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Endothelin-1 and oxygen saturation during exercise in normoxia and hyposia Giles, Luisa 2007-12-31

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Endothelin-1 and Oxygen Saturation During Exercise in N o r m o x i a and Hypoxia. by Luisa Giles B . S c , Staffordshire University, 2003 THESIS S U B M I T T E D IN P A R T I A L F U L F I L L M E N T OF T H E R E Q U I R E M E N T S FOR T H E D E G R E E OF M A S T E R OF S C I E N C E in T H E F A C U L T Y OF G R A D U A T E S T U D I E S (Human Kinetics)  T H E U N I V E R S I T Y OF B R I T I S H C O L U M B I A A p r i l 2007 © Luisa Giles, 2007  Abstract We tested the hypothesis that decrements in arterial oxyhaemoglobin saturation could be related to elevations in circulating endothelin-1 following 30 minutes of exercise at ventilatory threshold. Eight aerobically trained males (mean ± SEM: age 26.14 ± 1.77 years, height 182.36 ± 1 . 5 1 cm, mass 72.89 ± 2.62 kg) completed 2 maximal exercise tests (mean ± SEM: normoxia (n) 68.56 ± 2.06 mL.kg-^min- ; hypoxia ( F i 0 0.14)(h) 1  2  53.88 ± 1.35 mL.kg^.min" ), and two 30-minute steady state exercise protocols at the 1  power achieved at threshold during maximal exercise tests (mean ± SEM: power (Watts) 257.14 ± 21.57 (n) 191.25 ± 10.79 (Fi0 0.14)(h); HR (bpm) 161.7 ± 5.34 (n) 156.6 ± 2  3.45 (h)). When participants exercised for 30 minutes at ventilatory threshold inspiring 14%0 , a significant decrease in oxygen saturation (as measured by pulse oximetry) was 2  observed, when compared to values in normoxia (80.2 ± 1.17 % (h) vs 94.12 ± 0.24 % (n); p<0.001). This desaturation was not accompanied by significant changes in plasma endothelin-1 (ET-1), big endothelin-1 (BigET-1) or nitric oxide (NO). Both pulmonary artery pressure (PAP) and oscillatory compliance (OC) were significantly greater following exercise (F( i ) = 4.74 p< 0.05), compared to pre-exercise values. );  2  These  outcome variables were not different between normoxia and hypoxia. Plasma ET-1 or BigET-1 levels did not differ significantly over time or across conditions F(i i ) = 4.74 p> j  2  0.05). In conclusion, plasma ET-1 levels following 30-minutes of steady state exercise at ventilatory threshold are unrelated to decrements in oxyhaemoglobin saturation.  ii  Table of Contents Abstract Table o f Contents List of Tables List of Figures List of Abbreviations 1.0 Literature Review 1.1 Endothelin 1.1.1 Introduction 1.1.2 Endothelin and Exercise 1.1.3 Endothelin and H y p o x i a 1.1.4 Endothelin and N O 1.2 Exercise Induced Arterial Hypoxemia 1.2.1 Introduction 1.2.2 Prevalence 1.2.3 Mechanisms 1.2.4 Effects on V 0 x 2  m  •  ii iii v vi vii 1 1 1 5 7 10 11 11 12 13 1 5  a  1.2.5 E I A H and Altitude 1.2.6 Exercise modality 1.2.7 N O and E I A H 2.1 Statement o f the Problem 2.2 Objective 2.3 Hypothesis 3.0 Methodology 3.1 Subject Population 3.2 Procedures and Outcome Measures 3.2.1 Resting Pulmonary Function Test 3.2.2 V 0 a x Tests 2 m  3.2.3 Steady State Exercise Test in Hypoxia or Normoxia 3.2.4 ET-1 a n d B i g E T - 1 3.2.5 Nitric Oxide 3.2.6 Arterial Compliance 3.2.7 Pulmonary Artery Pressure 3.2.8 Data Anyalsis 3.3 Limitations 3.4 Delimitations 4.0 Results 5.0 Discussion 5.1 Introduction '• 5.2 ET-1 a n d B i g E T - 1 5.2.1 ET-1 / B i g E T - 1 and Exercise 5.2.2 E T - 1 / B i g E T - 1 and H y p o x i a 5.3 Pulmonary Artery Pressure 5.4 Nitric Oxide 5.5 Arterial Compliance  15 16 17 19 19 19 21 21 21 22 22 23 ...23 24 24 25 25 26 26 27 34 34 34 34 37 39 41 42  iii  5.6 Hypothesis Revisited 5.6.1 Hypothesis # 1 5.6.2 Hypothesis # 2... 5.6.3 Hypothesis #3 5.6.4 Hypothesis # 4 5.6.5 Hypothesis # 5 6.0 Conclusion 7.0 Future Studies 8.0 References 9.0 Appendix  :  -44 44 45 45 46 46 47 48 49 68  iv  List of Tables Table 1: Stimulators and Suppressors o f ET-1 Table 2: V 0 m a x Data  3 27  Table Table Table Table  29 30 31 32  2  3: 4: 5: 6:  Mean Mean Mean Mean  Steady State Data P A P and Arterial Compliance Nitric Oxide Values ( u M ) Plasma E T - 1 (fmol/mL)  v  List of Figures Figure Figure Figure Figure  1 2 3: 4: Peak V O 2 Values During M a x i m a l Exercise Tests  .  Figure 5: Oxygen Saturation during Steady State Exercise Figure 6: Oscillatory Compliance Pre and Post Exercise..; Figure 9: B i g E T - 1 Levels During Normoxia and Hypoxia Figure 10: Chart displaying plasma ET-1 levels after removal of the participant with values 10-12 times greater than other participants  1 2 2 28 29 30 33 68  vi  List of Abbreviations A-aD0 AC CC HR L-NAME NO OC PA0 Pa0 PAP RER Sa0 Sp0 VE V0 VC0 2  2  2  2  2  2  2  Alveolar to arterial pressure difference o f oxygen Arterial Compliance Capacitative Compliance Heart Rate N - N i t r o - L - A r g i n i n e M e t h y l Ester Nitric Oxide Oscillatory Compliance Partial pressure o f alveolar oxygen Partial pressure o f arterial oxygen Pulmonary Artery Compliance Respiratory Exchange Ratio Oxygen Saturation (measured directly) Oxygen Saturation (via pulse oximetry) Minute Ventilation Volume o f Oxygen Consumed Volume o f Carbon Dioxide Produced  1.0 Literature Review  1.1 Endothelin 1.1.1 Introduction The endothelium is involved in a variety o f vasoactive processes; one o f the common peptides secreted by these cells is endothelin (ET).  1  E T is a natural amino acid  peptide that is present in 3 isoforms; E T - 1 , E T - 2 and E T - 3 , each possess different genes with a different structure. ET-1 differs from E T - 2 by 2 amino acids and E T - 3 by 6 amino 2  acids (Figure 1).  *  i  ET-1 is produced in the endothelial cells from its precursors  preproendothelin and big E T . It is synthesized from a 212 amino acid gene product 3  called preproendothelin-1, following the removal o f a single peptide it is then processed by intracellular proteases to generate a biologically inactive 38 amino acid peptide called BigET-1.  Through the action of a endothelin converting enzyme ( E C E ) , BigET-1 is  cleaved to form the biologically active 21 amino acid peptide E T - 1 (Figure 2). " E T - 2 4  6  and E T - 3 are derived from there own precursors, although the detailed mechanisms o f such processes have not yet been determined. Figure 1  1  Figure 2 Inhibitors  Promoters  Picpro ET-1  Gone  Endothelial Cell  Prepro ET-1 mRN Furin4Jke  Nucleus  lET;  Prepro ET-1 peptide • 1  Enzyme Etwfejthelit*. Converting ^ Enzyme (ECE)  *Chyma»e -NonECE  8«g ET-1 ^  t a  "  O p r 0 t e a 9 e  >  Smooth Muscle Cell  ET-1 ET  ET  A  Schematic representation of the vascular endothelin system. ETa and E T B represent receptors that mediate the actions of endothelin. Reproduced from Galie et al 2004. 8  Figure 3: Leukocytes, MonoeyteS,  PUtekt,^  Macrophagsa  _  [ Aggregation T Adhesion  I Migration t Cytokine* Endothalla Cells  Production oft  VasculwSm«W*  • Prostacyclin ET-1 clearance  Muscle Call  * Nitric Oxide  Schematic representation of endothelin-1 effects in different cells types. Reproduced from Galie et al 2004.  2  Endothelin-1 (ET-1) is produced by the endothelium and it is described as one of the most potent vasoconstrictor peptides that is present in the l u n g . ' ' 1  9  It is produced  10  in response to a number of factors (Table 1), and acts on neighbouring endothelial and vascular smooth muscle cells (VSMC's) in a autocrine/paracrine manner stimulating the release of relaxing and contracting factors. ET-1 constricts isolated pulmonary arteries 11  and in the isolated perfused lung causes long lasting increases in vascular resistance. is a major isoform in the cardiovascular system,  13  12  It  plays a pivotal role in the maintenance  of basal vascular tone in humans and activates the sympathetic nervous system. ' 2  its ability to increase contractility of VSMC's and cardiomyocytes,  14  4  Due to  it has been  identified as a key factor in the development of vascular hypertrophy. Under normal 15  conditions, the effects of the ET-1 are carefully regulated through inhibition or stimulation of ET-1 release from endothelium. Table 1: Stimulators and Suppressors of ET-1. Stimulators  . Suppressors  Physical  Hormones  Others  Shear Stress  Vasopressin  Thrombin  Nitric Oxide  Hypoxia  Angiotensin  TGF  ANF  Thromboxane A 2  LDL  Cyclic G M P  Epinephrine  Endotixin  Insulin  Ca  Bradykinin Glucocorticoids  2  +  Phorbol esters '  Interleukin-1  Stimulators and suppressors o f ET-1. Reproduced from Morganti et al 2000.  3  Two receptor sub-types mediate the actions of ET-1: ET-a and E T - b .  6 , 1 1  In the  pulmonary vasculature they cause pressor and depressor responses, that mainly occur in 17  small vessels. ET-a receptors are found on VSMC's and have a higher affinity for ET-1 18  and ET-2 with a lower affinity for E T - 3 .  17  ET-b receptors are located on VSMC's and  endothelial cells and bind to each of the three isopeptides equally. When bound to ET-b 17  receptors, ET-1 induces positive chronotropic effects, but when bound to ET-a receptors it causes negative chronotropic effects.  19  Both ET-a and ET-b receptors can mediate  vasoconstriction in the peripheral vasculature of healthy humans and those with coronary heart failure (HF), but the degree to which ET-b receptors contribute to vasoconstriction is not yet known. Studies with receptor antagonists (RA's) suggest that both ET-a and ET-b receptors can mediate vasoconstriction.  