Salt-sensitive hypertension in ANP knockout mice is prevented by AT(1) receptor antagonist losartan

Mice harboring a functional deletion of the pro-atrial natriuretic peptide (ANP) gene (-/-) develop salt-sensitive hypertension relative to their wild -type (+/+) counterparts after prolonged (>1 wk) maintenance on high-salt ( HS, 8% NaCl) diet. We reported recently that the sensitization of arterial blood pressure (ABP) to dietary salt in the -/- mice is associated with fai lure to downregulate plasma renin activity. To further characterize the rol e and mechanism of ANG II in the sensitization of ABP to salt in the ANP "k nockout" mice, we measured ABP, heart rate (HR), and plasma catecholamine a nd aldosterone concentrations in -/- and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT(1) receptor antagonist DuP-753 (lo sartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last wee ks of the dietary regimen. Cumulative urinary excretion of fluid and electr olytes did not differ significantly between genotypes and was not altered b y chronic treatment with losartan. Basal ABP and HR were significantly elev ated in control -/- mice compared with control +/+ mice. Losartan did not a ffect ABP or HR in +/+ mice, but reduced ABP and HR in the -/- mice to the levels in the +/+ mice. Total plasma catecholamine was elevated by approxim ately tenfold in control -/- mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in -/- mice and ab rogated the difference in plasma catecholamine between -/- and +/+ mice on HS diet. Plasma aldosterone did not differ significantly between genotypes and was not altered by losartan. We conclude that salt sensitivity of ABP i n ANP knockout mice is mediated, at least in part, by a synergistic interac tion between ANG II and sympathetic nerve activity.