Acute salt loading induces sympathetic nervous system overdrive 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. Here, we further addressed the possible early mechanisms that may relate to the observed rise in BP in mice lacking SIK1. SIK1 knockout (sik1-/-) and wild-type (sik1+/+) littermate mice were challenged with either a high-salt (8% NaCl) or control (0.3% NaCl) diet for 7 days. Systolic BP was significantly increased in sik1-/- mice after 7 days of high-salt diet as compared with sik1+/+ mice and to sik1-/- counterparts on a control diet. The renin-angiotensin-aldosterone system and the sympathetic nervous system were assayed to investigate possible causes for the increase in BP in sik1-/- mice fed a 7-day high-salt diet. Although no differences in serum renin and angiotensin II levels were observed, a reduction in aldosterone serum levels was observed in mice fed a high-salt diet. Urinary L-DOPA and noradrenaline levels were significantly increased in sik1-/- mice fed a high-salt diet as compared with sik1-/- mice on a control diet. Similarly, the activity of dopamine ß-hydroxylase (DßH), the enzyme that converts dopamine to noradrenaline, was significantly increased in the adrenal glands of sik1-/- mice on a high-salt intake compared with sik1+/+ and sik1-/- mice on a control diet. Treatment with etamicastat (50 mg/kg/day), a peripheral reversible DßH inhibitor, administered prior to high-salt diet, completely prevented the systolic BP increase in sik1-/- mice. In conclusion, SIK1 activity is necessary to prevent the development of salt-induced high blood pressure and associated SNS overactivity.

Carbamazepine aggravates absence seizures in two dedicated mouse models.

BACKGROUND: The aim of this study was to evaluate the effect of carbamazepine (CBZ) upon chemically induced absence seizures and in a genetic absence seizures model in the mouse. METHODS: The γ-butyrolactone (GBL)-induced acute absence seizures and the stargazer spontaneous absence seizures mice models were used to characterize the aggravation of absence seizures induced by oral CBZ treatment. The effect of CBZ upon GABA inward-currents in Ltk cells expressing human recombinant α1ß2γ2, α2ß2γ2, α3ß2γ2 and α5ß2γ2 GABAA receptors was evaluated by means of patch clamp. RESULTS: GBL administration induced motor impairment in NMRI mice. High dose CBZ (25mg/kg body weight) had no effect on motor performance but exacerbated the behavioral incoordination observed for GBL. Also, coadministration of a high dose CBZ and GBL impaired spontaneous locomotion. Moreover, CBZ was investigated after oral administration to evaluate the potential to aggravate GBL-induced acute spike-and-wave discharges (SWD) in the electroencephalogram. High dose CBZ significantly aggravated SWD induced by GBL. Likewise, in the stargazer mouse model of genetic spontaneous absence seizures, CBZ significantly aggravated SWD frequency and duration. Pre-treatment with the T-type Ca(2+) channel blocker ethosuximide (200mg/kg body weight) prevented the CBZ aggravation of SWD induced by GBL and in the stargazer mouse. CBZ increased in a concentration dependent manner sub-maximal α1ß2γ2 and α3ß2γ2 GABA currents. CONCLUSION: CBZ aggravates absence seizures as assessed in two dedicated mouse models of absence seizures. Facilitation of sub-maximal α1ß2γ2, and α3ß2γ2 GABA currents by CBZ may play a role in CBZ-induced GABA-mediated aggravation of absence seizures.