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The asthmatic athlete: metabolic and ventilatory responses during exercise with and without pre-exercise.. 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 presenting this thesis 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 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 L% DE-6 (2/88) 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 = 57.0 ± 4.9 ml.kg-’.min-’), and 8 moderately trained (MT) (age = 24.1 ± 3.1 yrs; ht 183.1 ± 11.8 cm; wt = 78.6 ± 15.3 kg; VO2max = 51.3 ± 4.8 ml•kg 1min- ) with exercise-induced asthma (ETA) under 2 randomly assigned experimental 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. V02,minute ventilation (VE), respiratory exchange 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 V02,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 = 17), group data 11 Table 3 V02,VE, HR, RER, and Sa02 of highly trained (n = 9), group data 12 Table 4. V02,YE, HR, RER, and Sa02 of moderately trained (n=8) group data 12 Table 5. Lactate (mmol.Fl) of all subjects, highly trained and moderately trained, group data 13 Table 6 PEFR (l.sec-1) of all subjects, highly trained and moderately trained, group data 13 Table 7 Age, height, weight, VO2max, and PC2O, individual data of subjects in the Highly trained group 53 Table 8 Age, height, weight, VO2max, and PC2O, individual data of subjects in the Moderately trained group 54 Table 9 YE, V02 RER, PEFR, and Sa02 at 25 % VO2max with placebo, individual subject data ( n = 17) 55 Table 10 VE, V02 RER, PEFR, and 5a02 at 25 % VO2max with salbutamol, individual subject data ( n = 17) 56 Table 11 YE, V02 RER, PEFR, and Sa02 at 50% VO2max with placebo, individual subject data ( n = 17) 57 V Table 12 VE, V02RER, PEFR, and Sa02 at 50 % VO2max with salbutamol, individual subject data ( n = 17 ) 58 Table 13 VE, V02 RER, PEFR, and Sa02 at 75 % VO2max with placebo, individual subject data ( n = 17 ) 59 Table 14 VE, V02RER, PEFR, and Sa02 at 75 % VO2max with salbutamol, individual subject data ( n = 17) 60 Table 15 VE, V02RER, PEFR, and Sa02 at 90% VO2max with placebo, individual subject data ( n = 17 ) 61 Table 16 VE, V02RER, PEFR, and Sa02 at 90 % VO2max with salbutamol, individual subject data ( n = 17 ) 62 Table 17 VE, V02 RER, PEFR, and Sa02 at 25 % VO2max with placebo, individual subject data for the HT group 63 Table 18 VE, V02RER, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data for the HT group 63 Table 19 VE, V02RER, PEFR, and Sa02 at 50 % VO2max with placebo, individual subject data for the HT group 64 Table 20 VE, V02 RER, PEER, and Sa02 at 50 % VO2max with salbutamol, individual subject data for the HT group 64 Table 21 VE, V02RER, PEER, and Sa02 at 75 % VO2max with placebo, individual subject data for the HT group 65 Table 22 VE, V02RER, PEER, and Sa02 at 75 % VO2max with salbutamol, individual subject data for the HT group 65 Table 23 VE, V02RER, PEER, and Sa02 at 90 % VO2max with placebo, individual subject data for the HT group 66 vi Table 24 VE, V02RER, PEFR, and Sa02 at 90 % VO2max with salbutamol, individual subject data for the HT group 66 Table 25 VE, V02, RER, PEFR, and Sa02 at 25 % VO2max with placebo, individual subject data for the MT group 67 Table 26 VE, V02, RER, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data for the MT group 67 Table 27 VE, V02, RER, PEFR, and Sa02 at 50% VO2max with placebo, individual subject data for the MT group 68 Table 28 VE, V02, RER, PEFR, and Sa02 at 50 % VO2max with salbutamol, individual subject data for the MT group 68 Table 29 VE, V02RER, PEFR, and Sa02 at 75 % VO2max with placebo, individual subject data for the MT group 69 Table 30 VE, V02RER, PEFR, and Sa02 at 75 % VO2max with salbutamol, individual subject data for the MT group 69 Table 31 VE, V02RER, PEFR, and Sa02 at 90% VO2max with placebo, individual subject data for the MT group 70 Table 32 VE, V02, RER, PEFR, and Sa02 at 90 % VO2max with salbutamol, individual subject data for the MT group 70 Table 33 Pre and post medication and recovery PEFR measures with placebo, individual subject data ( n = 17 ) 71 Table 34 Pre and post medication and recovery PEFR measures with salbutamol, individual subject data ( n = 17 ) 72 Table 35 Pre and post medication and recovery PEER measures with placebo, individual subject data for the HT group 73 vII Table 36 Pre and post medication and recovery PEFR measures with salbutamol, individual subject data for the HT group 73 Table 37 Pre and post medication and recovery PEFR measures with placebo, individual subject data for the MT group 74 Table 38 Pre and post medication and recovery PEFR measures with salbutamol, individual subject data for the MT group 74 Table 39 Blood lactates (mmoltl) at 25, 50, 75, and 90 % VO2max with placebo, individual subject data ( n = 17 ) 75 Table 40 Blood lactates (mmol.l1)measures at rest and recovery conditions with placebo, individual subject data ( n = 17 ) 76 Table 41 Blood lactates ( mmol.1-1)at 25, 50,75, and 90 % VO2max with salbutamol, individual subject data (n = 17 ) 77 Table 42 Blood lactates (mmol•l-1)measures at rest and recovery conditions with salbutamol, individual subject data ( n = 17 ) 78 Table 43 Blood lactates ( mmol l) at 25, 50, 75, and 90 % VO2max with placebo, individual subject data for the HT group 79 Table 44 Blood lactates (mmoitl) measures at rest and recovery conditions with placebo, individual subject data for the lIT group 79 Table 45 Blood lactates (mmol.