This is self limited by endothelium induced  production of NO, and only occurs when nitric oxide synthase (NOS) is deficient. ' 20  2 1  The pressor response of ET-1 is predominantly mediated by ET-a receptors on V S M C , and the depressor response by ET-b receptors on endothelial cells. The binding of ET-1 to ET-a receptors on vascular smooth muscle has mitogenic and inotropic effects, resulting in vasoconstriction and cell proliferation that are greatly enhanced with 2 17 1Q 22  disease. ' ~ '  ET-b receptors in the lung are implicated in the clearance of ET-1 from  the circulation. '  They can cause vasodilation through receptors on the endothelial cells  via the release of NO and prostacyclin, and vasoconstriction via the receptors located on 13 17 18 24  VSMC's. ' ' '  Deficiency of lung ET-b receptor expression can result in increased  lung E T levels, that via ET-a receptors mediate lung vascular endothelin growth factor (VEGF) production that in turn increases vascular permeability and pulmonary oedema.  25  4  Circulating levels of ET-1 in healthy adults (0.4-0.8 fmol/mL) are below the pharmalogical threshold and considered to be below a level that produces contractions in humans.  Eighty percent of this peptide is secreted toward the vessel wall, suggesting  that levels of plasma ET-1 in the blood may not be reflective of local actions. a short plasma half-life of 2-5 min,  27  16  ET-1 has  due to this rapid clearance from the circulation  levels of its inactive precursor big ET-1 and the ET-1 /big ET-1 ratio may be more effective ways to assess the activation of the E T system in both venous and arterial beds.  28  1.1.2 Endothelin and Exercise Plasma ET-1 concentrations increase in parallel with exercise intensity,  29  and at  the onset of short-term exercise at maximum capacity they immediately increased by 50%.  30  Endothelial dysfunction can effect exercise capacity and correction of its  dysfunction has been associated with an increase in peak V 0 . ' 3 1  3 2  2  Individuals with  chronic heart failure who exhibited a significant increase in exercise performance (as measured by a 6 minute walk test) following treatment also showed a decrease in BigET1(2.0 ± 0 . 9 vs 1.5±0.6 fmol/mL), an increase in endothelial function, as measured by reactive hyperaemia, an enhancement of N O dilation and a decrease in brain natriuretic peptide (BNP: a hormone secreted by the heart in response to work).  33  Trained athletes  experienced a decreased plasma ET-1 response to exercise, where as this increased in untrained groups.  1  Differing training status and ET-1 responses to exercise were  accompanied by training dependent change in plasma volume.  Trained athletes  experienced a slight reduction in plasma volume where as untrained group experienced a plasma expansion, that could be explained by variances in hydration.  5  Following exercise until exhaustion at 65 % of maximum aerobic capacity plasma ET-1 significantly decreased by 21 % during the first 30 minutes of exercise but then returned to baseline values by the end of exercise. ventilatory threshold ( T y  E N T  34  Thirty minutes of exercise at 90 %  ) caused plasma ET-1 levels to significantly increase, with  peak levels occurring 30 minutes post exercise.  When subjects cycled at 130 % of the  power (W) measured at T ENT> plasma ET-1 levels continued to rise and were V  significantly greater than levels at 90 % T  V  E  N  T  intensity.  29  Following acute exercise  plasma ET-1 levels significantly increased in both healthy individuals, ' with cardiovascular disease. ' 38  " and those  39  During a graded exercise test in horses, plasma ET-1 concentrations remained constant, but increased immediately following exercise and then returned to pre-exercise values following 10 minutes of recovery.  40  This raises the possibility that plasma ET-1 is  produced in response to exercise cessation and therefore may not be a factor contributing to its termination. Performing exercise for 30 minutes at a heart rate of 145 beats per minute on either a cycle ergometer or a treadmill elicited different ET-1 responses. Jogging caused a 61.4% increase in ET-1 where as cycling caused an 11.8% increase. This maybe best explained by an augmented mechanical stimulation of the endothelial lining during jogging, causing the endothelial cells to increase ET-1 release.  41  In response to exercise the endothelium releases vasodilating factors such as N O into the exercising muscles, endothelium.  43  42  that inhibits the production of ET-1 in the vascular  A rationale for the elevated production of N O in response to exercise  6  could be that increased shear stress experienced during exercise elicits N O production and therefore prevent the rise in ET-1. A positive but non-significant correlation was found between systolic and diastolic pressure at rest, and the changes in ET-1 (systolic blood pressure vs. ET-1: r = 0.479; diastolic blood pressure vs. ET-1: r = 0.590) after 3 months of exercise training on a cycle ergometer for 30 min/day, 5 days/wk at 80% of T E N T V  "  This led to the  hypothesis that ET-1 plays a role in elevated PAP seen during exercise.  Plasma ET-1  levels during exercise have been significantly correlated with mean PAP (MPAP) in patients with interstitial lung disease during exercise in the horse.  45  and associated with an increase in PAP found  46  In conclusion, plasma ET-1 levels increase with exercise intensity and are subject to the exercise protocol. The variation in conclusions regarding plasma ET-1 levels in response to exercise maybe due to differences  in exercise protocol; short term  manoeuvres may not be suitable to induce ET-1 release as it is dependent on transcription and translation that requires greater time.  47  With this in mind it is important to interpret  the results of studies with different exercise protocols using caution.  1.1.3 Endothelin and Hypoxia Hypoxia is a potent stimulus of ET-1 synthesis in vivo and in vitro and causes 1 48  or more substances to be released that are capable of causing constriction. endothelial cells increase ET-1 synthesis,  50  49  Systemic  where as the pulmonary endothelial cells  exhibit a decreased or unchanged level of E T - 1 .  51  However, hypoxia can cause dilation in  the systemic arteries but constriction in the pulmonary vasculature.  52  7  Plasma ET-1 synthesis can be augmented by alveolar hypoxia, by exercise-induced tissue hypoxia.  54  but not always  The lungs have been identified as an important  source of plasma ET-1 production in response to hypoxia,  and receptor antagonism can  55  attenuate hypoxia induced pulmonary hypertension (PH).  56  The increased ET-1 levels  experienced in response to low oxygen, tension are reversible on return to a normoxic environment.  18  Subjects exposed to high altitude exhibited elevated plasma ET-1 levels that were proportional to PAP and inversely related to partial pressure of oxygen (PC_).  48  Ascension to an altitude of 5050 m from sea level caused a significant oxygen desaturation (98.6 +/- 0.2% at sea level to 80.8 +/- 0.4%) that was negatively correlated to plasma ET-1 levels (from 1.8 +/- 0.1 pg/mL at sea level to 2.7 +/- 0.2 pg/mL). altitude hypoxia can also result in PH in humans and animals. ' 58  59  57  High  This suggests that  exposure to high altitude and therefore decreases in oxygen saturation result in elevations in plasma ET-1. Hypobaric hypoxia resulted in an over expression of ET-1 mRNA and protein in the rat lung during the development of PH, without alteration in plasma ET-1 levels. This suggests that local changes in ET-1 may not be detectable in plasma and thus questions the meaningfulness of measuring circulating ET-1. During chronic hypoxia, contraction of SMC's are accompanied by an impaired production of pulmonary vascular N O , vasodilation.  60  that could have effects upon N O induced  Hypoxic exposure causes an increase in ET-1 and ET-1 mRNA in 1 ft  pulmonary artery cells of patients with primary pulmonary hypertension.  In response to  hypoxia there is an alteration in E T receptor distribution, ET-a receptor density increases during hypoxia where as ET-b receptors are lost.  This suggests that VSMC's could  8  experience enhanced vasoconstriction through ET-a receptors and reduced vasodilation and ET-1 clearance through ET-b receptors. Based on these and similar findings it could be suggested that a selective increase in the synthesis and release of ET-1 from the pulmonary artery in the lung could be responsible for hypoxic P H .  1 8  ET-1 levels during sleep in patients with lung disease have been assessed;  45  arterial ET-1 values at rest are significantly correlated with partial PaC>2 ( r = -0.935, p < 0.001) and PAP (r = 0.657, p < 0.001). During sleep, both healthy subjects with respiratory failure  62  61  and those  experienced an attenuated ventilation, that was sufficient to  account for the hypoxemia observed in patients with respiratory disease. In conjunction 45  with this, a significant increase in plasma ET-1 levels during arterial desaturation while sleeping, and a negative correlation with PaC>2 were found  4 5  Following 30 minutes of  desaturation to between 75 and 80% (through a variable mixture of oxygen and nitrogen) subjects experienced a 2.6 fold increase in plasma ET-1 levels (0.9 ± 0 . 1 1 Vs 2.34 ± 0.34 pmol/1).  63  High altitude pulmonary oedema (HAPE) is characterized by normal left arterial pressure and elevated P A P , condition. ' 25  increase  6 5  64  and ET-1 has been implicated in the development of this  Elevations in ET-1 may augment capillary hydrostatic pressure,  vascular permeability,  66  and cause a N O synthesis defect resulting in  vasoconstriction in the pulmonary vasculature.  In addition to this ET-1 binding to the  ET-a receptor stimulates the production of V E G F mRNA, via increases in the expression of hypoxia-inducible factor (HIF) that increases vascular permeability leading to oedema rye  *CQ  formation in the lung. ' '  "70  The elevation in plasma ET-1 in response to high altitude  has been directly linked to increased systolic pulmonary artery pressure (SPAP) and PAP  9  measured at high altitude, and decrements in SpC>2. '  With this in mind it could be  suggested that the enhanced release of ET-1 at altitude may represent one of the mechanisms provoking pulmonary vasoconstriction observed in subjects prone to HAPE.  72  1.1.4 Endothelin and NO The vasoconstricting actions of ET's only occur when nitric oxide synthase (NOS) is deficient, they have been described as self-regulating by inhibiting their own 90  vasoconstricting effects by generating NO.  