “limiting” factor for exercise performance in these athletes  50  (16). Although the exact etiology is still unknown, one of the causes is due to the excessive widening of ( A-a) D02  .  It would be interesting to determine whether HT  asthmatic athletes, who show arterial desaturation, are limited at maximal exercise.  Several investigators have found physiological parameters such as HR, V02, VE, FEVi, and work capacity in asthmatics during submaximal and/or maximal exercise to  be within normal range (1, 33, 53, 56). Anderson et al., (1) compared metabolic and ventilatory responses in 5 asthmatic subjects during a 6-8 minute test on both a cycle ergometer and a treadmill. The treadmill running did produce the greatest bronchoconstriction, indicated by a fall in PEFR measures, and the higher lactates were observed during the cycle. The levels of lactate observed in these asthmatics during the cycle were found to be higher when compared to non-asthmatics exercising at similar oxygen consumptions. Packe et al., (53) tested 10 untrained asthmatics with 10 matched non-asthmatics during progressive exercise test on a treadmill to 85 % maximal V0 . No 2 difference was found between the two groups with respect to V0 , VE, Sa02, and RER 2 during exercise, but RER values were higher in the asthmatics thus, indicating a normal fat metabolism in these subjects. Also, the similar levels of V02, VE, and Sa0 2 in comparison to the non-asthmatics, indicated no impairment of oxygen delivery to exercising muscle in asthmatics (53). Ingemann-Hansen et al., (33) measured metabolic and ventilatory variables (maximal V0 , VE, and HR) in asthmatics during a graded 2 bicycle exercise and found no difference between inhaled salbutamol and saline control. All of the studies to date, investigating the metabolic and ventilatory responses of asthmatics to exercise, have tested unfit subjects; therefore,the lower maximal oxygen consumption (VO2max), work capacity, and higher levels lactate reported in asthmatics have been due to the lower fitness level of these individuals.  51  In the literature, no study has looked at metabolic and ventilatory variables in highly trained athletes (VO2max  >  60 mi/kg/mm). if higher lactate levels and alterations in gas  exchange develop in asthmatics due to the presence of their disease, it is possible these abnormalities could limit these individuals in athletic performance.  52  APPENDIX B Tables  TABLE 7.  SUBJECT  Age, height, weight,VOmax, and PC2O, individual data of subjects in the Highly trained group  SEX  AGE  years  HEIGHT cm  WEIGHT kg  VO2max  PC2O  1 mlkgmin  1 mg•mI  HT group CL  F  22  175  63.3  57.8  3.9  JH  M  23  180  72.9  63.4  6.3  PMS  F  24  158  50.8  53.9  6.1  PH  M  24  180  72.8  63.3  15.8  PM  F  33  162  55.3  54.4  0.7  PR  M  32  190  85.0  58.8  11.5  RH  M  19  182  74.1  60.3  3.1  SH  F  35  170  64.0  50.3  15.6  SS  F  23  165  59.1  50.9  1.6  26±6  174 ± 11  66.4 ± 10.8  57.0 ± 4.9  7.2 ± 5.8  MEAN±SD  53  Age, height, weight,VOmax, and PC2O, individual data of subjects in the Moderately trained group  Table 8.  SEX  AGE years  HEIGHT cm  WEIGHT kg  VO2max mFkgmhr 1  PC2O  AB  M  23  192  87.0  57.0  11.2  GK  M  21  180  72.0  46.4  0.8  PK  M  23  187  85.1  57.3  8.9  RC  M  23  189  93.5  48.7  1.6  RF  M  23  175  71.4  53.1  9.4  SB  M  26  182  75.5  54.6  5.0  SM  M  23  200  96.0  48.6  15.9  CM  F  31  161  48.6  45.1  8.0  24±3  183 ± 12  78.6 ± 15.3  51.3 ± 4.9  7.6 ± 5.0  SUBJECT MT group  MEAN ±SD  54  Table 9.  SUBJECT  , RER, HR, PEFR, and Sa02 at 25 % VO2max with 2 YE, V0 placebo, individual subject data ( n = 17)  YE btps  V02 1 1•min-  RER  HR bpm  PEFR 1•sec-1  Sa02  33.2 31.9 26.7 32.5 23.8 34.8 27.1 24.6 34.1 39.4 34.2 29.2  1.16 1.14 0.73 1.20 0.76 1.49  0.89 0.78 0.89 0.80 0.84  500 640 410 600 355 520  96.0 96.5 97.3 97.3 96.5  0.78 0.74 0.71 0.87 0.77 0.85 0.78 0.78 0.72  96.0 101.3 113.0 105.8 91.3 114.5 99.8 110.5 106.5 117.8 113.8 85.5 81.5 101.8  0.89 0.87 0.77  97.8 118.0 108.3  560 545 490 730 470 600 530 670 620 680 440  25% CL JH PMS PH PM PR RH SH SS AB GK PK RC RF SB SM CM  39.8 28.4 32.2 37.2 28.1  MEAN±SD 31.6±4.8  0.98 0.83 1.26 1.67 1.23 1.29 1.26 1.17 1.23 1.47 0.95 1.16±.26  0.81±.06 103.7±10.9 550±102  55  96.5 97.3 97.8 97.8 97.3 96.0 96.8 96.3 97.3  96.9±0.6  Table 10  SUBJECT 25% CL iii PMS PH PM PR RH SH SS AB GK PK RC RE SB SM CM  , RER, HR, PEFR, and Sa02 at 25 % VO2max with 2 1. V0 E salbutamol, individual subject data (n = 17)  VE btps  V02 1•min 1  RER  HR bpm  PEFR 1•sec1  Sa02  32.4  1.13  0.81  36.5 36.0 36.7 20.0 30.8 24.2 30.6 24.4 31.0 32.0 35.3 39.5 26.3 32.1 38.6 26.1  1.31 1.09 1.28 0.67 1.32 0.88 1.01 1.00 1.47 1.24 1.37 1.32 1.03 1.30 1.55 0.92  0.85 0.86 