Increased central AT1-receptor activation, not systemic vasopressin, sustains hypertension in ANP knockout mice

Abstract

We tested the hypothesis that hypertension in atrial natriuretic peptide (ANP) knockout mice is caused in part by disinhibition of angiotensin II-mediated vasopressin release. Inactin-anesthetized F2 homozygous ANP gene-disrupted mice (−/−) and wild-type (+/+) littermates were surgically prepared for carotid arterial blood pressure measurement (ABP) and background intravenous injection of physiological saline or vasopressin V1-receptor antagonist (Manning compound, 10 ng/g body wt) and subsequent intracerebroventricular (left lateral ventricle) injection of saline (5 μl) or ANP (0.5 μg) or angiotensin II AT1-receptor antagonist losartan (10 μg). Only (−/−) showed significant decrease in ABP after intracerebroventricular ANP or losartan. Both showed significant hypotension after intravenous V1 antagonist, but there was no difference between their responses. We conclude that 1) vasopressin contributes equally to ABP maintenance in ANP-disrupted mice and wild-type controls; 2) permanently elevated ABP in ANP knockouts is associated with increased central nervous angiotensin II AT1-receptor activation; 3) disinhibition of central nervous angiotensin II AT1receptors in ANP-deficient animals does not lead to a significant increase in the importance of vasopressin as a mechanism for blood pressure maintenance.