Abstract MP13: Etamicastat Prevents Arterial Blood Pressure Increase in Mice Lacking Salt-inducible Kinase 1 (SIK1)
Loss of salt-inducible kinase 1 (SIK1) triggers an increase in blood pressure (BP) upon a chronic high-salt intake in mice (Circ Res 2015;116:642-52). Here, we address possible acute mechanisms that may relate to the observed high BP in mice lacking SIK1. SIK1 knockout (sik1-/-) and wild-type (sik1+/+) littermate mice were challenged for seven days with a normal- (0.3% NaCl) or high-salt (8% NaCl) diet. Systolic BP (SBP) was significantly increased in sik1-/- mice (137.0±17.2 mmHg) after seven days of high-salt intake, as compared to sik1+/+ mice counterparts (120.6±4.5 mmHg). The renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) were assayed in order to investigate the possible causes for the increase in SBP in sik1-/- mice fed a high-salt diet. No differences in renin (normal-salt: 463.4±17.9, high-salt: 462.9±28.9 pg/ml) and angiotensin II (normal-salt: 45.8±10.0, high-salt: 39.0±8.5 pg/ml) serum levels were observed. The activity of dopamine β-hydroxylase (DβH), the enzyme that converts dopamine (DA) to norepinephrine (NE), was significantly increased in the adrenal glands of sik1-/- mice fed a high-salt diet (356.7±32.8 nmol/mg protein) as compared to sik1-/- mice on a normal-salt diet (184.4±14.4 nmol/mg protein). Similarly, urinary catecholamines (DA, NE, epinephrine) and L-DOPA were significantly increased (3- to 7-fold increase) in sik1-/- mice fed a high-salt diet as compared to sik1-/- mice on a normal-salt intake. Altogether, this data supports the view that sik1-/- mice fed a high-salt diet develop SNS overactivity. Next, we addressed the question if reducing SNS activity in sik1-/- mice fed a high-salt diet would ameliorate hypertension. For that purpose, the effect of etamicastat, a peripheral reversible DβH inhibitor, was evaluated on the development of high BP upon high-salt diet. Etamicastat treatment (50 mg/kg/day), started prior to high-salt feeding, completely prevented SBP increase in sik1-/- mice fed a high-salt diet (116.8±4.7 mmHg). It is concluded that the SNS is involved in the development of salt-induced hypertension in sik1-/- mice and that the DβH inhibitor etamicastat is able to reduce SNS overactivity and high BP in this mouse model of hypertension.
Author Disclosures: N. Pires: A. Employment; Modest; BIAL - Portela & Cª, S.A. B. Igreja: A. Employment; Modest; BIAL - Portela & Cª, S.A. E. Moura: A. Employment; Modest; BIAL - Portela & Cª, S.A. M. Bonifácio: A. Employment; Modest; BIAL - Portela & Cª, S.A.. P. Serrão: None. P. Soares-da-Silva: None.
- © 2015 by American Heart Association, Inc.