0.81 0.77 0.72 0.82 0.73 0.76 0.74 0.87 0.91 0.72 0.78 0.85 0.87 0.82  90.0 106.0 117.3 108.3 97.3 102.8  97.3 97.3 98.3  98.8 116.3 100.3 106.8 111.5 89.0 89.8 104.8 106.0 125.5 106.0  490 630 420 710 485 590 660 565 535 710 510 640 640 650 720 710 450  1.17± .23  0.80± .06  104.5 ± 10.0  595 ±98  MEAN ±SD 31.3 ± 5.6  56  94.0 96.5 95.8 99.3 98.3 95.5 96.5 96.0 97.5 97.8 97.8 95.8  96.9 ± 1.4  Table 11  SUBJECT  , RER, HR. PEFR, and Sa02 at 50 % VO2max with 2 VE, V0 placebo, individual subject data ( n = 17)  YE btps  V02 1 1•min  RER  HR bpm  PEFR I•sec-1  Sa02  53.2 59.2 48.7 52.8 39.2 80.5 45.5 45.7 47.6 61.0 59.7 44.3  2.07 2.20 1.49 2.33 1.51 3.32 1.81 1.41 1.84 2.65 2.03 1.91 2.43 1.97 2.11 2.19 1.34  0.87 0.88 0.95 0.81 0.85 0.86 0.75 0.82 0.92 0.84 0.96 0.82 0.91 0.83 0.95 0.90 0.82  133.3 136.5 149.3 144.0 126.8 147.8 136.0 158.8 125.5 144.5 145.8  520 640 440 675 370 525 610 565 480 700 480 615  95.8 95.5 96.3 95.5 96.8 95.8 96.5 98.0 96.5 97.0 96.3 96.0 96.8  50%  •  CL JH PMS PH PM PR RH SH SS AB GK PK RC RF SB SM CM  70.1 49.5 53.3 50.7 37.9  MEAN ±SD 52.9 ± 10.8  2.03 ± .49  109.3 114.3 134.5 134.5 142.3 122.5  585 650 670 705 420  0.87 ± .06 135.6 ± 12.9 567 ± 104  57  97.5 97.0  96.5 ± 0.7  Table 12  SUBJECT 50% CL JH PMS PH PM PR RH SH SS AB GK PK RC RF SB SM CM  , RER, HR. PEFR, and Sa02 at 50 % VO2max with 2 VE, V0 salbutamol, individual subject data (n = 17)  YE btps  V02 1.min1  RER  HR bpm  PEFR 1•sec 1  Sa02  54.2 64.2 46.5 57.2 39.8 59.2 45.0 53.7 39.6 56.9 52.7 41.9 69.4 48.1 54.6 59.0 38.5  1.92 2.32 1.56 2.30 1.45 2.53 1.75 1.72 1.64 2.64 1.83 1.84 2.42 1.94 2.12 2.34 1.33  0.92 0.98 0.90 0.82 0.88 0.83 0.86 0.78 0.85 0.82 1.03  535 660 490 680 420 600 675 580 540  0.90 0.77 0.80 0.92 1.01 0.90  119.3 138.0 138.3 142.5 123.5 132.3 134.0 154.3 122.3 138.5 145.3 112.0 120.0 140.8 141.0 151.5 132.3  690 510 670 700 660 710 720 460  97.0 97.0 97.3 98.3 94.5 96.5 96.0 98.8 95.5 96.3 96.8 96.5 97.3 97.0 97.3 95.8  1.98±.39  0.88±.08  134.4±11.8  606±96  MEAN±SD 51.8±9.0  58  96.7±1.0  Table 13  VE, V02, RER, HR, PEFR, and Sa02 at 75 % VO2max with placebo, individual subject data (n = 17)  YE btps  V02 1mm 1  RER  HR bpm  PEFR 1.sec-1  Sa02  CL JH PMS PH PM PR RH SH SS AB GK  107.3 110.4  3.31 3.31 2.23 3.86 2.38 4.30 3.25 2.61 2.51  170.5 173.3 185.5 180.3 173.3 175.0 173.5 191.8 159.3 172.3 172.0  550  95.0  3.99 2.95  0.99 1.04 1.05 1.02 0.96 1.00 0.87 1.09 0.98 0.98 1.03  660 460 690 385 580 700 600 520 715  94.3 95.3 96.5 94.5 94.5 96.8 95.8 95.3 96.8  495  PK RC RE  71.8 120.3 79.0 90.5 81.5 63.0  3.44 3.62 3.00 3.25 3.47 1.95  0.90 1.01 0.92 1.04 1.01 0.90  150.0 161.3 168.0 171.3 179.5 160.8  620 640 660 730 735 510  96.3 94.3  SUBJECT 75%  SB SM CM  79.0 115.3 66.0 128.0 96.8 114.6 69.4 110.6 91.6  MEAN ±SD 93.8 ± 20.8  3.14 ± .65  0.99 ± .06 171.6 ± 10.1 602 ± 103  59  95.5  96.3 96.3  95.5 ± 0.9  Table 14  SUBJECT 75 % CL IH PMS PH PM PR RH SH SS AB GK PK RC RE SB SM CM  , RER, HR, PEFR, and Sa02 at 75 % VO2max with 2 VE, V0 salbutainol, individual subject data (n = 17)  VE btps  V02 I. min 1  RER  HR bpm  PEFR 1 1 . sec-  Sa02  106.9 115.4 71.7 120.0 65.4 95.7 100.5 113.3 68.7 102.0 94.3  3.02 3.55 2.21 3.72 2.24 3.72 3.02 2.98 2.34 4.16 2.81  1.08 1.07 0.99 1.03 0.98 0.92 1.04 0.94 0.96 0.95 1.11  163.8 170.8 170.0  95.8 96.3 95.3  70.7 125.7 84.1 88.9 89.3 66.5  3.28 3.74 3.13 3.23 3.45 1.89  0.97 0.81 0.89 1.01 1.07 1.03  176.3 169.0 160.5 170.0 186.3 149.5 171.5 176.0 154.3 159.5 175.3 173.8 182.3 165.3  520 690 485 710 460 610 690 590 550 720 500 680 700 670 730 740 470  3.09 ± .63  0.99 ± .08  169.0 ± 9.5  618 ± 101  MEAN ±SD 92.9 ± 19.6  60  94.0 96.5 95.0 97.0 96.0 96.0 95.3 95.5 95.8 97.0 95.3  95.8 ± 0.8  Table 15  , RER, HR, PEFR, and Sa02 at 90 % VO2max with 2 VE, V0 placebo, individual subject data (n = 17)  VE btps  V02 4 1mm  RER  HR bpm  PEFR 1 . sec-i  Sa02  CL  133.4  3.70  0.95  175.3  540  95.0  JH  167.6  3.98  1.16  189.0  680  93.5  PMS PH  107.7  2.60  1.12  195.0  480  94.8  4.30 2.91  1.08  188.0 195.8  PR  164.9  4.58  1.05 1.04  RH  184.4  4.33  0.92  188.5  SH  122.5 99.2  AB  178.1  4.88  GK  135.9  3.51  PK  108.9  4.36  163.6  4.41  RF  118.4  3.61  SB  147.2  SM  110.5  3.97 4.13  CM  89.5  2.40  0.91  180.5  700 675 660 740 740 510  91.5  RC  1.09 1.04 1.06 1.03 1.04 1.05 1.04 1.17 1.11  191.8  SS  2.72 3.01  700 450 550 650 580 525 750 490  97.8  PM  179.2 95.4  1.05 ± .07  186.7 ± 6.5  612 ± 102  94.7 ± 1.5  SUBJECT 90%  MEAN ±SD 135.7 ± 32.2 3.73 ± .76  61  181.5  175.8 189.8 187.3 177.0 184.5 190.8 190.8 192.8  92.5 94.0 95.0 94.5 94.3 95.8 95.5 96.3 94.8 96.0  Table 16  SUBJECT 90% CL JH PMS PH PM PR RH SH SS AB GK PK RC RF SB SM CM  , RER, HR, PEFR, and Sa02 at 90 % VO2max with 2 VE, V0 