DESCRIPTION: (Adapted from the applicant's abstract) The structurally related norepinephrine analogues [C-11]meta-hydroxyephedrine, [C-11]phenylephrine, and [C-11]epinephrine have been developed as radiotracers for non-invasive imaging studies of cardiac sympathetic innervation using positron emission tomography (PET). Striking alterations in the kinetic behavior of these neuronal tracers have been seen in PET studies of patients with diabetic autonomic neuropathy and heart failure. Associating the altered tracer kinetics with specific neuronal abnormalities has been difficult, as several hypothetical changes in neuronal function could cause such alterations. The major goal of the proposed studies is to correlate changes in the kinetics of these radiotracers to specific neuronal changes in cardiac sympathetic neurons using rat models of diabetic autonomic neuropathy and heart failure. The proposed studies will build on an existing foundation of kinetic studies performed in the isolated working rat heart. Kinetic studies in hearts isolated from rat models of diabetes and heart failure will be used to assess the sensitivity of the tracer kinetics to pathology-induced changes in cardiac sympathetic nerve populations. Following the tracer kinetic studies, direct in vitro measurements of several key components of cardiac sympathetic neurons will be performed in the same hearts to characterize the extent and severity of the pathology-induced neuronal changes. The in vitro studies will include determinations of the densities of neuronal norepinephrine transporters (NET) and vesicular monoamine transporters (VMAT), as well as tissue catecholamine levels. By identifying correlations between the kinetic data and the in vitro findings, insight into the specific underlying causes of perturbations in the tracer kinetics may be gained. This information should assist clinicians, who are studying cardiac sympathetic neurons with these agents, to interpret their clinical findings. In addition, these studies will provide new information concerning the affects of these diseases upon cardiac sympathetic nerve populations.