C. K. Chong

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

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.

Body fluid volume status and the renal response to atrial natriuretic peptide in rats

The effect of altering the volumes of different body fluid compartments on the renal response to atrial natriuretic peptide (ANP) was studied in anesthetized rats before and during administration of the peptide at 170 ng/min. Four different groups were used. In the first (De), reduction of total body water content was induced by 48 h water deprivation. In the second (De+NaCl), an acute intravenous infusion after the same 48 h dehydration was used to restore the extracellular, but not the intracellular, fluid compartment. In the third (Eu+NaCl), euvolemic rats were infused with isotonic saline at the same rate as in group De+NaCl to expand both intravascular and interstitial components of extracellular fluid. In the fourth group (Eu+BSA) an infusion of hyperoncotic (6%) bovine serum albumin in isotonic saline was used to expand the intravascular volume while contracting the interstitial volume. Excretion of water and salt was predictably reduced in the De group compared with the others. This reduction was associated with increased tubular reabsorption, both upstream from the medullary collecting duct and in the duct itself. Administration of ANP did not significantly affect diuresis and saluresis, or tubular transport. By contrast, there were marked and similar diuretic and natriuretic responses to ANP in groups De+NaCl and Eu+NaCl, associated with transport inhibition primarily in the medullary collecting duct. Surprisingly, the rats infused with hyperoncotic solution (Eu+NaCl) also failed to show marked excretory or duct transport responses to ANP. According to the study design, the two nonresponding groups had, respectively, a decreased or a normal intracellular compartment, and a decreased or increased plasma volume. The common feature of both nonresponding groups was a decreased interstitial fluid compartment, whereas the two responding groups had normal or increased interstitial volume. We suggest, therefore, that a replete interstitial fluid compartment is essential for the renal response to ANP.