salbutamol, individual subject data (n = 17)  YE btps  V02 I•min1  RER  HR bpm  PEFR I.sec1  Sa02  116.0 173.3 104.9 162.0 101.3 130.0 173.8 130.4 101.0 147.4 133.0 105.1 192.9 133.7 137.8 112.0  3.24 4.25 2.68 4.08 2.78 4.43 3.71 3.25 2.86 5.06 3.27 4.22 4.72 4.17 4.11 4.06  1.03 1.11 1.07 1.05 1.13 1.00 1.18 0.91 1.01 1.04 1.15 1.08 0.84 1.01  171.8 185.0 187.3 182.5 194.3 175.0 183.8 190.8 171.3 185.0 189.3 178.3 182.0  515 700 490 725 460 600 710  93.3 93.3 94.0 98.0 91.5 94.5 94.3 95.5 94.8 95.8 95.5 93.3 95.8 93.8 95.3 94.8  85.0  2.09  0.99 1.12 1.10  192.5 189.8 192.0 176.5  560 560 690 520 700 730 670 750 760 450  1.05 ± .09  183.9 ± 7.3  623 ± 108  94.6 ± 1.5  MEAN ±SD 131.8 ± 30.2 3.70 ± .81  62  Table 17  SUBJECT  , RER, PEFR, and Sa02 at 25 % VO2max with 2 VE, V0 placebo, individual subject data for NT group VE btps  V02 1• mm 1  RER  HR bpm  PEFR I. sec1  Sa02  33.2 31.8 26.7  1.16 1.14  96.0 101.3 113  500  96.0  640 410  96.5 97.3  0.75 1.49 0.98 0.82 1.26  0.89 0.78 0.89 0.80 0.84 0.78 0.74 0.71 0.86  105.8 91.3 114.5 99.8 110.5 106.5  600 355 520 560 545 490  96.5 96.5 97.3 97.8 97.8  1.06±.26  0.81±.06  104.3±7.9  513±89  96.9±0.7  25% CL IH PMS PH PM PR RH SH SS  32.5 23.8 34.8 27.1 24.6 34.1  MEAN±SD 29.8±4.3  0.73 1.20  Table 18 , RER, HR, PEFR, and Sa02 at 25 % VO2max with 2 VE, V0 salbutamol, individual subject data for the NT group SUBJECT  VE BTPS  V02 mm 1 1  RER  HR bpm  PEFR 1 sec1  Sa02  32.4 36.5 36.0 36.7 20.0 30.8 24.2 30.6 24.4  1.13 1.31 1.09 1.28 0.67 1.32 0.88 1.01 1.00  0.81  490  0.85 0.86 0.81 0.77 0.72 0.82 0.73 0.76  90.0 106.0  630 420  97.3 97.3 98.3  710 485 590 660 565 535  94.0 96.5 95.8 99.3 98.3  1.08±.21  0.79±.05  565±93  97.1±1.7  25% CL JH PMS PH PM PR RH SH SS  MEAN±SD 30.2±6.1  63  117.3 108.3 97.3 102.8 98.8 116.3 100.3 104.1±8.9  Table 19  SUBJECT  , RER, PEFR, and Sa02 at 50 %VO2max with 2 VE, V0 placebo, individual subject data for HT group  VE btps  V02 I-1 mm  RER  HR bpm  PEFR i . sec-i  Sa02  53.2 59.2 48.7 52.8 39.2 80.5 45.5 45.7 47.6  2.07  0.87  133.3  2.19 1.49 2.33 1.51 3.32 1.81 1.41 1.84  0.88 0.95 0.81 0.85 0.86 0.75 0.82 0.92  136.5 149.3 144.0 126.8 147.8 136.0 158.8 125.5  520 640 440 675 370 525 610 565 480  95.75 95.5 96.25 96.75 95.75 96.5 98 96.5  2.00± .59  0.86±.06  139.8± 11.0  536±98  96.4±.8  50% CL JH  PMS PH PM PR Rh SH SS  MEAN±SD 52.5± 11.9  Table 20  SUBJECT  2 at 50% VO2max with VE, V02, RER, FIR, PEFR, and Sa0 salbutamol, individual subject data for the HT group  YE btps  V02 mm I. 4  RER  HR bpm  PEFR I - sec 1  Sa02  54.2 64.2 46.5 57.2  1.92 2.32 1.56 2.30 1.45 2.53 1.75 1.72 1.64  0.92 0.98 0.90 0.82  119.3 138.0 138.3 142.5 123.5 132.3 134.0 154.3 122.3  535 660 490 680 420 600 675 580 540  97.0 97.0 97.3 94.5 96.5 96.0 98.8 95.5  575±89  96.6±1.3  50% CL JH PMS PH PM PR RH SH SS  39.8 59.2 45.0 53.7 39.6  MEAN±SD 51.0±8.7  1.91±.38  0.88 0.83 0.86 0.78 0.85  0.87±.06 133.8±11.1 64  Table 21  SUBJECT  , RER, PEFR, and Sa02 at 75 %VO2max with 2 VE, V0 placebo, individual subject data for UT group YE btps  V02 1• mini  RER  HR bpm  PEFR 1• sec1  Sa02  CL JH PMS PH PM PR RH  107.3 110.4 78.9 115.3 65.9 128.0  3.31 3.31 2.23 3.86 2.38 4.30  0.99 1.04 1.0475 1.02 0.96 0.99  170.5 173.3 185.5 180.3 173.3 175.0  550 660 460 690 385 580  95.0 94.3 95.3  96.8  3.25  0.87  173.5  SH  114.6  2.61  1.09  191.8  700 600  SS  69.4  2.51  0.98  159.3  520  95.8 95.3  3.08 ± .71  1.00 ± .06  175.8 ± 9.3  571 ± 106  95.2 ± 0.8  75%  MEAN ±SD 98.5 ± 22.2 Table 22  SUBJECT  96.8  VE, V02, RER, fIR, PEFR, and Sa02 at 75 % VO2max with salbutamol, individual subject data for the HT group YE btps  V02 I. mini  RER  HR bpm  PEFR I 1 sec  Sa02  106.9 115.4 71.7 120.0 65.4 95.7 100.5 113.3 68.7  3.02 3.55 2.21 3.72 2.24 3.72 3.02 2.98 2.34  1.08 1.07 0.99 1.03 0.98 0.92 1.04 0.94 0.96  163.8 170.8 170.0 176.3 169.0 160.5 170.0 186.3 149.5  520 690 485 710 460 610 690 590 550  95.8 96.3 95.3 94.0 96.5 95.0 97.0 96.0  589 ± 93  95.7 ± 0.9  75% CL JH PMS PH PM PR RH SH SS  94.5 94.5  MEAN ±SD 95.3 ± 21.4  2.98 ± .61  1.00 ± .06 168.4 ± 10.2 65  Table 23  , RER, PEFR, and Sa02 at 90 % VO2max with 2 VE, V0 placebo, individual subject data for HT group  VE btps  V02 1 4 mm  RER  HR bpm  PEFR I.