In response to exercise the endothelium  releases vasodilating factors such as NO into the exercising muscles.  42  N O inhibits the  production of ET-1 in the vascular endothelium, that implies that it may play a role in the production of ET-1 during exercise.  43  A rationale for the elevated production of N O in  response to exercise could be that increased shear stress experienced during exercise elicits N O production and therefore prevents the rise in ET-1. The enhanced vasoconstrictor response to ET-1 during exercise may also be due to an attenuated release of NO. L  - N A M E (N-Nitro-L-Arginine Methyl Ester), a competitive inhibitor of NO  production, partially inhibited endothelium dependent dilation (EDD) in both trained and sedentary rats, with the inhibition occurring to a greater extent in trained rats. in vascular wall shear stress during exercise  73  hyperaemia may augment  Increases EDD.  7 4  Following 16 weeks of exercise training patients with heart disease experienced greater E D D in coronary conduit arteries that was attributed to training induced production of NO.  In addition to this, 16 weeks of exercise training also increased E D D in  pulmonary arteries of pigs with disease but not in those without, and was attributed to  10  elevation in NO production and an attenuation of the constrictor substance prostaniod. With this in mind exercise training may enhance E D D in pulmonary and coronary arteries that may occur through an increase in the production of NO.  1.2 Exercise Induced Arterial Hypoxemia 1.2.1 Introduction During exercise ventilation and perfusion (V^/Q) ratios are matched effectively and arterial oxygen saturation (Sa02) is maintained.  77  This allows the body to preserve  homeostasis and meet the metabolic demands encountered during exercise.  In healthy  individuals S a 0 2 is maintained within 2-4% of resting values, when the body is unable to this such as during exercise, individuals experience exercise-induced arterial hypoxemia (EIAH). It is defined as a reduction in S a 0 2 below 95% , an individual 4% decrease in 78  S a 0 2 from baseline values , a persistent reduction in arterial O 2 pressure ( P a 0 2 ) by 79  more than 1 kPa  80  or a reduction in P a 0 2 by 10 mm H g .  8 1  Evaluating EIAH directly in the blood reveals that time profiles for P a 0 2 and S a 0 2 are different. P a 0 2 decreases at the onset of exercise, where as reductions in S a 0 2 become more pronounced at the end of maximal exercise,  82  suggesting that the intensity  of exercise can affect the level of hypoxemia. During incremental exercise at 50-60% V02  m a x  only 2 out of 6 highly trained runners experience a 17-20mmhg decrease in  P a 0 2 , but at 80-100% V 0 2  m a  x  a  n  individuals experienced this.  83  Mild EIAH has been defined as an absolute S a 0 2 of 93-95%, moderate EIAH in the range of 88-93%, and severe EIAH corresponds to S a 0 2 values <88% . Reductions 78  11  in both S a 0 to 92% and PaC_ to 7.3 kPa have become the standard for investigating 2  arterial oxygenation during exercise in normoxia. 1.2.2 Prevalence EAIH has been estimated to occur in around 50% of young highly fit males (VC_  60-70 mL.kg^.min- ) , and is accentuated in those elite trained athletes with 1  m a x  the highest V C _  m a x  .  7 9  78  The development of EIAH only in some elite athletes could be due  to variations in the ventilatory response to exercise. sportsmen and women with a relatively low V C _  m a x  84  More recently, untrained  (6 subjects with a V C _  m a x  < 57  mL.kg^.mhr ) also developed EIAH following 8 weeks of supra maximal interval 1  training; the development of EIAH was associated with a decrease in maximal ventilatory equivalent in C_ in spite of an increase in maximal ventilation during exercise.  85  The  significant decrease in the minimum SpC^ causing the development of EIAH suggests that training status can be accompanied by alterations in the degree of arterial desaturation developed during exercise. EIAH and pulmonary limitations are more prevalent in the female population. ' 81  Rfi 88  In trained females values for PaC_ and Sp02 are similar to those reported in males  however, the work capacity in females was lower suggesting that EIAH occurred at a much lower V C _ .  8 2  The presence of EIAH in individuals with normal aerobic capacities  is unique to women and has only been reported in men with a V C _ of predicted values.  89  m a x  greater than 150%  Female subjects who displayed moderate EIAH had a V C _  within 15% of predicted values,  87  where as males with a V C _  predicted have rarely exhibited E I A H .  78  m a x  m a x  within 15% of  The development of EIAH can be attributed to  12  gender related lung size; generally women have a smaller vital capacity, airway diameter and diffusion surface when compared to men of a similar stature, sitting height and body mass.  Individuals with a smaller relative lung size could have smaller airways, that  90  could lead to expiratory flow limitation, constraining the ability to compensate for inadequate alveolar to arterial O 2 exchange causing relative hypoventilation leading to EIAH.  9 1  Pre pubescent females do not experience EIAH, that suggests that EIAH in  women maybe related to maturational factors or exercise training.  92  1.2.3 Mechanisms Generally, healthy humans experience an increased A-a D O 2 with exercise and values of 15-25 mm Hg are common in elite athletes.  78  V02  m a x  EIAH.  93  A-a D O 2 increases until 80% of  is attained, above this a further enlargement is developed in those demonstrating During moderate and heavy exercise a widening A - a D 0 2 was significantly  greater than during rest and became accentuated during hypoxia.  In addition to this,  individuals experiencing EIAH experienced a significant decline in P a 0 2 from rest of at least 10 mm Hg larger than controls. The widened A-a D O 2 that occurs during exercise 94  can occur as a result of shunting, diffusion limitation or a humans the severity of EIAH correlates with A-a D O 2 , and  / Q mismatch '  . In  / Q mismatch maybe  responsible for 50% of this difference during rest . The multiple inert gas elimination technique (MIGET) has been used to measure in healthy subjects. The severity of exercise intensity. '  / Q inequality and diffusion limitation  / Q mismatch increases during hypoxia and with  During exercise < 65% V 0 2  m a  x ' A-a D O 2 can be explained by  v \ / Q mismatch, however at greater intensities even though V ^ / Q mismatch increases  13  other factors such as diffusion limitation may also explain A-a D C _ V  A  8 0  It is unclear why  /Q mismatch becomes accentuated with exercise although some mechanisms have  been implicated in this process. The increase in V  A  / Q mismatch with exercise could be  attributable to inflammatory markers released in the lung that subsequently effect small airways and arterioles in the periphery. One possible explanation for V 96  A  / Q mismatch  and also a diffusion limitation is the accumulation of interstitial pulmonary oedema. ' 97  98  Relative hypoventilation maybe another mechanism involved in EIAH; it can be seen as insufficient alveolar ventilation to maintain arterial blood gases at normal values. Based on the variance of a single relationship it has been suggested that relative hypoventilation can account for 50% of E I A H .  99  Increasing ventilation in mild hypoxia  could improve S a 0 2 by raising the gradient for gas exchange in the lung through augmented P A O 2 levels and a rightward shift of the oxyhaemoglobin dissociation curve via a reduction in arterial P C O 2 . During heavy exercise, levels of ventilation can explain up to 47% of variance in S a 0 2 ,  9 4  individuals experiencing the most severe hypoxemia are  most likely to have the lowest hyperventilatory response to exercise.  94  Studies that  augmented hyperventilation via normoxic helium breathing did not prevent E I A H , furthermore preventing arterial desaturation did not affect V V02  m a x  .  E  1 0 0  at sub maximal V O 2 or at  These both suggest that relative hypoventilation at maximum exercise may not  be a major contributor to the development of EIAH, however, it has been implicated during sub maximal exercise. During maximal exercise S a 0 is also affected by p H , 2  101  a low pH reduces the  affinity of O 2 to haemoglobin (Hb) and thus reduces.  14  1.2.4 Effects on V 0 2 a x m  EIAH may impair the delivery of O 2 to the working muscles,  102  it could affect the  unloading of O 2 from red blood cells and the diffusion into myocytes.  Females who  showed the most desaturation during normoxia experienced the most improvement in V 0 2 a x ^ desaturation was prevented. m  suggested that EIAH attenuates V 0 2 having measurable effects. ' 78  upon V 0 2  m a x  below 92%,  1 0 3  '  1 0 4  m a  x i  Studies preventing EIAH through inspired 0  trained subjects, with a desaturation of 3-4%  n  Reductions in SaOa can have detrimental effects  ; a 1% decrease in SaC^ can cause a 1% reduction in V 0 2 105  m a x  when SaC<2 is  or a 2% reduction in V 0 2 a x when S a 0 is greater that 95% . 2  m  work output can be impaired when S a 0 2 is reduced to 87% but not at 90%. where V C > 2 decrease.  