Energy metabolism disturbances induced by multiple ischemic preconditioning worsen the recovery of cardiac function in reperfusion

Abstract

Single ischelnic preconditioning improves functional recovery of isolated rat heart subjected to global ischemia and reperfusion. Two preconditioning cycles abolish this protective effect, while 4 cycles impair functional recovery of the heart. These phenomena are due to the fact that repetitive ischemic preconditioning reduces the content of phosphocreatine and adenine nucleotides in the heart before long-term ischemia, which prevents the recove13, of energy metabolism and induces additional damage to cardiomyocyte membranes during reperfusion.Key Words: rat heart; preconditioning; pump function; energy metabolism Repeated ischemia and reperfusion episodes protect the hem~ against prolonged ischemic and reperfusion stress. This so-called ischemic preconditioning (IP) is related to a decrease in the rate of phosphocreatine (Per) and ATP utilization and glycogenolysis during long-term ischelnia. This inhibits accumulation of catabolites and the development of acidosis in ischemized tissue and promotes recovery of oxidative respiration and cardiac function during subsequent reperfusion [7]. Most studies do not compare metabolic and functional effects of single and repeated cycles of IP. It was reported that compared to single IP, multiple IP does not improve myocardial protection [1,4,8] and even abolishes its beneficial effect [9,10]. This hinders the study of IP mechanisms and its use in clinical practice. The aim of the present study was to compare the effects of shlgle and multiple IP on functional and metabolic parameters of isolated working heart subjected to global ischemia. The study is focused on the assessment of cardiac function during reperfusion and determination of adenine MATERIALS AND METHODSHearts were isolated under urethane llarcosis (1.6-2.0 g/kg) flom Wistar rats weighing 250-300 g. The hearts were perfused by the method of R. Neely against constant Idling and resistance pressures of 20 and 90 cm H20 , respectively, with a I~'ebs--Henseleit bicarbonate buffer contahahag (in raM): 118 NaCI, 4.7 KC1, 3.0 CaC12, 0.5 Na2-EDTA , 1.2 KH2PO 4, 1.2 MgSO4, 25.0 NaHCO3, and 11.0 glucose, p H 7.4+ 0.1 at 37~ and oxygenated ~vith 95% O~ and 5% CO 2. Left ventricle pressure, coronary flow, and aortal pressure and output were recorded. Volume work was calculated as the product of cardiac output and mean aortal pressure; contractile fnnction was calculated as the product of developed pressure of the left ventricle and heart rate.In the control series the hea1~s were perfused for 50 lnin in a working regime for recording the initial parameters and then subjected to 15-rain global ischelnia and 30-rain reperfusion. The 50-min perfusion period was replaced with 3 types of IP. In the IP-I