• sec1  Sa02  CL  133.4  3.70  0.95  175.3  540  95.0  JH PMS PH PM PR RH SH  167.6 107.7 179.2 95.4 164.9 184.4 122.5  3.98 2.59 4.29 2.91 4.58 4.33 2.72  1.16 1.12 1.08 1.05 1.04 0.92 1.09  189.0 195.0 188.0 195.8 181.5 188.5 191.8  93.5  SS  99.2  3.01  1.04  175.8  680 480 700 450 550 650 580 525  1.05 ± .08  186.7 ± 7.6  572±87  SUBJECT 90%  MEAN ±SD 139.4 ± 35.2 3.57 ± .77 Table 24  SUBJECT  94.8 92.5  94.0 95.0 94.5 94.3 94.2 ± 0.9  VE, V02, RER, HR, PEFR, and Sa02 at 90% VO2max with salbutamol, individual subject data for the FIT group  VE btps  V02 4 1•min  RER  HR bpm  PEFR 1• sec1  Sa02  116.0 173.3 104.9 162.0 101.3 130.0 173.8 130.4 101.0  3.24 4.25 2.68 4.08 2.78 4.43 3.71 3.25 2.86  1.03 1.11 1.07 1.05 1.13 1.00 1.18 0.91 1.01  171.8 185.0 187.3 182.5 194.3 175.0 183.8 190.8 171.3  515 700 490 725 460 600 710 560 560  93.3 93.3 94.0  1.05 ± .08  182.4 ± 8.2  591 ± 99  90% CL JH PMS PH PM PR RH SH SS  MEAN ±SD 132.5 ± 30.1 3.48 ± .66  66  91.5 94.5 94.3 95.5 94.8  93.9 ± 1.2  Table 25  SUBJECT  ,RER, HR, PEFR, and Sa02, at 25 % VO2max, individual 2 VE, V0 subject data for the MT group YE btps  ‘102 1mm 4  RER  HR bpm  PEFR 1 1sec-  2 Sa0  AB  39.4  1.67  0.77  117.8  730  97.25  GK  34.2  1.23  0.85  113.8  470  96  PK  29.2  1.29  0.78  85.5  600  96.75  RC  39.8  1.26  0.78  81.5  530  96.25  RF  28.4  1.17  0.72  101.8  670  SB  32.2  1.23  0.89  97.8  620  SM  37.2  1.47  0.87  118.0  680  CM  28.1  0.95  0.77  108.3  440  MEAN±SD  33.6 ± 4.8  1.28 ± .21  0.80 ± .06  103.0±14.1  593 ± 103  25 %  Table 26  SUBJECT  97.25  96.9 ± 0.6  VE, V02, RER, HR, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data for the MT group YE btps  V02 4 1mm  RER  HR bpm  PEFR i sec 4  Sa02  31.0 32.0  1.47 1.24 1.37 1.32 1.03 1.30 1.55 0.92  0.72 0.78 0.85 0.87 0.82  106.8 111.5 89.0 89.8 104.8 106.0 125.5 106.0  710 510  35.3 39.5 26.3 32.1  0.74 0.87 0.91  650 720 710 450  95.5 96.5 96 97.5 97.8 97.8 95.8  1.27±.21  0.82±.07  104.9±11.7  628±99  25% AB GK PK RC RE SB SM CM  38.6 26.1  MEAN±SD 32.6±5.0  67  640 640  96.7±.9  Table 27  2 RER, HR, PEFR, and Sa02 at 50 % VO2max VE, V0 with placebo, individual subject data for MT group.  VE btps  V02 4 lmin  RER  HR bpm  PEFR 1 sec1  Sa02  AB  61.0  2.65  0.84  144.5  97.0  GK  59.7  2.03  0.96  145.8  PK  44.3 70.1 49.5 53.3 50.7 37.9  1.91  0.82  2.43  0.91  109.3 114.3  1.97 2.11  0.83 0.95  134.5  2.19  0.90  142.3  1.34  0.82  122.5  700 480 615 585 650 670 705 420  2.08 ± .39  0.88 ± .06  SUBJECT 50%  RC RF SB SM CM  MEAN ±SD 53.3 ± 10.1  Table 28  134.5  130.9 ± 14.0 603 ± 104  96.3 96.0 96.8 97.3 97.5 97.0  96.8 ± 0.5  , RER, HR, PEFR, and Sa02 at 50 % VO2max with 2 VE, V0 salbutamol, individual subject data for the MT group  VE btps  V02 1 1 mm-  RER  HR bpm  PEFR 1 sec 4  Sa02  AB GK  56.9 52.7  0.82  138.5  96.25  1.03  145.3  690 510  96.75  PK  41.9  0.90  112.0  670  96.5  RC  69.4  0.77  120.0  48.1  0.80  140.8  SB  54.6  0.92  141.0  97.3  SM  59.0  1.01  151.5  CM  38.5  0.90  132.3  700 660 710 720 460  97.3  RE  2.64 1.83 1.84 2.42 1.94 2.12 2.34 1.33 2.06±.41  0.89±.09  135.2±13.2  640±98  96.7±.6  SUBJECT 50%  MEAN±SD 52.6±9.8  68  97 95.8  Table 29  SUBJECT  2 RER, HR. PEFR, and Sa02 at 75 % VO2max with YE, V0 Placebo, individual subject data for MT group. VE btps  V02 4 1mm  RER  HR bpm  PEFR 1 1 sec-  Sa02  110.6 91.6 71.8 120.3 79.0 90.5 81.5  3.99 2.95 3.44 3.62 3.00 3.25 3.47 1.95  0.98 1.03 0.90 1.01 0.92 1.04 1.01 0.90  172.3 172.0 150.0 161.3 168.0 171.3 179.5 160.8  715 495 620 640 660 730 735 510  96.8 96.3 94.3  3.21 ± .61  0.97 ± .06  166.9 ± 9.2  638±94  95.9 ± 0.9  75% AB GK PK RC RF SB SM CM  63.0  MEAN ±SD 88.5 ± 19.2  Table 30  SUBJECT  95.5 96.3 96.3  , RER, HR. PEFR, and Sa02 at 75 % VO2max with 2 VE, V0 salbutamol, individual subject data for the MT group  YE btps  V02 Imin 1  RER  HR bpm  PEFR 1 1sec  2 Sa0  102.0  4.16 2.81 3.28 3.74 3.13 3.23 3.45 1.89  0.95 1.11  720 500 680 700 670 730 740 470  96 95.25  0.97 0.81 0.89 1.01 1.07 1.03  171.5 176.0 154.3 159.5 175.3 173.8 182.3 165.3  3.21 ± .67  0.98± .10  169.7 ± 9.3  651 ± 106  75% AB GK PK RC RF SB SM CM  94.3 70.7 125.7 84.1 88.9 89.3 66.5  MEAN±SD 90.2± 18.5  69  95.5 95.8 97.0 95.3  95.8 ± .7  Table 31  2 RER, HR, PEFR, and SaO2at 90 % VO2max with VE, V0 placebo, individual subject data for MT group.  VE btps  V02 1mm 4  RER  HR bpm  PEFR 1 sec1  Sa02  AB  178.1  4.88  1.06  189.8  95.8  GK  135.9  3.51  1.03  187.3  750 490  95.5  PK  108.9  4.36  1.04  177.0  700  91.5  RC  163.6  4.41  1.05  184.5  675  96.3  RF  118.4  3.61  1.04  190.8  660  94.8  SB  147.2  3.97  110.5  4.13  190.8 192.8  740 740  96.0  SM  1.17 1.11  CM  89.5  2.40  0.91  180.5  510  1.05±.07  186.7±5.6  658± 103  SUBJECT 90%  MEAN±SD 131.5±30.1 3.91±.75  95.8  95.1± 1.6  Table 32  , RER, HR, PEFR, and Sa02 at 90 % VO2max with 2 VE, V0 salbutamol, individual subject data for the MT group  SUBJECT  VE BTPS  V02 1 1 min  RER  HR bpm  PEFR 1 . sec  2 Sa0  AB  147.4  5.06  1.04  185.0  690  95.8  GK  133.0  3.27  1.15  189.3  520  95.5  PK  105.1  4.22  1.08  178.3  700  93.3  RC  192.9  4.72  0.84  182.0  730  95.8  RF  133.7  4.17  1.01  192.5  670  93.8  SB  137.8  4.11  0.99  189.8  750  95.3  SM  112.0  4.06  1.12  192.0  760  94.8  CM  85.0  2.09  1.10  176.5  