[l) at 25, 50, 75, and 90 % VO2max with salbutamol,individual subject data for the HT group 80 Table 46 Blood lactates (mmolt1)measures at rest and recovery conditions with salbutamol, individual subject data for the HT group 80 Table 47 Blood lactates (mmol.P1)at 25, 50, 75, and 90 % VO2max with placebo,individual subject data for the MT group 81 vi’ Table 48 Blood lactates (mmol.l1)measures at rest and recovery conditions with placebo, individual subject data for the MT group 81 Table 49 Blood lactates (mmol.1l) at 25, 50,75, and 90 % VO2max with salbutamol,individual subject data for the MT group 82 Table 50 Blood lactates (mmol.1l) measures at rest and recovery conditions with salbutamol, individual subject data for the MT group 82 Table 51 The duration of exercise test with salbutamol and placebo, individual subject data (n = 17 ) 83 Table 52 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.ml1 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 PEFR (l•sec-1)measures under salbutamol and placebo conditions at various exercise intensities and 3 to 15 minutes into recovery, all subject data ( n = 17 ) 16 Figure 2 PEFR (l•sec-1)measures under salbutamol and placebo conditions at various exercise intensities and 3 to 15 minutes into recovery, HT groupdata(n=9) 17 Figure 3 PEFR (l.sec1)measures under salbutamol and placebo conditions at various exercise intensities and 3 to 15 minutes into recovery, MT groupdata(n=8) 18 Figure 4 PEFR (l.secl) measures under salbutamol and placebo conditions at various exercise intensities and 3 to 15 minutes into recovery, PC2O <4.0mg. mF1 (n =6) group data 19 Figure 5 Blood lactate ( mmol.11)at various exercise intensities and 1 to 10 minutes into recovery, all subject data ( n = 17 ) 20 Figure 6 HR (bpm) responses at various exercise intensities, HT group data(n=9) 21 Figure 7 V02 (l.nthrl) responses at various exercise intensities (% VO2max), all subject data ( n = 17) 90 Figure 8 V02 (l•min4)responses at various exercise intensities (%VO2max), HT subject data 91 Figure 9 V02 (l.miir1)responses at various exercise intensities (% VO2max), MT subject data 92 Figure 10 VE (Fmin1)responses at various exercise intensities (% VO2max), all subject data ( n = 17) 93 Figure 11 VE (lmiir1)responses at various exercise intensities (% VO2max), Hi’ subject data 94 Figure 12 VE (1.mlir4)responses at various exercise intensities (% VO2max), HT subject data 95 x Figure 13 HR (bpm) responses at various exercise intensities (% VO2max), allsubjectdata(n=17) 96 Figure 14 HR (bpm) responses at various exercise intensities (% VO2max), MT subject data 97 Figure 15 RER responses at various exercise intensities (% VO2max), aflsubjectdata(n=17) 98 Figure 16 RER responses at various exercise intensities (% VO2max), HT subject data 99 Figure 17 RER responses at various exercise intensities (% VO2max), MT subject data 100 Figure 18 Sa02 responses at various exercise intensities (% VO2max), all subject data ( n = 17 ) 101 Figure 19 Sa02 responses at various exercise intensities (% VO2max), HT subject data 102 Figure 20 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.11)at various exercise intensities (% VO2max), 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 FEF25..7 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 HanJ00 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 (Sa02)and arterial oxygen tension (Pa02)in healthy 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 exercise- induced hypoxemia (Effi), defined as a reduction in Sa02 of 4% below resting values, is thought to be attributed to two causes: a lower alveolar P02 (PAO)due to an inadequate ventilatory response to exercise, and secondly, excessive widening of the alveolar-arterial P02 difference ((A-a)D02)) caused by veno-arterial shunt, ventilation/perfusion (VA/Q) 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-1min -1), and 8 moderately trained athletes (1 female, 7 males; age = 24.1 ± 3.1 yrs; ht. = 183.1 ± 11.8 cm; wt. = 78.8 ± 15.5 kg; V02 max = 51.2± 4.8 nil•kg -i.min1),with EIA 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 FEV1% 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 60 ml.kg-1min- for males and 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 mi1 for males and 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 a rate of 0.13 mlmin1. Aerosols were inhaled for periods of 2 minutes followed by 30 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•m11)every 5 minutes (34). FEVi was measured every 30 and 90 seconds after each concentration until a fall in FEV1 of 20 % (PC20), compared to the saline control was achieved. The percentage fall in FEV1 was calculated from the lowest FEV1 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: Ci = second last concentration (<20% FEV1fa11) C2 = last concentration (>20 % FEV1 fall) Ri = % fall FEV1 after Ci R2 = % fall FEV1 after C2 A PC2O 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 (V02), carbon dioxide (VCO2),and 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 supernatant was collected and split into duplicates before being stored at -70 0 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•mo11 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; V02,VE, fiR, RER, Sa02; 8 and 9 levels for PEFR and LA, respectively. The 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). V02,VE, FIR, RER, 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 post- medication 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 < 0.05 AU subjects passed the baseline criteria of a positive methacholine(PC2O 16.0 mg.mll) with a mean PC20 of 7.2 ± 5.8 mg•mP1 for the highly trained group and 7.6 ± 5.0 mg m11 for the moderately trained group. There was a statistically significant difference in 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 Placebo Variables 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 93.8 ± 20.8 135.7 ± 32.2 HRbpm 104.5± 10.0 134.4± 11.8 169.0±9.5 183.9±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-1:p = 0.003) when the 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 to V02,VE, HR, RER, Sa02, and LA (Tables 3-6). Table 3. V02,VE, HR, RER, and Sa02 of highly trained (n= 9), group data Salbutamol Placebo Variables 25% 50% 75% 90% 25% 50% 75% 90% V02 L/mm 1.08 ± 0.21 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 VEbips 30.2 ± 6.1 51.0 ± 8.7 95.3 ± 21. 132.5 ± 30. 29.8 ± 4.3 52.5 ± 11.9 98.5 ± 222 139.4 ± 35. 