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HIGH ALTITUDE PHYSIOLOGY AND PHYSIOPATHOLOGY,
FROM THE ORGANISM TO THE MOLECULE - HAPPOM
PREGNANGY AND HIGH ALTITUDE
DR. ANÍBAL LLANOSFACULTAD DE MEDICINA, UNIVERSIDAD DE CHILE
APRIL 18, 2005
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ATMOSPHERIC O2 LEVEL VS TIME
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EL O2 ES UN PRODUCTO DE DESHECHO DELMETABOLISMO VEGETAL, PARTICULARMENTEDE LA FOTOSÍNTESIS
ESTE PRODUCTO DE DESHECHO ES UTILIZADOPOR LOS ANIMALES COMO NUTRIENTE
O2 + GLUCOSA ! CO2 + H2O + ENERGIA
ESTA ENERGÍA ES EMPLEADA EN FUNCIONESDE SÍNTESIS, TRANSPORTE, METABOLISMO BASAL, CRECIMIENTO Y DESARROLLO, ETC.
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BIRTH WEIGHT FALLS WITH INCREASING ALTITUDE
TOTAL O2 CONSUMPTION IS REDUCED IN FETUSESAND NEWBORN WITH GROWTH RESTRICTION
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EFFECTS OF HIGH ALTITUDE ON INFANTBIRTH WEIGHT
AND INFANT OXIGENATION
-
a
-
Is high altitude a greater determinant than poor nutritionof intrauterine growth retardation and low birth weight ?
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High Altitude
Highincome
La Paz Santa CruzLow Altitude
Hypothesis: Babies born at high altitude have a lower birth weight than babies born at low altitude, independent of maternal economic status
Lowincome
Highincome
Lowincome
Effects of altitude vs. economic status on birth weightand body shape at birth
Giussani, D.A., Phillips, P.S., Anstee, S. & Barker, D.J.P.
Pediatric Research 49: 490, 2001
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2600
3000
3400
3800
a,b a
0.55
0.65
0.75 a,ba b
Birthweight
(g)
Headcircumference:
body length
La Paz Santa Cruz
incomehigh low
income
high low
a, P
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HypothesisIf oxygen has a role on fetal growth independent of genetic andnutritional factors, then:
Chick embryos from lowland hens incubated at high altitude shouldlead to fetal growth retardation
Chick embryos from hens native to high altitude, usually with growth restriction,should recover their growth whenincubated at sea level
1
2
-
Blood gas status : Chorio-allantoic vein
0
2
4
6
8
pH
0
20
40
60
80
PO2(mmHg)
SLSLSLHA
HAHAHASL
n = 16n = 16
n = 16n = 16
a
b
-
Fetal biometry at day 20 of a 21d incubation
Egg weight prior toincubation (g)
0
20
40
60
80
a a
SLSLSLHA
HAHAHASL
n = 16n = 16n = 16n = 16
Fetalweight (g)
0
10
20
30
b
c
-
Body length (mm)
0
20
40
60
80
Bi-parietal diameter (mm)
0
4
8
12
16b
a
SLSLSLHA
HAHAHASL
n = 16n = 16
n = 16n = 16
Fetal biometry at day 20 of a 21d incubation
-
0
HASLHASL
SLSL SLHA
1
2
3
4
5
6
7
8
SLSL SLHA
AORTICwall:lumen area
HAHAHAHA
*
500 μm
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SummaryHuman and chick embryo
Fetal oxygenation, independent of genetic or nutritional factors, has an important role in the control of fetal growth
Generations of residence at high altitude may influence the effects of hypoxia on the developing fetus
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HYPOTHESIS
THE CHRONICALLY HYPOXIC NEONATAL SHEEP AT PUTRE (3,600m) HAVE AN ALTERED CARDIOVASCULAR AND HORMONAL STATUSBASALLY AND DURING A SUPERIMPOSED EPISODE OF ACUTE
HYPOXIA
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Figure 1 Herrera EA et alNEWBORN SHEEP NEWBORN LLAMA
0
10
20
30
40
B B + LNAME
PAP
(mm
Hg)
SLSHHLSH
0
10
20
30
40
B B + LNAME
PAP
(mm
Hg)
SLLLHLLL
0
0,1
0,2
0,3
B B + LNAME
PVR
(mm
Hg.
mL-
1 .min
.Kg)
0
0,1
0,2
0,3
B B + LNAME
PVR
(mm
Hg.