max  2  106  8 6  Total  Instances  is maintained but SaCh continues to drop, work capacity tends to  106  1.2.5 EIAH and Altitude Decreases in SaC«2 are accentuated at altitude; in hypoxic environments highly 80  trained athletes usually experiences the greatest decrement in V 0 2 a x m  1 0 7  At altitude a  reduction in S a 0 2 has been observed and vasoconstriction in the pulmonary bed can provoke  / Q mismatch.  108  Athletes who experience EIAH at sea level (SaO^ <90%)  demonstrated a significant reduction in V 0 2 a x when exposed to mild hypoxia (71.1 ± m  5.3 Vs 67.2 ± 5 . 0 mL.kg-i.min- ) whereas non-EIAH athletes did not (67.2±7.6 Vs 1  66.2±8.2 mL.kg^.mhr ). 1  109  Based on these findings it could be hypothesized the degree  of arterial desaturation during maximum exercise at sea level may be reflective of the ability to maintain VO^max i roild hypoxia. n  15  1.2.6 Exercise modality When evaluating Sa0  directly in the blood, it appears that the intensity of  2  exercise determines the levels of E I A H .  82  Differences in cardiovascular responses to  various exercise modalities have been identified and the type and duration of exercise can affect EIAH. It is generally accepted that treadmill running results in a higher V C _ (4.83 ± 0.11 Vs 4 . 6 1 ± 0 . 1 4 ) ,  110  '  111  m a x  a lower Sp0 m (88.6 ± 0.6 Vs 92.6± 0.6) and more 2  consistently EIAH when compared to cycle ergometry. Following maximal treadmill running and cycle ergometry; EIAH occurred in all subjects performing exercise on a treadmill, where as this only occurred in five of the thirteen participants during cycle ergometry.  111  This has been attributed to the augmented ventilation experienced during  cycling, plus a widened A-a D C _ in running rather than cycling in athletes with the same VC_  7 8  . In support of this at 90% V O _  m a x  , V _ and alveolar ventilation were significantly  greater during cycling when compared to running protocols.  112  Generally, PaC_ was  greater during cycling than running (105 ± 2 and 94 ± 2 mm Hg, respectively) and was associated with a smaller A-aD02 (16 ± 2 vs. 22 ± 2 mm Hg, respectively) .  1 1 2  This  suggests that the difference in between running and cycling could be attributed to a difference in gas exchange and alveolar ventilation. In contrast, variations in S p 0 have 2  been analyzed in triathletes during running and cycling protocols with no difference in  being  found.  This  suggests  that  there  were  no  significant  differences  in  cardiorespiratory measures at maximal exercise between cycle ergometry and treadmill running in a group of subjects well trained in each exercise discipline. Faster ramping protocols can cause a more severe EIAH during cycling.  112  However, these results should  16  be interpreted with caution as the order of exercise tests was not randomized that may have resulted in an order effect. Based on the literature it could be suggested that EIAH may occur frequently during both cycling and running modalities depending on the exercise protocol, the type of ergometer and the training background of the subject. 1.2.7 N O and E I A H NO has been identified as a signalling substance that promotes adequate matching of V  A  and Q in the lungs,  VSMC's.  1 1 5 , 1 1 6  114  and has been related to vasodilation through the relaxation of  Elevated levels of NO can be attributed to shear stress placed on the  endothelium, that serves to attenuate ET-1 induced vasoconstriction. In response to exercise, the endothelium releases vasodilating factors such as NO into the exercising muscles.  42  The production rate of N O increases with exercise, ' 117  but has not been associated with alterations in Sp02, EIAH.  117  118  suggesting that it is not related to  In support of this, measurement of exhaled N O revealed no difference between  subjects with and without E I A H . systemic vasculature;  1 1 9  Exercise training increases production of N O in the  an up regulation of NO production in the systemic vasculature in  response to exercise or training could be mirrored in the pulmonary vasculature and may play a role in the matching of V  A  and Q and maintenance of low pulmonary vascular  resistance. Inhalation of NO during an exhaustive incremental exercise protocol moderated the drop in Pa02, implying that it maybe involved in EIAH through V regulation.  120  A  and Q  N O concentration in healthy humans have been positively correlated to  Pa02 and negatively correlated to A-aD02-  121  Breathing N O at altitude serves to increase  17  P a 0 2 and thus can have implications upon A-a D O 2 . This does not occur during exercise at sea level  120  or during simulated hypoxia at sea level.  117  Elevations in PAP have been  found in subjects exhibiting low levels of exhaled NO when exposed to hypoxia.  122  NO is activated and taken up rapidly by haemoglobin, therefore changes that occur in the pulmonary and systemic vasculature may not be detectable in expired air.  123  Furthermore, an increase in systemic/pulmonary vascular endothelial N O release may not be detectable in expired air due to its short half life in physiological systems.  124  18  2.1 Statement of the Problem ET-1 is a known constrictor peptide that has been negatively correlated to SpC>2 and Pa02- A decline in SpC>2 can have implications for oxygen delivery to the exercising muscles.  A n increase in ET-1 and therefore its constricting actions may serve to limit  exercise performance and reduce SpO^. To date no studies have investigated the differences in ET-1, BigET-1 (ET-1 precursor) or nitric oxide (NO) levels in healthy individuals during intense exercise in normoxia and hypoxia. The results of this study will determine if ET-1 and BigET-1 levels are increased during exercise in these conditions and will determine whether peptide levels correlate to variations in oxygen saturations. This may provide an insight into the involvement of ET-1 during exercise in healthy humans.  2.2 Objective The primary purpose of the study was to investigate the differences in ET-1 and BigET-1 production in athletes prior to, during and after exercise in athletes in normoxia and hypoxia. Furthermore, variations in ventilation, Sp02, arterial compliance (AC), NO, and PAP were measured to determine any relationships to the circulating peptides.  2.3 Hypothesis Based upon current literature the following hypotheses were derived: 1. Following exercise, plasma ET-1 and BigET-1 will be significantly increased. 2. Plasma ET-1 and BigET-1 will be significantly greater in hypoxia compared to normoxia. 3. Plasma ET-1 will be inversely correlated to Sa02.  19  4. Plasma NO, A C and PAP will be significantly different following exercise. 5.  Plasma NO, A C and PAP will be significantly different in normoxia and hypoxia.  20  3.0 Methodology 3.1 Subject Population Seven aerobically trained male athletes were studied to determine levels of plasma ET-1 and BigET-1, prior to, during and after exercise in normoxia and hypoxia. All subjects were non-smoking, had normal pulmonary function and were free of any history or symptoms of cardiopulmonary disease including exercise-induced asthma.  3.2 Procedures and Outcome Measures Subjects reported to the Cardiac Physiology and Rehabilitation Laboratory at U B C on five occasions; the first day consisted of an explanation of the study, signing of informed consent and familiarization with procedures. A l l exercise tests were performed a cycle ergometer at least 48 hours apart. The ergometer used was the Velotron Pro cycle ergometer (Racermate Inc, Seattle) controlled by Velotron Coaching Software (Version 1.5.186, RacerMate Inc, Seattle).  Prior to the first maximal exercise test, subjects  performed a resting pulmonary function test. Subjects breathed through a facemask, attached to a pitot tube pneumotach, with a low resistance, non-rebreathing valve (Hans Rudolph, Kansas City, MO) attached to the distal end of the pneumotach. On the second and third day subjects performed V 0 2  m a x  tests, once in normoxia and once in hypoxia  (Fi02 = 0.14). Day 4 and 5 consisted of a 30-minute steady state exercise protocol at the power achieved at ventilatory threshold in normoxia and hypoxia. The order of steadystate exercise tests was randomized and participants were blinded to the concentration of oxygen that they were inspiring. Throughout all tests Sp02 was measured continuously and recorded every 30 s and expired gases were measured on a breath-by-breath basis  21  using a computerized system (Medisoft Hyp'air), and averaged, every 15 s. Sp02 was measured continuously using 2 pulse oximeters (Ohmeda 3740, Louiseville, KY), one at the ear and one on the tip of the index finger. Prior to placing the oximeter on the ear and the finger a topical vasodilator cream was applied to increase local perfusion. During the hypoxic and normoxic exercise tests blood samples were withdrawn at various times throughout the protocol to measure ET-1, Big ET-1, and NO; PAP and A C were measured immediately before and after exercise.  3.2.1 Resting Pulmonary Function Test Using an automated ventilatory analysis system (Medisoft Hyp'air), participants performed resting pulmonary function tests, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEVi).  3.2.2 V 0 2 a x  T e s t s  m  Subjects performed two maximal exercise tests; one in normoxia and one in hypoxia (FIO2: 0.14). Prior to the test subjects were asked to refrain from exhaustive exercise for 24h, caffeine/alcohol for 12h, and food or drink for 2h prior to testing. After entering the lab subjects had their height and weight measured. Subjects then performed a self-selected cycling warm up (approximately 5 min). Following this, three minutes of resting data were collected prior to the test. The progressive exercise test started at 150 W and increased in a stepwise fashion of 30 W every three minutes until volitional exhaustion. To ensure that V 0 2  m a x  was attained at least 3 of the following criteria were  met: 1) a plateau in VO2 with the last stage increase, 2) attainment of at least 90% of agepredicted maximal heart rate (210 - [0.65 x age]), 3) RER > 1.1, 4) inability to maintain the imposed cycling speed despite maximal effort and verbal encouragement.  