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 96.6 ± 1.3 95.7 ± 1.0 93.9 ± 1.2 97.0 ± 0.7 964 ± 0.8 95.2 ± 0.8 94.2 ± 0.9 Table 4. VO2,VE, HR, RER, and Sa02 of moderately trained (n = 8), group data Salbutamol Placebo Variables 25% 50% 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 VEbtps 32.6 ± 5.0 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 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 97.1 ± 0.8 96.8 ± 0.5 95.9 ±0.9 95.1 ± 1.6 12 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-1)of all subjects, highly trained and moderately trained, group data LACTATE (mmol•11) n=17 n=9 n=8 CONDITION Salbutamol Placebo HT-Salb. HT-Placebo MT- Salb. MT- PL 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 8.8 ± 5.1 9.1 ± 3.3 7.7 ± 3.2 7.4 ± 3.9 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 ( lsec-1 ) of all subjects, highly trained and moderately trained, group data PEFRI•sec1 n=17 n=9 n8 CONDITION Salbutamol Placebo HT-Salb. 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 ± 90.6 588.5 ± 95.1 POST-MED 581.8 ± 100.4 545 ± 94.8 551.6 ± 98.6 522.8 ± 88.9 615.8 ± 97.0 570.0 ± 100.8 25 % VO2max 595.0 ± 98.2 550.6 ± 101.7 565.0 ± 92.8 513.3 ± 88.9 628.8 ± 98.8 592.5 ± 103.9 50 % VO2max 605.9 ± 96.4 567.7 ± 103.5 575.6 ± 88.7 536.1 ± 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 ± 97.5 526.1 ± 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•ml-1 (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), V02 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 10- 15 minutes post-exercise. 15 Figure 1. PEFR (1 •sec 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 a, 580 LI Ui 0 540 520 POST-MED.25% 50% 75% 90% 3mm 5mm 10mm 15mm Exercise Recovery 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). * 0 Salbutamol • Placebo 16 Figure 2. PEFR (1.sec-i) measures at various exercise intensities (% V02 max) and 3 to 15 minutes into recovery, Hi’ group data ( n =9) 600 580 560 [40. 520 500 i.i.i.i...i.i.i... POST-MED25 % 50 % 75 % 90 % 3 mm 5 mm 10 mm 15 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( * p < 0.05). * 0 Salbutamol • Placebo 17 Figure 3. PEER (1.sec-l) measures at various exercise intensities (%VO2max ), and 3 to 15 minutes into recovery, MT group data (n =8) 680 660 640 620 600• 580 560 1•1• I• I• I•I• POST 25 % 50 % 75 % 90 % 3 mm 5 mm io miii 15 miii - MED Exercise Recovery Values are means; open circles, salbutamol; closed circles, placebo : p = 0.078. ° Salbutamol • Placebo 18 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) Figure 4. PEER (l.secl) measures at various exercise intensities(% VO2max), and 3 to 15 minutes into recovery, PC2O < 4.0 mgm1-1 (n =6) group data. —0--- SALBUTAMOL ! 52O 5oo. 480 4. 440 I post-med 25% 50% 75% 90% 3 mm 5 mm 10 mm 15 mm Exercise Recovery 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 E 10 €0 C.) 0 Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = 0.688. —0— Salbutamol • Placebo REST 25% 50% 75% 90% 1mm 3mm 5mm 10mm Exercise Recovery 20 Figure 6. HR (bpm) responses at various exercise intensities (% VO2max), HT group data (n = 9). I I 50% 75% Exercise (% V02 max) 0— Salbutamol • Placebo 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). * 210 190 170 150- 130 110- 90 25% 90% 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, V02HR, PaCO2 measured in 5 asthmatics during a 6 minute graded bicycle exercise test. Recently, Pa02, PaCO2and 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•mt1). 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 % V02max 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•[1,but this was not 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•m14)) than the pre 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 non- asthmatic 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, V02 Sa02, RER, and LA. In 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.m11 to be a” gray area” or borderline hyper-responsiveness. Malo et a!., (41) suggested PC2O < 16 mg•mP1 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.ml1 in the present study. Also, data analysis performed on the more severe asthmatic subjects (PC20 <4.0 mgm1-1 ) revealed no significant difference in VE, V02RER, Sa02, and LA between the two experimental 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. Only one of the subjects found the exercise to be more difficult under the treatment of salbutamol. 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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. 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Sports Exerc. 18(3): 328-330, 1986. 33 APPENDIX A - Review of Literature EXERCISE INDUCED ASTHMA i) Introduction ii) Clinical Presentation iii) Diagnosis iv) Pulmonary function tests v) Pathogenesis a) Hypernea, Hypocapnea, and Lactic acidosis b) Heat and Water Loss theory vi) Prevention vii) 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 methacholine/histamine which provokes a fall in FEV1 to 20% below the control level. 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: FEV1,PEFR, and FEF 25-75% (MMEF). A change in large and small airway resistance is quantified by the ratio FEVi/FVC. A fall in FEV1 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 FEV1 (66). Both FEV1 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 post- exercise 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% CO2 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 CO2 actually increased airway resistance, measured by a greater decline in FEV1 compared to breathing room air. This author concluded that “EIA” is probably exercise- induced 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 = heat capacity of air (3.04 x 10 Kcal•L1 0 C1), Ti and Te are temperature of inspired and expired air, respectively in 0 C, Hv = latent heat of evaporization for water ( 5.8 Kcal.g1),and Wi and We = water content of the inspired and expired air at the mouth, respectively (mg H20•L in air -1). This equation demonstrates that high 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 heat- sensitive 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, f3i and P2. 