Cardiac noradrenergic nerve terminal function is abnormal in the failing heart. Both presynaptic and postsynaptic abnormalities have been observed. They include norepinepbrine (NE) depletion, reduced neuronal NE uptake activity, increased interstitial NE, f3-adrenoceptor down-regulation and deterioration of cardiac function. Since the changes are associated with a decrease of nerve growth factor (NGF), and can e prevented by antioxidant vitamins, this application is designed to elucidate the relative roles of oxidative stress and NGF on the adrenergic nerve terminal function and cardiac function in heart failure. We will measure the protein and mRNA expressions of cardiac NGF, NGF receptor TrKA, tissue oxidative stress (oxidized glutathione, hydroxyl free radicals, mitochondria DNA oxidation products) and myocyte apoptosis in pacing-induced cardiomyopathy. The findings will be correlated to the presynaptic myocardial NE uptake site density, NE histofluorescence, tyrosine hydroxylase profiles, as well as the postsynaptic myocardial B-adrenoceptor density and B-adrenergic sensitivity and cardiac function. Superoxide dismutase and selegiline, which have been shown to prevent cardiac sympathetic nerve abnormalities in heart failure, will be used to determine whether their effects are mediated via reductions of cardiac NE release and oxidative stress, and/or preservation of cardiac NGF. Studies also will be performed to determine if the beneficial effects of carvedilol in heart failure are mediated via its blocking actions on the a- or f3-receptors, or related causally to its antioxidant effect. Studies have shown that NE reduces cardiac NGF by an a-receptor action, whereas its apoptotic effects are mediated via the B-receptors Finally, a NGF minigene will be injected directly into the heart to determine if it will produce salutary effects on sympathetic nerve endings and cardiac function. Our research will not only elucidate the mechanisms responsible for noradrenergic nerve ending dysfunction, but also provide a potentially useful new modality for the treatment of heart failure.
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