mL-
1 .min
.Kg)
ab
a
bc
b
a
ab
a
bc
aa
c
A. PAP in NB sheep with and without L-NAME, B. PAP in NB llama with and without L-NAME, C. PVR in NB sheep with and without L-NAME, D. PVR in NB llama with and without L-NAME
A. B.
C. D.
Significant differences p
-
0
50
100
150
SAP
(mm
Hg)
0
100
200
300
400
HR
(min
-1)
0 60 120 180 Time (min)
0,00
0,20
0,40
Basal Hypoxemia Recovery
SVR
(mm
Hg.
ml-1
.min
.Kg)
†* *
SYSTEMIC CIRCULATION - NEWBORN SHEEP
p
-
0
5
10
FBF
(ml m
in-1
kg-
1 )
HYPOXEMIA
0
10
20
30
FVR
(mm
Hg
ml-1
min
kg)
FEMORAL CIRCULATION - NEWBORN SHEEP
0 60 120 180
TIME (min)
HAHA
SLSL
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POSSIBLE MECHANISMS INVOLVED IN THE PULMONARY VESSEL RESPONSES TO CHRONIC HYPOXIA
• NITRIC OXIDE• CARBON MONOXIDE• sGC AND PDE; cGMP• PROSTACYCLIN AND THROMBOXANE• ENDOTHELINS • OTHERS
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GUANYLATE CYCLASE MECHANISMS OF SMOOTH MUSCLE RELAXATION
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Figure 2 Herrera EA et al
0
15
30
45
60
SLSH HLSH SLLL HLLL
L-ci
trul
ine
form
atio
n (p
mol
. μg
prot
-1.3
0 m
in-1
)
0
0,25
0,5
0,75
1
SLSH HLSH SLLL HLLL
eNO
S/β-
actin
(a
rbitr
ary
units
)
0
0,25
0,5
0,75
1
SLSH HLSH SLLL HLLL
mR
NA
eN
OS/β-
actin
(a
rbitr
ary
units
)
0
0,25
0,5
0,75
1
SLSH HLSH SLLL HLLL
sGC
/ β-a
ctin
(a
rbitr
ary
units
)
A. B.
C. D.
A. RT-PCR of eNOS, B. Western blot of eNOS, C. NOS total activity, D. Western blot of sGCSignificant differences p
-
Figure 3 Herrera EA et al
0
0,25
0,5
0,75
1
SLSH HLSH SLLL HLLL
HO
-1/ β
-act
in
(arb
itrar
y un
its)
0
0,5
1
1,5
SLSH HLSH SLLL HLLL
HO
-2/ β
-act
in
(arb
itrar
y un
its)
0
0,5
1
1,5
SLSH HLSH SLLL HLLL
mR
NA
HO
-1/ β-
actin
(a
rbitr
ary
units
)
0
0,5
1
1,5
SLSH HLSH SLLL HLLL
mR
NA
HO
-2/ β-
actin
(a
rbitr
ary
units
)
A. B.
C. D.
A. RT-PCR of HO-1, B. RT-PCR of HO-2, C. Western blot of HO-1, D. Western blot of HO-2. Significant differences p
-
0
1
2
0
3
6
PUTREPUTRESTGO STGO
COX-1 COX-2
CO
X-1
/βac
tin
CO
X -2
/βac
tin
*
* p
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SUMMARY
• HIGH ALTITUDE NEWBORN LAMBS HAD PULMONARY HYPERTENSION WITH INCREASED PULMONARY VASCULAR RESISTANCE WHEN COMPARED TO LOWLAND NEWBORN LAMBS. HIGH ALTITUDE NEWBORN LAMBS HAD AN IMPORTANT NITRIC OXIDE TONE IN THE PULMONARY CIRCULATION
• NEWBORN LAMBS NATIVE TO HIGH ALTITUDE SHOW INCREASED CARDIAC OUTPUT AND LOWER SYSTEMIC VASCULAR RESISTANCE THAN LOWLAND NEWBORN SHEEP.
• FEMORAL BLOOD FLOW DECREASED AND FEMORAL VASCULAR RESISTANCE INCREASED BRISKLY DURING HYPOXIA IN HIGH ALTITUDE NEWBORN LAMBS .
