Salt-sensitive hypertension in ANP knockout mice is prevented by AT₁ receptor antagonist losartan

Abstract

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 failure to downregulate plasma renin activity. To further characterize the role and mechanism of ANG II in the sensitization of ABP to salt in the ANP “knockout” mice, we measured ABP, heart rate (HR), and plasma catecholamine and aldosterone concentrations in −/− and +/+ mice maintained on HS for 4 wk and treated with daily injections of AT1 receptor antagonist DuP-753 (losartan) or distilled water (control). Daily food and water intake and fluid and electrolyte excretion were also measured during the first and last weeks of the dietary regimen. Cumulative urinary excretion of fluid and electrolytes did not differ significantly between genotypes and was not altered by chronic treatment with losartan. Basal ABP and HR were significantly elevated in control −/− mice compared with control +/+ mice. Losartan did not affect 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 approximately ten-fold in control −/− mice compared with control +/+ mice. Losartan reduced plasma catecholamine concentration significantly in −/− mice and abrogated 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 in ANP knockout mice is mediated, at least in part, by a synergistic interaction between ANG II and sympathetic nerve activity.

Blood sampling methodology is crucial for precise measurement of plasma catecholamines concentrations in mice

“…Catheterization of the carotid artery remains the reference blood sampling method for catecholamine determination in mouse plasma. With arterial catheterization both NE and E concentrations appeared to be lower when compared to the other bleeding methods and are in the same range of those found by others using this methodology [7,13]. Nevertheless, the retro-orbital bleeding method for catecholamine determination is, in our opinion and based on results presented herein, of value.…”

“…Using these different procedures norepinephrine (NE) and epinephrine (E) plasma concentrations ranged from 4 nM to 140 nM ( Table 1). The lowest concentration of catecholamines (5 nM) was observed when an intra-arterial catheter was used [13] with apparently no effect of the anesthetic tribromoethanol, although E levels were not reported in this study [7]. In plasma samples obtained by tail vein incision, the concentration of catecholamines was 14 nM [11].…”

Angiotensin II Blockade Reverses Myocardial Fibrosis in a Transgenic Mouse Model of Human Hypertrophic Cardiomyopathy

“…This dose has been shown to reduce myocardial fibrosis in a variety of experimental models without significantly affecting blood pressure or heart rate. 8 Mice were weighed and water consumption was measured to calculate the precise daily intake of losartan. …”

Natriuretic peptide receptor B signaling in the cardiovascular system: protection from cardiac hypertrophy

“…In addition, NBR-BΔKC rats displayed elevated renin levels (own unpublished data), most likely as a result of enhanced sympathetic nerve activity in this model. This function seems to be specific for NPR-B, as it has not been found in genetic mouse models with altered ANP or NPR-A signaling [111,112]. Further studies are necessary to determine whether CNP-mediated and NPR-B play an exclusive role in controlling cardiovascular functions by regulating the autonomic nervous system, including regulation of renin secretion, and to distinguish direct effects on cardiomyocytes from indirect effects involving modulation of vagal and sympathetic nerve activity.…”