450  1.04±.10  185.7±6.2  658± 113  90%  MEAN±SD 130.9±32.3 3.96±.92  70  94.8± 1.0  Table 33  Pre and post medication and recovery PEFR measures with placebo, individual subject data (N = 17)  SUBJECT  Pre- med. PEFR  Post-med. PEFR  3 mm PEFR  5 mm PEFR  10 mm PEFR  15 mm PEFR  CL JH PMS PH PM PR RH SH SS AB GK PK RC RF SB SM CM  525 623 447 630 338 520 603 545 512 673 437 602 562 640 647 687 460  503 621 443 633 362 500 610 533 500 673 427 613  530 660 430 700 390 540 650 565 490 710 450  510 610 430 635 370 470 635 540 490 700 400 610 500 640 670 640 440  500 620 430 660 375 480 640 540 490 660 400 620  503 632 612 667 433  650 560 660 675 670 410  520 650 440 665 390 520 640 540 495 710 440 620 510 660 670 660 425  MEAN±SD  556±96  545±95  573± 108  562± 103  546103  541±97  71  500 640 650 550 440  Table 34  Pre and post medication and recovery PEFR measures with salbutamol, individual subject data (N = 17)  SUBJECT  Pre- med.  Post-med.  PEFR  PEFR  CL  480  483  JH  615 427 662 342 550 637 547 500 693 473 600 622 628 653 695 460  630 443 690 403 567 667 548 533 667 500 643  PMS PH PM PR RH SH SS AB GK  PK RC RF SB SM CM  MEAN±SD 564± 102  3 mm PEFR  5 mm PEFR  10 mm  15 mm  PEFR  PEFR  520 640 450 725 440 580 700 560 540  540 610 465  500  500 630 475 725 415 560 665 540 535 690 470 670 680 590 700 700 435 587± 103  633 663 717 433  700 510 680 690 670 720 710 460  660 700 585 430  570 475 690 420 570 670 560 550 680 505 640 680 640 700 610 440  582± 100  605± 103  584±92  582±91  670  72  700 425 570 675 540 530 680 510 640 660  Table 35  Pre and post medication and recovery PEFR measures with placebo, individual subject data for the FIT group  SUBJECT  Pre- med. PEFR  Post-med. PEFR  3 mm PEFR  5 mm PEFR  10 mm PEFR  15 mm PEFR  SS  525 623 447 630 338 520 603 545 512  503 621 443 633 362 500 610 533 500  530 660 430 700 390 540 650 565 490  520 650 440 665 390 520 640 540 495  510 610 430 635 370 470 635 540 490  500 620 430 660 375 480 640 540 490  MEAN±SD  527±92  523±89  551± 105  540±96  521±93  526±98  Table 36  Pre and post medication and recovery PEFR measures with salbutamol, individual subject data for the HT group  SUBJECT  Pre- med. PEFR  Post-med. PEFR  3 mm PEFR  5 mm PEFR  10 mm PEFR  is mm  CL JH PMS PH PM PR  480 615 427 662 342 550  483 630 443 690 403  540 610 465 700 425 570  500 570 475 690 420 570  500 630 475 725 415 560  RH SH  637 547 500  560 540  675 540 530  670  SS  667 548 533  520 640 450 725 440 580 700  560 550  665 540 535  573± 100  562±89  556±86  560±97  lIT group CL JH PMS PH PM PR RH SH  PEFR  HT group  MEAN±SD 529± 104  567  552±99  73  Table 37  Pre and post medication and recovery PEFR measures with placebo, individual subject data for the MT group  SUBJECT  Pre- med. PEFR  Post-med. PEFR  3 mm PEFR  5 mill PEFR  10 mm PEFR  15 mill PEFR  AB GK PK RC RF SB SM CM  673 437 602 562 640 647 687 460  673 427 613 503 632 612  710 440 620 510 660 670 660 425  700 400 610  667 433  710 450 650 560 660 675 670 410  640 440  660 400 620 500 640 650 550 440  MEAN±SD  589±95  570±101  598± 113  587± 112  575113  558± 101  Table 38  Pre and post medication and recovery PEFR measures with salbutamol, individual subject data for the MT group  SUBJECT  Pre- med. PEFR  Post-med. PEFR  3 mm PEFR  5 mm PEFR  10 mm PEFR  is mill PEFR  AB  693  667  680  680  690  GK  473  510  600 622  660 660 700 585 430  505 640 680 640 700 610 440  470  PK  700 510 680 690 670 720 710 460  680 590 700 700 435  643 ± 99  608 ± 94  612 ± 92  617 ± 108  MT group  500 640 670  MT group  RC RE SB SM CM  628 653 695 460  500 643 670 633 663 717 433  MEAN ±SD  603±91  616 ± 97  74  640  670  Table 39  Blood lactates (mmol.l-l) at 25, 50,75, and 90 % VO2max with placebo, individual subject data ( n = 17)  Lactate  Placebo  ) 4 ( mmoll  25 %  50 %  75 %  90 %  CL  1.30  1.53  6.34  7.27  il-I  1.23  6.46  19.04  PMS  1.42  1.91 1.87  6.13  PH  1.55  8.86  PM  0.97 1.83  9.07 14.83  1.47  3.66  13.48  PR  1.26  2.05  8.12  8.79  RH  0.82  0.82  4.84  18.15  SH  0.63  1.02  8.90  11.76  SS  0.56  1.46  4.45  9.72  AB GK  1.69  2.08  5.85  15.16  2.77 1.06  7.73 2.17  11.93  PK  3.40 1.34  RC  0.93 0.87  3.33 4.24  7.24  RF  0.88 1.08  11.95  SB  1.83  2.42  5.90  11.61  SM  0.56  1.07  3.43  6.72  CM  0.75  0.93  1.79  5.61  MEAN±SD  1.20±.58  1.58±.67  5.42±2.20  11.13±4.02  Subjects  75  6.86  Table 40  Blood lactate (mmol.1 ) measures at rest and recovery conditions with 1 placebo, individual subject data (n = 17)  1 mm  3 mm  5 mm  0.94  17.22  16.03  18.15  15.69  PH  0.84  10.08  1.34  13.19 7.84  12.22  PR  13.61 9.18  6.07  6.46  RH  1.11  15.68  15.34  AB  1.00  13.47  15.41  13.36 13.94  12.05 10.26  GK  1.13  10.96  8.78  10.33  8.69  PK  1.18  7.37  