Development of cell injury in sustained acute ischemia

Abstract

Sudden induction of ischemia by occlusion of a major branch of a coronary artery in mammalian heart sets into motion a series of events that culminates in the death of markedly ischemic myocytes. The changes begin within 8-10 seconds of occlusion and include 1) cessation of aerobic metabolism, 2) depletion of creatine phosphate, 3) onset of anaerobic glycolysis (AG), and 4) accumulation of products of anoxic metabolism in the ischemic tissue. Functional defects appear simultaneously, including depressed contractile activity and electrocardiographic changes. The demand of the ischemic myocytes for energy exceeds the supply of high-energy phosphate (approximately P) possible from AG; as a consequence, myocyte adenosine diphosphate increases, and adenylate kinase is activated to capture the approximately P bond of adenosine diphosphate. Adenosine monophosphate is a product of this reaction; it accumulates and is progressively degraded to nucleosides and bases that are lost from the myocyte. The pace of development of the short-term metabolic changes slows after 40-60 minutes of ischemia, at which time most of the severely ischemic myocytes are irreversibly injured. Early in the irreversible phase of injury tissue is characterized as follows by: 1) very low approximately P content (creatine phosphate less than 1-2% and adenosine triphosphate less than 10% of control), 2) a depressed adenine nucleotide pool that consists principally of adenosine monophosphate, 3) virtual cessation of AG, 4) low pH and low glycogen content, 5) high inosine and hypoxanthine contents, 6) a markedly increased osmolar load consisting chiefly of lactate, and 7) characteristic ultrastructural changes including cell swelling and evidence of generalized mitochondrial and marked sarcolemmal damage. Sarcolemmal disruption is the feature that we hypothesize causes irreversibility; however, its pathogenesis is unknown.