Hypoxia reduces atrial natriuretic peptide clearance receptor gene expression in ANP knockout mice

We tested the hypotheses that hypoxic exposure is associated with exacerbated pulmonary hypertension and right ventricular (RV) enlargement, reduced atrial natriuretic peptide (AMP) clearance receptor (NPR-C) expression, and enhanced B-type natriuretic peptide (BNP) expression in the absence of AMP. Male wild-type [AMP(+/+)], heterozygous [AMP(+/-)], and homozygous [AMP(-/-)] mice were studied after a 5-wk hypoxic exposure (10% O₂). Hypoxia increased RV AMP mRNA and plasma AMP levels only in AMP(+/+) and AMP(+/-) mice. Hypoxia-induced increases in RV pressure were significantly greater in AMP(-/-) than in AMP(+/+) or AMP(+/-) mice (104 ± 17 vs. 45 ± 10 and 63 ± 7%, respectively) as were increases in RV mass (38 ± 4 vs. 26 ± 5 and 29 ± 4%, respectively). NPR-C mRNA levels were greatly reduced in the kidney, lung, and brain by hypoxia in all three genotypes. RV BNP mRNA and lung and kidney cGMP levels were increased in hypoxic mice. These findings indicate that disrupted AMP expression worsens hypoxic pulmonary hypertension and RV enlargement but does not alter hypoxia-induced decreases in NPR-C and suggest that compensatory increases in BNP expression occur in the absence of AMP.