The purpose of this proposal is to determine the underlying mechanism and the treatment or prevention of acute myocardial beta-adrenergic receptor (betaAR) desensitization during cardiopulmonary bypass (CPB). Two hypotheses are to be tested, i.e., 1) acute myocardial betaAR sensitization during CPB is localized to the betaAR moiety and results from receptor phosphorylation and 2) intervention with intravenous metoprolol upon initiation of CPB will prevent myocardial betaAR desensitization during CPB. The hypotheses are the result of previous work by the PI who has reported that acute myocardial betaAR desensitization occurs within three hours of CPB. The PI now wishes to elucidate the mechanisms underlying betaAR desensitization by examining which kinases (GRK1-6, and PKA) are present in the human ventricle and atrium and then quantitate changes with CPB at the mRNA level using quantitative PCR and at the protein level using functional assays. The PI also proposes to perform an interventional trial designed to determine if prevention of intraoperative betaAR desensitization by administering IV metoprolol upon initiating cardiopulmonary bypass will prevent or limit postbypass myocardial dysfunction. The examination of the betaAR signal transduction pathway with and without metoprolol using atrial biopsies obtained before and after CPB include the analysis of betaAR number, subtype, functional coupling of receptors to G-proteins, and the determination of adenyl cyclase levels. Clinical outcomes to be assessed include changes in ejection fraction determined by transesophageal echo, level of post-CPB inotropic support, ICU hospital stay, and overall morbidity and mortality. It is anticipated that prevention of myocardial betaAR desensitization during cardiac surgery should lead to enhanced myocardial performance at the time of separation from CPB and use of fewer inotropic drugs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057447-03
Application #
2857908
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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Booth, John V; Ward, Erin E; Colgan, Kelly C et al. (2004) Metoprolol and coronary artery bypass grafting surgery: does intraoperative metoprolol attenuate acute beta-adrenergic receptor desensitization during cardiac surgery? Anesth Analg 98:1224-31, table of contents
Lee, Trevor W R; Grocott, Hilary P; Schwinn, Debra et al. (2003) High spinal anesthesia for cardiac surgery: effects on beta-adrenergic receptor function, stress response, and hemodynamics. Anesthesiology 98:499-510
Hagen, Scott A; Kondyra, Amy L; Grocott, Hilary P et al. (2003) Cardiopulmonary bypass decreases G protein-coupled receptor kinase activity and expression in human peripheral blood mononuclear cells. Anesthesiology 98:343-8
Booth, John V; Spahn, Donat R; McRae, Robert L et al. (2002) Esmolol improves left ventricular function via enhanced beta-adrenergic receptor signaling in a canine model of coronary revascularization. Anesthesiology 97:162-9
Kilts, J D; Gerhardt, M A; Richardson, M D et al. (2000) Beta(2)-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both G(s) and G(i). Circ Res 87:705-9
Booth, J V; Landolfo, K P; Chesnut, L C et al. (1998) Acute depression of myocardial beta-adrenergic receptor signaling during cardiopulmonary bypass: impairment of the adenylyl cyclase moiety. Duke Heart Center Perioperative Desensitization Group. Anesthesiology 89:602-11
Gerhardt, M A; Booth, J V; Chesnut, L C et al. (1998) Acute myocardial beta-adrenergic receptor dysfunction after cardiopulmonary bypass in patients with cardiac valve disease. Duke Heart Center Perioperative Desensitization Group. Circulation 98:II275-81