CALCIUM OVERLOAD AND APOPTOSIS IN VASCULAR TOXICITY

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Toxicant-induced cardiovascular disease is an important and useful model for studying pathological and toxicological mechanisms. The goal of this proposal is to define toxicological mechanisms of action for the cardiovascular-specific toxicant allylamine, using well developed and previously described in vivo toxicant-induced models of vascular pathology. The synthetic primary amine allylamine rat model is used to study toxicological mechanisms involved in myocardial necrosis, atherosclerosis and vascular smooth muscle cell death. The role of calcium overload in allylamine-induced myocardial necrosis and atherosclerotic-like lesions will be assessed by administration of stereoisomers of the calcium channel blocker verapamil, and quantification of cardiovascular lesions, aortic physiology and aortic myosin heavy chain isoforms. The aortic medial vascular smooth muscle toxicity resulting from biochemical manipulation of allylamine intoxication (i.e., combination with beta-aminopropionitrile, phenelzine or hydralazine) will be characterized as either apoptosis or cellular necrosis. Apoptosis will be quantified via aortic in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and aortic DNA fragmentation by gel electrophoresis and enzyme- linked immunoassay (ELISA). These studies will aid in understanding the mechanisms of xenobiotic amine toxicity and the pathogenesis of cardiovascular disease.