Myocardial ischemia is the single most frequent cause of death in the U.S.A. This study will define the sequence of events during ischemia which determine the degree of recovery which can be expected when adequate blood flow is restored. Total ischemia and graded ischemia will be produced in isolated blood perfused interventricular septa from rabbits and rats. The following cellular components will be tested at critical times during ischemia and after reperfusion: sarcolemmal potassium exchange with 42K; sarcolemmal divalent cation permeability with 133Ba and 85Sr; sarcoplasmic reticulum (and sarcolemmal) function with 47Ca; sarcoplasmic reticulum with ryanodine; mitochondrial function with respiration and Ca uptake; and sarcolemmal calcium pumping with vanadate and 47Ca. Tissue high energy phosphate contents, including ATP, will be determined in relation to alterations of each of the cellular functions to test the hypothesis that impairment of function is related to ATP availability. The concept of compartmentation of functions related to ATP production from glycolytic versus mitochondrial sources will be explored. These latter studies will be particularly enhanced by recent observations of increased GTP and ATP production in ischemic muscle perfused with glutamic acid. Ultrastructural studies including freeze fracture studies of the sarcolemma will be performed with Dr. Joy Frank in order to relate morphological alterations of integral membrane proteins and glycocalyx with specific alterations in ionic permeability during ischemia. In this way the role of these structures in ionic binding and channel formation will be explored. A number of interventions shown to be effective in improving recovery of septa after ischemia will be studied. The interventions include glutamate, reduced calcium reperfusion, hypothermia, and elevated Mg (in the rat). A comparative study of rat and rabbit ventricle response to ischemia will be conducted. This comparison will take advantage of the greater sensitivity of rat ventricle to ischemia, its different response to Mg, and the relatively greater role of sarcoplasmic reticulum and/or calcium induced calcium release, in rat heart compared to rabbit heart. The proposed studies will improve the ability to predict the result of myocardial reperfusion in man at surgery or with thrombolysis and to create conditions (during the first minutes of reperfusion) to maximize the recovery of cellular functions.
| Frank, J S; Beydler, S; Wheeler, N et al. (1988) Myocardial sarcolemma in ischemia: a quantitative freeze-fracture study. Am J Physiol 255:H467-75 |
