Hypoxia and the Pulmonary Circulation Thorax: First Published As 10.1136/Thx.49.Suppl.S19 on 1 September 1994

Thorax 1994;49 Supplement:S19-S24 S19

Hypoxia and the pulmonary circulation Thorax: first published as 10.1136/thx.49.Suppl.S19 on 1 September 1994. Downloaded from

Inder S Anand

The first description of the effects of hypoxia arterial segments upstream from arterioles on the pulmonary circulation was made by 30-50 ,um in diameter.'7 Laser technology later Bradford and Dean in the UK exactly 100 confirmed hypoxic vasoconstriction in small years ago.' However, scientific interest in this (30-200 ,um diameter) arterioles.'8 How re- field only began with the discovery of hypoxic duced oxygen tension triggers pulmonary pulmonary vasoconstriction in the cat by von vasoconstriction is still being investigated, but Euler and Liljestrand2 in 1946, and in man a we do know that a reduction in oxygen tension year later in Andre Coumand's laboratory.3 in the lung depolarises resting membrane po- Despite extensive research in this field for tential of pulmonary vascular smooth muscle, nearly half a century, we still do not fully resulting in Ca2" influx through the voltage understand the mechanism of hypoxic vaso- dependent Ca2" channels.'9 The mechanism constriction or why the response of the pul- by which hypoxia is sensed by the pulmonary monary vasculature to hypoxia is diametrically vascular smooth muscle remains unclear. For opposite to that of the systemic circulation. a long time a vasoconstrictive mediator has Teleologically, hypoxic pulmonary vaso- been thought to be involved. A number of constriction serves a useful purpose. It acts as a potential mediators such as histamine,20 sero- local homeostatic mechanism and, by diverting tonin, noradrenaline,22 angiotensin II,23 vaso- blood away from the unventilated or poorly constrictive prostaglandins,24 leukotrienes,25 ventilated lung, helps to maintain ventilation- reduced ATP,26 and cytochrome P-45027 have perfusion homogeneity and thus arterial oxy- been investigated and excluded. The en- genation. It is not surprising, therefore, to find thusiasm for a possible mediator of hypoxic that a similar response exists in most animal pulmonary vasoconstriction has therefore species." waned, and there is increasing interest in the hypothesis that oxygen tension is sensed directly by the vascular smooth muscle. The pos- Mechanism of acute hypoxic pulmonary sible role of K+ channels in hypoxic pulmonary vasoconstriction vasoconstriction has been suggested for some

The mechanism by which a fall in oxygen time,2829 but the most exciting development in http://thorax.bmj.com/ tension is sensed and translated into vaso- this field has been the finding by Weir and constriction in the pulmonary circulation is colleagues that hypoxia inhibits an outward K+ still not fully understood. We know that pul- current in isolated pulmonary arterial smooth monary vasoconstriction is initiated within sec- muscle cells causing depolarisation of the rest- onds of the onset of alveolar hypoxia,9 and that ing membrane potential.30 This could then lead the pulmonary artery pressure gradually rises to an influx of extracellular Ca2+ through the over the next few minutes. It is a remarkable voltage-dependent Ca2+ channels and con- coincidence that the sequently to vasoconstriction. It is stimulus-response curve interesting on September 28, 2021 by guest. Protected copyright. of the pulmonary vasculature to hypoxia in that the type I cells in the carotid body also humans resembles that of the carotid body sense hypoxia by a similar mechanism.3132 Fur- chemoreceptors to acute hypoxia and of the ther studies are needed to define these K+ bone marrow to chronic hypoxia.'0'3 In each channels more fully, and to determine how they case the threshold of Po2 is approximately are modulated by hypoxia. 70-80 mmHg. Below this value the response becomes increasingly strong. The inflection point of each ofthese curves is almost identical Effects of chronic hypoxia to that of the haemoglobin oxygen dissociation The clinical effects ofhypoxia are most evident curve, suggesting that similar mechanisms may in chronic hypoxic states. In addition to vaso- be involved in the sensing of oxygen in these constriction, structural changes in the terminal diverse systems in the body. portions of the pulmonary arterial tree33 and polycythaemia34 contribute to the maintenance of chronic hypoxic pulmonary hypertension. Site of hypoxic pulmonary This occurs when the alveolar oxygen tension vasoconstriction remains below the threshold for pulmonary The small muscular pulmonary arteries are the vasoconstriction of approximately 75 mm Hg. major site of hypoxic pulmonary vaso- Such a degree of chronic hypoxia is seen in constriction. Oxygen tension of both the al- conditions like chronic bronchitis and em- veolar air and the pulmonary artery perfusate physema, hypoventilatory states, and in its pure can directly influence these vessels, although form at high altitude. It is therefore interesting alveolar hypoxia is much more effective.'4-6 that an almost identical "remodelling" of the VA Medical Center, Minneapolis, Staub and colleagues used the micropuncture pulmonary vasculature occurs in response to Minnesota 55417, USA technique to show that hypoxia increased pul- alveolar hypoxia in these diverse states. In 1968 I S Anand monary vascular resistance predominantly in Donald Heath and his colleagues coined the S20 Anand

