Post on 15-Oct-2018
HipoxiaHipoxiayy
Stress OxidativoStress Oxidativo
Claus BehnClaus BehnUniversidad de ChileUniversidad de Chile
HAPPOM, ALFAHAPPOM, ALFAArica, 220405Arica, 220405
Cementerio Cementerio de de montañistas montañistas a 4.800 m a 4.800 m (Chimborazo, (Chimborazo, 6.310 m)6.310 m)
0 2 4 6 8 100
200
300
400
500
600
700
800
37.6 mm Hg
PB
PAO2
253 mm Hg
Altura (km)
Pres
ión
(mm
Hg)
VO2max decrease at HA
30
40
50
60
70
Sandoval et al., 2002
n = 14
SLon return from HAHA3,670 mSLbefore HA
p < 0.01p < 0.01VO
2max
(ml/k
g m
in)
750 700 650 600 550 500 450 4000
20
40
60
80
100
120
140
160
180
Valor observado
Valor esperado
o
O2
oVO
2max
(% v
alor
a n
ivel
del
mar
)
PB (mmHg)
PaO2 PaO2 (mm Hg)(mm Hg)
EdadEdad(años)(años)
.
VOVO22max vs edad en mujeres y hombresmax vs edad en mujeres y hombres
Hipoxia Hipoxia Falta de oxígeno en relación a Falta de oxígeno en relación a los requerimientos de ATP aeróbicolos requerimientos de ATP aeróbico
Stress oxidativoStress oxidativoExceso de factores oxidantes Exceso de factores oxidantes (especies reactivas del oxígeno) (especies reactivas del oxígeno) en relación a en relación a las capacidades antioxidanteslas capacidades antioxidantes
En hipoxia puede aumentar En hipoxia puede aumentar el gasto de ATP por efecto delel gasto de ATP por efecto delstress oxidativostress oxidativo
IschemiaIschemia →→ hypoxia hypoxia →→ ATP depletion ATP depletion →→ CaCa--proteaseprotease
∩∩Xantine dehydrogenase Xantine dehydrogenase →→
xanthine oxidase xanthine oxidasexanthine oxidase xanthine oxidase
∩∩ ∩∩
hypoxanthine hypoxanthine →→ xanthine xanthine →→ uric aciduric acid
∩∩ ∩∩
OO22 OO22..-- OO22 OO22
..--
Haber Haber -- Weiss reactionsWeiss reactions::
O2O2..-- ++ Fe Fe ++++++ →→ FeFe++++ + + OO22
FeFe++++ +H+H22OO22→→ FeFe++++++++ OHOH-- + OH+ OH••
OO22..-- ++ HH22OO22 →→ OO22+OH+OH-- + OH+ OH••
HerHernnáándezndez,L.A.;,L.A.; GrishamGrisham, M.B.;, M.B.; GrangerGranger, D.N. , D.N. ((19871987))Am. Am. J.J. PhysiolPhysiol.,, 253, G49.,, 253, G49--G53.G53.
