Dissociation between anti-infarct effect and anti-edema effect of ischemic preconditioning ESTHER SANZ, DAVID GARCfA DORADO, JUAN OLIVER&, JO% A. BARRABfiS, MIGUEL A. GONZALEZ, MARISOL RUIZ-MEANA, JULIA SOLARES, MARfA J. CARRERAS, ANA GARCfA-LAF’UENTE, MANUEL DESCO, AND J. SOLER-SOLER Seruicio de Cardiologia, Hospital General Universitario Vail d ‘Hebron, Barcelona 08035, Spain Sanz, Esther, David Garcia Dorado, Juan Oliveras, Jo& A. Barrabhs, Miguel A. Gonzalez, Marisol Ruiz- Meana, Julia Solares, Maria J. Cameras, Ana Garcia- Lafuente, Manuel Desco, and J. Soler-Soler. Dissociation between anti-infarct effect and anti-edema effect of ischemic preconditioning. Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H233-H241, 1995.-This study tested the hypothesis that preconditioning, by reducing catabolite accumulation during ischemia, reduces osmotic swelling and myocardial necrosis during subsequent reperfusion. Farm pigs were randomly allocated to one of three groups of treatment: a control group undergoing a 48-min coronary occlusion (CO> of the middle left anterior descending artery, a preconditioned group (2 cycles of 5min CO and 5min reperfusion before the 48-min CO), or an intracoronary perfusion group receiving a substrate- free anoxic buffer perfusion into the area at risk between minutes 5 and 10 of the prolonged CO. Animals were killed after 30 min (n = 23) or 6 h (n = 31) of reperfusion. Compared with the control group, both ischemic preconditioning and washout of ischemic by-products by transient anoxic perfusion reduced myocardial edema after 30 min of reperfusion (P < 0.002) by 35 and 32%, respectively, but only ischemic precondi- tioning reduced final infarct size (by 55%, P < 0.006). Myocardial lactate content before reperfusion, measured in an additional series of 12 experiments, was reduced by 35% in animals receiving preconditioning or intracoronary perfusion. Thus ischemic preconditioning has a marked protective effect against reperfusion edema, and this effect can be explained by reduced catabolite accumulation during ischemia. However, there is no evidence from this study indicating that reduced catabolite accumulation and limited reperfusion edema ex- plain the important anti-infarct effect of ischemic precondition- ing. osmotic swelling; catabolite accumulation; catabolite washout; glycolysis ISCHEMIC PRECONDITIONING reduces the extent of myocar- dial necrosis secondary to a prolonged coronary occlu- sion (22). This reduction has been observed in a large variety of experimental models (4, 22, 28, 37), and its magn .itude is greater than that described i.n interven- tions aimed to limit myocardial reperfusion injury. The mechanism responsible for this beneficial effect is not known. The benefit is not explained by increased collat- eral flow (22, 24, 37) but by an improved tolerance to ischemia, reperfusion, or both. It is also independent from myocardial stunning produced by the precondition- ing episodes of ischemia (20,23). Ischemic precondition- ing reduces ATP use and delays depletion of ATP during ischemia, but this delay appears too small to account for the marked protective effect observed on infarct size (1, 13, 24). A series of recent studies has suggested that stimulation of A1 adenosine receptors may be involved in the genesis of myocardial protection induced by isch- emit preconditioning (33). Activation of ATP-sensitive K+ channels could be involved in the protective effect of adenosine (lo), but the precise mechanism linking pre- conditioning to adenosine is not clear (17). Many other proposed mechanisms to explain preconditioning, includ- ing production of endogenous protective substances other than adenosine (16, 36) and changes in gene expression (39>, have not been conclusively tested, whereas increased resistance against oxygen free radi- cals (34) and reduced neutrophil-mediated injury (18) have not received experimental support. It has been hypothesized that reduced accumulation of catabolites during ischemia, due to substrate deple- tion and slowed metabolic activity, could contribute to the improved tolerance of preconditioned myocardium to a prolonged coronary occlusion and reperfusion (2, 13, 24, 38). Reduced accumulation of lactate, hydrogen ion, Pi, and other ischemic by-products could contribute to slower progression of acidosis during ischemia (13, 31), less toxic effects during ischemia and reperfusion (2, 38), and less osmotic cell swelling during reperfusion (9). However, a cause-effect relationship between re- duced catabolite accumulation and infarct size limita- tion has not been established, and the effects of precon- ditioning on osmotic cell swelling induced by reperfusion have not been previously analyzed. The purpose of this study was to investigate the role of reduced catabolite accumulation in the genesis of the beneficial effect of ischemic preconditioning on infarct size. The effects of preconditioning the myocardium with two cycles of 5 min of coronary occlusion and 5 min of reperfusion on myocardial edema and myocardial necrosis secondary to a prolonged coronary occlusion were compared with the effects of intercalating a brief period of intracoronary perfusion with anoxic, substrate- free buffer after the first 5 min of the prolonged coronary occlusion episode. This perfusion was aimed to limit selectively catabolite accumulation by washing out ischemic by-products accumulated during the first min- utes of coronary occlusion. MATERIALS AND METHODS Animalpreparation. Eighty-one large white farm pigs (mean weight 38 kg) were used for this study. Animals were premedi- cated with 10 mg/kg im azaperone (Stresnil, Janssen Pharmaceutical) and aspirin (250 mg iv), anesthetized with 10 mg/kg iv metomidate (Nokemil, Janssen Pharmaceutical), intu- bated, and mechanically ventilated with room air (Monaghan 228 ventilator, Littleton, CO). A continuous infusion of thio- pental was used to maintain anesthesia throughout the experi- ment. The right mammary vein was catheterized with a 19-gauge cannula for intravenous delivery of drugs, and the 0363-6135/95 $3.00 Copyright :(:: 1995 the American Physiological Society HZ33 by 10.220.33.6 on April 6, 2017 http://ajpheart.physiology.org/ Downloaded from