term "hypoxic hypertensive pulmonary vas- Andes who have lived at high altitude far longer culature disease" to describe this form of pul- than their American counterparts appear to Thorax: first published as 10.1136/thx.49.Suppl.S19 on 1 September 1994. Downloaded from monary vascular disease.35 The most striking develop a lesser degree of pulmonary hyper- effect of alveolar hypoxia is muscularisation of tension despite being at higher altitude. Pul- pulmonary arterioles <70 ,um in diameter which monary artery pressures are normal in these normally contain only a single elastic lamina subjects at 2240 m (15 (2) mm Hg)43 and without any smooth muscle. This distal ex- 2640 m (13 (3) mm Hg),44 mildly increased at tension of smooth muscle causes the small altitudes between 3700 and 4370 m (20 (3) to pulmonary arterioles to develop a distinct 23 (4) mm Hg),45-4 and moderately increased media with smooth muscle sandwiched be- at an altitude of 4540 m (28 (10) mm Hg).49 tween an inner and an outer elastic lamina. The curve relating pulmonary artery pressure This was first described in Quechua Indians of and ambient oxygen tension is less steep in the Cerro de Pasco (4330 m) in the Peruvian Andes Andean people than in their North American by Arias-Stella and Saldafia.36 Later Heath and counterparts, which suggests a blunted hypoxic coworkers37-39 made a number of studies on vasoconstrictive response. This may be a Quechuas, Aymaras, mestizos, and white res- manifestation ofadaptation to chronic hypoxia. idents of La Paz, Bolivia (3800 m) and, while Unfortunately few data are available from confirming muscularisation of pulmonary ar- the Himalayas where large populations also live terioles, found that remodelling was much more at high altitude. Roy catheterised seven men at complex than had originally been envisaged by Leh, Ladakh (3600 m) who were presumably Arias-Stella and Saldafia.36 Moreover, con- ofLadakhi origin.50 The pulmonary artery pres- siderable individual and ethnic variations in the sure at rest was 20 (4 5) mm Hg and rose to response to high altitude hypoxia were seen. 26 (5) mm Hg with modest exercise. The rest- Remodelling was more common in the Aymara ing pressures are, therefore, almost identical to and Quechua Indians than the mixed mestizos those quoted for the Andean people at similar or long term white residents of La Paz. Heath altitude. The Andean highlanders, however, et al also found longitudinal smooth muscle in showed a greater increase in pulmonary artery the intima of small pulmonary arteries and pressure with similar exercise (32 (8) mm Hg). development of inner muscular tubes of cir- Does this mean that the Himalayan people are cularly orientated smooth muscle cells, internal less reactive to hypobaric hypoxia than the to the fascicles oflongitudinal muscle, lining the Andean highlanders? Groves and coworkers pulmonary arteries and arterioles.3839 Similar have recently reported the pulmonary artery histological changes are seen in patients with pressures in the native Tibetan highlanders of chronic obstructive lung disease at sea level,40 Lhasa, Tibet (3600 M).5' They found normal but the development of longitudinal muscle pressures at rest (15 (1) mg, PIo2 = 97 mm Hg) and inner muscular tubes in the intima is much which did not increase significantly with further

more prominent and occurs more frequently. hypoxia (19 (3) mm Hg, PIo2 = 62 mm Hg). http://thorax.bmj.com/ The similarity of the remodelling in cor pul- Higher pulmonary artery pressures have been monale and in the natives of high altitude reported in two Chinese studies from Quinghai suggests that it is caused by sustained alveolar province in Tibet (3950 m) but it is un- hypoxia. It remains unclear, however, how pul- clear whether they studied Tibetan or Han monary arterioles come to be muscularised. It subjects.5253 is unlikely to be the result of work hypertrophy We have examined the lungs of seven La- since these vessels have no muscle in normal dakhi highlanders who had never been to low

