There is considerable evidence indicating that autonomic nervous system control of cardiac function is altered with age. Diminution of neural input with age, and failure of the effector organ to adjust to this alteration, leads to the breakdown of homeostatic mechanisms regulating the heart. It is the primary goal of this study to explore further this hypothesis. We will focus on neurotransmission processes at the adrenergic neuroeffector junction of the heart. To study neurotransmission changes with age, we will concentrate on prejunctional and postjunctional sites. We will explore the contribution of altered release, metabolism, uptake (neuronal and extraneuronal) of norepinephrine (NE), and of altered prejunctional modulation of NE release, to the decline in adrenergic nervous control of the heart. We will also determine the capacity of the heart to adjust its beta adrenergic receptor mechanism to changes in neurotransmission. A new aspect of this proposal is a more direct approach to studying the contribution of postjunctional events to the reduction in cardiac responses to adrenergic influences, with particular emphasis on the capacity of postjunctional beta adrenoceptors to develop super- and subsensitivity in the older heart. Studies of the postjunctional sites will involve experiments with antagonist binding. To study changes in adrenergic neural activity, we propose to determine spontaneous neural activity as reflected by changes in turnover rates of NE, and changes in the release of NE induced by nerve stimulation; the former represents a new area of study, while the latter continues our study of stimulation frequency-dependent release of NE. We will also explore in greater detail the role of extraneuronal uptake mechanisms. The studies will provide information on the effects of aging on various processes of adrenergic neurotransmission at the cardiac neuroeffector junction, as well as help us understand the causes of the breakdown in homeostatic mechanisms between the heart and its adrenergic innervation. The findings will direct attention to potential problems in using therapeutic agents in the elderly that have an effect on the adrenergic neuroeffector junction.
