Question: 

Salt uptake is an independent risk factor for hypertension. The molecular mechanisms responsible for salt-induced hypertension are ill-defined but it seems clear that a genetic predisposition is required. eNOS polymorphisms seem to be associated with salt-induced hypertension. This hypothesis was tested using heterozygous eNOS mice that display many aspects of eNOS polymorphism.

Methodology: 

eNOS knockout mice were crossed with their corresponding wild-type mice to receive eNOS+/- mice. Salt loading was administered by adding NaCl to tap water at 0,5, 1 und 2 % NaCl (4 or 8 weeks; eNOS+/+: n=9; eNOS+/-: n=19). Control treatment was performed on mice with tap water only (eNOS+/+: n=11; eNOS+/-: n=16).

Results: 

Blood pressure at the start of treatments was similar in male and female eNOS+/+ (119±12 and 120±23 mmHg) and male and female eNOS+/- (129±12 und 132±12 mmHg) but significantly higher in heterozygous eNOS. Administration of 2 % salt loading caused an increase in blood pressure in all female mice (eNOS+/+: 162±23 mmHg; eNOS+/-: 163±19 mmHg). However, male eNOS+/+ tolerated salt loading (122±4 mmHg) whereas male heterozygous eNOS mice did not (163±15 mmHg). Female eNOS+/- developed a strong myocardial hypertrophy (eNOS+/-: HW/BW: 8.56 vs. 6.59 mg/g; ANF mRNA 4.91-fold increased; SERCA2a Expression 0.97-fold of control), developed a strong renal fibrosis and an increase in plasma sodium. The function of cardiomyocytes was improved (dL/L: salt: 9.77 vs. control: 6.08%). Male eNOS+/- developed no myocardial hypertrophy although the increase in blood pressure was similar than in female eNOS+/- (HW/BW: 9.44 vs. 8.95 mg/g; ANP: 1.18-fold). However, they developed a cardial dysfunction (SERCA2a: 0.54-fold). Male eNOS+/- developed a renal hyperfiltration and a moderate increase in plasma sodium.

Conclusion: 

In an experimental model of moderate salt loading we observed sex-specific differences in cardiac and renal adaptation to salt loading in combination with the loss of one eNOS allele underlying genetic variability in the adaptation top salt loading.