Effect of sarcolemmal anion transport system blockers on the development of ischemia-induced myocardial edema and recovery of contractile function during reperfusion

Abstract

Subtotal 30-min ischemia leads to myoglobin release and increases water content in the heart. Reperfusion partially restores the developed pressure. Addition of furosemide (a Na +, K+,2CI --symport blocker) or NMA (inhibitor of Na § to perfusate decreases myocardial water content, reduces myoglobin loss, and completely restores myocardial contractile function. The low-rate perfusion of isolated heart and its reperfusion with solutions containing DIOA (inhibitor of K+,C1--co-transport) or IAA-94 (C1-channel blocker) increases water accumulation and myoglobin release from the myocardium, and deteriorated its contractile function during reperfusion.Key Words: myocardial ischemia; edema; Na+, K+, Na+/H § K+, amiloride derivatives Similar to other cells, cardiomyocytes possess a system regulating their volume [4,6,7,10]. The volume regulation system is activated by swelling or shrinkage of cardiomyocytes [10,13,14]. An increase in the cardiomyocyte volume stimulates efflux of the osmotically active substances (osmolytes) from the cells, which decreases the amount of intracellular water. An important role in this process is played by CI-channels and K+,2Cl--symport. The decrease of the cell volume is accompanied by opposite processes: entry of CI-, Na +, and K § into the cytoplasm via Na+,K +, 2Cl--uniport and Na § via Na+/H+-exchange [7,10,13].A decrease in the coronary blood flow modulates activity of proteolytic and lipolytic enzymes, induces accumulation of metabolic products in the ischemic region, and activates Na+/H+-exchange [2,8,9,15]. These changes may form the basis for an increase in the intracellular osmotic pressure and water entry into the cytoplasm [1,5,11]. It is supposed that extreme cardiomyocyte swelling may be a cause of mechanical rupture of the sarcolemma [6,12]. Department of Biochemistry, Voronezh State Medical AcademyThe role of sarcolemmal anion-transporting mechanisms (CI-channels, K+,C1 --and K+,Na+,2C1--symport, and Na+/H+-exchange) in the development of cardiomyocyte edema and their ischemic and reperfusion damage is not clear. Our aim was to study the effects of these ion-exchange sarcolemmal systems on myocardial edema during subtotal ischemia and reperfusion. MATERIALS AND METHODSExperiments were performed on hearts perfused according to the Langendorff technique. Random-bred albino rats were decapitated under ether narcosis, the hearts were isolated and placed into cold Ringer--Lock solution. The initial solution contained (in mM): 140 NaC1, 0.5 NaH2PO 4, 5 KCI, 5 Tris-OH (pH 7.4), 11 glucose, and 2 CaCI z. The heart was perfused with oxygenated solution through cannulated aorta at the rate of 10 ml/min/g wet tissue at 37~ To stabilize the contractile activity, the heart was perfused with initial solution for 15 min. The cardiac parameters during this period were considered as control (100%). Subtotal ischemia was modeled by reducing the perfusion 0007-4888/99/0004-0363522.00 e1999 Kluwer Academic/Plenum Publishers