22  During both tests heart rate was recorded every 30 seconds using a portable heart rate monitor (Polar Vantage XL). Minute ventilation (V_), oxygen consumption (VO2) and CO2 output (VCO2) were measured using a computerized system. Ventilatory threshold was calculated using a combination of ventilatory equivalents and RER.  3.2.3 Steady State Exercise Test in Hypoxia or Normoxia Subjects were given 20 minutes to perform a self-selected warm up on the cycle ergometer and then asked to perform a 30-minute exercise protocol at the power achieved at ventilaltory threshold.  Minute ventilation, VO2 and VCO2 were measured at 15-s  averages throughout the exercise test and %Sp02 was measured continuously and recorded every 30 seconds. Prior to and following each steady state exercise test participants were weighed and then consumed water to replenish any fluids lost during the exercise test in an attempt to maintain plasma volume.  3.2.4 ET-1 and BigET-1 Venous blood samples were taken from right antecubital fossa vein cannulated with a 21 gauge intravenous cannula. During the hypoxic and normoxic exercise tests blood samples were taken at various times throughout the protocol (Time: pre-, 10-, 20minutes during exercise and immediately following, termination of exercise).  10-, 20-,  30- minutes post  Samples were immediately placed on ice and centrifuged at  3000 g for 10 min. Plasma was frozen and stored at -80°C until assayed.  Following  extraction the plasma concentrations of ET-1 and BigET-1 were determined by enzyme immunoassay (Medicorp Inc, Montreal Quebec). The coefficient of variation for ET-1 and BigET-1 was 9.6% and 9.5% respectively.  23  3.2.5 Nitric Oxide Plasma N O levels were determined using a ratio of circulating nitrite/nitrate (NOx). Venous blood samples were also taken from right antecubital fossa vein cannulated with a 21 gauge intravenous cannula, immediately before and after both exercise tests. Samples were immediately centrifuged at 2500g for 15 min and stored at - 8 0 ° C before analysis. NOx concentrations in different dilutions of plasma ultrafiltrate were determined by a colorimetric assay kit (Biovision Inc, Mountain View, Ca) based on a three-step Griess reaction. The sample range of the NO assay was 1-40 u M .  3.2.6 Arterial Compliance A C was measured immediately before and after the steady state exercise tests. Radial arterial pulse waves were recorded using an arterial tonometer sensor array. The waveform was calibrated by the oscillometric method with a cuff on the opposite arm and a calibration system internal to the device.  The tonometer sensor array adjusts itself  automatically to obtain the optimal waveform and repeats the calibration until the waveform is stable. When the waveform is calibrated and stable, 30 second long analog tracings of the waveform was digitized at 200 samples per second and stored in a personal computer system for compliance analysis. The diastolic decay of the waveform was mathematically analyzed and two models of arterial compliance were calculated based on a modified Windkessel model of circulation. Capacitative compliance (CC; that which represents compliance of the large vessels) was derived from analysis of diastolic slope of decay of the waveform and oscillatory compliance (OC; that which represents compliance of small vessels) was derived from oscillatory component of diastolic decay.  24  Intra- and inter- visit measurements of arterial compliance have been known to differ by less than 3 and 4% respectively indicating a good reliability of measure.  3.2.7 Pulmonary Artery Pressure PAP was measured immediately before and after the normoxic and hypoxic exercise tests. Doppler echocardiography was carried out in the semi-recumbent partial left lateral position. Triplicate estimates of tricuspid regurgitant jet velocity were made and the PAP calculated using the simplified Bernoulli equation and assuming R A pressure of 10 mmHg and a zero gradient across the pulmonary valve. Measures were taken before and immediately after the steady state exercise tests. The standard error of estimate in testing intra- and interobserver reproducibility of Doppler systolic time intervals is less than 5%.  126  3.2.8 Data Analysis Data analysis were completed using SPSS software (SPSS Inc, version 11). Tests for normality of distribution and homogeneity of variance were performed prior to further statistical analysis. Standard t-tests were used to determine differences in data between maximal exercise tests.  Plasma ET-1 and BigET-1 levels were analyzed using a 2  (Groups: normoxia and hypoxia) x 7 (Time: pre-, 10-, 20-, and immediately following, 10-, 20-, 30- minutes post termination of exercise) analysis of variance (ANOVA) with repeated measures on the second variable. A C , NO and PAP were analyzed using a 2 (Groups: normoxia and hypoxia) x 2 (Time: pre and post exercise) repeated measures A N O V A . In addition, correlation of the Sa02 to other outcome variables was analyzed using the Pearson product moment calculation. For all tests significance was set at a = .05.  25  3.3 Limitations The primary limitation of the study that was that ET-1 was measured in plasma. As only 20% of the peptide is circulating in venous blood, it may not be representative of what is happening at a different site of the body. Measurements of both PAP and A C are time sensitive. Athletes were instructed to remove themselves from the ergometer and lie down as quick as possible while PAP, A C and a blood sample were taken. Due to the number of variables being measured and the possibility of time delay between subjects, this proved to be a confounding variable within the study. Measurements for PAP were measured once the participants removed themselves from the cycle ergometer and therefore the hypoxic stimulus was removed. This meant that any affects resulting from the hypoxic stimulus might have been normalized. Any significant differences that were found in the study cannot be applied to other bodies of individuals. Subjects for this study were selected based upon fitness level, that limited the randomization of the study  3.4 Delimitations In an attempt to reduce the amount of variability within the study subject hydration levels were controlled to ensure that differences in plasma ET-1 are not due to an exercise-induced alteration in plasma volume. Furthermore, time of testing was controlled due to circadian alterations in ET-1.  26  4.0 Results Seven male athletes (mean ± SEM: age 26.14 ± 1.77 years, height 182.36 ± 1.51 cm, mass 72.89 ± 2.62 kg) exercised at the Cardiac Physiology and Rehabilitation lab on 4 occasions. Maximal exercise tests (mean ± SEM: normoxia (n) 68.56 ± 2.06 mL.kg" min" ^hypoxia (FiC^ 0.14)(h) 53.88 ± 1.35 mL.kg^.min" ), and two 30-minute steady 1  state exercise protocols at the power achieved at threshold during maximal exercise tests (mean ± SEM: power (Watts) 257.14 ± 21.57 (n) 191.25 ± 10.79 ( F i 0 0.14)(h); HR 2  (bpm) 161.7 ± 5.34 (n) 156.6 ± 3.45 (h)) were completed. Ventilatory data for maximal exercise tests were analyzed, significant increases in peak V 0  2  (p = 0.001), V C 0  2  (p = 0.003) and %Sp0 (p = 0.000) were found when 2  participants exercised in normoxia compared to hypoxia. Mean peak data for maximal exercise tests can be found in Table 2. Table 2: \Oo , ma  Data  Condition V E (L/min)  V0  2  Peak  VC0  2  Peak  RER  HR (beats/min)  S p 0 (%)  ( m L . k g " l . m i n " l ) ( m L . k g " 1.min" 1)  2  N  178.01 ± 9.49  65.86 ± 2.06  74.72 ± 2.44  1.13 ± 0 . 0 1  190.43 ± 3 . 1 9  94.54 ± .24  H  163.67 ± 7 . 7  53.88 ± 1.35 *  63.4 ± 1 . 9 9 *  1.18 ± 0 . 0 3  183.1 ± 2 . 7 2  85.39 ± 1.17 *  Mean ± S E M * significant difference between normoxia and hypoxia p<0.05 V E p=0.264, V 0 2 * p=0.000, V C 0 2 * p=0.004, H R p=0.108, S p 0 * p= 0.000 2  27  Figure 4: Peak V O 2 Values During M a x i m a l Exercise Tests Peak V 0 2 V a l u e s During M a x i m a l Exercise T e s t s 80  70  60 A  I  50 I Normoxia I Hypoxia  j= 40 n  OJ  a.  S >  30  20  10  Mean ± S E M * significant difference between normoxia and hypoxia p<0.05  During steady state exercise tests significant increases i n mean V O 2 (p=0.012) , V C O 2 (p=0.036) and %SpC<2 (p= 0.00) were found when participants exercised i n normoxia compared to hypoxia. Mean steady state data can be found i n table 3.  28  Table 3: Mean Steady State Data Condition  V E (1/min)  V C _ (mL.kg"  V C C _ (mL.kg"  H  R  S  P°2 ( )  Power (watts)  %  (beats/min) l.min" )  ^.min" )  1  1  N  98.17 ± 9 . 6 6  48.77 ± 2 . 2 8  46.13 ± 2 . 6 6  161.7 ± 5 . 3 4  94.12 ± 0 . 3 2  0.94 ± 0.01  257.14 ± 2 1 . 5 7  H  85.03 ± 6 . 0 3  39.03 ± 0 . 8 0 *  37.94 ± 1.56*  154.9 ± 3 . 4 5  80.2 ± 1.70*  0.97 ± 0 . 0 2  188.6 ± 1 0 . 7 9 *  Mean ± S E M * significant difference between normoxia and hypoxia p<0.05 V 0 * p=0.04 V E p=0.271, V C 0 * p=0.021, H R p=0.303, Sa 0 * p= 0.00, R E R p=0.334, P o w e r p=0.02 2  2  2  Figure 5: Oxygen Saturation during Steady State Exercise Mean S t e a d y S t a t e S p 0 2 V a l u e s During N o r m o x i a a n d H y p o x i a 100  95  90  o  • Normoxia • Hypoxia  85  a  80  75  70  Mean ± S E M * significant difference between normoxia and hypoxia p<0.05  Both P A P and O C were significantly greater following exercise (Fpja) = 4.74 p< 0.05), compared to pre exercise values.  This difference could not be found when  comparing normoxia and hypoxia (F(i,i2) = 4.74 p> 0.05), although oscillatory  29  compliance (OC) was on average higher during normoxia. Mean values for PAP, A C and NO can be found in Tables 4 and 5. Table 4: Mean PAP and Arterial Compliance Condition  P A P Pre (mmHg)  P A P Post (mmHg)  C C Pre CCPost (mL/mmHg xlO) (mL/mmHg xlO)  N  28.7 ± 1.21  34.89 ± 2 . 