Pressure-flow-volume relationships in pulmonary circulation of normal highlanders

Lockhart, A; Zelter, Marc; Mensch-Dechêne, J; Antezana, Gerardo; Paz-Zamora, Mario; Vargas, Enrique; Coudert, J

doi:10.1152/jappl.1976.41.4.449

Cited by 36 publications

(8 citation statements)

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“…Even if we assume that pulmonary pressures were similar in lowlanders and high-altitude natives, we cannot exclude the possibility of a differential functional significance of the increased pulmonary pressure during maximal exercise in the two groups; i.e., shunting may become more pronounced in lowlanders at high altitude. During supplemental O 2 at high altitude, pulmonary arterial pressures during rest and exercise are significantly lowered (14). In the present study, supplemental O 2 decreased A-aPO 2 by 3 and 7 mmHg in the lowlanders after 2 and 8 wk, respectively.…”

Section: Discussionsupporting

confidence: 50%

Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives

Lundby¹,

Calbet²,

Hall³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

113

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-We aimed to test effects of altitude acclimatization on pulmonary gas exchange at maximal exercise. Six lowlanders were studied at sea level, in acute hypoxia (AH), and after 2 and 8 wk of acclimatization to 4,100 m (2W and 8W) and compared with Aymara high-altitude natives residing at this altitude. As expected, alveolar PO2 was reduced during AH but increased gradually during acclimatization (61 Ϯ 0.7, 69 Ϯ 0.9, and 72 Ϯ 1.4 mmHg in AH, 2W, and 8W, respectively), reaching values significantly higher than in Aymaras (67 Ϯ 0.6 mmHg). Arterial PO 2 (PaO 2 ) also decreased during exercise in AH but increased significantly with acclimatization (51 Ϯ 1.1, 58 Ϯ 1.7, and 62 Ϯ 1.6 mmHg in AH, 2W, and 8W, respectively). Pa O 2 in lowlanders reached levels that were not different from those in high-altitude natives (66 Ϯ 1.2 mmHg). Arterial O 2 saturation (SaO 2 ) decreased during maximum exercise compared with rest in AH and after 2W and 8W: 73.3 Ϯ 1.4, 76.9 Ϯ 1.7, and 79.3 Ϯ 1.6%, respectively. After 8W, Sa O 2 in lowlanders was not significantly different from that in Aymaras (82.7 Ϯ 1%). An improved pulmonary gas exchange with acclimatization was evidenced by a decreased ventilatory equivalent of O2 after 8W: 59 Ϯ 4, 58 Ϯ 4, and 52 Ϯ 4 l⅐ min ⅐ l O2 Ϫ1 , respectively. The ventilatory equivalent of O2 reached levels not different from that of Aymaras (51 Ϯ 3 l⅐ min ⅐ l O2 Ϫ1 ). However, increases in exercise alveolar PO2 and PaO 2 with acclimatization had no net effect on alveolar-arterial PO2 difference in lowlanders (10 Ϯ 1.3, 11 Ϯ 1.5, and 10 Ϯ 2.1 mmHg in AH, 2W, and 8W, respectively), which remained significantly higher than in Aymaras (1 Ϯ 1.4 mmHg). In conclusion, lowlanders substantially improve pulmonary gas exchange with acclimatization, but even acclimatization for 8 wk is insufficient to achieve levels reached by high-altitude natives. chronic hypoxia; acute normoxia; ventilation HIGH-ALTITUDE NATIVES from North America (8), Tibet (27), and South America (19, 25) have unique pulmonary gas transport abilities, maintaining low alveolar-arterial PO 2 difference (A-aPO 2 ) at maximum exercise, thus preserving arterial PO 2 (Pa O 2 ) and saturation (Sa O 2 ). This confers a clear advantage to high-altitude natives compared with the lowlanders during exercise at altitude. Although pulmonary gas exchange in high-altitude natives has been the focus of several studies, only a few reports exist on pulmonary gas exchange during exercise in lowlanders acclimatized to high altitude. The classic study by Dempsey et al. (8) investigated lowlanders acclimatized to 3,100 m for 4, 21, and 45 days and compared these with firstto third-generation high-altitude residents. Despite the limited number of subjects analyzed (4 lowlanders), a comparatively low exercise A-aPO 2 was observed in the natives, whereas the lowlanders seemed to reduce their exercise A-aPO 2 as the altitude exposure was prolonged (8). More recently, Calbet et al. (5, 6) also found reduced exercise A-aPO 2 in seven lowlanders after chronic (9 wk) compared ...

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Section: Discussionsupporting

confidence: 50%

Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives

Lundby¹,

Calbet²,

Hall³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

113

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“…Short-term correction of hypoxia by oxygen inhalation, in a similar population, showed no effects on Ppa at rest, but decreased the exercise-induced increment [19], suggesting the presence of pulmonary vasoconstriction during exercise and, thus, a dynamic regulation of pulmonary vascular resistance. Moreover, the fall in pulmonary vascular resistance during unilateral pulmonary occlusion demonstrated the ability of pulmonary vessels to passively distend in chronic hypoxia [17].…”

