Pulmonary vascular adaptations to augmented polycythemia during chronic hypoxia

Abstract

We previously found that augmentation of polycythemia by exogenous human recombinant erythropoietin (EPO) failed to worsen the severity of hypoxic pulmonary hypertension in rats. We asked whether this unexpected finding was related to reductions in cardiac output, left ventricular end-diastolic pressure, pulmonary vascular resistance, or some combination of these factors. Four groups of Sprague-Dawley rats were studied over a 3-wk period: hypoxic (0.5 ATM) and normoxic animals each injected with EPO (500 U/kg sc thrice weekly) or saline (control animals). As observed previously, we found that pulmonary arterial (PA) pressures and right ventricular hypertrophy were not increased in EPO-treated rats despite significant increases in hematocrit and blood viscosity. Cardiac outputs, blood volumes, and left ventricular end-diastolic pressures were similar in EPO-treated and control rats. Acute PA pressure responses to acute normoxia in hypoxic rats and to acute hypoxia in normoxic rats were similar, suggesting no differences in vasoreactivity. However, lungs isolated from EPO-treated hypoxic rats had lower pulmonary vascular resistance than saline-treated hypoxic rats when perfused with blood from normocythemic donor rats. PA medial thickness and the percentage of muscularized small PAs were significantly lower in EPO-treated hypoxic rats. These results indicate that augmented polycythemia fails to worsen hypoxic pulmonary hypertension in rats because of a decrease in the severity of structural remodeling.

Chronic inborn erythrocytosis leads to cardiac dysfunction and premature death in mice overexpressing erythropoietin

“…This supports the hypothesis that a gradual increase of hematocrit does not lead to a reduction of cardiac output as observed for acutely raised red cell volume. However, it should be kept in mind that the hematocrit of 0.63 in the experiments of Petit et al 13 was much lower than the hematocrit of our tg mice studied. Blood viscosity increases exponentially with hematocrit.…”

“…In rats, when hematocrit was raised over a 3-week period to a value of 0.63 by the administration of EPO 500 units thrice weekly, 13 mean arterial pressure, left ventricular end-diastolic pressure, right ventricular peak pressure, and cardiac output did not differ from the values in control animals (hematocrit 0.47). This supports the hypothesis that a gradual increase of hematocrit does not lead to a reduction of cardiac output as observed for acutely raised red cell volume.…”

Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α

“…The polycythemia in hypoxic rats by EPO administration did not worsen pulmonary hypertension but instead was associated with decreased vascular remodeling (40).The pathophysiology of hypoxic pulmonary hypertension is exceedingly complex and incompletely understood. As described in the Introduction, several genes whose protein products have been implicated in this process are induced by hypoxia and contain HIF-1 binding sites.…”

Pulmonary artery pressure in chronic obstructive pulmonary disease without resting hypoxaemia

“…20 In contrast, some investigators have reported that augmentation of polycythaemia by exogenous human recombinant erythropoietin failed to worsen the severity of hypoxic pulmonary hypertension in rats. 21,22 As none of the current patients had resting hypoxaemia, the possibility of secondary polycythaemia was very low.…”