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Am J Physiol Regul Integr Comp Physiol 274: R255-R261, 1998;
0363-6119/98 $5.00
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Vol. 274, Issue 1, R255-R261, January 1998

Salt-sensitive hypertension in ANP knockout mice: potential role of abnormal plasma renin activity

L. G. Melo1, A. T. Veress1, C. K. Chong1, S. C. Pang2, T. G. Flynn3, and H. Sonnenberg1

1 Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8; Departments of 2 Anatomy and Cell Biology and 3 Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6

Atrial natriuretic peptide (ANP), a peptide hormone produced by the heart, exerts a chronic hypotensive effect. Knockout mice with a homozygous disruption of the pro-ANP gene (-/-) are incapable of producing ANP and are hypertensive relative to their wild-type (+/+) siblings. Previous studies showed that arterial blood pressure (ABP) was further increased in conscious -/- mice kept for 2 wk on 2% salt, but not in anesthetized -/- mice after 1 wk on 8% salt. To determine whether inconsistencies in observed effects of salt on ABP of -/- mice are due to duration of increased salt intake and/or the state of consciousness of the animals, we measured ABP from an exteriorized carotid catheter during and after recovery from anesthesia with ketamine-xylazine in adult +/+ and -/- mice kept on low (LS; 0.008% NaCl)- or high (HS; 8% NaCl)-salt diets for 3-4 wk. Conscious ABP ± SE (mmHg) of +/+ mice did not differ significantly on either diet (HS, 113 ± 3; LS, 110 ± 5). However, on HS diet -/- mice had significantly higher ABP (135 ± 3; P < 0.001) than both -/- (115 ± 2) and +/+ (110 ± 5) mice on LS diet. Anesthesia decreased ABP in all groups, but the genotype- and diet-related differences were preserved. Plasma renin activity (PRA, ng ANG I · ml-1 · h-1) in blood collected at termination of experiment was appropriately different on the 2 diets in +/+ mice (HS, 4.9 ± 1.9; LS, 21 ± 2.8). However, PRA failed to decrease in -/- mice on HS diet (HS, 18 ± 2.9; LS, 19 ± 3.7). Independent of genotype, concentration of endothelin-1 (ET-1, pg/mg protein) and endothelial constitutive NOS (ecNOS, density/100 µg protein) was significantly elevated in kidneys of mice fed on HS diet (ET-1 -/-, 31 ± 4.7 and +/+, 32 ± 4.1; ecNOS -/-, 160 ± 19 and +/+, 156 ± 19) compared with mice fed on LS diet (ET-1 -/-, 19 ± 1.9 and +/+, 21 ± 1.8; ecNOS -/-, 109 ± 13 and +/+, 112 ± 18). We conclude that, regardless of the state of alertness, -/- mice develop salt-sensitive hypertension after prolonged feeding on HS, in part due to their inability to reduce PRA, whereas the specific renal upregulation of ecNOS and ET-1 in response to HS intake may be an ANP-independent adaptive adjustment aimed at improving kidney function and counteracting the pressor effect of salt.

aldosterone; angiotensin; endothelin-1


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