High salt intake inhibits nitric oxide synthase expression and aggravates hypertension in rats with chronic renal failure

The pathophysiology of hypertension in chronic renal failure is complex, but sodium retention and volume expansion play an important role. High salt intake may aggravate hypertension in chronic renal failure, but the mechanisms of this action are not well established. In this study, we have tested the hypothesis that high salt intake aggravates hypertension in rats with chronic renal failure by decreasing nitric oxide synthase (NOS) expression and by increasing sympathetic nervous system activity. Sprague-Dawley rats were subjected to 5/6 nephrectomy (CRF) or sham-operation and fed a regular rat chow. Half of the rats were allowed to drink distilled water and half water containing 1% NaCl. Blood pressure was measured weekly by tail-cuff. Four weeks after nephrectomy or sham-surgery, animals were sacrificed and brains immediately separated and frozen. Norepinephrine (NE) content and NOS-mRNA gene expression were measured in the posterior hypothalamic (PH) nuclei, the locus coeruleus (LC), the paraventricular nuclei (PVN), and in the mesenteric vessels. The endogenous concentration of NE was greater in the PH, LC, and PVN of CRF rats than it was in control animals both during a normal and a high dietary salt intake. In control and CRF rats, the concentration of NE was greater (p < 0.01) during a high than during a normal salt intake in the PH, LC, PVN, and in the mesenteric vessels. A high salt intake reduced the nNOS-mRNA gene expression in the PH (from 100 +/- 2.4 to 46 +/- 1.0;p < 0.01), LC (from 92 +/- 1.9 to 69 +/- 1.2; p < 0.01) and PVN (from 63 +/- 0.8 to 46 +/- 1.3) of CRF rats. A similar reduction occurred in the PH (from 36 +/- 0.8 to 23.6 +/- 1.2), LC (from 33 +/- 1.4 to 24 +/- 1.1) and PVN (from 37 +/- 1. to 27 +/- 1.0) of control rats. High salt intake significantly reduced the nNOS-mRNA gene expression in the mesenteric arteries of control rats, but not in those of CRF rats. In conclusion, these studies provide evidence that in control and CRF rats, high salt intake inhibits nNOS-mRNA expression in the brain, resulting in activation of the sympathetic nervous system and higher blood pressure.