subjects and hypoxic vasoconstriction occurs altitude and who suffered accidental deaths. on September 28, 2021 by guest. Protected copyright. in vessels proximal to these arterioles. It is more Their small pulmonary arteries were thin walled likely that some smooth muscle growth factors with no medial hypertrophy of the muscular are involved. Once pulmonary arterioles be- pulmonary arteries, muscularisation of the ar- come muscularised they can constrict in re- terioles, or any of the other changes described sponse to hypoxia and vasoconstriction moves in the pulmonary vasculature of the Andean to a more peripheral site in the pulmonary vas- highlander.54 Similar thin walled pulmonary cular tree.4' arteries with normal pulmonary artery pressures are seen in a number of mammals indigenous to high altitude - for example, the Pulmonary artery pressure at high llama,5556 mountain viscacha,57 yak, 5859 and altitude snow pig.60 Heath and Harris have suggested The structural changes described in the native that this lack of pulmonary vascular re- highlanders are associated with chronic pul- modelling and absence of pulmonary hyper- monary hypertension. As stated above, how- tension in these animals is an expression of ever, pulmonary hypertension does not develop genetic adaptation to hypobaric hypoxia.57 in high altitude residents until the alveolar By losing the property of pulmonary vaso- oxygen tension falls below 75 mm Hg, which constriction the species finds it advantageous occurs at an altitude of approximately 2100 M.42 to avoid the harmful effects of pulmonary Thus the pulmonary artery pressure is normal hypertension at high altitude at the expense of (15 (3) mmHg) in residents of Denver, Co- the benefits of ventilation-perfusion homo- lorado (1600 m), borderline (19(6) mm Hg) in geneity. Indeed, the hypoxic pulmonary vaso- Flagstaff, Arizona (2100 m), and raised (24 (7) constrictive response appears to be genetically mm Hg) in Leadville, Colorado (3100 m).'0 determined,6' and the loss or blunting of this In contrast to North American high altitude response in certain species indigenous to high residents, the Aymaras and Quechuas of the altitude may be explained in simple Mendelian Hypoxia and the pulmonary circulation S21 terms.62 The absence ofmuscularisation ofpul- dilated pulmonary trunk. Histological ex-

monary arterioles and the lack of pulmonary amination of the lung was carried out by Don- Thorax: first published as 10.1136/thx.49.Suppl.S19 on 1 September 1994. Downloaded from hypertension in the Ladakhi and Tibetan ald Heath in Liverpool and showed changes in people, who come from the same ethnic stock the pulmonary arteries, arterioles, and venules. and have lived in the Himalayas longer then The pulmonary arteries showed severe medial their Andean counterparts,63 therefore suggests hypertrophy with crenation of the elastic lam- that the pulmonary circulation of the native inae, suggesting vasoconstriction. There was Himalayan people is remarkably well adapted muscularisation ofthe pulmonary arterioles. In to hypobaric hypoxia and perhaps better ad- contrast, the Tibetan age matched controls had apted than that of the Andean people. thin walled pulmonary arteries and a single Does this difference in the degree of ad- elastic lamina in the pulmonary arterioles. aptation of the Andean and Himalayan people Clearly, alveolar hypoxia was responsible for really matter? Several differences in the re- the pulmonary vascular disease in these patients sponse ofthese populations to alveolar hypoxia causing pulmonary hypertension, right vent- have been reported. Tibetan residents have a ricular hypertrophy and dilatation, and con- higher alveolar ventilation and increased vent- gestive heart failure. Lack of intimal ilatory sensitivity to hypoxia than the native proliferation, plexiform lesions, fibrinoid nec- Andean highlanders.64 The haemoglobin re- rosis, or necrotising arteritis distinguished this sponse is lower in the Himalayan than the condition from cases of primary pulmonary Andean highlander.65 These factors may ex- hypertension described in infants and children plain why chronic mountain sickness is com- living at high altitude in Colorado.69 In one mon in the Andean people but is seldom seen case of subacute infantile mountain sickness, in the native Himalayan population, although however, there was migration ofmyocytes from it is frequently found amongst the Han Chinese the media of small pulmonary arteries into the residents of Tibet.66 intima.68 Heath has shown that such features are characteristic ofearly plexogenic pulmonary arteriopathy, forming the pathological basis of Subacute mountain sickness primary pulmonary hypertension.70 Could this The benefits of adaptation to alveolar hypoxia mean that the disease described in infants and in the Tibetan people are best seen when they children in Colorado was a late manifestation are compared with lowlanders who migrate to of infantile subacute mountain sickness? live permanently at high altitude. One such The possibility of further investigating this large experiment occurred with the Chinese infantile syndrome is now unlikely because, occupation of Tibet in 1952 when large num- since its recognition, Han infants born at low bers of Chinese people of Han origin moved level are no longer taken to high altitude. The from mainland China to live permanently in incidence ofthe disease has therefore decreased

