Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia

J Clin Invest. 1991 Jan;87(1):155-62. doi: 10.1172/JCI114965.


To determine whether exposure to chronic hypoxia and subsequent development of pulmonary hypertension induces alterations of endothelium-dependent relaxation in rat pulmonary vascular bed, we studied isolated lung preparations from rats exposed to either room air (controls) or hypoxia (H) during 1 wk (1W-H), 3 wk (3W-H), or 3W-H followed by 48 h recovery to room air (3WH + R). In lungs pretreated with meclofenamate (3 microM), the endothelium-dependent vasodilator responses to acetylcholine (10(-9)-10(-6) M) and ionophore A23187 (10(-9)-10(-7) M) were examined during conditions of increased tone by U46619 (50 pmol/min). Acetylcholine or A23187 produced dose-dependent vasodilation in control lungs, this response was reduced in group 1W-H (P less than 0.02), abolished in group 3W-H (P less than 0.001), and restored in group 3WH + R. In contrast, the endothelium-independent vasodilator agent sodium nitroprusside remained fully active in group 3W-H. The pressor response to 300 pM endothelin was greater in group 3W-H than in controls (6.8 +/- 0.5 mmHg vs. 1.6 +/- 0.2 mmHg, P less than 0.001) but was not potentiated by the endothelium-dependent relaxing factor (EDRF) antagonists: hydroquinone (10(-4) M); methylene blue (10(-4) M); and pyrogallol (3 x 10(-5) M) as it was in controls. It was similar to controls in group 3W-H + R. Our results demonstrate that hypoxia-induced pulmonary hypertension is associated with a loss of EDRF activity in pulmonary vessels, with a rapid recovery on return to a normoxic environment.

MeSH terms

  • Acetylcholine / pharmacology
  • Animals
  • Blood Pressure / drug effects
  • Calcimycin / pharmacology
  • Chronic Disease
  • Endothelins / pharmacology
  • Endothelium, Vascular / physiology
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / physiopathology*
  • Male
  • Nitric Oxide / physiology*
  • Nitroprusside / pharmacology
  • Pulmonary Circulation*
  • Rats
  • Rats, Inbred Strains


  • Endothelins
  • Nitroprusside
  • Nitric Oxide
  • Calcimycin
  • Acetylcholine