Angiotensin II receptor expression and inhibition in the chronically hypoxic rat lung

1 Angiotensin II (AII) binding density and the effect of chronic AII receptor blockade were examined in the rat model of hypoxia-induced pulmonary hypertension. 2 [I-125]-[Sar(1),Ile(8)]AII binding capacity was increased in lung membranes from rats exposed to hypoxia (10% fractional inspired O-2) for 7 days compared to normal rats (B-max 108+/-12 vs 77+/-3 fmol mg(-1) protein; P<0.05), with no significant change in dissociation constant. Competition with specific AII receptor subtype antagonists demonstrated that AT(1) is the predominant subtype in both normal and hypoxic lung. 3 Rats treated intravenously with the AT(1) antagonist, GR138950C, 1 mg kg(-1) day(-1) rather than saline alone during 7 days of exposure to hypoxia developed less pulmonary hypertension (pulmonary arterial pressure: 21.3+/-1.7 vs 28.3+/-1.1 mmHg; P<0.05), right ventricular hypertrophy (right/left ventricle weight ratio: 0.35+/-0.01 vs 0.45+/-0.01; P<0.05) and pulmonary artery remodelling (abundance of thick-walled pulmonary vessels: 9.6+/-1.4% vs 20.1+/-0.9%; P<0.05). 4 The reduction in cardiac hypertrophy and pulmonary remodelling with the AT(1) antagonist was greater than that achieved by a dose of sodium nitroprusside (SNP) that produced a comparable attenuation of the rise in pulmonary arterial pressure during hypoxia. 5 The data suggest that AII, via the AT(1) receptor, has a role in the early pathogenesis of hypoxia-induced pulmonary hypertension in the rat.