3 h de isquemia + 1 h de reperfusión 3 h de isquemia + 1 h de reperfusión causan más daño tisular que causan más daño tisular que
4 h de isquemia + 0 h reperfusión4 h de isquemia + 0 h reperfusión
PARKS DA & GRANGER DN (1986)PARKS DA & GRANGER DN (1986)Am. J. Physiol 250:G749Am. J. Physiol 250:G749--G753G753
12 14 16 18 20 22 24
225
250
275
300
325
350
Sandoval et al., 2002
Max
imal
exe
rcis
e in
tens
ity (
Wat
t)
Maximal oxygen pulse (mlO2 / beat)
MOP correlates with maximal ventilation at HA
120 140 160 180 200 22012
14
16
18
20
22
Sandoval et al., 2002
r = 0.76p 0.005
Max
imal
oxy
gen
puls
e (m
lO2/b
eat)
Maximal ventilation (l/min)
[ HCO[ HCO3 3 ]]pH = pK + log pH = pK + log ------------------------------------------------------
a PCOa PCO22
20 30 40 50 60 70 80 90 1000
10
20
30
40no aclimatizados
aclimatizados
PA
CO
2(mm
Hg)
PAO2(mm Hg)
Putre
50
52
54
56
58
60
62
64
*PO
2 cap
(mm
Hg)
Acclimatized Newcomers
pre-exercise post-exercise
2 4 6 8 10 12
80
85
90
95
100
105
110
115
120
r = 0.7; p < 0.01
A & N (0701)Putre (3,600 m)
Postexercise heart rate variability coefficen(SDRR/1/RR)
90 100 110 120 130 140
80
85
90
95
100
105
110
115
120 A & N (0701)Putre (3,600 m)
Max
imal
exe
rcis
e in
tens
ity (W
att)
Postexercise heart rate (beat/min)
2 3 4 5 6 7 8 9 10 11 12 13
-9
-8
-7
-6
-5
-4
-3
-2
-1
0N r = 0.67
p < 0.05D
elta
PC
O2
(mm
Hg)
2 3 4 5 6 7 8 9 10 11 12 13
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
A
2 3 4 5 6 7 8 9 10 11 12 13-8
-6
-4
-2
0
2
4
6
8
10
r = 0.9p < 0.01
Postexercise heart rate variability coefficient(SDRR/1/RR)
2 3 4 5 6 7 8 9 10 11 12 13-8
-6
-4
-2
0
2
4
6
8
10
Del
ta c
apilla
ry [H
CO
3] (m
mol
/l)
Postexercise heart rate variability coefficient (SDRR/1/RR)
CollahuasiCollahuasi
15
20
25
30
35
40
45
50**
**
**
*pCO
2 (m
mH
g)
pre HA post HA pre SL post SL
PrePre-- and postexercise capillary blood and postexercise capillary blood PCOPCO22 at high altitude (HA) and sea level at high altitude (HA) and sea level (SL)(SL) n =16, p< 0,05*; 0,01**; 0,001*** Jiménez et al, n =16, p< 0,05*; 0,01**; 0,001*** Jiménez et al,
20002000
16
18
20
22
24
26
28
preHA post HA pre SL post SL
*
*****
Extr
acel
lula
r HC
O3- (m
mol
/L)
PrePre-- and postexercise extracellular [HCOand postexercise extracellular [HCO33] at high altitude (HA) ] at high altitude (HA) and sea leveland sea level (SL)(SL)
n =16, p< 0,05*; 0,01**; 0,001*** Jiménez et al, 2000n =16, p< 0,05*; 0,01**; 0,001*** Jiménez et al, 2000
7,35
7,40
7,45
7,50
7,55
**
***B
lood
pH
pre HA post HA pre SL post SL
PrePre-- and postexercise capillary blood pH at high altitude (HA) and postexercise capillary blood pH at high altitude (HA) and sea level (SL)and sea level (SL)
n =16, p< 0,05*; 0,01**; 0,001*** Jiménez et al., 2000n =16, p< 0,05*; 0,01**; 0,001*** Jiménez et al., 2000
Base Base excess excess vs. vs. capillarycapillary POPO2 2 atat HAHA
-18 -16 -14 -12 -10
50
52
54
56
58
60
62
64
66
68
Cajigal et al., 2002
r = 0.75p < 0.005
Capi
llary
PO 2
(mm
Hg)
Base excess (mmol/l)
-6.5
-5.5
-4.5
-3.5
-2.5
-1.5
-0.5
0.5
1.5
92 94 96 98 100 102 104 106 108 110 112
[Cl]P (mmol/l)
Bas
e ex
cess
(mm
ol/l)
Photo: Edwards AFB Altitude Chamber
Hypobaric hypoxia effects on erythrocyte bandHypobaric hypoxia effects on erythrocyte band 3 3 NBDNBD--taurine transport and protein oxidative taurine transport and protein oxidative
statestate..
