Abstract 11991: Effects of Clozapine at Different Doses on Blood Pressure and Renal Sodium Transporters in Mice

Abstract

Introduction: one of major side effects of clozapine (common antipsychotic drug) is hypertension. Kidney regulates blood pressure by initiating and responding to renin-angiotensin-aldosterone system (RAAS) physiologically and pathophysiologically;the pathogenesis of hypertension is linked to, generally, the increases in the protein expressions and functions of renal sodium transport proteins along the nephron with or without RAAS activation. Methods: we examined the blood pressures (BP) and protein expressions of major sodium transport proteins profiled along the renal tubules in the C57Bl6/J male mice (9 weeks old, n=4-5/group) treated with clozapine at three doses of 5,10 and 20 mg/ kg for 1 week via intraperitoneal injection. Result: blood pressures (tail-cuff, BP98A, softron, Japan) were higher in clozapine at 20mg/kg/day than vehicle (SBP: 130±1.64 vs 109±1.39, DBP: 87 ±4.12 vs 69±2.10 mmHg, n=5/group) and not altered at 5 & 10 mg/kg/day. BW was similar between groups. There were no differences in serum/urine creatinine and electrolytes except for a slight increase in serum sodium at dose of 20 mg/kg (152.8±0.71 vs 150.6±0.40, mmol/L).The renal protein expressions of NaPi2 (western blotting, 199±26 , % of vehicle), NKCC2(184±20), NCC(213±14), and ENaC-α(217±47)were higher at 20 mg/kg than vehicle. No increases were found in protein expressions of NHE3, αNKA, ENaC-β and ENaC-γ. The expressions of renin, AT1R and ACE at 20mg/kg were similar between groups while ACE2 was decreased (42±10). Renal protein expression of NKCC2 was increased in 5mg/kg (360±80, % of vehicle) and 10mg/kg (247±50) groups; NCC was increased at 5 mg/kg (175±9); α NKA was increased in 5mg/kg (216±5) and 10mg/kg (163±2) groups. Additional mice were treated with clozapine at 20mg/kg/day via osmotic mini-pump for 1 week (mini-pump) or administrated by intraperitoneal injection for 2 weeks (2wks). Increases of renal NKCC2 (mini-pump:180±21, 2wks:153±18) and NCC (mini-pump:171±22, 2 wks:160±23) were also found in those models. Conclusions: increases of renal sodium transport proteins, mainly NCC and NKCC2, contribute to the dose-related increase of BP in mice treated with clozapine and may play an important role in the pathogenesis of theclozapine-induced hypertension.