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The interaction of salt sensitivity and obesity in development of cardiac hypertrophy is incompletely understood. The SHHF/Mcc-fa(cp) (SHHF) rat model was used to examine the effect of high salt on cardiac hypertrophy and expression of endothelin (ET) and nitric oxide synthase (NOS) isoforms. Homozygous lean (+/+) and obese (fa(cp)/fa(cp)) SHHF were fed a low-salt diet (0.3% NaCl) for seven days followed by a high-salt diet (8.0% NaCl) for seven days. To assess the role of ET in mediating cardiac hypertrophy and gene expression with high salt, additional groups were treated with an ET(A)/ET(B) receptor antagonist (bosentan) while on high salt. Obese SHHF showed an increase in systolic blood pressure and cardiac hypertrophy in response to the high-salt diet. High salt resulted in decreased expression of preproET as well as all three NOS isoforms in the Obese, while cytokine induced NOS (iNOS) and neuronal NOS (nNOS) increased in Leans. Though the salt-sensitive component of the hypertension observed in the Obese was prevented by bosentan, cardiac hypertrophy still occurred and expression of all NOS isoforms remained lower in Obese compared to Lean. Endothelial NOS (eNOS) expression increased in the Lean with bosentan. These studies suggest that cardiac hypertrophy is independent of the level of hypertension and may be mediated by altered production of NOS isoforms in salt-sensitive, obese SHHF.

Gender and obesity may influence response to pharmacological modulation of the renin-angiotensin system. We used SHHF/Mcc-fa(cp) rats to study effect of obesity and gender on the ability of an AT1 receptor antagonist to decrease blood pressure. After 2 weeks treatment with irbesartan (50 mg/kg), only lean and obese males showed significant decreases in blood pressure, while obese females were completely resistant. Lean females showed a trend toward lowering of pressure (p=0.06). However, irbesartan similarly shifted angiotensin II dose response curves to the right in all groups. Twelve weeks of irbesartan also failed to decrease blood pressure, but did significantly reduce heart weight in obese females. In untreated rats, obese females had lower plasma renin activity and serum angiotensin converting enzyme activity compared to lean males, while lean and obese females had increased urinary endothelin excretion. Despite an otherwise similar genetic background contributing to hypertension and heart failure, obese females have different patterns of humoral activation compared to lean males, which may contribute to their resistance to the depressor effects of irbesartan.