TT5050 Protein carbonylProtein carbonyl(sec) (sec) ((nmolnmol//mg proteinmg protein))
Normoxia Normoxia 420.8 420.8 ±± 28.6 7.9 28.6 7.9 ±± 3.53.5
PosthypoxiaPosthypoxia 487.1 487.1 ±± 49.5 12.4 49.5 12.4 ±± 3.63.6
p p value value 0.02 0.030.02 0.03
ValuesValues are are meansmeans ±± SD. n = 8 SD. n = 8 individualsindividuals..CeledCeledóón et al, 2002n et al, 2002
V.Parinacota, 2001V.Parinacota, 2001
Santiago I (670 m)Santiago I (670 m) Santiago IISantiago II
Calama I(2500 m)Calama I(2500 m) Calama IICalama II
Conchi (3000 m)Conchi (3000 m)
Volcán San Pedro (6125 m)Volcán San Pedro (6125 m)
Camp. Base (5000 m)Camp. Base (5000 m)
A A BBInmunofluorescencia Inmunofluorescencia de proteina banda 3 (AEde proteina banda 3 (AE--1) 1) en glen glóóbulos rojos debulos rojos dell mismo mismo individuo antes de subir 5600 msnm (individuo antes de subir 5600 msnm (AA) y dos d) y dos díías despuas despuéés del descenso (s del descenso (BB). ). NNóótese el aumento del ntese el aumento del núúmero de sitios reconocidos por la IgG autmero de sitios reconocidos por la IgG autóóloga luego del loga luego del descenso.descenso. Araneda et al, 2003Araneda et al, 2003
TOTAL BANDA 3 FRAGMENTOS
0
50000
100000
150000
200000
250000
300000
350000
400000
**
***
UN
IDAD
ES D
ENSI
TOM
ETR
ICAS
Pre-Entrenamiento Post-Entrenamiento
Proteina banda 3 en eritrocitos de ciclistas de montaña. Proteina banda 3 en eritrocitos de ciclistas de montaña. Fragmentación (antígeno senescente) en relación con Fragmentación (antígeno senescente) en relación con entrenamiento en altura (Rio Blanco/ Portillo). entrenamiento en altura (Rio Blanco/ Portillo).
Araneda et al.,2004Araneda et al.,2004
[[ UUric
acid
ric
acid]] PP
(( mg
mg /
dl/dl ))
Band 3 protein sBand 3 protein susceptibiliusceptibility to proteases ty to proteases [[%%]]
3.5
4
4.5
5
5.5
6
6.5
7
7.5
8
0.00 10.00 20.00 30.00 40.00 50.00 60.00
PutrePutre
AricaAricaR = 0.58 R = 0.58 p < 0.02 p < 0.02 n = 14n = 14
IschemiaIschemia →→ hypoxia hypoxia →→ ATP depletion ATP depletion →→ CaCa--proteaseprotease
∩∩Xantine dehydrogenase Xantine dehydrogenase →→
xanthine oxidase xanthine oxidasexanthine oxidase xanthine oxidase
∩∩ ∩∩
hypoxanthine hypoxanthine →→ xanthine xanthine →→ uric aciduric acid
∩∩ ∩∩
OO22 OO22..-- OO22 OO22
..--
Santiago I Calama I Conchi Calama II Santiago II0,00
0,02
0,04
0,06
0,08
0,10
0,12
0,14
0,16
0,18
**m
oles
/Litr
o)(
MD
Aμ
-0,04 0,00 0,04 0,08 0,12 0,16
0
2
4
6
8
10
(Conchi-SantiagoI)
(Cam
p. B
ase)
AMS
Scor
e
Δ MDA
Sant Pre Sant Post Lag Pre Lag Post0,00
0,02
0,04
0,06
0,08
0,10
0,12
0,14
0,16
0,18
0,20
0,22
(μm
oles
/Litr
o)M
DA
*
HuaynaHuayna--PotosíPotosí
Bolivianos vs ChilenosBolivianos vs Chilenos
