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

Abstract

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.

The time course of salt-induced hypertension, and why it matters

“…48,57,58 Treatments that prevent or limit the response of this system (for example, administration of a mineralocorticoid agonist such as desoxycorticosterone acetate, infusion of exogenous angiotensin II or removal of kidney mass, which limits the upper range of renal salt-excreting capacity) have often been used to increase the acute salt sensitivity of experimental animals. In a similar manner, the impairment of any other system that normally contributes to the ability of renal sodium excretion to adapt to a new level of salt intake (for example, atrial natriuretic peptide, 59 sympathetic activity [60][61][62][63] and nitric oxide 64 ) is also expected to promote salt sensitivity of blood pressure.…”

Recent Aspects in the Genetic Renal Mechanisms Involved in Hypertension.

“…ANFexhibits vasodilation, suppression of plasma renin activity, inhibition of the synthesis and release of aldosterone, and promotes diuresis and natriuresis. In experimental models, ANPknockout mice develop salt-sensitive hypertension (63,64) in part due to their inability to reduce plasma renin activity (64). On the other hand, disruption of the guanylate cyclase-A gene results in salt-resistant hypertension in mice (65).…”

Cardiac hypertrophy in transgenic rats expressing a dominant-negative mutant of the natriuretic peptide receptor B

“…Disruption of the murine NPR-A gene resulted in salt-resistant hypertension, cardiac hypertrophy, and fibrosis (10)(11)(12). Gene targeting of ANP led to salt-sensitive hypertension and cardiac hypertrophy, whereas BNP knockout mice exhibited a marked cardiac fibrosis without hypertension or hypertrophy (13)(14)(15).…”