SUBSTRATE EFFECTS ON SARCOLEMMAL PERMEABILITY IN THE NORMOXIC AND HYPOXIC PERFUSED RAT-HEART

Objectives: Based on the hypothesis that provision of glucose is good and fatty acids are bad for the ischaemic myocardium, the aims of this study were to determine i) the effects of different substrates on sar colemmal permeability during normoxia, low-flow hypoxia (HLF) and repe rfusion, ii) whether increased membrane permeability is associated wit h ultrastructural damage and increased influx of Ca2+ into cells and i ii) whether changes in membrane permeability correlate with myocardial function and high energy phosphate metabolism. Methods: The isolated rat heart subjected to HLF was used as model of global ischaemia, and sarcolemmal permeability assessed by release of LDH from and influx of lanthanum and Ca2+ into myocardial tissue. Myocyte structural injury was also evaluated quantitatively, and mechanical activity was monitor ed throughout the experimental protocol. Results: Regardless of the su bstrate used, HLF caused a 80 - 90% and 20 - 40% reduction in myocardi al oxygen uptake and coronary flow rate, respectively. Palmitate (0.5 mM conjugated to 0.1 mM albumin) or substrate-free perfusion caused ul trastructural damage and loss of normal sarcolemmal integrity during b oth normoxia and HLF Although reperfusion reversed injury in some cell s, in general, myocytes exhibited myofibrillar contracture, while memb rane integrity recovered to some extent, as indicated by reduced lanth anum influx. Intracellular Ca2+ increased significantly upon reperfusi on. Mechanical function as well as tissue high energy phosphates were significantly depressed during both HLF and reperfusion. Glucose, on t he other hand. protected against ischaemia-induced structural damage a nd loss of sarcolemmal integrity. Reperfusion in these experiments res ulted in almost complete recovery of normal morphology, ultrastructure and sarcolemmal integrity, while intracellular Ca2+ remained unchange d. Mechanical function and tissue high energy phosphates were signific antly higher in glucose-perfused hearts than in palmitate-perfused or substrate-free hearts. Glucose was also able to attenuate the harmful effects of palmitate on myocardial ultrastructure, membrane integrity, mechanical function, energy metabolism and prevented Ca2+ overloading during reperfusion. Conclusion: The results provide new evidence for the protective role of glucose during myocardial ischaemia and reperfu sion. Although the exact mechanism of the beneficial actions of glucos e remains to be established, the results suggest that glycolytic flux and thus glycolytically derived ATP protect against ischaemic damage v ia preservation of membrane integrity.