Gasometría ArterialGasometría ArterialParámetros La Paz (3600) p La Paz (3600)
pH 7.24 ± 0.29 0.27 7.44 ± 0.38PaO2(mmHg) 59.57 ± 4.82 0.33 57.28 ± 3.63
PaCO2(mmHg) 29.12 ± 4.43 0.52 30.40 ± 2.47SaO2(%) 91.68 ± 2.15 0.66 91.21 ± 1.82
HCO3(mEq/L) 19.27 ± 2.19 0.14 20.72 ± 1.30Base Excess(mEq/L) -6.76±3.25 0.97 -6.81±2.18
Parámetros Huayna Postosi(4800) p Huayna Potosi (4800)pH 7.44 ± 0.21 0.74 7.45 ± 0.29
PaO2(mmHg) 43.71 ± 2.92 0.94 43.83 ± 3.37PaCO2(mmHg) 24.80 ± 2.80 0.25 26.80 ± 3.16
SaO2(%) 81.78 ± 3.46 0.43 83.16 ± 2.47HCO3(mEq/L) 16.67 ± 1.27 0.003* 19.48 ± 1.43
Base Excess(mEq/L) -9.02±1.84 0.84 9.23±1.94
Cytosol free amino groups (upper) and red cell membrane SH Cytosol free amino groups (upper) and red cell membrane SH groups (lower) in highlanders (A) and lowlanders (B)groups (lower) in highlanders (A) and lowlanders (B)
Fetos Madres0
5
10
15
20
25
30
35
40
45
Tiol
es P
lasm
atic
os (n
Mol
es/m
g P
rot)
*
Fetos Madres0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
*
Tiol
es P
lasm
a/M
embr
ana
GR
Fetos Abajo Fetos Arriba0
10
20
30
40
50
*Ti
oles
Pla
smat
icos
(nM
oles
/mg
Pro
t)
-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 141618202224262830323436384042444648
R=0,54Ti
oles
Pla
smat
icos
(nM
oles
/mg
Pro
t)
Hidroperoxidos Plasmaticos (uMoles/Litro)
MadresFetos
Antioxidant capacity and remnant, protease susceptible band 3 protein
0 10 20 30 40 50 60160
180
200
220
240
260
280
300
Benitez et al., 2002
r=0.74p<0.002n=16
Plas
ma
antio
xida
nt c
apac
ity (u
M T
rolo
x eq
uiv)
Remnant protease susceptible band 3 protein ( % )
HCO3-
HCO3
Cl-CO2
CO2 + H2O
H+
H+ +
Lac-
+
CO2 H2O HCO3-
Na+Lac-Na+
H+
H2O+
+
H+H2OCO2+ HCO3
-
Músculo
EspacioInstersticial
Plasma
Soldados NA - Arica
r=0.28p>0.05n=15
0
5
10
15
20
25
30 35 40 45 50
Soldados NA - Putre
r=0.62p<0.05n=15
0
2
4
6
8
10
12
14
16
30 35 40 45 50 55 60
dife
renc
ia d
e la
ctat
o (m
mol
/L)
r=0.08p>0.05n=15
0
2
4
6
8
10
12
14
16
30 35 40 45 50 55VO2 max (ml/kg/min)
dife
renc
ia d
e la
ctat
o (m
mol
/L)
r=0.60p<0.05n=15
0
2
4
6
8
10
12
14
16
18
30,00 35,00 40,00 45,00 50,00
VO2 max (ml/kg/min)
Soldados A - Arica Soldados A - Putre
-60
-50
-40
-30
-20
-10
0
10
20
30
40D
elta
Pow
er/[L
acta
te] (
Wat
t/mm
ol/l)
p<0.0001
Río Blanco groupLive low-train low
Portillo groupLive high-train low
Haber Haber -- Weiss reactionsWeiss reactions::
O2O2..-- ++ Fe Fe ++++++ →→ FeFe++++ + + OO22
FeFe++++ +H+H22OO22→→ FeFe++++++++ OHOH-- + OH+ OH••
OO22..-- ++ HH22OO22 →→ OO22+OH+OH-- + OH+ OH••
HerHernnáándezndez,L.A.;,L.A.; GrishamGrisham, M.B.;, M.B.; GrangerGranger, D.N. , D.N. ((19871987))Am. Am. J.J. PhysiolPhysiol.,, 253, G49.,, 253, G49--G53.G53.