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SUMMARY (cont)•eNOS EXPRESSION MEASURED BY WESTERN BLOT, IS DECREASED IN THE LUNG OF HIGHLAND NEWBORN SHEEP. NEVERTHELESS IS ACTIVITY IS INCREASED
• sGC, HO-1, EXPRESSION MEASURED BY WESTERN BLOT, IS DECREASED IN THE LUNG OF HIGHLAND NEWBORN SHEEP
• COX-2 mRNA EXPRESSION, ENZYMES INVOLVED IN THE PRODUCTION OF SEVERAL PG, AMONG THEM PGI2 ARE REDUCED IN THE LUNG OF HIGHLAND NEWBORN SHEEP
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SINCE CHRONIC HYPOXIA MODIFIES THE CONTRACTILE CAPACITY OF SMALL ARTERIES, WE STUDIED THIS VARIABLE IN SMALL RESISTANCE ARTERIES OF HIGHLAND AND LOWLAND NEWBORN SHEEP
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HYPOTHESISIN HIGHLAND NEWBORN SHEEP SMALL ARTERIES FROM THE PULMONARY AND SYSTEMIC CIRCULATION HAVE A HIGHER CONTRACTILE CAPACITY THAN SMALL ARTERIES IN LOWLAND NEWBORN SHEEP
Ex vivo RESPONSESPOTASSIUM CHLORIDENOREPINEPHRINESODIUM NITROPRUSSIDE
AIMTO STUDY IN PULMONARY AND FEMORAL SMALL ARTERIES FROM HIGHLAND AND LOWLAND NEWBORN SHEEP
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PULMONARY ARTERIESRESPONSE TO KCl
LLNB HLNB
p
-
PULMONARY ARTERIESRESPONSE TO SODIUM NITROPRUSSIDE
LLNB HLNB
p
-
0,0
5,0
10,0
15,0
% K
max
0,0
1,0
2,0
pD2
†
FEMORAL ARTERIESRESPONSE TO KCl
LLNB HLNB
p
-
0
50
100
150
% K
max
0
3
6
pD2
LLNB HLNB
†
FEMORAL ARTERIESRESPONSE TO NOREPINEPHRINE
p
-
0
50
100
% K
max
0
3
6
pD2
LLNB HLNB
p
-
FEMORAL ARTERIESRESPONSE TO SODIUM NITROPRUSSIDE
LLNB HLNB2,5
5
7,5
pD2
†
p
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CONCLUSIONS
1.- IN THE PULMONARY ARTERIES, HIGHLAND NEWBORN SHEEP SHOW A GREATER CONTRACTILE CAPACITY THAN LOWLAND NEWBORN SHEEP.
2.- IN THE FEMORAL ARTERIES, HIGHLAND NEWBORN SHEEP SHOW A LOWER CONTRACTILE CAPACITY THAN LOWLAND NEWBORN SHEEP, WITH A MAJOR ROLE OF ADRENERGIC-DEPENDENT MECHANISMS.
3.- IN PULMONARY AND FEMORAL ARTERIES, HIGHLAND NEWBORN SHEEP SHOW A GREATER SENSITIVITY TO SNP THAN LOWLAND NEWBORN SHEEP, CONSISTENT WITH AN INCREASED ACTIVITY OF NOS AND THE ROLE OF NO IN THE CONTROL OF THE PULMONARY AND PERIPHERAL VASCULAR BEDS IN THE NEWBORN LAMB OF THE ANDEAN ALTIPLANO.
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WHICH IS THE PITUITARY-ADRENAL AXIS FUNCTION INCHRONICALLY HYPOXIC NEWBORN LAMBS?
WE INITIALLY MEASURED ACTH AND CORTISOL PLASMA CONCENTRATION BASALLY AND DURING A SUPERIMPOSED EPISODE OF ACUTE HYPOXIA
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NEWBORN SHEEP IN LOW AND HIGH ALTITUDESCORTISOL RESPONSE TO HYPOXIA
0
40
80
120
160
Meanbaseline
H15 H45 R45
Time
Cor
tisol
(ng/
ml)
SLSL
HAHA
-
0
50
100
150
200
250
0 50 100 150 200 250
ACTH (pg/ml)
Cor
tisol
(ng/
ml)
SLSL
0
50
100
150
200
250
0 50 100 150 200 250
ACTH (pg/ml)
Cor
tisol
(ng/
ml)
HAHA
HIGH AND LOW ALTITUDE NEWBORN LAMBS
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THE CORTISOL RESPONSE TO ACTH IS BLUNTED IN THE HIGH ALTITUDE NEWBORN SHEEP
WHETHER THE ADRENAL FUNCTION REMAINED ALTEREDLATER IN LIFE NEEDS TO BE INVESTIGATED AS WELL ASTHE MECHANISMS PRODUCING THIS BLUNTING
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• I HAVE SHOWED YOU EFFECTS OF HIGH ALTITUDE CHRONICHYPOXIA ON INFANT BIRTH WEIGHT AND INFANT OXIGENATION
• I HAVE ALSO SHOWED YOU EFFECTS OF HIGH ALTITUDE CHRONIC HYPOXIA ON ANIMAL BIRTH WEIGHT, CARDIOVASCULAR AND ENDOCRINE FUNCTION
• WHETHER THESE CHANGES INDUCED BY CHRONIC HYPOXIACAN PROGRAMME FETAL ORIGINS OF ADULT DISEASE REMAINSTO BE ELUCIDATED