Tibet at altitudes of3000-4000 m. This enorm- considerably. Recent data show, however, that http://thorax.bmj.com/ ous demographic change offered a unique op- the arterial oxygen saturation is higher in portunity for scientists to study the differences Tibetan than Han newborn infants at Lhasa,7' in the long term effects of alveolar hypoxia on suggesting that alveolar hypoventilation in the people of different ethnic backgrounds. Han infants may have contributed to the pulmonary hypertension in subacute infantile mountain sickness. The rarity with which SUBACUTE INFANTILE MOUNTAIN SICKNESS Tibetan infants develop this syndrome is another

In 1987 we went to Tibet to study the Hima- indication that the Tibetan people are adapted on September 28, 2021 by guest. Protected copyright. layan variety of chronic mountain sickness.66 to alveolar hypoxia. Subacute infantile moun- During these studies we came across a new tain sickness has not been seen in other high disease which was termed "subacute infantile altitude areas. This is probably because such a mountain sickness",6768 and were able to ex- large movement of lowlanders to high altitude amine the records of 15 patients who had died has not occurred anywhere else. There is, how- of this syndrome. The condition was found in ever, some historical evidence that a similar infants and children of both sexes aged 3-16 condition might have affected infants born to (mean 9) months. Of the 15 patients 14 were Spanish immigrants to the Andean mining of Han origin and one was Tibetan. All except town of Potosi (4070 m) during the 16th cen- the Tibetan infant and a Han girl of 14 months tury. The Spanish soon learned not to take were born at low altitude and later taken to their infants to Potosi until they were over the live in Lhasa (3700 m). The average duration age of one year.72 of their stay at high altitude was only 2- 1 months. The infants presented with features of congestive heart failure including dyspnoea, ADULT SUBACUTE MOUNTAIN SICKNESS cough, irritability, sleeplessness, cyanosis, The sudden movement of large numbers of puffiness of the face, and oliguria. Clinical Indian troops to high altitude in the Himalayas examination revealed tachycardia, tachypnoea, during the 1962 India-China war was re- cardiomegaly, heptomegaly, and rales in the sponsible for our increasing awareness of chest. Chest radiography confirmed the pres- mountain-related illnesses and, in particular, ence of cardiac enlargement. Haemoglobin of acute mountain sickness.73 This experience levels were not increased. encouraged formulation of rational ac- The most striking feature at postmortem climatisation protocols that allowed men to be examination was an enlarged heart, right vent- deployed at much higher altitudes. The recent ricular hypertrophy and dilatation, and a experience of military activity at extreme al- S22 Anand titudes (>6000 m) in the Himalayas has made a significant increase in total body water, us aware of another syndrome called "adult plasma and blood volume, and total body ex- Thorax: first published as 10.1136/thx.49.Suppl.S19 on 1 September 1994. Downloaded from subacute mountain sickness".74 changeable sodium. Renal blood flow fell. In 1988 40 healthy soldiers (average age Plasma levels of noradrenaline, aldosterone, 22 years) stationed at extreme altitude and erythropoietin increased but the atrial (5800-6700 m) for an average of 18 weeks natriuretic peptide and renin activity did not exhibited this syndrome. All were Garhwalis change. These findings suggest that salt and from the same ethnic background and were water accumulation seen in these normal born and had spent most of their lives at an asymptomatic subjects at extreme altitude altitude of about 2000 m. They were moved could have resulted from mechanisms acting to high altitude after a proper acclimatisation to reduce the renal blood flow, independent of procedure spread over five weeks. None of changes in haemodynamics. Similar mech- them had developed acute mountain sickness. anisms could also have contributed to the The posts they manned were snowbound with pathogenesis of adult subacute mountain sick- no local inhabitants or permanent settlements ness. in the vicinity. Access to most of these areas Only 10-20% of subjects stationed at ex- was only possible by helicopter. The average treme altitude were affected by this syndrome. night temperature at their posts varied from The factors responsible for this observation are -200C to -400C. Their daily routine con- not yet known. The cohort stationed at extreme sisted of patrolling several kilometres of the altitude was homogenous in terms of race, age, slopes and other combat activities. build, and level of exertion. The incidence of The illness started after the soldiers had spent the syndrome increased with altitude and with an average of 11 weeks at that altitude. They the duration of stay at extreme altitude. In- developed increasing shortness of breath and terestingly, the occurrence of the disease has oedema and later gross anasarca. Most ofthem decreased dramatically since the adoption of responded to intermittent doses of diuretics. measures to reduce the period ofstay at extreme After an average stay of 18 weeks at extreme altitude. One factor that may be important altitude they were finally airlifted to sea level needs to be considered. The syndrome of adult and were investigated within three days. Most subacute mountain sickness was seen in its ofthem started spontaneous diuresis on leaving most florid form in only two ethnic groups: the extreme altitude. Apart from features of severe Garhwalis74 - as described in detail here - and congestive heart failure with oedema and as- six months earlier in the Gurkhas79 on whom cites, they had polycythaemia (mean haem- detailed studies could not be done. Both these atocrit 61%) and 18 had papilloedema. Chest populations come from submountainous areas radiography, ECG and echocardiography con- of 2000-3000 m. It is possible that the soldiers firmed cardiomegaly, right ventricular hyper- who developed this syndrome were exposed to

