Loss of endothelium-dependent relaxant activity in the pulmonary circulation of rats exposed to chronic hypoxia.
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.
Adnot
S
S
Département de Physiologie, INSERM U 296, Hôpital Henri Mondor, Les Ulis, France.
Raffestin
B
B
Eddahibi
S
S
Braquet
P
P
Chabrier
P E
PE
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002908:Chronic Disease; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D011652:Pulmonary Circulation; D051381:Rats; D011919:Rats, Inbred Strains
D016232:Endothelins; D009599:Nitroprusside; D009569:Nitric Oxide; D000001:Calcimycin; D000109:Acetylcholine