Investigations by the P.I. have demonstrated an age-related decrease in norepinephrine (NE) release at the cardiac neuroeffector junction. The pattern of alterations in NE release is gender dependent. Changes in cardiac adrenergic nerve function may provide a useful biomarker of the aging process in both sexes. We are proposing studies which will 1) establish uptake and release of NE and the NE analog metaiodobenzylquanidine (MIBG) from cardiac adrenergic nerves as biomarkers of aging, 2) elucidate the physiologic and molecular mechanisms for the age-related reduction in NE release and the capacity of dietary restriction (DR) and gender to influence NE release, and 3) non-invasively measure age-related changes in adrenergic control of the heart by scintigraphic imaging of the uptake and release of radiolabeled MIBG from cardiac adrenergic nerve terminals in the whole animal. We have found the reduction in NE release is related to a decrease in function of neuronal calcium channels. Prolongation of life span by DR may be due in part to preserving the integrity of neuronal calcium channels during aging and promoting the availability of calcium to stimulate exocytotic release of NE. To explore this hypothesis and to carry out the studies cited above we will use cardiac synaptosome preparations (a technique developed in the P.I.'s laboratory) which permit a molecular approach to the study of adrenergic neurotransmission. NE and MIBG uptake and potassium-induced NE and MIBG release from cardiac synaptosomes will be determined at 6, 12, 18 and 24 months of age in ad lib. and DR fed Fischer 344 and Brown Norway (BN) rats of both sexes. BN is being studied to determine that the results are not strain dependent. We believe these studies will establish NE and MIBG uptake and release as reliable, reproducible, and sensitive biomarkers of aging. The molecular mechanisms responsible for changes in NE release as a function of DR, age and gender will be examined in cardiac synaptosomes by using pharmacological probes which affect calcium channel function and NE release, and by determining the kinetics of 45-Ca2+ movement through neuronal Ca2+ channels. Radiolabeled MIBG will be injected into rats and scintigraphic imaging will be used as a non-invasive means of estimating NE uptake and turnover as a function of DR, age, and gender. We believe that these studies will lead to the development of MIBG uptake and release in the human heart as a valid biomarker for testing future interventions in the aging process.
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