13i receptors 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 non- asthmatics (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.L1 (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 vii) Circulatory, Ventilatory, and Metabolic Responses to Exercise 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 ventilation- perfusion (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. Arterial oxygen (Pa02) and arterial PCO2 of normal subjects stay relatively consistant throughout exercise, although some HT athletes (VO2max > 68 ml.kg.miw1 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 V02. No difference was found between the two groups with respect to V02,VE, Sa02, and RER 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 Sa02 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 V02,VE, and HR) in asthmatics during a graded 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. Age, height, weight,VOmax, and PC2O, individual data of subjects in the Highly trained group SUBJECT SEX AGE HEIGHT WEIGHT VO2max PC2O years cm kg mlkgmin1 mg•mI1 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 MEAN±SD 26±6 174 ± 11 66.4 ± 10.8 57.0 ± 4.9 7.2 ± 5.8 53 Table 8. Age, height, weight,VOmax, and PC2O, individual data of subjects in the Moderately trained group SUBJECT SEX AGE HEIGHT WEIGHT VO2max PC2O years cm kg mFkgmhr1 MT group 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 MEAN ±SD 24±3 183 ± 12 78.6 ± 15.3 51.3 ± 4.9 7.6 ± 5.0 54 Table 9. YE, V02RER, HR, PEFR, and Sa02 at 25 % VO2max with placebo, individual subject data ( n = 17) SUBJECT YE V02 RER HR PEFR Sa02 btps 1•min- bpm 1•sec-1 25% CL 33.2 1.16 0.89 96.0 500 96.0 JH 31.9 1.14 0.78 101.3 640 96.5 PMS 26.7 0.73 0.89 113.0 410 97.3 PH 32.5 1.20 0.80 105.8 600 97.3 PM 23.8 0.76 0.84 91.3 355 96.5 PR 34.8 1.49 0.78 114.5 520 96.5 RH 27.1 0.98 0.74 99.8 560 97.3 SH 24.6 0.83 0.71 110.5 545 97.8 SS 34.1 1.26 0.87 106.5 490 97.8 AB 39.4 1.67 0.77 117.8 730 97.3 GK 34.2 1.23 0.85 113.8 470 96.0 PK 29.2 1.29 0.78 85.5 600 96.8 RC 39.8 1.26 0.78 81.5 530 96.3 RF 28.4 1.17 0.72 101.8 670 SB 32.2 1.23 0.89 97.8 620 97.3 SM 37.2 1.47 0.87 118.0 680 CM 28.1 0.95 0.77 108.3 440 MEAN±SD 31.6±4.8 1.16±.26 0.81±.06 103.7±10.9 550±102 96.9±0.6 55 Table 10 1E. V02,RER, HR, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data (n = 17) SUBJECT VE V02 RER HR PEFR Sa02 btps 1•min bpm 1•sec- 25% CL 32.4 1.13 0.81 90.0 490 97.3 iii 36.5 1.31 0.85 106.0 630 97.3 PMS 36.0 1.09 0.86 117.3 420 98.3 PH 36.7 1.28 0.81 108.3 710 PM 20.0 0.67 0.77 97.3 485 94.0 PR 30.8 1.32 0.72 102.8 590 96.5 RH 24.2 0.88 0.82 98.8 660 95.8 SH 30.6 1.01 0.73 116.3 565 99.3 SS 24.4 1.00 0.76 100.3 535 98.3 AB 31.0 1.47 0.74 106.8 710 95.5 GK 32.0 1.24 0.87 111.5 510 96.5 PK 35.3 1.37 0.91 89.0 640 96.0 RC 39.5 1.32 0.72 89.8 640 97.5 RE 26.3 1.03 0.78 104.8 650 97.8 SB 32.1 1.30 0.85 106.0 720 97.8 SM 38.6 1.55 0.87 125.5 710 95.8 CM 26.1 0.92 0.82 106.0 450 MEAN ±SD 31.3 ± 5.6 1.17± .23 0.80± .06 104.5 ± 10.0 595 ±98 96.9 ± 1.4 56 Table 11 VE, V02RER, HR. PEFR, and Sa02 at 50 % VO2max with placebo, individual subject data ( n = 17) SUBJECT YE V02 RER HR PEFR Sa02 btps 1•min bpm I•sec-1 50% CL 53.2 2.07 0.87 133.3 520 95.8 JH 59.2 2.20 0.88 136.5 640 95.5 • PMS 48.7 1.49 0.95 149.3 440 96.3 PH 52.8 2.33 0.81 144.0 675 95.5 PM 39.2 1.51 0.85 126.8 370 96.8 PR 80.5 3.32 0.86 147.8 525 95.8 RH 45.5 1.81 0.75 136.0 610 96.5 SH 45.7 1.41 0.82 158.8 565 98.0 SS 47.6 1.84 0.92 125.5 480 96.5 AB 61.0 2.65 0.84 144.5 700 97.0 GK 59.7 2.03 0.96 145.8 480 96.3 PK 44.3 1.91 0.82 109.3 615 96.0 RC 70.1 2.43 0.91 114.3 585 96.8 RF 49.5 1.97 0.83 134.5 650 SB 53.3 2.11 0.95 134.5 670 97.5 SM 50.7 2.19 0.90 142.3 705 97.0 CM 37.9 1.34 0.82 122.5 420 MEAN ±SD 52.9 ± 10.8 2.03 ± .49 0.87 ± .06 135.6 ± 12.9 567 ± 104 96.5 ± 0.7 57 Table 12 VE, V02RER, HR. PEFR, and Sa02 at 50 % VO2max with salbutamol, individual subject data (n = 17) SUBJECT YE V02 RER HR PEFR Sa02 btps 1.min- bpm 1•sec 50% CL 54.2 1.92 0.92 119.3 535 97.0 JH 64.2 2.32 0.98 138.0 660 97.0 PMS 46.5 1.56 0.90 138.3 490 97.3 PH 57.2 2.30 0.82 142.5 680 98.3 PM 39.8 1.45 0.88 123.5 420 94.5 PR 59.2 2.53 0.83 132.3 600 96.5 RH 45.0 1.75 0.86 134.0 675 96.0 SH 53.7 1.72 0.78 154.3 580 98.8 SS 39.6 1.64 0.85 122.3 540 95.5 AB 56.9 2.64 0.82 138.5 690 96.3 GK 52.7 1.83 1.03 145.3 510 96.8 PK 41.9 1.84 0.90 112.0 670 96.5 RC 69.4 2.42 0.77 120.0 700 97.3 RF 48.1 1.94 0.80 140.8 660 97.0 SB 54.6 2.12 0.92 141.0 710 97.3 SM 59.0 2.34 1.01 151.5 720 95.8 CM 38.5 1.33 0.90 132.3 460 MEAN±SD 51.8±9.0 1.98±.39 0.88±.08 134.4±11.8 606±96 96.7±1.0 58 Table 13 VE, V02, RER, HR, PEFR, and Sa02 at 75 % VO2max with placebo, individual subject data (n = 17) SUBJECT YE V02 RER HR PEFR Sa02 btps 1mm bpm 1.sec-1 75% CL 107.3 3.31 0.99 170.5 550 95.0 JH 110.4 3.31 1.04 173.3 660 94.3 PMS 79.0 2.23 1.05 185.5 460 95.3 PH 115.3 3.86 1.02 180.3 690 96.5 PM 66.0 2.38 0.96 173.3 385 94.5 PR 128.0 4.30 1.00 175.0 580 94.5 RH 96.8 3.25 0.87 173.5 700 96.8 SH 114.6 2.61 1.09 191.8 600 95.8 SS 69.4 2.51 0.98 159.3 520 95.3 AB 110.6 3.99 0.98 172.3 715 96.8 GK 91.6 2.95 1.03 172.0 495 96.3 PK 71.8 3.44 0.90 150.0 620 94.3 RC 120.3 3.62 1.01 161.3 640 RE 79.0 3.00 0.92 168.0 660 95.5 SB 90.5 3.25 1.04 171.3 730 96.3 SM 81.5 3.47 1.01 179.5 735 96.3 CM 63.0 1.95 0.90 160.8 510 MEAN ±SD 93.8 ± 20.8 3.14 ± .65 0.99 ± .06 171.6 ± 10.1 602 ± 103 95.5 ± 0.9 59 Table 14 VE, V02RER, HR, PEFR, and Sa02 at 75 % VO2max with salbutainol, individual subject data (n = 17) SUBJECT VE V02 RER HR PEFR Sa02 btps I. min1 bpm 1 . sec-1 75 % CL 106.9 3.02 1.08 163.8 520 95.8 IH 115.4 3.55 1.07 170.8 690 96.3 PMS 71.7 2.21 0.99 170.0 485 95.3 PH 120.0 3.72 1.03 176.3 710 PM 65.4 2.24 0.98 169.0 460 94.0 PR 95.7 3.72 0.92 160.5 610 96.5 RH 100.5 3.02 1.04 170.0 690 95.0 SH 113.3 2.98 0.94 186.3 590 97.0 SS 68.7 2.34 0.96 149.5 550 96.0 AB 102.0 4.16 0.95 171.5 720 96.0 GK 94.3 2.81 1.11 176.0 500 95.3 PK 70.7 3.28 0.97 154.3 680 95.5 RC 125.7 3.74 0.81 159.5 700 RE 84.1 3.13 0.89 175.3 670 95.8 SB 88.9 3.23 1.01 173.8 730 97.0 SM 89.3 3.45 1.07 182.3 740 95.3 CM 66.5 1.89 1.03 165.3 470 MEAN ±SD 92.9 ± 19.6 3.09 ± .63 0.99 ± .08 169.0 ± 9.5 618 ± 101 95.8 ± 0.8 60 Table 15 VE, V02RER, HR, PEFR, and Sa02 at 90 % VO2max with placebo, individual subject data (n = 17) SUBJECT VE V02 RER HR PEFR Sa02 btps 1mm4 bpm 1 . sec-i 90% 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 107.7 2.60 1.12 195.0 480 94.8 PH 179.2 4.30 1.08 188.0 700 97.8 PM 95.4 2.91 1.05 195.8 450 92.5 PR 164.9 4.58 1.04 181.5 550 94.0 RH 184.4 4.33 0.92 188.5 650 95.0 SH 122.5 