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 AT₁ receptors in ANP-deficient animals does not lead to a significant increase in the importance of vasopressin as a mechanism for blood pressure maintenance.