Maximal oxygen pulse (SL vs. HA)
13 14 15 16 17 18 19
13
14
15
16
17
Viola et al., 2002
Max
imal
oxy
gen
puls
e at
HA
(ml O
2/ be
at)
Maximal oxygen pulse at SL(ml O2/beat) )
MOP decrease and [Fe]s at HA
80 100 120 140 160 180
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Viola et al., 2002
r = 0.6p < 0.05
Δ M
OP
SL -
HA (m
L/be
at)
Serum iron concentration at HA (ug/ dl)
[Fe]s changes on HA - SL commuting
1 20
20406080
100120140160180200220240260
Viola et al., 2002
**
*
Pre ExercisePost Exercise
SLHA
Seru
m ir
on c
once
ntra
tion
(ug/
dl)
[Fe]s at HA vs [Fe]s change SL - HA
80 100 120 140 160 180-60
-40
-20
0
20
40
60
80
100
120
140
Viola et al., 2002
Fes c
once
ntra
tion
chan
ge S
L-H
A(u
g/dL
)
Serum iron concentration at HA (ug/dl)
Plasma antioxidant capacity vs. [Fe]p
40 60 80 100 120 140 160 180160
180
200
220
240
260
280
300
Viola et al., 2002
R=-0,48p<0,06n=16
Plasma Fe concentration (ug/dl)
Plas
ma
antio
xida
nt c
apac
ity (u
M T
rolo
x)
Plasma antioxidant capacity vs. transferrin saturation
10 20 30 40 50 60160
180
200
220
240
260
280
300
Viola et al., 2002
Pl
asm
a an
tioxi
dant
cap
acity
(u
M T
rolo
x)R=-0,55p<0,03n=16
Percent transferrin saturation
Plasma antioxidant capacity vs. [Ferritin]p
40 60 80 100 120 140 160 180 200 220 240160
180
200
220
240
260
280
300
Viola et al, 2002
r=-0.77p<0.001n=16
Pla
sma
antio
xida
nt c
apac
ity
(uM
Tro
lox)
Plasma ferritin concentration(ng/dl)
Summary•• Hypobaric hypoxia (HH) decreasesHypobaric hypoxia (HH) decreases VOVO22maxmax•• The decrease of maximal oxygenThe decrease of maximal oxygen pulsepulse at HHat HH
directlydirectly relatesrelates to serum iron concentrationto serum iron concentration..•• Fe Fe inverselyinversely relatesrelates to to plasmaplasma antioxidant capacity antioxidant capacity •• Antioxidant supplementationAntioxidant supplementation preservespreserves oxygen supply oxygen supply
and work performance at high altitudeand work performance at high altitude..•• Antioxidant capacity may playAntioxidant capacity may play a role ina role in acclimatization acclimatization
toto high altitude by protecting anion exchangehigh altitude by protecting anion exchange, , thus thus allowing compensation of respiratory alkalosisallowing compensation of respiratory alkalosis. .
•• ByBy loweringlowering base base excessexcess, , anan antioxidantantioxidant protectedprotectedanionanion exchange should increase ventilation and Hb exchange should increase ventilation and Hb desaturationdesaturation, , thus favouring Othus favouring O2 2 deliverydelivery atat HHHH
HipoxiaHipoxiayy
Stress OxidativoStress OxidativoClaus BehnClaus Behn
Universidad de ChileUniversidad de Chilecbehn@med.uchile.clcbehn@med.uchile.cl
HAPPOM, ALFAHAPPOM, ALFAArica, 220405Arica, 220405