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PULMONARY CIRCULATION AT HIGH ALTITUDE
Jean COUDERT
Laboratoire de Physiologie – Biologie du SportFaculté de Médecine – Université d’AuvergneCLERMONT-FERRAND, FRANCE
The most striking changes at High Altitude (HA)
! Pulmonary Arterial Hypertension (PAH)
! In Acclimatized Lowlanders at HA
! In HA natives (Highlanders)
PLAN1) Values of pulmonary Arterial Pressures (PAP) at HA2) Factors acting upon these values
! Exercise! Ambient temperature (cold, heat)! Individual reactivity! Age! Others
3) Mechanisms involved
3-1 Pulmonary Arteriolar Vasoconstriction (PAV)! Effects of hypoxia! Cellular responses
3-2 Structural changes
4) Effects of Hypoxic PAV and Structural Changes induced by Hypoxia
5) Summary
Values of PAP at HA
1) Values in LA PAZ (3700m)
2) Values at different altitudes
Values in LA PAZ (3700m)
67 normal male Highlanders
(Arch. Inst. Biol. Andina, 1971)
Data compared with values obtained in Lima (n = 22)
(Banchero et al, Circulation, 1966)
Ageyear
Ht%
Hbg%
PaO2mmHg
SaO2%
PaCO2mmHg
CaO2vol.%
CvO2vol.%
LA PAZ(3700m)
m
SD
23.6
4.8
48.8
4.1
16.5
2.6
58.5
9.2
28.0
4.6
90.1
4.38
19.3
2.12
15.0
2.09
LIMA(150m)
m
SD
20.7
1.28
44.1
2.59
14.8
0.88
95.7
2.06
19.04
0.998
15.04
1.26
LA PAZ(3700m)
m
SD
5
1.9
29
6.6
21
4.2
9
2.7
6.43
1.69
3.91
1.09
265
80
148
43
13
3.8
s d m
PaP (mmHg)
RAP(mmHg)
WPP(mmHg)
COl.min-1
CIl.min-1.m-2
PRdynes.sec-1.cm-5
T a
LIMA(150m)
m
SD
2.6
1.3
22
3.5
12
2.2
3.97
0.97
160
46.7
73
24.4
6
2.1
6.5
1.68
Values at different altitudes
From GROVES et al, J. Appl. Physiol., 1987
Factors interfering with PAP at HA
1) Muscular exercise (Lockhart et al, J. Appl. Physiol., 1976)
6 normal male Highlanders in LA PAZ
At rest and during exercise (75W) breathing air (PIO2 = 100mmHg)
and 30% oxygen (PIO2 = 150mmHg)
2) Ambient temperature (Coudert J., Séminaire CNRS/NSF., 1980)
21 normal male Highlanders in LA PAZ
2–1 Heat exposure (13 subjects)
2–2 Cold exposure (8 subjects)
2-3 Responses to local cold exposure in pathological chronic hypoxia (COPD)
(Bedu et al, Am. J. Respir. Crit. Care Med., 1996)
From BIGH J, in « Hypoxia and Cold », Eds. SUTTON JR, HOUSTON CS, COATES G, 1987
Individual reactivity
Case of Highlander, studied in LA PAZ, one month after HAPO
oo
O
AGE
! Foetus, at sea level (SL) and at HA :
! PAP and PVR very high
! Newborn :
! ↓ Adult level
" after 10 days, at SL
" after 1 – 5 months, at HA (Morococha, 4540m)
GAMBOA R. and MARTICORENA E., Arch. Inst. Biol. Andina,1971
SEX
Possible protection against pulmonary hypertension,in female by sexual hormones
(↓ expression of endotheline-1 by estradiol)
Earley S. et al, Am. J Physiol. Lung Cell Mol Physiol., 2002
MECHANISMS
1) Pulmonary Arterial Vasoconstriction (PAV)
! Acute hypoxia
! Cellular responses
2) Structural changes
! Chronic hypoxia
" histological changes of the pulmonary arterioles
" cellular and molecular responses
EFFECTS OF ACUTE HYPOXIA
Pulmonary Arteriolar Vasoconstriction
very short delay of the responses
N2 and O2 TESTS
Effects of hypoxia and hyperoxia of short duration on the
pulmonary circulation of Highlanders and Lowlanders
living at 3750m
COUDERT J. et al, Prog Resp Res, 1975
CELLULAR RESPONSES INDUCED BY ACUTE HYPOXIA
Hypoxia inhibits K+ current in an oxygen sensitive potassium channel
! Cellular membrane depolarisation
! Opening of Ca2+ channels
! ↑ Intracellular Ca2+
! Contraction of pulmonary arteriolar smooth muscle cell
From BRIJ S.O. and PEACOCK A.J., Thorax, 1998
CONTRACTIONe.g. smooth muscle cell
HYPOXIAmay directly activate theHIF-1 binding sequence
Cellular responses to hypoxia in the pulmonary circulation
?
