AUTONOMIC RECEPTOR FUNCTION IN LV HYPERTROPHY & FAILURE

首席研究员和她的同事已经确定

The principal investigator and her colleagues have identified several alterations in beta-adrenergic and muscarinic receptor function and adenylate cyclase activity in left ventricular hypertrophy and failure. These include: 1) decreases in the beta- adrenergic receptor high affinity agonist binding sites in left ventricular failure, 2) decrease in muscarinic receptor density in left ventricular failures, 3) decreased adenylate cyclase activity in left ventricular failure, and 4) decreased muscarinic inhibition of adenylate cyclase activity in left ventricular failure. The first goal of this application is to delineate the biochemical mechanisms underlying these alterations. This will be accomplished by 1) identifying a potentially altered receptor- protein by photoaffinity labelling of the beta-adrenergic receoptor and two dimensional electrophoresis to identify the molecular weight and isoelectric point of the beta-adrenergic receoptor in theleft ventricular of animals with left ventricular hypertrophy and failure, 2) to examine guanine nucleotide regulatory protein function in left ventricular hypertrophy and failure. The second goal of this application is to define the time course and generality of the defects. This will be accomplished by examining 1) another model of left ventricular hypertrophy, i.e. renal hyeprtension, 2) the progression of changes in high affinity beta-adrenergic and muscarinic agonist binding, muscarinic density and modulation of adenylate cyclase activity and functions as left hypertrophy progresses from mild to severe left ventricular hypertrophy, 3) changes in beta2-adrenergic receptors in normal, left ventricular hypertrophy, and failure, 4) changes in alpha-adrenergic receptors. The third goal of the present application is to determine the selectivity of defects for cardiac muscle by using a purified sarcolemma preparation and finally the study of isolated myocytes to remove most of the non- myocyte tissue before preparing membranes. It is proposed that these studies will enhance our understanding at the cellular levle, of one of the most important problems in clinical cardiology, i.e., left ventricular hypertrophy and heart failure.