0 7 f  20.51 ± 1.85  H  29.29 ± 2 . 0 1 34.53 ± 2 . 7 0 t  18.03 ± 1 . 4 1  O C Pre (mL/mmHg xlOO)  OC Post (mL/mmHg xlOO)  16.78 ± 2 . 5 8  9 ±0.81  12.6 ± 1.65 t  19.2 ± 1 . 9 6  8.04 ± 0 / 7 0  10.69 ± 1.04 f  Mean ± S E M * significant difference between normoxia and hypoxia p<0.05 t significant difference between pre and post exercise p<0.05 C C : Capacitative Compliance  Mean ± S E M t significant difference between pre and post exercise  30  Figure 7: Pulmonary Artery Pressure Pre and Post Exercise  Pulmonary Artery Pressure During Steady State  Normoxia Hypoxia  Pre  Post  Mean ± S E M t significant difference between pre and post exercise  Circulating N O did not differ significantly over time or across conditions ( F 2 ) = 4.74 ( U  p> 0.05), however were on average higher during normoxia.  Table 5: Mean Nitric Oxide Values (uM) Condition  Pre-Exercise  Post-Exercise  N  1.48 ± 0 . 5 5  1.50 ± 0 . 5 3  H  0.95 ± 0 . 1 7  0.95 ±0.16  Mean ± S E M  Plasma ET-1 or BigET-1 levels did not differ significantly over time or across conditions F(i,i2) = 4.74 p> 0.05), and were not significantly correlated to alterations in oxygen saturation. In addition, both peptides were not significantly different when A E T -  31  1/BigET-1 was analysed ( F  ( U 2  ) = 4.74 p> 0.05).  However B i g E T - 1 decreased 10  minutes into exercise and then increased throughout exercise, returning to pre- exercise levels at the end of exercise. O n average B i g E T - 1 levels were higher during hypoxia. Mean data for E T - 1 levels can be found below in Table 6 below. Figure 8: Plasma ET-1 Levels During Normoxia and Hypoxia  Plasma ET-1 levels During Normoxia and Hypoxia  Normoxia Hypoxia  Pre  Exercise 10 Exercise 20  Post  Time (min)  Recovery  Recovery  Recovery  10  20  30  Mean ± S E M  Table 6: Mean Plasma ET-1 (fmol/mL) Condition  Pre  Exercise 10  Exercise 20  Exercise 30  Recovery 10 Recovery 20 Recovery 30  N  1.96 ± 1 . 5 1  1.89 ± 1.48  2.05 ± 1.60  2.06 ± 1.57  1.97 ± 1 . 4 9  1.95 ± 1.50  2.11 ± 1 . 5 2  H  2.18 ± 1.73  1.94 ± 1 . 6 5  1.99 ± 1 . 6 4  2.25 ± 1.70  2.04 ± 1.70  2.0 ± 1.56  1.88 ± 1 . 4 7  Mean ± S E M  32  Figure 9: B i g E T - 1 Levels During N o r m o x i a and Hypoxia  BigET-1 levels During Normoxia and Hypoxia 0.25  Normoxia I Hypoxia  Pre  Exercise 10 Exercise 20 Exercise 30 Recovery 10  Recovery 20  Recovery 30  Time (min)  Mean ± S E M  33  5.0 Discussion 5.1 Introduction Seven aerobically trained males underwent 30 minutes o f exercise at ventilatory threshold.  Following exercise we found that P A P and O C significantly increased  compared to pre-exercise values. The administration o f 14 % C_ during exercise failed to elicit changes i n these parameters when compared to normoxia, but resulted in a significant reduction i n oxygen saturation. In addition, N O , plasma ET-1 and B i g E T - 1 levels did not differ significantly over time or following hypoxic exposure. Circulating levels of B i g E T - 1 dropped 10 minutes into exercise and then returned almost to preexercise levels by the end o f the protocol. Furthermore, on average B i g E T - 1 trended towards higher values during hypoxia, where as N O tended to be lower. Correlation analysis suggests that outcome variables were not related to alterations in oxygen saturation following exercise in normoxia and hypoxia.  5.2 ET-1 and BigET-1 5.2.1 ET-l/BigET-1 and Exercise ET-1 and its pre-cursor B i g E T - 1 are part of a vasoconstrictive pathway that may serve to reduce blood flow and increase pressure in vessels through the constriction o f smooth muscle. M u c h o f ET-1 is secreted by vascular smooth muscle cells towards the vessel wall, resulting i n the remaining 20% distributed into circulation. Consequently, 16  plasma levels are the result of spill over from the vascular endothelium into the bloodstream.  34  ET-1 is secreted by a number o f cells including vascular smooth muscle cells in response to exercise. Matsakas et a l . found that plasma ET-1 increased 2-fold following 1  at 20 minutes o f exercise in a 60 minutes exercise protocol. Mean plasma E T - 1 levels measured prior to, during and following exercise within the current study ranged from 1.89 - 2.11 fmol/mL(n) and 1.81 - 2.25 fmol/mL(h). These levels are considerably higher when compared to normal circulating levels for healthy adults (0.4 -0.8 fmol.ml).  26  It  should be noted that one participant exhibited plasma E T - 1 levels 1 0 - 1 2 times higher than all other participants within the group that served to elevate the overall mean. When these values were omitted from the results ET-1 levels resembled values similar to those found by Matsaki et a l .  26  The participant who experienced elevated E T - 1 levels  comparable to patients with cardiovascular disease had similar A C , P A P , B i g E T - 1 and N O levels to the remainder o f the group. One possible explanation for this elevation in ET-1 without variation in other parameters could be a desensitization o f E T - 1 receptors, resulting in an elevated amount o f circulating plasma E T - 1 required to initiate a similar response. Circulating levels o f B i g E T - 1 (0.02 - 0.06 fmol/mL (n) and 0.05 - 0.11 fmol/mL (h)) within this study were considerably lower than other values in healthy humans (0.61.8 f m o l / m L ) .  127  This could have occurred due to a number o f reasons such as assay  sensitivity or an attenuated action o f E C E . Results in normoxia are i n accordance with Lenz et a l .  54  and Letizia et a l .  1 2 8  who  found that exercise did not alter plasma ET-1 and B i g E T - 1 . One possible explanation for these findings could be the similarities between rate o f uptake and release o f E T - 1 , resulting in unchanged peptide levels. It could be suggested that this rate o f uptake and  35  release in healthy humans maybe more efficient than their less healthy counterparts, resulting in elevated levels o f E T - 1 . Furthermore, tissue hypoxia induced solely by maximal exercise may not be enough o f a stimulus to induce the production o f this peptide.  54  In contrast to this study, Maeda et a l .  29  found a difference between plasma E T - 1  levels following steady state exercise at 130% o f ventilatory threshold on a cycle ergometer. This difference could have occurred for a number of reasons; the exercise intensity was less i n our study, therefore was not enough to induce changes in ET-1 levels. Moreover, when comparing the power outputs from participants in both studies (257.14 ± 57.07 vs. 164.8 ± 1 1 . 2 watts, for the present study and Maeda et a l . , 29  respectively); athletes within the current study were on average cycling at a higher resistance, suggesting that they were stringer cyclists. Supporting the notion that fitter cyclists have a lower endothelin response to exercise, Matsakas et a l . found that trained 1  athletes experienced a decreased plasma ET-1 response to exercise, where as the ET-1 response to exercise increased in untrained groups. In addition, 3 months of aerobic 1  training decreased resting plasma ET-1 levels  4 4  and can prevent the abnormal rise o f this  peptide in response to acute exercise in normotensive subjects.  129  Consequently, the  differing ET-1 responses between the current study and others with similar stimuli may be due to a difference in training status. This higher training status may have resulted i n an alteration in vasomotor function in the vascular smooth due to adaptations in the endothelium and smooth muscle cells. . Furthermore, as our athletes were aerobically 73  trained, they could have experienced an attenuated E T - 1 response to exercise, or the stimulus required to induce its production is greater or takes longer than in untrained  36  individuals.  Another possible contributor might be that experienced cyclists are more  efficient, with less unnecessary movement resulting in decreased mechanical stimulations of the endothelium and less production of the peptide during exercise. If ET-1 production is dependent upon a stimulus greater than a particular threshold, one might speculate that aerobically trained athletes have increased the threshold at which production occurs. To establish i f exercise intensity caused discrepancies between studies, a protocol whereby athletes exercise above threshold for 30 minutes or at threshold for greater than 30 minutes maybe useful to determine this. However, after observing athletes within this study cycle for 30 minutes at threshold it is questionable whether many would be able to sustain exercise above ventilatory threshold for greater than 30 minutes. Consequently, the duration o f exercise may not be sufficient to induce changes in E T - 1 . The endothelin peptide is not stored in vesicles, therefore secretion is dependent upon transcription and translation.  47  This pathway supports the hypothesis that short term maneuvers might not  result in ET-1 release as protein synthesis is required. Although both peptides did not differ significantly over time or across conditions B i g E T - 1 followed a similar pattern to that demonstrated i n work by, Richter et a l .  34  Ten  minutes after the onset o f exercise, plasma B i g E T - 1 levels dropped but then returned to baseline levels by the end o f exercise. B i g E T - 1 tended to be higher during hypoxia when compared to normoxia, where as N O tended to be lower.  5.2.2 ET-1/ BigET-1 and Hypoxia ET-1 is synthesized in the lung in response to h y p o x i a . hypoxia Smith et a l .  