INCREASED TOLERANCE OF THE CHRONICALLY HYPOXIC IMMATURE HEART TO ISCHEMIA - CONTRIBUTION OF THE K-ATP CHANNEL

Background Hypoxia from birth in immature rabbits increases the tolera nce of isolated hearts to ischemia compared with age-matched normoxic rabbits. We determined whether this increased tolerance to ischemia wa s due to an alteration in the ATP-sensitive potassium (K-ATP) channel and whether increased K-ATP channel activation was associated with inc reases in intracellular lactate. Methods and Results Isolated immature rabbit hearts (7 to 10 days old) were perfused with bicarbonate buffe r at 39 degrees C in the Langendorff mode at a constant pressure. Sali ne-filled latex balloons were placed in the left and right ventricles for measurement of developed pressure. A K-ATP channel agonist (bimaka lim) or a K-ATP channel antagonist (glibenclamide) was added 15 minute s before a global ischemic period of 18 minutes, followed by 35 minute s of reperfusion. Rabbits raised from birth in hypoxic conditions (FIO 2=0.12) displayed significantly enhanced recovery of developed pressur e. The right ventricle was more tolerant of ischemia than the left ven tricle in normoxic and hypoxic hearts. Bimakalim (1 mu mol/L) increase d the recovery of left ventricular developed pressure in normoxic hear ts to values not different from those of hypoxic controls (43+/-3% to 67+/-5%) and slightly increased developed pressure in hypoxic hearts ( 67+/-5% to 72+/-5%). Glibenclamide (3 mu mol/L) abolished the cardiopr otective effect of hypoxia (67+/-5% to 43+/-5%). Constant-flow studies indicated that the effects of bimakalim and glibenclamide were indepe ndent of their actions on coronary flow. Ventricular lactate and lacta te dehydrogenase concentrations were elevated in hypoxic hearts compar ed with normoxic control hearts. Conclusions Increased tolerance to is chemia exhibited by chronically hypoxic rabbit hearts is associated wi th increased activation of the K-ATP channel. This increased K, activi ty may be the result of increased intracellular concentrations of lact ate.