2.72 1.09 191.8 580 94.5 SS 99.2 3.01 1.04 175.8 525 94.3 AB 178.1 4.88 1.06 189.8 750 95.8 GK 135.9 3.51 1.03 187.3 490 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 1.17 190.8 740 96.0 SM 110.5 4.13 1.11 192.8 740 CM 89.5 2.40 0.91 180.5 510 MEAN ±SD 135.7 ± 32.2 3.73 ± .76 1.05 ± .07 186.7 ± 6.5 612 ± 102 94.7 ± 1.5 61 Table 16 VE, V02RER, HR, PEFR, and Sa02 at 90 % VO2max with salbutamol, individual subject data (n = 17) SUBJECT YE V02 RER HR PEFR Sa02 btps I•min-1 bpm I.sec-1 90% CL 116.0 3.24 1.03 171.8 515 93.3 JH 173.3 4.25 1.11 185.0 700 93.3 PMS 104.9 2.68 1.07 187.3 490 94.0 PH 162.0 4.08 1.05 182.5 725 98.0 PM 101.3 2.78 1.13 194.3 460 91.5 PR 130.0 4.43 1.00 175.0 600 94.5 RH 173.8 3.71 1.18 183.8 710 94.3 SH 130.4 3.25 0.91 190.8 560 95.5 SS 101.0 2.86 1.01 171.3 560 94.8 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 MEAN ±SD 131.8 ± 30.2 3.70 ± .81 1.05 ± .09 183.9 ± 7.3 623 ± 108 94.6 ± 1.5 62 Table 17 VE, V02RER, PEFR, and Sa02 at 25 % VO2max with placebo, individual subject data for NT group SUBJECT VE V02 RER HR PEFR Sa02 btps 1• mm bpm I. sec-1 25% CL 33.2 1.16 0.89 96.0 500 96.0 IH 31.8 1.14 0.78 101.3 640 96.5 PMS 26.7 0.73 0.89 113 410 97.3 PH 32.5 1.20 0.80 105.8 600 PM 23.8 0.75 0.84 91.3 355 96.5 PR 34.8 1.49 0.78 114.5 520 96.5 RH 27.1 0.98 0.74 99.8 560 97.3 SH 24.6 0.82 0.71 110.5 545 97.8 SS 34.1 1.26 0.86 106.5 490 97.8 MEAN±SD 29.8±4.3 1.06±.26 0.81±.06 104.3±7.9 513±89 96.9±0.7 Table 18 VE, V02RER, HR, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data for the NT group SUBJECT VE V02 RER HR PEFR Sa02 BTPS 1 mm1 bpm 1 sec-1 25% CL 32.4 1.13 0.81 90.0 490 97.3 JH 36.5 1.31 0.85 106.0 630 97.3 PMS 36.0 1.09 0.86 117.3 420 98.3 PH 36.7 1.28 0.81 108.3 710 PM 20.0 0.67 0.77 97.3 485 94.0 PR 30.8 1.32 0.72 102.8 590 96.5 RH 24.2 0.88 0.82 98.8 660 95.8 SH 30.6 1.01 0.73 116.3 565 99.3 SS 24.4 1.00 0.76 100.3 535 98.3 MEAN±SD 30.2±6.1 1.08±.21 0.79±.05 104.1±8.9 565±93 97.1±1.7 63 Table 19 VE, V02 RER, PEFR, and Sa02 at 50 %VO2max with placebo, individual subject data for HT group SUBJECT VE V02 RER HR PEFR Sa02 btps I - mm1 bpm i . sec-i 50% CL 53.2 2.07 0.87 133.3 520 95.75 JH 59.2 2.19 0.88 136.5 640 95.5 PMS 48.7 1.49 0.95 149.3 440 96.25 PH 52.8 2.33 0.81 144.0 675 PM 39.2 1.51 0.85 126.8 370 96.75 PR 80.5 3.32 0.86 147.8 525 95.75 Rh 45.5 1.81 0.75 136.0 610 96.5 SH 45.7 1.41 0.82 158.8 565 98 SS 47.6 1.84 0.92 125.5 480 96.5 MEAN±SD 52.5± 11.9 2.00± .59 0.86±.06 139.8± 11.0 536±98 96.4±.8 Table 20 VE, V02, RER, FIR, PEFR, and Sa02 at 50% VO2max with salbutamol, individual subject data for the HT group SUBJECT YE V02 RER HR PEFR Sa02 btps I. mm4 bpm I - sec1 50% CL 54.2 1.92 0.92 119.3 535 97.0 JH 64.2 2.32 0.98 138.0 660 97.0 PMS 46.5 1.56 0.90 138.3 490 97.3 PH 57.2 2.30 0.82 142.5 680 PM 39.8 1.45 0.88 123.5 420 94.5 PR 59.2 2.53 0.83 132.3 600 96.5 RH 45.0 1.75 0.86 134.0 675 96.0 SH 53.7 1.72 0.78 154.3 580 98.8 SS 39.6 1.64 0.85 122.3 540 95.5 MEAN±SD 51.0±8.7 1.91±.38 0.87±.06 133.8±11.1 575±89 96.6±1.3 64 Table 21 VE, V02RER, PEFR, and Sa02 at 75 %VO2max with placebo, individual subject data for UT group SUBJECT YE V02 RER HR PEFR Sa02btps 1• mini bpm 1• sec-1 75% CL 107.3 3.31 0.99 170.5 550 95.0 JH 110.4 3.31 1.04 173.3 660 94.3 PMS 78.9 2.23 1.0475 185.5 460 95.3 PH 115.3 3.86 1.02 180.3 690 PM 65.9 2.38 0.96 173.3 385 94.5 PR 128.0 4.30 0.99 175.0 580 94.5 RH 96.8 3.25 0.87 173.5 700 96.8 SH 114.6 2.61 1.09 191.8 600 95.8 SS 69.4 2.51 0.98 159.3 520 95.3 MEAN ±SD 98.5 ± 22.2 3.08 ± .71 1.00 ± .06 175.8 ± 9.3 571 ± 106 95.2 ± 0.8 Table 22 VE, V02, RER, fIR, PEFR, and Sa02 at 75 % VO2max with salbutamol, individual subject data for the HT group SUBJECT YE V02 RER HR PEFR Sa02btps I. mini bpm I sec1 75% CL 106.9 3.02 1.08 163.8 520 95.8 JH 115.4 3.55 1.07 170.8 690 96.3 PMS 71.7 2.21 0.99 170.0 485 95.3 PH 120.0 3.72 1.03 176.3 710 PM 65.4 2.24 0.98 169.0 460 94.0 PR 95.7 3.72 0.92 160.5 610 96.5 RH 100.5 3.02 1.04 170.0 690 95.0 SH 113.3 2.98 0.94 186.3 590 97.0 SS 68.7 2.34 0.96 149.5 550 96.0 MEAN ±SD 95.3 ± 21.4 2.98 ± .61 1.00 ± .06 168.4 ± 10.2 589 ± 93 95.7 ± 0.9 65 Table 23 VE, V02RER, PEFR, and Sa02 at 90 % VO2max with placebo, individual subject data for HT group SUBJECT VE V02 RER HR PEFR Sa02 btps 1 mm4 bpm I.• sec-1 90% 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 107.7 2.59 1.12 195.0 480 94.8 PH 179.2 4.29 1.08 188.0 700 PM 95.4 2.91 1.05 195.8 450 92.5 PR 164.9 4.58 1.04 181.5 550 94.0 RH 184.4 4.33 0.92 188.5 650 95.0 SH 122.5 2.72 1.09 191.8 580 94.5 SS 99.2 3.01 1.04 175.8 525 94.3 MEAN ±SD 139.4 ± 35.2 3.57 ± .77 1.05 ± .08 186.7 ± 7.6 572±87 94.2 ± 0.9 Table 24 VE, V02, RER, HR, PEFR, and Sa02 at 90% VO2max with salbutamol, individual subject data for the FIT group SUBJECT VE V02 RER HR PEFR Sa02 btps 1•min4 bpm 1• sec-1 90% CL 116.0 3.24 1.03 171.8 515 93.3 JH 173.3 4.25 1.11 185.0 700 93.3 PMS 104.9 2.68 1.07 187.3 490 94.0 PH 162.0 4.08 1.05 182.5 725 PM 101.3 2.78 1.13 194.3 460 91.5 PR 130.0 4.43 1.00 175.0 600 94.5 RH 173.8 3.71 1.18 183.8 710 94.3 SH 130.4 3.25 0.91 190.8 560 95.5 SS 101.0 2.86 1.01 171.3 560 94.8 MEAN ±SD 132.5 ± 30.1 3.48 ± .66 1.05 ± .08 182.4 ± 8.2 591 ± 99 93.9 ± 1.2 66 Table 25 VE, V02,RER, HR, PEFR, and Sa02, at 25 % VO2max, individual subject data for the MT group SUBJECT YE ‘102 RER HR PEFR Sa02 btps 1mm4 bpm 1sec- 25 % 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 97.25 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 96.9 ± 0.6 Table 26 VE, V02, RER, HR, PEFR, and Sa02 at 25 % VO2max with salbutamol, individual subject data for the MT group SUBJECT YE V02 RER HR PEFR Sa02 btps 1mm4 bpm i sec4 25% AB 31.0 1.47 0.74 106.8 710 95.5 GK 32.0 1.24 0.87 111.5 510 96.5 PK 35.3 1.37 0.91 89.0 640 96 RC 39.5 1.32 0.72 89.8 640 97.5 RE 26.3 1.03 0.78 104.8 650 97.8 SB 32.1 1.30 0.85 106.0 720 97.8 SM 38.6 1.55 0.87 125.5 710 95.8 CM 26.1 0.92 0.82 106.0 450 MEAN±SD 32.6±5.0 1.27±.21 0.82±.07 104.9±11.7 628±99 96.7±.9 67 Table 27 VE, V02 RER, HR, PEFR, and Sa02 at 50 % VO2max with placebo, individual subject data for MT group. SUBJECT VE V02 RER HR PEFR Sa02 btps lmin4 bpm 1 sec-1 50% AB 61.0 2.65 0.84 144.5 700 97.0 GK 59.7 2.03 0.96 145.8 480 