55  5 5 , 5 7  Following systemic  found that ET-1 levels increased, which were associated with an  37  increase i n lung weight and pulmonary perfusion pressure. In this study a comparison o f plasma ET-1 and B i g E T - 1 levels in normoxia and hypoxia found no alterations in their serum concentration, suggesting that the duration o f hypoxic exposure was not long enough to elicit an adequate ET-1 response. Analysis o f plasma samples revealed that B i g E T - 1 was greater (NS) during hypoxia compared to normoxia.  The tendency for B i g E T - 1 to be higher i n hypoxia  would lead to the hypothesis that ET-1 would also be higher. A s plasma E T - 1 did not alter across conditions this suggests that the assay may not have been sensitive enough to detect the production o f B i g E T - 1 or the stability o f the precursor in venous blood was inadequate in this group o f participants.  A s vascular reactivity to bigET-1 requires a  conversion to E T - 1 to elicit full haemodynamic effects, it could be hypothesized that highly trained athletes experience a reduction in the actions o f E C E in an attempt to reduce the likelihood o f the vasoconstrictive actions o f E T - 1 . Many studies have found that hypoxia is a potent stimulus o f E T - 1 production, which has been associated to decrements in oxygen saturation. Morganti et a l .  57  found  that ascension to an altitude o f 5050m from sea level over a period o f 8 hours caused a significant oxygen desaturation (98.6 ± 0.2% at sea level to 80.8  ±  0.4%) that was  negatively correlated to plasma ET-1 levels (from 0:72 ± 0.04 fmol/mL at sea level to 1.08 ± 0.08 fmol/mL). In the current study oxygen saturation was significantly lower i n hypoxia when compared to normoxia. These reductions in oxygen saturation were similar to those experienced by participants in the study by Morganti et a l . ; however, they were 57  not accompanied by alterations in ET-1 or B i g E T - 1 .  The discrepancy could have  occurred for a number o f reasons. For example, participants i n the study by Morganti et  38  al.  were at exposed to altitude over a long period o f hours, where as participants within  this study experienced hypoxia for only 30 minutes. In addition, some participants within this study have had previous exposure to altitudes o f 2500m and greater. It is not known how this previous exposure to altitude could affect ET-1 and B i g E T - 1 response to hypoxia. To the authors knowledge there is no literature that documents the duration o f hypoxic exposure required to induce ET-1 production.  However, as the duration o f  exposure in this study is considerably less than others, this suggests that durations o f greater than 30 minutes while breathing 14% O 2 are required. Battistini et a l .  28  suggested that due to the rapid clearance o f E T - 1 from the  circulation levels o f its inactive precursor BigET-1 and the E T - l / b i g ET-1 ratio may be a more effective way to assess the activation o f the E T system i n both venous and arterial beds.  However, as plasma B i g E T - 1 levels within this study were so small the ratios  were not an effective way to measure this.  5.3 Pulmonary Artery Pressure Plasma ET-1 has been implicated in the pathophysiology o f conditions associated with vasoconstriction such as pulmonary hypertension and coronary heart disease  1 8 j13  °"  132  . ET-1 causes  mitogenesis o f human pulmonary artery  smooth muscle  cells  ( P A S M C ' s ) , v i a the E T a receptor, which could be associated with vascular remodelling and therefore alter pressures in V S M C ' s .  1 3 3  Selective increase i n the synthesis and  release o f ET-1 from pulmonary endothelial cells could account for hypoxic P H and vascular remodelling. Overproduction o f this peptide may contribute to smooth muscle hypertrophy and remodelling of the pulmonary vasculature associated with chronic hypoxic P H . 18  39  ET-1 has been associated with an increase i n P A P found during exercise in the horse.  46  A positive correlation was found between systolic/diastolic pressure and the  changes in E T - 1 after 3 months o f exercise training on a cycle ergometer for 30 min/day, 5 days/wk at 80% o f ventilatory threshold ( T  V E N T  ) in humans. This highlights the role of  ET-1 in B P and led to the hypothesis that ET-1 plays a role i n elevated P A P seen during exercise. Elevations in P A P through ET-1 could cause uneven vasoconstriction resulting in a ventilation perfusion mismatch ( V / Q ) , leading to exercise induced arterial A  hypoxemia ( E I A H ) . With this in mind it was hypothesized that the elevated P A P observed following exercise could be correlated to alterations E T - 1 . Resting values for systolic pulmonary artery pressure in our study were similar to the normal values found by Chemla et a l .  1 3 4  (28.7 ± 1.21 vs 23 ± 3 mmhg). Following 30 minutes o f exercise at ventilatory threshold participants in the current study experienced significantly greater P A P compared to preexercise values. A s plasma ET-1 and B i g E T - 1 levels did not alter significantly over time or across conditions it could be concluded that ET-1 and its pre-cursor B i g E T - 1 were not involved in exercise induced changes in P A P . The elevation i n P A P is likely due to elevations in cardiac output accompanying exercise. Ascent to high altitude is associated with increases i n pulmonary artery pressure, which occurs through hypoxic pulmonary vasoconstriction.  135  A number o f vasoactive  substances such as E T - 1 are involved in the pressor response to h y p o x i a .  136  Modesti et al.  further highlighted the involvement of ET-1 in high altitude pulmonary hypertension through the use o f endothelin receptor antagonists. Administration o f Bosentan an E T a and E T b receptor antagonist (62.5 mg for 1 day and 125 mg for the following 2 days;  40  n=10), attenuated the pressor response in participants following a rapid ascent to 4559m.  137  Following hypoxic exposure participants in this study did not experience  either an alteration in P A P or plasma E T - 1 . This data further supports the notion that endothelin plays a role i n augmentation o f P A P during hypoxia o f several hours duration. Shorter exposures, such as i n the present study are likely not sustained enough to elicit vasoconstriction and production to E T - 1 . McEniery et a l .  1 3 8  found that when using a receptor antagonist (BQ-123) in  normotensive individuals there was little effect on the peripheral vasdilator response to forearm exercise, but normalised the exercise-induced vasodilatation in hypertensive patients. This suggests that the endothelium maybe actively involved i n exercise induced vasodilatation in the hypertensive patients but not in healthy humans. A t altitude, there is a transient hypertension that resolves on return to sea level.  Perhaps exposures to  hypoxia o f at least several hours duration induce a hypertensive response which can be altered by plasma E T - 1 .  5.4 Nitric Oxide Normal vascular tone is maintained through a balance o f dilating and constricting factors. Nitric Oxide is a potent vasodilator that causes the relaxation o f vascular smooth muscle.  139  The production rate of N O increases with exercise due to increased shear  117 118  stress,  '  which may serve to attenuate ET-1 induced vasoconstriction. It has been  hypothesized that elevations in N O could be associated with arterial hypoxemia through ventilation-perfusion V V Q mismatch.  140  However, measurements o f exhaled N O have  not been associated with alterations i n S p 0 , or in athletes with and without E I A H 2  1 1 7  '  1 1 9  41  The current study found that plasma N O did not significantly change following normoxic or hypoxic exercise. Oxygen saturation was significantly reduced during exercise in hypoxia, without a concomitant change in N O levels, which supports the notion that there is little relationship between N O and Sa02. Furthermore, an increase in O C following exercise suggests that the increase in arterial stiffness following exercise occurs independent o f N O production. In support o f this finding, Otsuki et a l .  1 4 1  recently  found that N O could not be associated with arterial pulse wave velocities when comparing strength-trained, endurance-trained and healthy controls. The absence o f variation in both ET-1 and N O further suggests that they are not involved i n exercise-induced alterations in vascular smooth muscle, Furthermore the hypoxic stimulus within this study was not great enough to alter levels o f each substance.  5.5 Arterial Compliance ET-1 has been hypothesized to play a role in maintaining basal vascular tone, and perhaps arterial compliance.  Arterial compliance is increased in endurance-trained  athletes and decreased in strength-trained athletes.  141  Plasma E T - 1 was decreased i n nine  endurance trained males athletes following 30 minutes o f cycling at 60% of maximum aerobic power (1.73 ± 0.44 to 0.8 ± 0.24 fmoL/ml), whereas untrained athletes experience an increase i n E T - 1 (1.04 ± 0.24 to 1.33 ± 0.44 fmoL/ml). been increased by arterial infusion o f E T - 1 .  1 4 2  1  Arterial stiffness has also  Moreover, E T - 1 has been identified as  being involved i n the maintenance o f basal vascular tone i n humans that has led to the hypothesis that there is a relationship between arterial stiffness and the endothelium. Following 30-minutes exercise at ventilatory threshold we found that O C was greater compared to pre-exercise values. It did not significantly change when participants  42  exercised in normoxia compared to hypoxia; however, there was a trend towards O C being higher during normoxia indicating more compliant arteries.  This increased  compliance was not accompanied by changes i n either plasma E T - 1 / B i g E T - 1 or N O , suggesting that the exercise induced alterations in compliance o f arteries are not related to these peptides. In support o f this, Qtsuki et a l .  