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(Circulation. 1997;95:1278-1285.)
© 1997 American Heart Association, Inc.

Articles

Increased Tolerance of the Chronically Hypoxic Immature Heart to Ischemia

Contribution of the K_ATP Channel

John E. Baker, PhD; Brian D. Curry, MS; Gordon N. Olinger, MD; Garrett J. Gross, PhD

the Departments of Pharmacology and Toxicology (J.E.B., B.D.C., G.J.G.) and Cardiothoracic Surgery (J.E.B., G.N.O.), Medical College of Wisconsin, Milwaukee.

Correspondence to John E. Baker, PhD, Department of Cardiothoracic Surgery, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail jbaker{at}post.its.mcw.edu

Background Hypoxia from birth in immature rabbits increases the tolerance of isolated hearts to ischemia compared with age-matched normoxic rabbits. We determined whether this increased tolerance to ischemia was due to an alteration in the ATP-sensitive potassium (K_ATP) channel and whether increased K_ATP channel activation was associated with increases in intracellular lactate.

Methods and Results Isolated immature rabbit hearts (7 to 10 days old) were perfused with bicarbonate buffer at 39°C in the Langendorff mode at a constant pressure. Saline-filled latex balloons were placed in the left and right ventricles for measurement of developed pressure. A K_ATP channel agonist (bimakalim) or a K_ATP channel antagonist (glibenclamide) was added 15 minutes before a global ischemic period of 18 minutes, followed by 35 minutes of reperfusion. Rabbits raised from birth in hypoxic conditions (FIO₂=0.12) displayed significantly enhanced recovery of developed pressure. The right ventricle was more tolerant of ischemia than the left ventricle in normoxic and hypoxic hearts. Bimakalim (1 µmol/L) increased the recovery of left ventricular developed pressure in normoxic hearts 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 µmol/L) abolished the cardioprotective effect of hypoxia (67±5% to 43±5%). Constant-flow studies indicated that the effects of bimakalim and glibenclamide were independent of their actions on coronary flow. Ventricular lactate and lactate dehydrogenase concentrations were elevated in hypoxic hearts compared with normoxic control hearts.

Conclusions Increased tolerance to ischemia exhibited by chronically hypoxic rabbit hearts is associated with increased activation of the K_ATP channel. This increased K_ATP activity may be the result of increased intracellular concentrations of lactate.

Key Words: cardiovascular diseases • heart defects, congenital • hypoxia • ions • ischemia

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