Section: Discussionmentioning

confidence: 81%

Pulmonary hypertension in high-altitude chronic hypoxia: response to nifedipine

Antezana

Antezana²,

Aparicio³

et al. 1998

Eur Respir J

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The vasoconstrictive effect of hypoxia upon pulmonary artery vessels is well known in most mammalian species, including humans. A pure form of hypoxic pulmonary artery hypertension can be seen in high-altitude residents. A loss of adaptation to chronic hypoxia, known as chronic mountain sickness (CMS), is observed in 5-10% of people sojourning above 3,000 m and is characterized by excessive polycythaemia (H-Hb), pulmonary hypertension and nonspecific neurological symptoms [1]. Ongoing pulmonary vasoconstriction leads to increased vascular resistance and pulmonary artery pressure (Ppa), which are probable maladaptive responses to high altitude since they result in minimal improvement in ventilation-perfusion matching and increased workload for the right ventricle.In addition to vasoconstriction, chronic alveolar hypoxia is associated with structural changes in the media of terminal portions of pulmonary arterioles [2], such as smooth muscle cell proliferation, thickening of the media, proliferation and turgescence of endothelial cells. Recently, this vascular remodelling has been found in only a few residents at high altitude [3], but it is admitted that sustained hypoxia is able to increase muscularization of the small pulmonary vessels and to increase even further the pulmonary vascular resistance.A reduction in Ppa, under hypoxic conditions, has been obtained by the calcium channel-blocker nifedipine in healthy humans exposed to acute normobaric hypoxia [4] or in subjects suffering from high-altitude pulmonary oedema in hypobaric hypoxia [5]. In other aetiologies of pulmonary hypertension, such as primary pulmonary hypertension [6] or secondary to obstructive pulmonary disease [7,8], nifedipine and felodipine were efficient in decreasing Ppa. Calcium antagonists have also been shown to be efficient in experimental hypoxic pulmonary vasoconstriction [9,10].Reversal of hypoxic pulmonary hypertension with calcium channel-blockers has not been evaluated in a population chronically exposed to high altitude. Venesection has been used to treat CMS, but no modification of pulmonary haemodynamics has been reported.The objectives of this study were to assess pulmonary hypertension in native residents at high-altitude by echocardiography, to analyse the relationship between Ppa and H-Hb, and to study the effect of acute administration of nifedipine on pulmonary pressure. In the presence of reversible vascular changes in altitude-induced pulmonary hypertension, a nifedipine-induced vasodilatation could be anticipated. Materials and methods SubjectsThirty males and one females, native residents of La Paz (3,500-4,100 m), Bolivia, were included in this nonrandomized study. Asymptomatic subjects were recruited Systolic pulmonary arterial pressure (Ppa) was studied by Doppler echocardiography, at rest and after sublingual nifedipine, in 31 asymptomatic residents at 3,600 m. Individuals were separated into two groups according to resting Ppa: a group with low Ppa (ð4.7 kPa, n=17) and a group with high Ppa (>4.7 kPa, n=14). Ind...

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“…Early studies proposed that the initial increase in pulmonary vascular resistance in response to hypoxic exposure is largely due to hypoxic pulmonary vasoconstriction; whereas the structural changes in the pulmonary vascular bed following sustained exposure to hypoxia are the major determinant of elevated vascular resistance with disease progression ( Sime et al, 1971 ; Lockhart et al, 1976 ; Fried et al, 1983 ). Interestingly, however, studies show no active PASMC proliferation in end-stage lung tissue from idiopathic and hereditary pulmonary arterial hypertensive patients ( Majka et al, 2008 ) suggesting active proliferation occurs early in the disease process as we observed in mice.…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension

Garcia

Yellowhair

Detweiler

et al. 2022

Front. Mol. Biosci.

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Acid-sensing ion channel 1a (ASIC1a) is a voltage-independent, non-selective cation channel that conducts both Na+ and Ca2+. Activation of ASIC1a elicits plasma membrane depolarization and stimulates intracellular Ca2+-dependent signaling pathways in multiple cell types, including vascular smooth muscle (SM) and endothelial cells (ECs). Previous studies have shown that increases in pulmonary vascular resistance accompanying chronic hypoxia (CH)-induced pulmonary hypertension requires ASIC1a to elicit enhanced pulmonary vasoconstriction and vascular remodeling. Both SM and EC dysfunction drive these processes; however, the involvement of ASIC1a within these different cell types is unknown. Using the Cre-LoxP system to generate cell-type-specific Asic1a knockout mice, we tested the hypothesis that SM-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling, whereas EC-Asic1a opposes the development of CH-induced pulmonary hypertension. The severity of pulmonary hypertension was not altered in mice with specific deletion of EC-Asic1a (TekCre-Asic1afl/fl). However, similar to global Asic1a knockout (Asic1a−/-) mice, mice with specific deletion of SM-Asic1a (MHCCreER-Asic1afl/fl) were protected from the development of CH-induced pulmonary hypertension and right heart hypertrophy. Furthermore, pulmonary hypertension was reversed when deletion of SM-Asic1a was initiated in conditional MHCCreER-Asic1afl/fl mice with established pulmonary hypertension. CH-induced vascular remodeling was also significantly attenuated in pulmonary arteries from MHCCreER-Asic1afl/fl mice. These findings were additionally supported by decreased CH-induced proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) from Asic1a−/- mice. Together these data demonstrate that SM-, but not EC-Asic1a contributes to CH-induced pulmonary hypertension and vascular remodeling. Furthermore, these studies provide evidence for the therapeutic potential of ASIC1a inhibition to reverse pulmonary hypertension.

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Pressure-flow-volume relationships in pulmonary circulation of normal highlanders

Cited by 36 publications

References 0 publications

Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives

Pulmonary gas exchange at maximal exercise in Danish lowlanders during 8 wk of acclimatization to 4,100 m and in high-altitude Aymara natives

Pulmonary hypertension in high-altitude chronic hypoxia: response to nifedipine

Smooth muscle Acid-sensing ion channel 1a as a therapeutic target to reverse hypoxic pulmonary hypertension

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