PULMONARY CIRCULATION AT HIGH ALTITUDE. Jean COUDERT

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1 PULMONARY CIRCULATION AT HIGH ALTITUDE Jean COUDERT Laboratoire de Physiologie Biologie du Sport Faculté de Médecine Université d Auvergne CLERMONT-FERRAND, FRANCE

2 The most striking changes at High Altitude (HA)! Pulmonary Arterial Hypertension (PAH)! In Acclimatized Lowlanders at HA! In HA natives (Highlanders)

3 PLAN 1) Values of pulmonary Arterial Pressures (PAP) at HA 2) 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

4 Values of PAP at HA 1) Values in LA PAZ (3700m) 2) Values at different altitudes

5 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)

6 Age year Ht % Hb g% PaO 2 mmhg PaCO 2 mmhg SaO 2 % CaO 2 vol.% CvO 2 vol.% LA PAZ (3700m) m SD LIMA (150m) m SD

7 RA P(mmHg) PaP (mmhg) s d m WP P(mmHg) CO l.min -1 CI l.min -1.m -2 PR dynes.sec -1.cm -5 T a LA PAZ (3700m) m SD LIMA (150m) m SD

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9 Values at different altitudes

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11 From GROVES et al, J. Appl. Physiol., 1987

12 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 (PIO 2 = 100mmHg) and 30% oxygen (PIO 2 = 150mmHg)

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14 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)

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17 2-3 Responses to local cold exposure in pathological chronic hypoxia (COPD) (Bedu et al, Am. J. Respir. Crit. Care Med., 1996)

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22 From BIGH J, in «Hypoxia and Cold», Eds. SUTTON JR, HOUSTON CS, COATES G, 1987

23 Individual reactivity Case of Highlander, studied in LA PAZ, one month after HAPO

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25 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

26 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

27 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

28 EFFECTS OF ACUTE HYPOXIA Pulmonary Arteriolar Vasoconstriction very short delay of the responses

29 N 2 and O 2 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

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34 CELLULAR RESPONSES INDUCED BY ACUTE HYPOXIA Hypoxia inhibits K+ current in an oxygen sensitive potassium channel! Cellular membrane depolarisation! Opening of Ca 2+ channels! Intracellular Ca 2+! Contraction of pulmonary arteriolar smooth muscle cell

35 From BRIJ S.O. and PEACOCK A.J., Thorax, 1998

36 Cellular responses to hypoxia in the pulmonary circulation K + K + Hypoxia inhibits K + current in a delayed rectifier K channel K+ current inhibition leads to membrane depolarisation CALCIUM Ca2 + Ca 2+ influx through voltage gated channels Nuclear synthesis? HIF-1 CONTRACTION e.g. smooth muscle cell HYPOXIA may directly activate the HIF-1 binding sequence Gene products e.g. erythropoietin From Brij S.O. and Peacock A.J., Thorax, 1998

37 VOIES DE REPONSES A L HYPOXIE, INDUITES PAR HIF-1 Hémoprotéine oxygène Sensor O2 O 2 O Hémoprotéine oxygène Sensor 2 Phosphorylation des protéines Factor X HIF-1 α + β Induction des gènes des enzymes de la glycolyse Induction du gène vegf Induction des gènes I-NOS et HO-1 Induction du gène EPO Induction du géne de la tyrosine hydroxylase Métabolisme anaérobie Angiogénèse Vasodilatation Erythropoïèse Respiration augmentée From Coudert J., Urgence pratique, 66, 2004

38 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

39 From Heath and Williams, 1977

40 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 HIF 1 )

41 Cellular responses to hypoxia in the pulmonary circulation Cell surface receptor vasoconstrictor growth factors e. g. ET-1, PDGF Hypoxia upregulates the stress activated MAP kinases PROLIFERATION and REMODELLING of all three cell types Activation of second messenger signal e.g. DAG, IP3 PKC K + Phosphorylation events e.g.? MAP kinases? HIF-1 Nuclear synthesis Gene products e.g. erythropoietin K + Hypoxia inhibits K + current in a delayed rectifier K channel K+ current inhibition leads to membrane depolarisation CALCIUM Ca2 + Ca 2+ influx through voltage gated channels CONTRACTION e.g. smooth muscle cell HYPOXIA may directly activate the HIF-1 binding sequence From Brij S.O. and Peacock A.J., Thorax, 1998

42 EFFECTS OF HYPOXIC PVC AND STRUCTURAL CHANGES INDUCED BY CHRONIC HYPOXIA PVC Improvement in ventilation perfusion relationships? Structural changes PAH Right ventricular hypertrophy

43 Regional distribution of pulmonary blood flow, at HA COUDERT J. et al Respiration, 1975

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46 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

47 2) of PAP and PR during exercise and cold exposure in hyperreactive subjects (triggering factor of HAPE? and predictive factor of HAPE?)

48 Δ PAPmax= Ex hypoxiarest normoxia

49 3) PAH : useful factor?! No improvement of the perfusion of the apex in standing position! Risk of «chronic pulmonary heart» with right cardiac insufficiency

50 Co authors of the studies performed in LA PAZ, in the laboratories of IBBA ANTEZANA G. BARRAGAN L. BRIANCON L. CUDKOWICZ J DURAND J. LOCKHART A. MENSH-DECHENE J. PAZ-ZAMORA M. SPIELVOGEL H. VARGAS E. ZELTER M.

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