Nuclearsynthesis
K+ current inhibition leadsto membrane depolarisation
HIF-1
Gene products e.g.erythropoietin
From Brij S.O. and Peacock A.J., Thorax, 1998
K+
K+
Hypoxia inhibits K+
current in a delayedrectifier K channel
↑CALCIUM Ca2+ Ca2+ influx throughvoltage gated channels
HIF-1 α + β
Hémoprotéine oxygène Sensor O2
Hémoprotéine oxygène Sensor O2 O2
Phosphorylation des protéines
Factor X
VOIES DE REPONSES A L’HYPOXIE, INDUITES PAR HIF-1
Métabolismeanaérobie
Induction des gènes desenzymes de la glycolyse
Induction du géne dela tyrosine hydroxylase
Induction dugène EPO
Induction dugène vEGF
Angiogénèse Vasodilatation Erythropoïèse Respirationaugmentée
Induction des gènesI-NOS et HO-1
From Coudert J., Urgence pratique, 66, 2004
STRUCTURAL RESPONSES INDUCED BY CHRONIC HYPOXIA
! Bands of smooth muscle develop in the small pulmonary arteries (arterioles)
! Smooth muscles bonded by internal and external elastic laminae
! Narrowing of the lumen of the pulmonary arterioles and increase of PVR
From Heath and Williams, 1977
STRUCTURAL CHANGES : CELLULAR AND MOLECULAR
! Hypoxic proliferation and intracellular signaling (PKC and MAP kinases)
! Hypoxia and the upregulation of growth mitogens
! Nuclear synthesis
! Proliferation and remodelling of all three cell types of the pulmonary arterioles
(Possible regulation by HIF1)
Cellular responses to hypoxia in the pulmonary circulation
PKC
Nuclearsynthesis
PROLIFERATION and REMODELLINGof all three cell types
?
Phosphorylationevents e.g.MAP kinases
Hypoxia upregulatesthe stress activatedMAP kinases
From Brij S.O. and Peacock A.J., Thorax, 1998
CONTRACTIONe.g. smooth muscle cell
HYPOXIAmay directly activate the HIF-1 binding sequence
?
K+ current inhibition leads to membrane depolarisation
HIF-1
Gene products e.g.erythropoietin
K+
K+
Hypoxia inhibits K+
current in a delayedrectifier K channel
↑CALCIUM Ca2+ Ca2+ influx throughvoltage gated channels
Activationof secondmessengersignal e.g.DAG, IP3
Cell surface receptorvasoconstrictor growth factors e. g. ET-1, PDGF
EFFECTS OF HYPOXIC PVC AND STRUCTURAL CHANGESINDUCED BY CHRONIC HYPOXIA
Structural changes PAH Right ventricular hypertrophy
PVC Improvement in ventilation perfusion relationships ?
Regional distribution of pulmonary blood flow, at HA
COUDERT J. et al Respiration, 1975
SUMMARY
1) At rest : PAP and Pulmonary Resistances (PR)are higher at HA than at SL
! in LL, importance of PVC
! in HL, importance of structural changes
2) ↑ + + + of PAP and PR
during exercise and cold exposure
↑ + + + in hyperreactive subjects
(triggering factor of HAPE ? and predictive factor of HAPE ?)
Δ PAPmax=Ex hypoxia-rest normoxia
3) PAH : useful factor ?
! No improvement of the perfusion of the apex in standing position
! Risk of « chronic pulmonary heart » with right cardiac insufficiency
Co authors of the studies performed in LA PAZ,in the laboratories of IBBA
ANTEZANA G.BARRAGAN L.BRIANCON L.CUDKOWICZ JDURAND J.LOCKHART A.MENSH-DECHENE J.PAZ-ZAMORA M.SPIELVOGEL H.VARGAS E.ZELTER M.