trophy, and dilatation, but no left ventricular some degree of perinatal hypoxia. Heath has http://thorax.bmj.com/ enlargement or pulmonary venous congestion. shown in experimental animals that variable Haemodynamic measurements showed mild exposure to perinatal hypoxia exaggerates the pulmonary hypertension (mean 26 (5) mm Hg) effects of agents inducing vasoconstrictive pul- at rest, not responsive to oxygen, which rose monary hypertension in later life.80 Whether to an average of 40 mm Hg with mild exercise. a similar phenomenon contributed to the The pulmonary wedge pressures and cardiac pathogenesis of this syndrome remains to be output were normal. All the abnormalities re- determined.

verted to normal 12-16 weeks later. Both the human syndromes described here on September 28, 2021 by guest. Protected copyright. The pathogenesis of this condition is not have a number of similarities with brisket dis- clear but a number of factors might have con- ease in cattle. The length of exposure to hypo- tributed to congestive heart failure - namely, baric hypoxia required for the development of hypoxic pulmonary vasoconstriction, structural clinical features is almost identical. Hypoxic remodelling of the pulmonary vasculature, and pulmonary hypertension seems to play an im- polycythaemia. Since none of the patients died portant part in all three conditions. The com- and no histological examination of the lungs mon clinical finding is one of severe congestive was carried out, the structural changes in these heart failure. The morphological changes in lungs are not known. Experimental data suggest the lungs in brisket disease8" and in subacute that histological changes due to hypobaric hyp- infantile syndrome67 are entirely muscular in oxia are reversible over a period of a few nature. Although histological data are not avail- months.3375 Similar data on humans do not able for the adult syndrome, it is likely that exist. Other factors that might have contributed similar changes might be seen in this condition to pulmonary hypertension include the pul- as well. Removal from high altitude results in monary vasoconstrictive effects of cold76 and complete resolution of brisket disease82 and of exercise at extreme altitude." adult subacute mountain sickness.74 There is Since the most striking finding in the adult anecdotal evidence that this also occurs in the syndrome was massive fluid retention, we de- infantile syndrome. It would therefore appear cided to examine the response ofthe kidney and that both the infantile and adult forms of the the neuroendocrine system to extreme altitude. subacute syndrome are the human counterpart Body fluid compartments, renal blood flow, of brisket disease in cattle. and several plasma hormones were measured in a group of normal asymptomatic soldiers Even a superficial reading of this chapter will stationed at extreme altitude (>6000 m) for make obvious the enormous contributions that approximately 10 weeks.78 The results showed Donald Heath made to the subject of hypoxia Hypoxia and the pulmonary circulation S23

