N‐acetylcysteine Causes Fluid Retention and Heart Failure in F1‐Generation of Mice Derived From a Cross Between Balb/C and C57BL/6J

Abstract

Acute decompensation in heart failure, characterized by reduced cardiac output and fluid congestion, dramatically increases mortality. However, not all patients decompensate and the role of genetic risk factors is not well studied. We have demonstrated that Balb/C mice develop heart failure and edema when treated with angiotensin II (AngII) and high sodium diet while C57BL/6J mice do not. Contrary, adding the antioxidant N‐acetylcysteine (NAc) to AngII and sodium treatment causes heart failure and fluid retention in the previously protected strain, C57BL/6J while Balb/C mice react very little to NAc‐treatment.The present investigation used the first filial (F1)‐generation derived from a cross between Balb/C and C57BL/6J to study heart and kidney function after treatment with either AngII (0.5μg/min/kg) and 3% sodium diet or AngII, 3% sodium diet and different doses of NAc (150, 300, 600 or 1200 mg/kg/24h) for four days. F1‐mice were as resistant to AngII and high sodium treatment as C57BL/6J mice. However, with increased dose of NAc, F1‐mice developed extreme peripheral edema and heart failure. About 80% of the F1‐mice treated with NAc at 1200 mg/kg/24h accumulated fluid under the skin and in the abdominal cavity, while none of the mice treated with AngII and high sodium did. Using echocardiography we could demonstrate that F1‐mice treated with 600 and 1200 mg/kg/24h NAc had reduced cardiac output (Control 21.2 ± 0.7 ml/min vs. 600 mg 15.0 ± 1.3 ml/min p<0.05, Control 21.8 ± 1.1 ml/min vs. 1200 mg 17.5 ± 0.8 ml/min p<0.05) and thickened left posterior wall (Control 0.8 ± 0.03 mm vs. 600 mg 1.04 ± 0.04 mm p<0.05, Control 0.9 ± 0.02 mm vs. 1200 mg 1.05 ± 0.05 mm p<0.05). Urine collection in metabolic cages showed that NAc treatment increased fractional excretion of sodium (Control 0.2 ± 0.03 % vs. 600 mg 3.1 ± 0.9 % p<0.05, Control 0.7 ± 0.2 % vs. 1200 mg 4 ± 0.7 % p<0.05) but did not stimulate fractional excretion of water (Control 0.3 ± 0.04 % vs. 600 mg 1.0 ± 0.3 % p<0.05, Control 0.6 ± 0.1 % vs. 1200 mg 1.0 ± 0.2 % ns). Interestingly, NAc, a well known and widely used antioxidant, increased the oxidative stress in both urine (Control 0.002 ± 0.0005 nmol/24h vs. 600 mg 0.009 ± 0.003 nmol/24h p<0.05, Control 0.003 ± 0.0008 nmol/24h vs. 1200 mg 0.006 ± 0.002 nmol/24h, ns ) and plasma in a dose‐dependent manner up to 1200mg/kg/24h (Control 4.6 ± 0.2 nM vs. 600 mg 5.5 ± 0.5 nM, p<0.05, Control 5.1 ± 0.5 nM vs. 1200 mg 5.9 ± 0.9 nM, ns ). Blood pressure (tail cuff method) was not affected by any of the NAc‐doses, and neither was glomerular filtration rate (GFR) as assessed with FITC‐inulin clearance in awake mice.In conclusion, in F1‐mice derived from a cross between Balb/C and C57BL/6J, the antioxidant NAc induced fluid retention, heart failure and edema. The underlying mechanisms does not seem to be oxidative stress dependent, but may be affected by glutathione metabolism.Support or Funding InformationSwedish heart and lung Foundation, Ake Wiberg Foundation, Swedish society of Medical research