The mechanism of irreversible cellular damage during myocardial ischemia will be investigated in isolated perfused rat hearts. Preliminary data indicate that high levels of intracellular products of glycogenolysis accelerate the transition from reversible to irreversible damage independent of changes in tissue high energy phosphates. The hypothesis to be tested is that accumulation of glycolytic products (lactate, NADH, H+, etc.) in response to decreased coronary flow and oxidative metabolism initiates a series of secondary reactions that ultimately cause irreversible damage to the tissue. The proposed work will determine the temporal relation between tissue levels of glycolytic products during ischemia and the loss of contractile function in ischemic hearts subsequently reperfused under aerobic conditions. Accumulation of glycolytic products during ischemia will be varied by prior glycogen depletion, maintenance of different rates of ischemic coronary flow with anoxic perfusate and use of glycolytic inhibitors. Studies are proposed to allow identification of the responsible product(s). The temporal relationship between onset of irreversible damage and the appearance of alterations in mitochondrial, sarcolemmal and sarcoplasmic reticular functions will be determined in ischemic tissue exposed to a wide range of intercellular concentrations of glycolytic products to help characterize the mechanisms of glycolytic product induced cellular damage. The concentration of these products will be varied together and individually. Inhibitors of glycolysis will be developed in an attempt to provide prolonged protection to ischemic myocardium.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Geisinger Medical Center
United States
Zip Code
Karmazyn, M; Tani, M; Neely, J R (1993) Effect of prostaglandins I2 (prostacyclin) and F2 alpha on function, energy metabolism, and calcium uptake in ischaemic/reperfused hearts. Cardiovasc Res 27:396-402
Tani, M; Neely, J R (1991) Deleterious effects of digitalis on reperfusion-induced arrhythmias and myocardial injury in ischemic rat hearts: possible involvements of myocardial Na+ and Ca2+ imbalance. Basic Res Cardiol 86:340-54
Morgan, H E; Baker, K M (1991) Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation 83:13-25
Tani, M (1990) Effects of anti-free radical agents on Na+, Ca2+, and function in reperfused rat hearts. Am J Physiol 259:H137-43
Tani, M; Neely, J R (1990) Intermittent perfusion of ischemic myocardium. Possible mechanisms of protective effects on mechanical function in isolated rat heart. Circulation 82:536-48
Tani, M; Neely, J R (1990) Vascular washout reduces Ca2+ overload and improves function of reperfused ischemic hearts. Am J Physiol 258:H354-61
Tani, M; Neely, J R (1990) Mechanisms of reduced reperfusion injury by low Ca2+ and/or high K+. Am J Physiol 258:H1025-31
Tani, M; Neely, J R (1990) Na+ accumulation increases Ca2+ overload and impairs function in anoxic rat heart. J Mol Cell Cardiol 22:57-72
Tani, M (1990) Mechanisms of Ca2+ overload in reperfused ischemic myocardium. Annu Rev Physiol 52:543-59
Tani, M; Neely, J R (1989) Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange. Circ Res 65:1045-56

Showing the most recent 10 out of 11 publications