96.3 PK 44.3 1.91 0.82 109.3 615 96.0 RC 70.1 2.43 0.91 114.3 585 96.8 RF 49.5 1.97 0.83 134.5 650 97.3 SB 53.3 2.11 0.95 134.5 670 97.5 SM 50.7 2.19 0.90 142.3 705 97.0 CM 37.9 1.34 0.82 122.5 420 MEAN ±SD 53.3 ± 10.1 2.08 ± .39 0.88 ± .06 130.9 ± 14.0 603 ± 104 96.8 ± 0.5 Table 28 VE, V02 RER, HR, PEFR, and Sa02 at 50 % VO2max with salbutamol, individual subject data for the MT group SUBJECT VE V02 RER HR PEFR Sa02 btps 1 mm-1 bpm 1 sec4 50% AB 56.9 2.64 0.82 138.5 690 96.25 GK 52.7 1.83 1.03 145.3 510 96.75 PK 41.9 1.84 0.90 112.0 670 96.5 RC 69.4 2.42 0.77 120.0 700 97.3 RE 48.1 1.94 0.80 140.8 660 97 SB 54.6 2.12 0.92 141.0 710 97.3 SM 59.0 2.34 1.01 151.5 720 95.8 CM 38.5 1.33 0.90 132.3 460 MEAN±SD 52.6±9.8 2.06±.41 0.89±.09 135.2±13.2 640±98 96.7±.6 68 Table 29 YE, V02 RER, HR. PEFR, and Sa02 at 75 % VO2max with Placebo, individual subject data for MT group. SUBJECT VE V02 RER HR PEFR Sa02 btps 1mm4 bpm 1 sec-1 75% AB 110.6 3.99 0.98 172.3 715 96.8 GK 91.6 2.95 1.03 172.0 495 96.3 PK 71.8 3.44 0.90 150.0 620 94.3 RC 120.3 3.62 1.01 161.3 640 RF 79.0 3.00 0.92 168.0 660 95.5 SB 90.5 3.25 1.04 171.3 730 96.3 SM 81.5 3.47 1.01 179.5 735 96.3 CM 63.0 1.95 0.90 160.8 510 MEAN ±SD 88.5 ± 19.2 3.21 ± .61 0.97 ± .06 166.9 ± 9.2 638±94 95.9 ± 0.9 Table 30 VE, V02RER, HR. PEFR, and Sa02 at 75 % VO2max with salbutamol, individual subject data for the MT group SUBJECT YE V02 RER HR PEFR Sa02 btps Imin1 bpm 1sec 75% AB 102.0 4.16 0.95 171.5 720 96 GK 94.3 2.81 1.11 176.0 500 95.25 PK 70.7 3.28 0.97 154.3 680 95.5 RC 125.7 3.74 0.81 159.5 700 RF 84.1 3.13 0.89 175.3 670 95.8 SB 88.9 3.23 1.01 173.8 730 97.0 SM 89.3 3.45 1.07 182.3 740 95.3 CM 66.5 1.89 1.03 165.3 470 MEAN±SD 90.2± 18.5 3.21 ± .67 0.98± .10 169.7 ± 9.3 651 ± 106 95.8 ± .7 69 Table 31 VE, V02 RER, HR, PEFR, and SaO2at 90 % VO2max with placebo, individual subject data for MT group. SUBJECT VE V02 RER HR PEFR Sa02 btps 1mm4 bpm 1 sec-1 90% AB 178.1 4.88 1.06 189.8 750 95.8 GK 135.9 3.51 1.03 187.3 490 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 1.17 190.8 740 96.0 SM 110.5 4.13 1.11 192.8 740 95.8 CM 89.5 2.40 0.91 180.5 510 MEAN±SD 131.5±30.1 3.91±.75 1.05±.07 186.7±5.6 658± 103 95.1± 1.6 Table 32 VE, V02RER, HR, PEFR, and Sa02 at 90 % VO2max with salbutamol, individual subject data for the MT group SUBJECT VE BTPS V02 RER HR PEFR Sa02 1 min1 bpm 1 . sec 90% 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 MEAN±SD 130.9±32.3 3.96±.92 1.04±.10 185.7±6.2 658± 113 94.8± 1.0 70 Table 33 Pre and post medication and recovery PEFR measures with placebo, individual subject data (N = 17) SUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm 15 mm PEFR PEFR PEFR PEFR PEFR PEFR CL 525 503 530 520 510 500 JH 623 621 660 650 610 620 PMS 447 443 430 440 430 430 PH 630 633 700 665 635 660 PM 338 362 390 390 370 375 PR 520 500 540 520 470 480 RH 603 610 650 640 635 640 SH 545 533 565 540 540 540 SS 512 500 490 495 490 490 AB 673 673 710 710 700 660 GK 437 427 450 440 400 400 PK 602 613 650 620 610 620 RC 562 503 560 510 500 500 RF 640 632 660 660 640 640 SB 647 612 675 670 670 650 SM 687 667 670 660 640 550 CM 460 433 410 425 440 440 MEAN±SD 556±96 545±95 573± 108 562± 103 546103 541±97 71 Table 34 Pre and post medication and recovery PEFR measures with salbutamol, individual subject data (N = 17) SUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm 15 mm PEFR PEFR PEFR PEFR PEFR PEFR CL 480 483 520 540 500 500 JH 615 630 640 610 570 630 PMS 427 443 450 465 475 475 PH 662 690 725 700 690 725 PM 342 403 440 425 420 415 PR 550 567 580 570 570 560 RH 637 667 700 675 670 665 SH 547 548 560 540 560 540 SS 500 533 540 530 550 535 AB 693 667 700 680 680 690 GK 473 500 510 510 505 470 PK 600 643 680 640 640 670 RC 622 670 690 660 680 680 RF 628 633 670 660 640 590 SB 653 663 720 700 700 700 SM 695 717 710 585 610 700 CM 460 433 460 430 440 435 MEAN±SD 564± 102 582± 100 605± 103 584±92 582±91 587± 103 72 Table 35 Pre and post medication and recovery PEFR measures with placebo, individual subject data for the FIT group SUBJECT Pre- med. Post-med. 3 mm 5 mm 10 mm 15 mm PEFR PEFR PEFR PEFR PEFR PEFR lIT group CL 525 503 530 520 510 500 JH 623 621 660 650 610 620 PMS 447 443 430 440 430 430 PH 630 633 700 665 635 660 PM 338 362 390 390 370 375 PR 520 500 540 520 470 480 RH 603 610 650 640 635 640 SH 545 533 565 540 540 540 SS 512 500 490 495 490 490 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. Post-med. 3 mm 5 mm 10 mm is mm PEFR PEFR PEFR PEFR PEFR PEFR HT group CL 480 483 520 540 500 500 JH 615 630 640 610 570 630 PMS 427 443 450 465 475 475 PH 662 690 725 700 690 725 PM 342 403 440 425 420 415 PR 550 567 580 570 570 560 RH 637 667 700 675 670 665 SH 547 548 560 540 560 540 SS 500 533 540 530 550 535 MEAN±SD 529± 104 552±99 573± 100 562±89 556±86 560±97 73 Table 37 Pre and post medication and recovery PEFR measures with placebo, individual subject data for the MT group SUBJECT Pre- med. Post-med. 3 mm 5 mill 10 mm 15 mill PEFR PEFR PEFR PEFR PEFR PEFR MT group AB 673 673 710 710 700 660 GK 437 427 450 440 400 400 PK 602 613 650 620 610 620 RC 562 503 560 510 500 500 RF 640 632 660 660 640 640 SB 647 612 675 670 670 650 SM 687 667 670 660 640 550 CM 460 433 410 425 440 440 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. Post-med. 3 mm 5 mm 10 mm is mill PEFR PEFR PEFR PEFR PEFR PEFR MT group AB 693 667 700 680 680 690 GK 473 500 510 510 505 470 PK 600 643 680 640 640 670 RC 622 670 690 660 680 680 RE 628 633 670 660 640 590 SB 653 663 720 700 700 700 SM 695 717 710 585 610 700 CM 460 433 460 430 440 435 MEAN ±SD 603±91 616 ± 97 643 ± 99 608 ± 94 612 ± 92 617 ± 108 74 Table 39 Blood lactates (mmol.l-l) at 25, 50,75, and 90 % VO2max with placebo, individual subject data ( n = 17) Lactate Placebo ( mmoll4) 25 % 50 % 75 % 90 % Subjects CL 1.30 1.53 6.34 7.27 il-I 1.23 1.91 6.46 19.04 PMS 1.42 1.87 6.13 9.07 PH 0.97 1.55 8.86 14.83 PM 1.83 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 1.69 2.08 5.85 15.16 GK 2.77 3.40 7.73 11.93 PK 1.06 1.34 2.17 6.86 RC 0.93 0.88 3.33 7.24 RF 0.87 1.08 4.24 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 75 Table 40 Blood lactate (mmol.11)measures at rest and