This proposal is designed to test the hypothesis that long-term regional biochemical alterations persist in tissue which has healed after experimental transmural or non-transmural ischemic injury, and that some of these changes differ in the 2 models. These studies are based on data from this laboratory demonstrating a region of increased myosin concentration, decreased norepinephrine concentration, decreased B-adrenergic receptor numbers, and increased adenylate cyclase activity in non-infarcted tissues surrounding a healed numbers, and increased adenylate cyclase activity in non-infarcted tissues surrounding a healed transmural scar. Furthermore, regions of increased adenylate cyclase activity correlate anatomically with regions of enhanced eletrophysiologic responsiveness to sympathetic nerve stimulation. The proposed studies will extend these biochemical observations to include detailed studies of regional B and A-adrenergic receptor characteristics, adenylate cyclase activity, phosphatidylinositol turnover, response to pharmacologic intervention. histological measurements of regional cell diameter and infarct size, and autoradiography of B-and A- adrenergic ligand binding in models of transmural and non-transmural healed myocardial infarction. Four specific projects are proposed: 1) analysis of regional B and A- adrenergic receptor numbers and ligand affinity by direct radioligand binding, determination of receptor subtypes and receptor affinity states, in tissues within, surrounding and remote from areas of transmural and non- transmural healed myocardial infarction; 2) effects of regional changes in A and B-adrenergic receptor characteristics on adenylate cyclase activity and phosphatidylinositol turnover, mechanism for altered adenylate cyclase activity and response of altered receptor to pharmacologic interventions after transmural and non-transmural healed myocardial infarction; 3) assessment of regional myocyte diameter and correlation of these findings with infarct size by histologic methods; 4) autoradiographic localization of changes in A and B-adrenergic receptors in transmural and non-transmural healed myocardial infarction. These experiments will lead to a better understanding of quantitative and qualitative regional differences in the biochemical changes after healing of transmural and non-transmural infarction; and at the same time, provide insight into possible biochemical mechanisms which may contribute to the chronic cardiac instabilities observed in healed myocardial infarction.
