| Iron-overload cardiomyopathy is a leading cause of cardiovascular morbidity and mortality in the second and third decades of life worldwide, and occurs in patients with common genetic disorders such as hereditary hemochromatosis and beta-thalassemia major. Although the exact mechanism of iron-induced heart failure remains to be elucidated, the toxicity of iron in biological systems is hypothesized to be attributed to its ability to catalyze the generation of reactive oxygen species (ROS). There is preliminary evidence to suggest that non-transferrin-bound iron uptake in the myocardium may occur through L(long)-type calcium channels, and that calcium channel blockers (CCBs) may possess antioxidant properties. This thesis first examines the dose-dependent effects of chronic iron-loading on free radical mediated injury to lipid membranes, as quantified by the production of cytotoxic aldehydes. Secondly, it was hypothesized that the administration of two calcium channel blockers (nifedipine and amlodipine), would decrease iron-uptake in the myocardium, and decrease reactive oxygen species production in a murine model of iron-overload cardiomyopathy. The findings show that there are significant dose-dependent increases in heart tissue concentrations of iron, and ROS production in comparison to control mice in both models. Furthermore, the findings show that nifedipine is partially effective in limiting iron-uptake in the heart, but does not inhibit the production ROS in the heart of chronically iron-loaded mice. Investigations performed with amlodipine show that it also significantly inhibits the production of oxygen free radicals in chronically iron-loaded mice. These findings provide evidence for the first time of the possible iron inhibiting and antioxidant properties of L-type calcium channel blockers in an in-vivo model of chronic iron-overload. |
