High salt diet is associated with increased risk of adverse cardiovascular events due to its effects on blood pressure, vascular stiffening, and fibrosis. The kidney maintains Na+ homeostasis in times of dietary excess by excreting it in urine. Additionally, the brain’s thirst centers sense excess Na+ and increase water intake. Recent work showed mice given high Na+ loads, provided in chow and water, have changes in glucocorticoid, mineralocorticoid, and urea production that lead to increased free water absorption, conservation of fluid with less water intake, and a switch to a catabolic state. However, mice given a salt load were not followed beyond a few weeks of treatment nor were the same results seen when free access to water was given. Therefore, we were interested in the metabolic changes that occur with long‐term dietary Na+ manipulation with free access to water. Mice were fed an 8% NaCl diet (HSD) beginning at~10 weeks of age and given free access to water. After three months, the HSD mice weighed significantly less than the controls (30.1±2.4g vs 33.3±2.8g), and this trend continued through 16 months of HSD treatment when the HSD animals weighed ~10g less than the controls (33.8±1.7g vs 44.8±7.4g). At 12 months, the HSD group consumed more food (19.9±1.0g vs 11.7±0.5g), therefore the weight loss cannot be accounted for through consumption. The HSD cohort also consumed more water (14.5±3.5mL vs 2.0±0.4mL) and produced more urine (16.4±2.7mL vs 4.0±0.2mL) than their control counterparts. At both 8 months and 16 months, the blood urea nitrogen levels in the HSD treated animals were significantly lower, suggesting these animals did not have increased urea production. Additionally, the HSD mice had 12.8% body fat at 8 months treatment as compared to 25.0% body fat in age‐matched controls. However, lean mass by weight was not significantly different between the HSD and control animals (27.9±0.4g vs 28.7±0.4g), suggesting there was no muscle wasting due to salt consumption. To address the physiological mechanism by which high salt intake reduced body fat and weight, mice were studied in metabolic cages to measure the major determinants of energy balance after just 5 weeks HSD, prior to the divergence in body weight. There was no difference in feeding between groups, however water intake was significantly elevated in the HSD animals. Total activity also did not differ between the HSD and control animals. Energy expenditure was significantly increased in HSD mice during the light cycle and there was a strong trend towards increased 24 hour energy expenditure (P=0.09). Finally, the respiratory quotient was significantly reduced in the HSD cohort during both the light and dark cycles, demonstrating increased whole‐body fat oxidation. Taken together, these data demonstrate that animals given an increased salt load have a higher metabolic demand and increased fatty acid oxidation, which were associated with reduced body weight and adiposity. These results suggest that the effects of sodium extend beyond blood press...

Percutaneous transluminal coronary angioplasty (PTCA) has greatly benefited patients with occluded coronary arteries, but its benefits have been undermined by a high incidence of restenosis. The introduction of coronary stents has significantly improved the short and long term outcome but restenosis still occurs in approximately 15 to 30% of patients within 6 months. Research efforts are now being directed toward combination stenting and drug delivery. Among the therapeutic targets being pursued are agents that can impede smooth muscle cell migration and proliferation, as these processes are critical components of restenosis injury. We propose that inhibiting the conversion of ribonucleotides to deoxyribonucleotides will impede cell proliferation and, as such, limit the degree of restenosis. Therefore, we tested whether the potent ribonucleotide reductase inhibitors Didox (3,4-dihydroxybenzohydraxamic acid) and Imidate (ethyl-3,4,5-hydroxybenzimidate) can limit the neointimal proliferation associated with restenosis using a rat carotid model of balloon dilatation injury. Results demonstrated that both Didox and Imidate significantly reduced intimal thickening, resulting in a 71 and 62% decrease in the intima/media ratio, respectively. Similar efficacy was seen with the commercially available ribonucleotide reductase inhibitor hydroxyurea, demonstrating the importance of this enzyme in vascular remodeling. Results from cell proliferation studies suggest that the mechanism of protection is inhibition of smooth muscle cell (SMC) proliferation. In addition, Didox and Imidate (100 M) are potent inhibitors of SMC migration, which may also contribute to their vascular protective effects. These results suggest that inhibition of ribonucleotide reductase may provide a potent strategy to prevent post-PTCA restenosis.