Cardiovascular measurements relevant to heart size in copper-deficient rats.

Dietary copper deficiency in animals is often associated with cardiac enlargement and anemia. In this study we examined the hypothesis that anemia leads to a high cardiac output state that results in work-induced (physiological) cardiac hypertrophy. Blood pressure was measured by carotid cannulation and cardiac output was measured by aortic flow probe in anesthetized, open-chested rats that had been subjected to various degrees of dietary copper deficiency for five weeks. Cardiac output was unaffected by dietary copper deficiency. However, the components of cardiac output were found to vary reciprocally, heart rate decreasing and stroke volume increasing with copper deficiency. Further, total peripheral resistance, calculated as the ratio of mean arterial blood pressure and cardiac output, was depressed by dietary copper deficiency. These findings suggest that bradycardia and depression of vascular resistance induced by copper deficiency contribute to increased venous filling and a resultant increase in stroke volume; these factors may lead to cardiac hypertrophy. A significant correlation between stroke volume and heart weight in rats of varying copper status supports this conclusion.

Early and advanced glycation end-products are increased in dietary copper deficiency.

The hypothesis that nonenzymatic glycosylation of proteins (glycation) contributes to damage associated with dietary copper deficiency has depended largely on indirect evidence. Thus far, the observation of an elevated percentage of glycated hemoglobin in copper-deficient rats has provided the only direct evidence of an increase in glycation. We sought further direct evidence of increased glycation in copper deficiency. Male weanling rats were fed a copper-adequate (CuA, 6.4 mg Cu/kg diet) or copper-deficient diet (CuD, 0.4 mg Cu/kg diet) for 5 weeks. Rats fed the CuD diet were copper deficient as judged by depressed organ copper concentrations and a variety of indirect indices. Measurements of hemoglobin A(1) and serum fructosamine (both early glycation end-products) as well as serum pentosidine (an advanced glycation end-product) indicated that all three compounds were elevated in CuD rats relative to CuA rats. This finding further supports the view that glycation is enhanced and thus may contribute to defects associated with dietary copper deficiency.

Defects of copper deficiency in rats are modified by dietary treatments that affect glycation.

We examined the hypothesis that nonenzymatic glycosylatin of proteins (glycation) contributes to the defects of copper deficiency. We studied copper-adequate and -deficient rats while altering two factors known to affect glycation: type of dietary carbohydrate and amount of food intake. Copper deficiency caused cardiac enlargement and anemia, decreased erythrocyte osmotic fragility, enhanced heart lipid peroxidation, increased the percentage of glycated hemoglobin (Hb A1) and reduced staining of lens crystallins on SDS-PAGE gels (suggestive of glycation). Increasing dietary sucrose reduced organ copper concentration, exacerbated the rise in Hb A1 and worsened the anemia caused by copper deficiency. Food restriction ameliorated heart and erythrocyte defects, reduced the percentage of glycated hemoglobin and heart peroxidation and also improved heart and liver copper status in copper-deficient rats. These findings indicate that copper deficiency enhances glycation and that sucrose may exacerbate some defects of copper deficiency by enhancing glycation. Inhibition of defects of copper deficiency by food restriction suggests that glycation and/or peroxidation may contribute to those defects.