7.49  6.07  RC  0.44  7.43  3.33  RF  7.53  12.58  11.26 16.16  12.21  SB  0.56 1.36  7.53 13.38  7.80 7.43  14.95  14.91  SM  0.37  8.71  7.18  7.83  4.68  CL  0.93  7.36  6.90  10.33  7.41  PMS  1.47  12.36  10.13  7.15  PM  1.22  13.22  10.58  SH  0.87  15.05  SS  0.64  8.34  6.92  CM  0.64  3.52  12.00 12.10 9.35 4.6  6.64 10.48 8.08 5.24  4.64  3.89  MEAN ± SD  0.94 ± .33  11.15 ± 3.66  10.68 ± 3.62  10.35 ± 3.63  8.32 ± 3.57  Lactate  Rest  (mmol•l ) 1 Subjects JH  Placebo  76  12.34  10 mm  Table 41  Blood lactates (mmol.l) at 25, 50,75, and 90 % VO2max with 1 salbutamol, individual subject data (n = 17)  Lactate (mmol 11)  Salbutamol 25 %  Subjects CL JH PMS PH PM PR RH SH SS AB GK PK  0.39 0.76 1.18 0.57 0.91 0.27 2.85 1.08 0.95 1.02 0.97 0.49  RC RF SB SM CM MEAN ± SD  50 %  75 %  90 %  1.17 2.42 1.39 1.50 1.77 0.22 2.59 1.43 1.73 1.74 1.63  7.97 8.73 4.28  8.26 17.62  6.03 3.29 2.49 8.85 8.57 3.74 5.99 5.59 2.45  8.86 7.74 12.67 4.28 16.63 11.52 7.64 7.95 9.98  1.57 3.18 1.93 0.59 0.60  0.80 2.13 1.21 2.08 0.83 0.95  6.58 4.14 9.93 3.81 3.78  8.95 9.73 13.48 16.42 6.55 6.72  1.14 ± 0.82  1.51 ± 0.62  5.66 ± 2.42  10.29 ± 3.87  77  Table 42  Lactate ) 1 (mmol1  Blood lactate ( mmol.l) measures at rest and recovery conditions with 1 salbutamol, individual subject data ( n = 17)  Rest  1 mill  3 mm  5 mill  10 mm  9.05 18.88  6.60 19.04  0.20  7.06 6.42  0.80  7.30  5.50 5.50 7.09 3.07 15.10 9.53 7.33 4.21 9.19  0.22  8.70  7.53  0.36  9.08  6.21  1.34  11.71  8.94  0.91  14.95  14.34  1.17  8.02  6.31  0.29  7.22  4.68  0.65  9.79±4.14  8.24±4.24  0.82±0.49  Salbutamol  Subjects CL  9.10  10.47  JH  16.66  19.31  PMS  8.99  PH  10.51  PM  12.16  PR  4.94 21.46  SS AB  9.14  GK  9.15  PK  9.93  RC  9.26  RF SB SM CM  12.57 9.63 7.71  6.09 8.49 12.87 8.28 17.39 13.51 8.00 7.06 10.51 9.09 8.43 12.07 13.68 8.66 7.66  MEAN±SD  11.11 ±3.97  10.68±3.67  RH SH  12.17 8.75  16.72  78  9.48 3.88 18.31 11.69 7.80 6.84  0.66 1.06 0.91 0.36 2.14 0.87 0.75 1.23  Table 43  Blood lactates (mmolt ) at 25, 50,75, and 90 % VO2max with placebo, 1  individual subject data for the HT group Lactate  Salbutamol  ) 1 (mmol•l  25 %  50 %  75 %  90 %  CL  1.30  1.53  6.34  7.27  JH  1.23  1.91  6.46  19.04  PMS PH  1.42  1.87  6.13  0.97 1.83  1.55 1.47  8.86 3.66  9.07 14.83  1.26  2.05  8.12  8.79  RH  0.82  0.82  4.84  18.15  SH  0.63  1.02  8.90  11.76  SS  0.56  1.46  4.45  9.72  MEAN±SD  1.11±0.41  1.52±0.40  6.42±1.91  12.46±4.22  Subjects  PM PR  Table 44  13.48  Blood lactate ( mmol.1 ) measures at rest and recovery conditions with 1 placebo, individual subject data for the HT group  Lactate (mmol1 ) 4 Subjects  Rest Placebo  1 mm  3 mm  CL  0.93  7.36  6.90  10.33  7.41  JH  0.94  17.22  16.03  18.15  15.69  PMS  1.47  12.36  10.13  7.15  PH  0.84  13.61  13.19  12.22  PM  1.22 1.34  12.00 7.84  10.58  PR  13.22 9.18  RH SH SS  1.11  15.68  15.34  6.07 13.36  6.64 10.08 10.48 6.46 12.05  0.87  15.05  12.10  12.34  0.64  8.34  9.35  6.92  8.08 5.24  MEAN ± SD  1.04 ± 0.27  12.45 ± 3.45  11.43 ± 3.16  10.79 ± 3.81  9.12 ± 3.29  79  5 mm  10 mm  Table 45  Blood lactates (mmoltl) at 25, 50,75, and 90 % VO2max with salbutamol, individual subject data for the Hi’ group  Lactate (mmol 11) Subjects  Salbutamol  25 %  50 %  75 %  90 %  CL JH  0.39  1.17  7.97  8.26  0.76 1.18  2.42  8.73  17.62  1.39 1.50  4.28  8.86  6.03  7.74  3.29  12.67  2.49  4.28  PMS PH PM  0.57 0.91  PR  0.27  1.77 0.22  RH  2.85  2.59  8.85  16.63  SH  1.08  1.43  8.57  11.52  SS  0.95  1.73  3.74  7.64  MEAN ± SD  1.00 ± 0.76  1.58 ± 0.70  5.99 ± 2.59  10.58 ± 4.42  Table 46  Blood lactate ( mmol.1 ) measures at rest and recovery conditions with 1 salbutamol, individual subject data for the HT group 1 mill  3 mm  0.20  9.10  JH  0.66  PMS  Lactate  Rest  (mmol•1 ) 1 Subjects  Salbutamol  CL  5 mm  10 mill  10.47  9.05  16.66  19.31  18.88  0.80  8.99  6.09  7.06  PH  1.06  10.51  8.49  6.42  PM  0.91  12.16  12.87  9.48  PR RH  0.36 2.14  4.94  8.28  SH  0.87  21.46 12.17  17.39 13.51  3.88 18.31 11.69  6.60 19.04 5.50 5.50 7.09 3.07 15.10 9.53  SS  0.75  8.75  8.00  7.80  7.33  MEAN ± SD  0.86 ± 0.55  11.64 ± 4.88  11.69 ± 4.69  10.57 ± 5.75  8.75 ± 5.12  80  Table 47  Blood lactates ( 1 mmol•F at 25,50, 75, and 90 % VO2max with placebo, )  individual subject data for the MT group Lactate ) 1 ( mmoll Subjects  Placebo 25 %  50 %  75 %  90 %  GK PK RC RE SB SM CM  2.77 1.06 0.93 0.87 1.83 0.56 0.75  3.40 1.34 0.88 1.08 2.42 1.07 0.93  7.73 2.17 3.33 4.24 5.90 3.43 1.79  11.93 6.86 7.24 11.95 11.61 6.72 5.61  MEAN ± SD  131 ± .74  1.65 ± 0.90  4.30 ± 2.04  9.63 ± 3.45  Table 48  Blood lactate ( mmol•l-l) measures at rest and recovery conditions with placebo, individual subject data for the MT group  Lactate ) 1 (mmolP subjects  Rest Placebo  1 mm  3 mm  5 mm  10 mill  AB GK PK RC RE SB SM  1.00  15.41 8.78 7.80 7.43 11.26 16.16 7.18 4.60  13.94 10.33 7.49 7.43 12.21 14.95  10.26 8.69 6.07 3.33 7.53 14.91 4.68  CM  1.13 1.18 0.44 0.56 1.36 0.37 0.64  13.47 10.96 7.37 7.53 13.38 12.58 8.71 3.52  MEAN ± SD  0.84 ± 0.38  9.69 ± 3.53  9.83 ± 4.12  9.85 ± 3.61  81  7.83 4.64  3.89 7.42 ± 3.86  Table 49  Blood lactates ( mmol.1 ) at 25,50,75, and 90 % VO2max with 4 salbutamol, individual subject data for the MT group  Lactate ) 1 ( mmol1 Subjects AB GK PK RC RF SB SM CM  Salbutamol 25 %  50 %  75 %  90 %  1.02  1.74  0.97 0.49 1.57 3.18 1.93 0.59 0.60  1.63 0.80 2.13 1.21 2.08 0.83 0.95  5.99 5.59 2.45 6.58 4.14 9.93 3.81 3.78  7.95 9.98 8.95 9.73 13.48 16.42 6.55 6.72  MEAN±SD  1.29±.91  1.42±.55  5.28±2.32  9.97±3.40  Table 50  Blood lactate ( mmol•l) measures at rest and recovery conditions with 1 salbutamol, individual subject data for the MT group  Lactate ) 1 (mmol•1 Subjects  Rest Salbutamol  AB GK PK RC RF SB SM CM MEAN ± SD  1 mm  3 mm  5 mm  1.23 0.22 0.36 1.34 0.91 1.17 0.29 0.65  9.14 9.15 9.93 9.26 12.57 16.72 9.63 7.71  7.06 10.51 9.09 8.43 12.07 13.68 8.66 7.66  6.84 7.30 8.70 9.08 11.71 14.95 8.02 7.22  4.21 9.19 7.53 6.21 8.94 14.34 6.31 4.68  .77 ± .45  10.52 ± 2.85  9.64 ± 2.28  9.23 ± 2.78  7.68 ± 3.24  82  10 mm  Table 51  The duration of exercise test with salbutamol and placebo, individual subjectdata(n= 17)  Subjects  Salbutamol  Placebo  CL  16.2  15.5  JH  19.2  20.0  PMS  19.1  16.5  PH  15.3  PM  20.0  17.2 20.0  PR  20.0  16.5  RH  20.0  20.0  SH  16.1  16.3  SS  20.0  20.0  AB  20.0  20.0  GK  17.1  17.1  PK  20.0  20.0  RC  17.3  17.3  RF  20.0  20.0  SB  20.0  20.0  SM CM  17.1  17.1  16.4  20.0  MEAN±SD  18.5±1.8  18.4±1.8  83  Table 52  Subjects  The duration of exercise test with salbutamol and placebo, individual subject data for the HT and MT groups  Placebo  Salbutamol  Subjects  Time (mm) lIT group  Placebo Time ( mm)  Salbutamol  MT group  CL  15.5  16.2  AB  20.0  20.0  JH  20.0  19.2  GK  17.1  17.1  PMS  16.5  19.1  PK  20.0  20.0  PH  17.2  15.3  RC  17.3  17.3  PM  20.0  20.0  RF  20.0  20.0  PR  16.5  20.0  SB  20.0  20.0  RH  20.0  20.0  SM  17.1  17.1  SH  16.3  16.1  CM  20.0  16.4  SS  20.0  20.0  MEAN ±SD  18.0 ± 1.9  18.4 ± 2.0  18.9 ± 1.46  18.5 ± 1.7  84  Table 53  RMANOVA Summary (N= 17)  Effect  DEPENDENT VARIABLES V02 1 lmin  VE 4 l•min  HR bpm  p =008* p = .492  p  Sex (5) Drug (D)  p p  Trained (T)  p  =  condition (C)  p  =  DXS  p=.927  p=.738  DXT  p  .439  DXCXT  p=. 454 p = .578  p = .482 p=.283  DXCXS  = =  =  .000  *  .531 .902 .000  =  RER  .843  p  =  .903  p  =  p  =  .936  p  =  p  =  .971  p  =  .000  p  =  .000  p  =  .950 .747 .574 .000  p  =  .777  p  =  .332  p  =  .786  p= .138 p = .137  p  =  .000  p  p  =  .786  =  Sa02  p=.209 p =.003* p=007* p= .289  p=.764 p = 851 p553 p = .274  cc*p <005 Table 54  Effect  RMANOVA Summary for PEFR and Blood lactate measurements  DEPENDENT VARIALBLES PEFR l•sec 1  LACTATE (mmol.l)  Drug(D) Sex(S) Trained(T) Condition(C)  p = .002* p = .000* p=.215 p = .000*  p = .688 p = .259 p=.342 p = .000*  DXS DXT DXC  p=.334 p=.8’75 p=.00l*  p=.816 p=.5l7 p—838  DXCXT DXCXS  p=.24.’7 p=.392  p=.369 p=.947 a = p <0.05  85  Table 55  RMANOVA summary for the HT group  DEPENDENT VARIABLES  Effect V02 1 1•min  VE 1 l•min  HR bpm  RER  Sa02  Drug ( D)  p=.429  p.345  p.010*  p1.00  p=.699  Condition (C)  p=0(JrJ*  p=000*  p=0(J0*  p_0(J(J*  p_000*  DXC  p=.’13ó  p=.243  * 002 p=  p’740  p=322  DEPENDENT VARIABLES Effect  PEFR 1•sec 1  Drug (D)  * 009 p=.  Condition (C)  p=OIJO*  DXC  * 031 p=.  Lactate 1 mmol•1  * 000 p=.  *  86  p <0.05  Table 56  RMANOVA summary for the MT group  DEPENDENT VARIABLES  Effect V02 1 lmin  VE lmin 1  HR bpm  RER  Sa02  Drug (D)  p=.869  p=.945  p=.l46  p=.8l9  p.955  Condition (C)  p=0(J0*  p=0(J(J*  p=0(JO*  p=(J(JO*  p=015*  DXC  p=.825  p=.9l5  p=.O’75  p=.’749  p=.762  DEPENDENT VARIABLES Effect  PEFR 1 1•sec  Lactate mmol•1’  Drug (D)  p=.O78  p=.836  Condition (C)  * 000 p=.  p=0(J0*  DXC  p=.8O6  * 027 p=. *  87  p <0.05  Table 57  RMANOVA summary for subjects with a PC20 < 4.0 mg/mi  DEPENDENT VARIABLES  EFFECT  Drug (D)  Condition(C) DXC  V0 2 1 lmiir  yE 1 Fmin  bpm  p =.058 p =.0OO p =.395  p =.717 p =YJJ p =.663  p =.206 p J(J* p =.477  HR  RER  Sa02  p =.806 p yjij* p =.ll0  p =.336 p YJJ p=.9&3  DEPENDENT VARIABLES Effect  PEFR 1 1sec  Lactate 1 mmol•1  Drug (D)  p =.031*  p .477  DxC  p=04’7*  p =470 <005  88  Table 58  Baseline Spirometry for the HT group  HT GROUP  FVC  FEV1  FEV1/FVC%  CL IH PMS PH PM PR RH SH SS  5.09 6.32 4.19 4.53 3.77 5.00 5.31 4.15 4.34  4.34 5.22 3.49 3.84 2.54 3.53 4.91 3.62 3.71  85 83 83 85 67 71 92 87 85  MEAN ± SD  4.74 ± 0.78  3.91 ± 0.81  82 ± 7.9  Table 59  Baseline Spirometry for the MT group  MT GROUP  FVC  FEVi  FEV1/FVC%  AB GK PK RC RF SB SM CM  8.37 5.61 6.56 6.30 5.91 6.00 6.94 3.91  6.24 4.05 5.17 4.06 4.96 4.96 6.20 3.30  75 72 78 64 83 83 89 82  MEAN ± SD  6.20 ± 1.26  4.87 ± 1.04  78 ± 7.7  89  APPENDIX C Figures  Figure 7.  ) responses at various exercise intensifies (% VO2max), 1 V02 ( 1mlir aflsubjectsdata(n= 17)  4.5 3.5,  0  2.5 0 S  1.5  0.5  I  25%  50%  Salbutamol Placebo  —  75%  90%  Exercise (%VO2max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p=O.531  90  Figure 8.  ) responses at various exercise intensities ( %VO2max), 1 V02 ( l.minHT subjects data  4.5. 4.0• 3.5. 3.O  0 •  25%  50%  75%  Salbutamol Placebo  90%  Exercise ( % V02 max)  Values  are means ± SD; open circles, salbutamol; closed circles, placebo p = .429  91  Figure 9.  V02 ( lmin) responses at various exercise intensities (%VO2max), 1 MT subjects data  5.0 4.5. 4.O  3.5. 3.O 0 >  2.5 -0-  2.O 1.5  Salbutamol Placebo  1.0•  O.5  •  25%  •  50%  •  75%  90%  Exeitise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p  92  =  .869  Figure 10.  VE (l.minl )responses at various exercise intensities (%VO2max), aflsubjectdata(n= 17)  180 160 140 120’ .E  100 0 —0-——  Salbutamol  60  •  Placebo  40 20  •  25%  50%  I  75%  90%  Exercise ( % VO2max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .492  93  Figure 11.  VE (l.min-l )responses at various exercise intensities (%VO2max), HT subject data  180 160 140 120 1oo  80  0  Salbutamol  60  •  Placebo  40 20  25%  50%  75%  90%  Exeicise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p  94  =  .345  Figure 12.  1 )responses at various exercise intensities (%V O2max), VE ( l•minMT subject data  180 160 140 120 1100. 80 -0-  60  Salbutamol Placebo  40 20  I  25%  I  •  50%  •  I  75%  90%  Exercise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p  95  =  .945  Figure 13.  HR (bpm) responses at various exercise intensities (%VO2max), all subject data ( n = 17)  210190  -  170  -  a 1500  130-  .  Salbutamol Placebo  11090  I  25%  50%  •  I  75%  •  90%  Exercise ( % VO2max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .138  96  Figure 14.  HR (bpm) responses at various exercise intensities (%VO max), 2 MT subject data  200 180 160 140 120  0 •  100 80  I  25%  50%  •  I  Salbutamol Placebo  -  75%  90%  Exercise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p  97  =.  146  Figure 15.  RER responses at various exercise intensities (%VO2max), all subject data ( n = 17)  1.1  -  1.00.9  -  —00.8  -  0.7-  I  25%  50%  •  Salbutamol Placebo  I  75%  90%  Exeicise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p =.936  98  Figure 16.  RER responses at various exercise intensities (%“O2max), HT subject data  1.2 1.1 1.0•  0.9  -0-  Salbutamol Placebo  0.8 0.7  I  25%  •  I--—  50% 75% Exercise ( % V02 max)  1  90%  Values are means ± SD; open circles, salbutamol; closed circles, placebo p =1.00  99  Figure 17.  RER responses at various exercise intensities (%VO2max), MT subject data  1.21.1  -  1.00.90 •  0.8 -  0.7  -  25%  I  I  50%  75%  Salbutamol Placebo  90%  Exercise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p  100  =  .819  Figure 18.  Sa02 measures at various exercise intensities (%VO2max), all subject data ( n = 17)  99. 98  0  Salbutamol  •  Placebo  97.  92  I  25%  I  50% 75% Exercise ( % VO2max)  90%  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p= .747  101  Figure 19.  Sa02 measures at various exercise intensities (%VO2max), HT subject data  99. 0 •  98  Salbutamol Placebo  97. 96 Ti)  95 94. 93 92  I  25%  50%  •  I  75%  90%  Exercise ( % V02 max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p= .699  102  Figure 20.  Sa02 measures at various exercise intensities (%VO2max), HT subject data  99  -  0 •  98 =  Salbutamol Placebo  97, 96’  1)  95. 94. 93  —i  25%  -.  •  50%  I  75%  90%  Exeicise ( % VO2max)  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p= .955  103  Figure 21.  Blood lactate ( mmol•1 1 ) at various exercise intensities (% VO2max) and 1 to 10 minutes into recovery, HT subject data  18 16 14  0 •  Salbutamol Placebo  25%  50% 75% Exeitise  0  E  ‘  6  0  4 2 0  ist  90%  1 mm  3 mm 5 mm Recovery  io mm  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .463  104  Figure 22.  Blood lactate ( mmoll 1 ) at various exercise intensities (% VO2max) and 1 to 10 minutes into recovery, MT subject data  14 12  O •  Salbutainol Placebo  8 E 6 4.  2  0•  I—I—I.I.I.I.I.I.  REST 25%  50% 75% Exercise  90%  1mm  3mm 5mm Recovery  10mm  Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .836  105  

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