Pulmonary vascular dysfunction secondary to pulmonary arterial hypertension: insights gained through retrograde...

Here, we tested the hypothesis that severe pulmonary arterial hypertension impairs retrograde perfusion. To test this hypothesis, pulmonary arterial hypertension was induced in Fischer rats using a single injection of Sugen 5416 followed by 3 wk of exposure to 10% hypoxia and then 2 wk of normoxia. This Sugen 5416 and hypoxia regimen caused severe pulmonary arterial hypertension, with a Fulton index of 0.73 ± 0.07, reductions in both the pulmonary arterial acceleration time and pulmonary arterial acceleration to pulmonary arterial ejection times ratio, and extensive medial hypertrophy and occlusive neointimal lesions. Whereas the normotensive circulation accommodated large increases in forward and retrograde flow, the hypertensive circulation did not. During forward flow, pulmonary artery and double occlusion pressures rose sharply at low perfusion rates, resulting in hydrostatic edema. Pulmonary arterial hypertensive lungs possessed an absolute intolerance to retrograde perfusion, and they rapidly developed edema. Retrograde perfusion was not rescued by maximal vasodilation. Retrograde perfusion was preserved in lungs from animals treated with Sugen 5416 and hypoxia for 1 and 3 wk, in lungs from animals with a milder form of hypoxic hypertension, and in normotensive lungs subjected to high outflow pressures. Thus impaired retrograde perfusion coincides with development of severe pulmonary arterial hypertension, with advanced structural defects in the microcirculation.