30 Post J, Hume J, Archer S, Weir E. Direct role for potassium and the pulmonary circulation. For me it has channel inhibition in hypoxic pulmonary vasoconstriction. been a great privilege to have been associated Am Physiol 1992;262:C882-C890. Thorax: first published as 10.1136/thx.49.Suppl.S19 on 1 September 1994. Downloaded from 31 Lopez-Barneo J, Lopez-Lopez JR, Urena J, Gonzalez C. with some of his work. Over the years I have Chemotransduction in the carotid body: K+ current mod- come to know Donald well. His enquiring ulated by Po, in type I chemoreceptor cells. Science 1988; 241:580-2. mind, equable humour, resilient character, and 32 Lopez-Lopez J, Gonzalez C, Urena J, Lopez-Barneo J. Low transparent straightforwardness have always Po2 selectively inhibits K channel activity in chemoreceptor cells of the mammalian carotid body. Gen shown through even during the stresses of our Physiol 1989;93:1001-15. scientific expeditions at high altitude. 33 Heath D, Edwards C, Winson M, Smith P. Effects on the right ventricle, pulmonary vasculature, and carotid bodies of the rat on exposure to and recovery from simulated 1 Bradford J, Dean H. The pulmonary circulation. _7 Physiol high altitude. Thorax 1973;28:24-8. 1894;16:34-96. 34 Barer G, Bee D, Wach R. Contribution of polycythaemia 2 von Euler U, Liljestrand G. Observations on the pulmonary to pulmonary hypertension in simulated high altitude in arterial blood pressure in the cat. Acta Physiol Scand 1946; rats. Jf Physiol 1983;336:27-38. 12:301-20. 35 Hasleton P, Heath D, Brewer D. Hypertensive pulmonary 3 Motley H, Cournand A, Werko L, Himmelstein A, Dresdale vascular disease in states of chronic hypoxia. J7 Pathol D. The influence of short periods of induced anoxia upon Bacteriol 1968;95:431-40. pulmonary artery pressures in man. Am .7 Physiol 1947; 36 Arias-Stella J, Saldafia M. The terminal portion of the 150:315. pulmonary arterial tree in people native to high altitudes. 4 Satchell G. Intrinsic vasomotion in the dogfish gill. _7 Exp Circulation 1963;28:915-25. Biol 1962;39:503-12. 37 Heath D, Smith P, Rios-Dalenz J, Williams D, Harris P. 5 Shelton G. The effect of lung ventilation on blood flow to Small pulmonary arteries in some natives of La Paz, the lungs and body of the amphibians, Xenopus laevis. Bolivia. Thorax 1981;36:599-604. Respir Physiol 1970;9:183-96. 38 Heath D, Williams D, Rios-Dalenz J, Calderon M, Gosney 6 Millard R, Johansen K. Ventricular outflow dynamics in the J. Small pulmonary arterial vessels ofAymara Indians from lizard, Varanus niloticus: responses to hypoxia, hypercarbia the Bolivian Andes. Histopathology 1990;16:565-71. and diving. .7 Exp Biol 1974;60:871-80. 39 Heath D, Williams D. Pulmonary vascular remodelling in 7 Cueva S, Sillau H, Valenzuela A, Ploog H. High altitude a high-altitude Aymara Indian. Int _7 Bionieteorol 1991 ;35: induced pulmonary hypertension and right heart failure 203-7. in broiler chickens. Res Vet Sci 1974;16:370-4. 40 Wilkinson M, Langhorne C, Heath D, Barer G, Howard P. 8 Reeves J, Wagner Jr W, McMurtry I, Grover R. Physiological A pathophysiological study of 10 cases of hypoxic cor effects of high altitude on the pulmonary circulation. pulmonale. QJfMed 1988;66:65-85. In: Robertshaw D, ed. International review of physiology: 41 Wach R, Emery C, Bee D, Barer G. Effect of alveolar environnental physiology III. Vol 20. Baltimore: University pressure on pulmonary artery in chronically hypoxic rats. Park Press, 1979:289-310. Cardiovasc Res 1987;21:140-50. 9 Jensen K, Micco A, Czartolomna J, Latham L, Voelkel N. 42 Grover R. Chronic hypoxic pulmonary hypertension. In: Rapid onset of hypoxic vasoconstriction in isolated lungs. Fishman A, ed. 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