recovery conditions with placebo, individual subject data (n = 17) Lactate Rest 1 mm 3 mm 5 mm 10 mm (mmol•l1) Placebo Subjects JH 0.94 17.22 16.03 18.15 15.69 PH 0.84 13.61 13.19 12.22 10.08 PR 1.34 9.18 7.84 6.07 6.46 RH 1.11 15.68 15.34 13.36 12.05 AB 1.00 13.47 15.41 13.94 10.26 GK 1.13 10.96 8.78 10.33 8.69 PK 1.18 7.37 7.80 7.49 6.07 RC 0.44 7.53 7.43 7.43 3.33 RF 0.56 13.38 11.26 12.21 7.53 SB 1.36 12.58 16.16 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 6.64 PM 1.22 13.22 12.00 10.58 10.48 SH 0.87 15.05 12.10 12.34 8.08 SS 0.64 8.34 9.35 6.92 5.24 CM 0.64 3.52 4.6 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 76 Table 41 Blood lactates (mmol.l-1)at 25, 50,75, and 90 % VO2max with salbutamol, individual subject data (n = 17) Lactate Salbutamol (mmol 11) 25 % 50 % 75 % 90 % Subjects CL 0.39 1.17 7.97 8.26 JH 0.76 2.42 8.73 17.62 PMS 1.18 1.39 4.28 8.86 PH 0.57 1.50 6.03 7.74 PM 0.91 1.77 3.29 12.67 PR 0.27 0.22 2.49 4.28 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 AB 1.02 1.74 5.99 7.95 GK 0.97 1.63 5.59 9.98 PK 0.49 0.80 2.45 8.95 RC 1.57 2.13 6.58 9.73 RF 3.18 1.21 4.14 13.48 SB 1.93 2.08 9.93 16.42 SM 0.59 0.83 3.81 6.55 CM 0.60 0.95 3.78 6.72 MEAN ± SD 1.14 ± 0.82 1.51 ± 0.62 5.66 ± 2.42 10.29 ± 3.87 77 Table 42 Blood lactate ( mmol.l-1)measures at rest and recovery conditions with salbutamol, individual subject data ( n = 17) Lactate Rest 1 mill 3 mm 5 mill 10 mm (mmol11) Salbutamol Subjects CL 9.10 10.47 9.05 6.60 0.20 JH 16.66 19.31 18.88 19.04 0.66 PMS 8.99 6.09 7.06 5.50 0.80 PH 10.51 8.49 6.42 5.50 1.06 PM 12.16 12.87 9.48 7.09 0.91 PR 4.94 8.28 3.88 3.07 0.36 RH 21.46 17.39 18.31 15.10 2.14 SH 12.17 13.51 11.69 9.53 0.87 SS 8.75 8.00 7.80 7.33 0.75 AB 9.14 7.06 6.84 4.21 1.23 GK 9.15 10.51 7.30 9.19 0.22 PK 9.93 9.09 8.70 7.53 0.36 RC 9.26 8.43 9.08 6.21 1.34 RF 12.57 12.07 11.71 8.94 0.91 SB 16.72 13.68 14.95 14.34 1.17 SM 9.63 8.66 8.02 6.31 0.29 CM 7.71 7.66 7.22 4.68 0.65 MEAN±SD 11.11 ±3.97 10.68±3.67 9.79±4.14 8.24±4.24 0.82±0.49 78 Table 43 Blood lactates (mmolt1)at 25, 50,75, and 90 % VO2max with placebo, individual subject data for the HT group Lactate Salbutamol (mmol•l1) 25 % 50 % 75 % 90 % Subjects CL 1.30 1.53 6.34 7.27 JH 1.23 1.91 6.46 19.04 PMS 1.42 1.87 6.13 9.07 PH 0.97 1.55 8.86 14.83 PM 1.83 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 MEAN±SD 1.11±0.41 1.52±0.40 6.42±1.91 12.46±4.22 Table 44 Blood lactate ( mmol.11)measures at rest and recovery conditions with placebo, individual subject data for the HT group Lactate Rest 1 mm 3 mm 5 mm 10 mm (mmol14) Placebo Subjects 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 6.64 PH 0.84 13.61 13.19 12.22 10.08 PM 1.22 13.22 12.00 10.58 10.48 PR 1.34 9.18 7.84 6.07 6.46 RH 1.11 15.68 15.34 13.36 12.05 SH 0.87 15.05 12.10 12.34 8.08 SS 0.64 8.34 9.35 6.92 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 Table 45 Blood lactates (mmoltl) at 25, 50,75, and 90 % VO2max with salbutamol, individual subject data for the Hi’ group Lactate Salbutamol (mmol 11) 25 % 50 % 75 % 90 % Subjects CL 0.39 1.17 7.97 8.26 JH 0.76 2.42 8.73 17.62 PMS 1.18 1.39 4.28 8.86 PH 0.57 1.50 6.03 7.74 PM 0.91 1.77 3.29 12.67 PR 0.27 0.22 2.49 4.28 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.11)measures at rest and recovery conditions with salbutamol, individual subject data for the HT group Lactate Rest 1 mill 3 mm 5 mm 10 mill (mmol•11) Salbutamol Subjects CL 0.20 9.10 10.47 9.05 6.60 JH 0.66 16.66 19.31 18.88 19.04 PMS 0.80 8.99 6.09 7.06 5.50 PH 1.06 10.51 8.49 6.42 5.50 PM 0.91 12.16 12.87 9.48 7.09 PR 0.36 4.94 8.28 3.88 3.07 RH 2.14 21.46 17.39 18.31 15.10 SH 0.87 12.17 13.51 11.69 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 ( mmol•F1)at 25,50, 75, and 90 % VO2max with placebo, individual subject data for the MT group Lactate Placebo ( mmoll1) 25 % 50 % 75 % 90 % Subjects GK 2.77 3.40 7.73 11.93 PK 1.06 1.34 2.17 6.86 RC 0.93 0.88 3.33 7.24 RE 0.87 1.08 4.24 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 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 Rest 1 mm 3 mm 5 mm 10 mill (mmolP1) Placebo subjects AB 1.00 13.47 15.41 13.94 10.26 GK 1.13 10.96 8.78 10.33 8.69 PK 1.18 7.37 7.80 7.49 6.07 RC 0.44 7.53 7.43 7.43 3.33 RE 0.56 13.38 11.26 12.21 7.53 SB 1.36 12.58 16.16 14.95 14.91 SM 0.37 8.71 7.18 7.83 4.68 CM 0.64 3.52 4.60 4.64 3.89 MEAN ± SD 0.84 ± 0.38 9.69 ± 3.53 9.83 ± 4.12 9.85 ± 3.61 7.42 ± 3.86 81 Table 49 Blood lactates ( mmol.14)at 25,50,75, and 90 % VO2max with salbutamol, individual subject data for the MT group Lactate Salbutamol ( mmol11) 25 % 50 % 75 % 90 % Subjects AB 1.02 1.74 5.99 7.95 GK 0.97 1.63 5.59 9.98 PK 0.49 0.80 2.45 8.95 RC 1.57 2.13 6.58 9.73 RF 3.18 1.21 4.14 13.48 SB 1.93 2.08 9.93 16.42 SM 0.59 0.83 3.81 6.55 CM 0.60 0.95 3.78 6.72 MEAN±SD 1.29±.91 1.42±.55 5.28±2.32 9.97±3.40 Table 50 Blood lactate ( mmol•l-1)measures at rest and recovery conditions with salbutamol, individual subject data for the MT group Lactate Rest 1 mm 3 mm 5 mm 10 mm (mmol•11) Salbutamol Subjects AB 1.23 9.14 7.06 6.84 4.21 GK 0.22 9.15 10.51 7.30 9.19 PK 0.36 9.93 9.09 8.70 7.53 RC 1.34 9.26 8.43 9.08 6.21 RF 0.91 12.57 12.07 11.71 8.94 SB 1.17 16.72 13.68 14.95 14.34 SM 0.29 9.63 8.66 8.02 6.31 CM 0.65 7.71 7.66 7.22 4.68 MEAN ± SD .77 ± .45 10.52 ± 2.85 9.64 ± 2.28 9.23 ± 2.78 7.68 ± 3.24 82 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 17.2 PM 20.0 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 17.1 17.1 CM 16.4 20.0 MEAN±SD 18.5±1.8 18.4±1.8 83 Table 52 The duration of exercise test with salbutamol and placebo, individual subject data for the HT and MT groups Subjects Placebo Salbutamol Subjects Placebo Salbutamol Time (mm) Time ( mm) lIT group 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 VE HR RER Sa02 lmin1 l•min4 bpm Sex (5) p = .000 * p =008* p = .843 p = .903 p = .950 Drug (D) p = .531 p = .492 p= .138 p = .936 p = .747 Trained (T) p = .902 p = .786 p = .137 p = .971 p = .574 condition (C) p = .000 p = .000 p = .000 p = .000 p = .000 DXS p=.927 p=.738 p=.209 p=.764 D X T p = .439 p = .482 p =.003* p = 851 p = .777 DXCXT p=.454 p=.283 p=007* p553 D X C X S p = .578 p = .786 p= .289 p = .274 p = .332 