1 4 1  found that the relationship between  pulse wave velocity(PWV) and A C to ET-1 was linear (i.e. as P W V increases so does ET-1 where as when A C increases ET-1 decreases) and the relationship between these factors were independent o f blood pressure. They did not find a relationship between mean blood pressure and ET-1 but did find that endurance-trained athletes exhibited less ET-1 than their strength-trained counterparts and this was associated with a reduction i n arterial compliance. Hypertensive subjects exhibit abnormalities and reductions i n the oscillatory component o f the diastolic waveform following pulse contour analysis when compared to healthy controls (0.075 versus 0.052 m L / m m H g , P<.05).  1 4 3  This difference suggests that  there could be an association between increased pressures in the pulmonary artery and decreased compliance o f peripheral vessels. In contrast we found that as the pressure i n the pulmonary artery increased following exercise the compliance i n the peripheral vessels also increased. This finding suggests that stiffness in the peripheral arteries is independent o f larger vessels such as the pulmonary artery in healthy athletes.  43  5 . 6 Hypothesis Revisited 5.6.1 Hypothesis # 1 Based o f previous literature a number of hypothesis were derived; below is a summary o f how our data supports or does not support the original hypothesis and why this may have occurred. The first hypothesis that plasma ET-1 and BigET-1 would be significantly increased following exercise. Data within this study did not support this hypothesis; which may have occurred for the following reasons: 1. Training Status 2. Exercise Intensity 3. Exercise Duration The notion that as individuals become more aerobically trained the ET-1 production in response to exercise is attenuated has been supported by Maeda et a l . They found that 44  following 3 months o f aerobic exercise participants produced less endothelin i n response to exercise. A s athletes in this study were aerobically trained the possibility that they experienced an attenuated ET-1 response to exercise exists. The intensity at which individuals were exercising may not have been enough to elicit a significant ET-1 response. Maeda et a l .  29  found a significant increase in plasma  ET-1 in response to exercise at 130% Tvent; athletes within the current study were exercising at ventilatory threshold. The rationale for this intensity was based upon the fitness level o f the athletes; as they were highly trained their ventilatory threshold may have been considerably elevated compared to untrained individuals. For these athletes to exercise above threshold for 30 minutes may not have been possible. Furthermore, as  44  athletes become more trained they may increase the threshold that is required to elicit production o f E T - 1 . In addition the duration o f exercise may not have been long enough to elicit the production o f E T - 1 . Previous literature highlighted ET-1 may not be produced in response to short term exercise as it requires time for transcription and translation,  47  suggesting that E T - 1 may be involved in a more long term response to exercise 5.6.2 Hypothesis # 2 The second hypothesis that plasma ET-1 and B i g E T - 1 would be significantly greater following exercise in hypoxia compared to normoxia, was also not supported. However, B i g E T - 1 tended to be higher during hypoxia compared to normoxia, without an accompanying rise i n E T - 1 . This may have occurred as the conversion o f B i g E T - 1 to its active precursor could have required a longer duration. In addition, we hypothesized that individuals may have experienced a down regulation o f E C E as a mechanism to limit the vasoconstrictive action o f E T - 1 ; which also may be a product o f training status. When comparing the oxygen saturation of individuals with this study to those in other studies that found a difference in E T - 1 , it appeared that our hypoxic stimulus was considerably shorter. Due to the nature o f the formation o f the peptide, it could be possible that the duration o f hypoxia was not long enough to elicit ET-1 production. 5.6.3 Hypothesis # 3 Levels o f ET-1 did not alter over time or across condition, with this in mind the data did not support hypothesis # 3 ; furthermore analysis also revealed no significant correlation between ET-1 and  SaO"2.  45  5.6.4 Hypothesis # 4 The hypothesis that plasma N O , A C and P A P would be significantly different following exercise was somewhat supported. Oscillatory compliance, which represents peripheral vessels, and P A P were significantly greater following exercise when compared to pre-exercise values. The elevations in P A P could be due to the exercise-induced rise in cardiac output. 5.6.5 Hypothesis # 5 The fifth hypothesis that plasma N O , A C and P A P would be significantly different in normoxia or hypoxia was not supported; however, N O tended to be higher in normoxia. This data suggests a down regulation o f vasodilators in hypoxia.  46  6.0 Conclusion N o associations were found between plasma E T - 1 / B i g E T - 1 and any other outcome variables that were measured throughout the study. The response o f this peptide is slow as it requires time for transcription and translation.  This suggests that the  endothelin pathway may not be involved i n the physiological responses to steady state exercise or to short term hypoxic exposure during exercise. Exercise for 30-minutes at ventilatory threshold was a sufficient stimulus to increase both P A P and O C . A s both outcome variables significantly increased following exercise this suggests that stiffness of the peripheral vessels cannot be related to increased pressures i n the pulmonary artery.  47  7.0 Future Studies Future studies could attempt to investigate ET-1 production i n response to exercise training by measuring plasma ET-1 levels prior to, during and after following an exercise training protocol. It would also be interesting to document i f alterations in plasma ET-1 occur how long it takes for then to return to pre-training levels. In addition attempting to determine the level and duration o f hypoxia that is required to stimulate ET-1 production would be valuable Furthermore, the exercise intensity and duration needed to induce ET-1 production would enable us to further understand the involvement of the endothelin system during short term hypoxic exposure.  48  8.0 References 1. Matsakas A , Mougios V . 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Hypertension.  1995;26:503-508.  67  9.0 A p p e n d i x  Figure 10: Chart displaying plasma ET-1 levels after removal of the participant with values 10-12 times greater than other participants  P l a s m a ET-1  Levels During Normoxia and  Hypoxia  Normoxia • Hypoxia  Pre  Exercise 10  Exercise 20  Post  Recovery 10  Recovery 20  Recovery 30  68  Raw Data Individual Peak V 0 2 _ _ Data V0 Peak (ml/kg/min) N H 66.2 50.1 60.2 55.4 66.8 55.8 62.8 49.9 61.2 51.4 . 76.4 55 67.4 59.6  VE(l/min)  2  1 2 3 4 5 6 7  N 196.6 • 132 181.4' 181.2 157.9 204 193  VC0  H 197.5 137.1 171.6 157,5 149.8 153.1 179.1  2  N 76 71 74.1 68.3 68.1 85.9 79.7  (ml/kg/min) H 59.6 65.1 64.5 57.7 60 63,3 73,6  H R (beats/min) N 190 183 179 198 197 185 201  H 172 180 178 188 190 182 192  S p 0 (%) 2  N 94.6 93.2 94.4 95 95.2 94.7 94.7  H 79.2 86.1 84.3 88.3 87.2 84.9 . 87.7  Individual Mean Steady State Data V 0 (ml/kg/min) N H 46.96 . 40.28 42.97 39.77 57.67 38.83 55.24 37.03 47.32 ' 35.44 41.29 41.31 49.97 40.57 2  1 2 •3 4 5 6 7  V E (1/min) N H 95.35 109.7 67.03 79.03 131.25 79.28 ' 133.23 73.22 79.04 64.66 82.39 87.28 . 98.92 102.09  V C 0 (ml/kg/min). . N H 41.55 - 37.56 41.45 . 40.55 55.96 37.99 54.76 33.22 44.36 32.38 37.27 39.96 47.57 43.99 2  H R (beats/min) N H 153.3 156,2 152.19 162.02 162.87 141.56 . 179.25 153.41 167.61 • 152.2 140.1 148.9 • 176.77 169.9  S p 0 (%) N H 93.47 73.53 95.3 87.3 93.03 77.03 93.87 84.07 95.13 78.9 94.3 80.17 93.77 80.5  RER  2  N .88 .96 .97 .99 .94 .9 .95  .  H .93 1.02 .98 .9 .91 .97 1.08  Individual P A P and Arterial Compliance P A P (mmhg) Normoxia  1 2 3 4  Pre 28 35 27.4 26.4  '  Post 30 43 .31 33.8  P A P (mmhg) Hypoxia ' Pre 28.9 40.8 27.4 28.7  Post 37.9 46.3 30.2 25.5  C C Normoxia ( m L / m m h g 5x10) Pre Post 19.95 18.65 .18.7 7.6 23.7 23 23.3 12.6  C C Hypoxia (mL/mmhg xlO) Pre Post 13.2 22.1 15.1 25,4 23.7 20 ' 21.2 14.8  O C Normoxia ( m L / m m h g xlOO) Pre 'Post 10.05 16.2 9.45 11.5 13.2 10.6 7.75 6.3  O C Hypoxia ( m L / m m h g xlOO) Pre Post 7.1 .10.4 6.2 15.4 6.9 8.3 9.8 11.4  5 6 7.  29 30 25.1  36 41.2 29.2  34 38.8 29  28.6 26 24.6  11.7 27 19.2  26.1 19.2 10.3  19.8 17.6 15.6  18,1 23.5 10.55  7.9 7.7 ' 7  19.7 13.5 10.4  10.4 9.7 6.2  12.4 9.8 7.1  Individual Plasma ET-1 (fmol/ml) -1 n 1 0.168 2 0.173 3 0.337 4 0.216 5 0.486 6 1.397 7 10.954  10 h 0.541 0.141 0.22 0.484 0.412 0.889 12.541  n 0.1254 0.159 0.065 0 0.434 1.764 10.69  20  h  • n 0.1706 0.295 0.169 0.076 0.33 1.72 11.59  0.318 0.101 0.263 0.33 0.195 0.559 11.83  30  h -0.41 0.173 0.279 0.151 . 0.225 0.838 11.83  n 0.1186 0.1186 0.272 0 0.339 2.109 15.6  40 •  h 0.313 0.373 0.22 0.2843 0.386 1.812 12.374  n 0.564 0.166 0.105 0.258 0.378 1.436 10.86  50 H 0.157 0.159 0.086 0.37 0.435 0.847 12.24  Individual Nitric Oxide Values fuM) Normoxia 1 2 3 4 5 6 7  Pre 3.390 0.383 1.173 0.476 0.778 0.442 3.724  Hypoxia Post 3.045 0.394 0.965 0.527 1.084 0.525 3.934  Pre 0.417 0.340 0.976' , 0.640 1.435 1.091 1.446  Post 0.473 0.455 0.982 0.687 1.348 1.244 1.435  n 0.568 0.092 0.135 0.219 0.484 1.262 • 10.9  60  h 0.236 0.155 0.237 0.446 0.439 1.198 11.3  N 0.72 0.161 0.19 0.088 0.588 1.924 11.12  h 0.2181 0.1344 0.27 0.216 0.449 1.162 10.681  


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