The influence of haemoglobin concentration, arterial oxygen content and blood viscosity on hypoxic pulmonary vasoconstriction in acute and chronic hypoxemia

During acclimatisation to high altitude, haemoconcentration occurs that may exacerbate hypoxic pulmonary vasoconstriction (HPV) due to the increase in blood viscosity (4). Independent to the frictional force of viscosity, erythrocytes can augment HPV via nitric oxide scavenging by oxyhaemaglobin and reactive oxygen species generation by deoxyhaemaglobin (2), or attenuate HPV via the generation of nitric oxide (1) and S-nitrosothiol (3). The balance between these regulatory processes is thought to vary depending on the duration of hypoxia (5). Moreover, for the same arterial partial pressure of oxygen (PaO2), haemoconcentration will increase arterial oxygen content (CaO2), and recent evidence suggests this may decrease the HPV response. Therefore, we sought to determine the role of erythrocyte-dependent modulation of HPV in humans by performing two sequential studies. Pulmonary artery systolic pressure (PASP; echocardiography) was assessed during (i) an isovolemic haemodilution at sea level (n=10) in normoxia and during acute isocapnic hypoxia (PaO2 40 ± 2 mmHg); and (ii) before and after a hypervolemic haemodilution (n=11) to normalise haemoglobin concentration (Hb) to sea level values following 6 ± 2 days of acclimatization to 5050 m above sea level, and during a further decrease in PaO2 via acute pokilocapnic hypoxia (FiO2=0.15). Blood viscosity was measured using a cone and plate viscometer at a shear rate of 225 s-1and CaO2 was determined from Hb and PaO2 via sampling from a radial artery catheter. In the sea level trial, haemodilution decreased Hb concentration from 14.2 ± 0.9 to 11.4 ± 0.5 g dl-1. Despite a decrease in viscosity (3.5 ± 0.3 vs.2.8 ± 0.3 cP, P<0.001), haemodilution increased PASP in both normoxia (1.6 ± 1.5 mmHg, P=0.008) and hypoxia (4.5 ± 2.4 mmHg, P<0.001). PASP was elevated with acute hypoxia to a greater extent following haemodilution (4.9 ± 5.3 vs. 7.8 ± 5.3 mmHg; interaction P=0.005), as reflected in a greater PASP/CaO2 slope post haemodilution (-1.14 ± 1.2 vs. -2.16 ± 1.3 mmHg/ml dl-1, P<0.001). In chronic hypoxia, Hb concentration (16.1 ± 0.9 vs. 14.1 ± 1.0 g dl-1, P<0.001) blood viscosity (4.5 ± 0.6 vs. 3.7 ± 0.4 cP, P<0.001) and CaO2 (18.8 ± 1.4 vs. 16.7 ± 1.3 ml dl-1, P<0.001) were all reduced following haemodilution. However, PASP remained unchanged (22.7 ± 5.2 vs. 24.5 ± 5.2 mmHg, P=0.14). In contrast, acute pokilocapnic hypoxia increased PASP both pre (2.4 ± 2.1 mmHg, P=0.004) and to a greater extent post haemodilution (5.1 ± 4.2 mmHg, P=0.002). Collectively, these findings demonstrate that haemodilution augments the HPV response to acute but not chronic hypoxia, and the increase in PASP appears to be independent to mechanical viscosity with moderate changes in haemoglobin concentration. Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD, Jr., Kraus D, Ho C, Gladwin MT, and Patel RP. Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107: 566-574, 2006. Deem S, Swenson ER, Alberts MK, Hedges RG, and Bishop MJ. Redblood-cell augmentation of hypoxic pulmonary vasoconstriction: hematocrit dependence and the importance of nitric oxide. Am J Respir Crit Care Med 157: 11 Gaston B, Singel D, Doctor A, and Stamler JS. S-nitrosothiol signaling in respiratory biology. Am J Respir Crit Care Med 173: 1186-1193, 2006. Kerbaul F, Van der Linden P, Pierre S, Rondelet B, Melot C, Brimioulle S, and Naeije R. Prevention of hemodilution-induced inhibition of hypoxic pulmonary vasoconstriction by N-acetylcysteine in dogs. Anesth Analg99: 547-551, table of contents, 2004. Swenson ER. Hypoxic pulmonary vasoconstriction. High Alt Med Biol 14: 101-110, 2013. 81-1186, 1998. Where applicable, the authors confirm that the experiments described here conform with the ethical requirements.