cc*p <005 Table 54 RMANOVA Summary for PEFR and Blood lactate measurements Effect DEPENDENT VARIALBLES PEFR l•sec1 LACTATE (mmol.l) Drug(D) p = .002* p = .688 Sex(S) p = .000* p = .259 Trained(T) p=.215 p=.342 Condition(C) p = .000* p = .000* DXS p=.334 p=.816 DXT p=.8’75 p=.5l7 DXC p=.00l* p—838 DXCXT p=.24.’7 p=.369 DXCXS p=.392 p=.947 a = p <0.05 85 Table 55 RMANOVA summary for the HT group Effect DEPENDENT VARIABLES V02 VE HR RER Sa02 1•min l•min1 bpm 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* D X C p=.’13ó p=.243 p=002* p’740 p=322 DEPENDENT VARIABLES Effect PEFR Lactate 1•sec mmol•11 Drug (D) p=.009* Condition (C) p=OIJO* p=.000* DXC p=.031* * p <0.05 86 Table 56 RMANOVA summary for the MT group Effect DEPENDENT VARIABLES V02 VE HR RER Sa02 lmin1 lmin1 bpm 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* D X C p=.825 p=.9l5 p=.O’75 p=.’749 p=.762 DEPENDENT VARIABLES Effect PEFR Lactate 1•sec mmol•1’ Drug (D) p=.O78 p=.836 Condition (C) p=.000* p=0(J0* D X C p=.8O6 p=.027* * p <0.05 87 Table 57 RMANOVA summary for subjects with a PC20 < 4.0 mg/mi EFFECT DEPENDENT VARIABLES V02 yE HR RER Sa02 lmiir1 Fmin1 bpm Drug (D) p =.058 p =.717 p =.206 p =.806 p =.336 Condition(C) p =.0OO p =YJJ p J(J* p yjij* p YJJ DXC p =.395 p =.663 p =.477 p =.ll0 p=.9&3 DEPENDENT VARIABLES Effect PEFR Lactate 1sec mmol•11 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 5.09 4.34 85 IH 6.32 5.22 83 PMS 4.19 3.49 83 PH 4.53 3.84 85 PM 3.77 2.54 67 PR 5.00 3.53 71 RH 5.31 4.91 92 SH 4.15 3.62 87 SS 4.34 3.71 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 8.37 6.24 75 GK 5.61 4.05 72 PK 6.56 5.17 78 RC 6.30 4.06 64 RF 5.91 4.96 83 SB 6.00 4.96 83 SM 6.94 6.20 89 CM 3.91 3.30 82 MEAN ± SD 6.20 ± 1.26 4.87 ± 1.04 78 ± 7.7 89 2.5 0 APPENDIX C Figures Figure 7. V02 ( 1mlir)responses at various exercise intensifies (% VO2max), aflsubjectsdata(n= 17) 4.5 3.5, 1.5 0.5 0 Salbutamol S Placebo 25% I — 50% 75% Exercise (%VO2max) 90% Values are means ± SD; open circles, salbutamol; closed circles, placebo : p=O.531 90 4.5. 4.0• 3.5. 3.O Figure 8. V02 ( l.min-1)responses at various exercise intensities ( %VO2max), HT subjects data 0 Salbutamol • Placebo 25% 50% 75% Exercise ( % V02 max) 90% Values are means ± SD; open circles, salbutamol; closed circles, placebo p = .429 91 Figure 9. V02 ( lmin-1)responses at various exercise intensities (%VO2max), MT subjects data 5.0 4.5. 4.O 3.5. 3.O 2.50 > 2.O Salbutamol 1.5 Placebo 1.0• O.5 • • • 25% 50% 75% 90% Exeitise ( % V02 max) Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .869 -0- 92 Figure 10. VE (l.minl )responses at various exercise intensities (%VO2max), aflsubjectdata(n= 17) 180 160 140 120’ .E 100 0 60 ____ 40 20 Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .492 25% —0-—— Salbutamol • Placebo • I 50% 75% Exercise ( % VO2max) 90% 93 Figure 11. VE (l.min-l )responses at various exercise intensities (%VO2max), HT subject data 180 160 140 120 1oo 80 _ _ 60 40 20 Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .345 0 Salbutamol • Placebo 25% 50% 75% 90% Exeicise ( % V02 max) 94 VE ( l•min-1 )responses at various exercise intensities (%V O2max), MT subject data 180 160 140 120 1100. 80 60 40 20 Exercise ( % V02 max) Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .945 Figure 12. -0- Salbutamol Placebo I • I • I 25% 50% 75% 90% 95 Figure 13. HR (bpm) responses at various exercise intensities (%VO2max), all subject data ( n = 17) Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .138 210- 190 - 170 - a 150- 130- 110- 90 0 Salbutamol . Placebo 25% I • I • 50% 75% 90% Exercise ( % VO2max) 96 200 180 160 140 120 100 Figure 14. HR (bpm) responses at various exercise intensities (%VO2max), MT subject data 80 0 Salbutamol • Placebo 25% I • I - 50% 75% Exercise ( % V02 max) 90% Values are means ± SD; open circles, salbutamol; closed circles, placebo : p =. 146 97 I • I 50% 75% Exeicise ( % V02 max) Salbutamol Placebo Figure 15. RER responses at various exercise intensities (%VO2max), all subject data ( n = 17) 1.1 - 1.0- 0.9 - 0.8 - 0.7- 90% Values are means ± SD; open circles, salbutamol; closed circles, placebo : p =.936 —0- 25% 98 HT subject data I • I--— 50% 75% Exercise ( % V02 max) Values are means ± SD; open circles, salbutamol; closed circles, placebo p =1.00 Figure 16. RER responses at various exercise intensities (%“O2max), 1.2 1.1 1.0• 0.9 0.8 0.7 -0- Salbutamol Placebo 25% 1 90% 99 Figure 17. RER responses at various exercise intensities (%VO2max), MT subject data 1.1 - 1.0- 0.9- 0.8 - ______ 0.7 - Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .819 1.2- 25% 0 Salbutamol • Placebo I I 50% 75% Exercise ( % V02 max) 90% 100 99. 98 97. Values are means ± SD; open circles, salbutamol; closed circles, placebo : p= .747 101 Figure 18. Sa02 measures at various exercise intensities (%VO2max), all subject data ( n = 17) 0 Salbutamol • Placebo 92 25% I I 50% 75% Exercise ( % VO2max) 90% Figure 19. Sa02 measures at various exercise intensities (%VO2max), HT subject data 99. 98 97. 96 Ti) 95 94. 93 Values are means ± SD; open circles, salbutamol; closed circles, placebo : p= .699 102 0 Salbutamol • Placebo 92 25% I • I 50% 75% Exercise ( % V02 max) 90% Figure 20. Sa02 measures at various exercise intensities (%VO2max), HT subject data 99 - 98 _______ = 97, 96’ 1) 95. 94. Values are means ± SD; open circles, salbutamol; closed circles, placebo : p= .955 0 Salbutamol • Placebo 93 —i -. • I 25% 50% 75% Exeicise ( % VO2max) 90% 103 Figure 21. Blood lactate ( mmol•11 ) at various exercise intensities (% VO2max) and 1 to 10 minutes into recovery, HT subject data 18 16 14 0 E ‘ 6 0 4 2 0 ist 25% 50% 75% 90% 1 mm 3 mm 5 mm io mm Exeitise Recovery Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .463 0 Salbutamol • Placebo 104 Figure 22. Blood lactate ( mmoll1 ) at various exercise intensities (% VO2max) and 1 to 10 minutes into recovery, MT subject data 14 12 _______ E8 6 4. 2 0• Values are means ± SD; open circles, salbutamol; closed circles, placebo : p = .836 O Salbutainol • Placebo I—I—I.I.I.I.I.I. REST 25% 50% 75% 90% 1mm 3mm 5mm 10mm Exercise Recovery 105

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