The goals of this proposal are to characterize pathogenetic factors which contribute to catecholamine-induced cardiomyopathy and assess their relationship to insulin deficient diabetes mellitus. The methods are designed to define etiologic mechanisms in terms of metabolism, tissue chemical analysis and morphology, and to relate these changes to alterations in functional properties of myocardium. We have shown that alpha adrenergic pathways are involved in the development of myofiber injury. Presently unclear is whether this relates to increased coronary resistance (ischemia?) or primary injury to myofiber membrane systems. A newly developed isolated working rabbit heart system using red cell enhanced buffer perfusate will be employed. Preliminary studies indicate levels of coronary flow, MVO2, and mechanical performance comparable to in vivo preparations. Measurements will include 02 and substrate utilization, high energy phosphates, and marker enzymes of glucose and palmitate utilization. Determinants of coronary regulation will be examined in each model. Experiments are designed to identify these potential mechanisms as primary or cofactors in the genesis of myocyte damage and their relationship to the insulinopenic diabetic state. Immediate effects of acute catecholamine exposure in concentrations known to produce myofiber injury will be determined. Studies will also be done to explore the hypothesis that repeated episodes of myofiber injury by adrenergic agonist will lead to progressive myofiber loss, reduced cardiac performance and the appearance of heart failure. It is anticipated that diabetic animals will exhibit enhanced sensitivity to catecholamine damage, with earlier and more severe functional deterioration. We have shown that endogenous release of catecholamines evoked by tyramine produces identical cardiac lesions. Studies are proposed to determine catecholamine distribution and concentrations, effects of catecholamine depletion with reserpine, morphologic and functional consequences of repeated release episodes, and the relationship of each of these to the diabetic state. The reversibility (or progression) of functional metabolic and biochemical changes will be examined, and the effects of insulin replacement in the diabetic animals subjected to catecholamine challenges will be determined.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL020401-09A2
Application #
3336133
Study Section
Cardiovascular Study Section (CVA)
Project Start
1976-09-01
Project End
1990-04-30
Budget Start
1987-05-01
Budget End
1988-04-30
Support Year
9
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Offstad, J; Kirkeboen, K A; Ilebekk, A et al. (1994) ATP gated potassium channels in acute myocardial hibernation and reperfusion. Cardiovasc Res 28:872-80
Downing, S E (1993) Wall tension and myocardial dysfunction after ischemia and reperfusion. Am J Physiol 264:H386-93
McGowan Jr, F X; Lee, F A; Chen, V et al. (1992) Oxidative metabolism and mechanical function in reperfused neonatal pig heart. J Mol Cell Cardiol 24:831-40
Downing, S E; Chen, V (1992) Effects of catecholamine stimulation on myocardial hibernation. Am Heart J 123:589-96
Downing, S E; Chen, V (1992) Acute hibernation and reperfusion of the ischemic heart. Circulation 85:699-707
Jiang, J P; Chen, V; Downing, S E (1991) Modulation of catecholamine cardiomyopathy by allopurinol. Am Heart J 122:115-21
Downing, S E; Chen, V (1990) Myocardial hibernation in the ischemic neonatal heart. Circ Res 66:763-72
Jiang, J P; Downing, S E (1990) Catecholamine cardiomyopathy: review and analysis of pathogenetic mechanisms. Yale J Biol Med 63:581-91
Chen, V; Chen, Y H; Downing, S E (1987) An improved isolated working rabbit heart preparation using red cell enhanced perfusate. Yale J Biol Med 60:209-19
Downing, S E; Chen, V (1986) Dissociation of adenosine from metabolic regulation of coronary flow in the lamb. Am J Physiol 251:H40-6

Showing the most recent 10 out of 17 publications