慢性低氧未成熟心脏对缺血耐受性的增加。ATP敏感性钾通道的作用。

Increased tolerance of the chronically hypoxic immature heart to ischemia. Contribution of the KATP channel.

作者信息

Baker J E, Curry B D, Olinger G N, Gross G J

机构信息

Department of Pharmacology, Medical College of Wisconsin, Milwaukee 53226, USA.

出版信息

Circulation. 1997 Mar 4;95(5):1278-85. doi: 10.1161/01.cir.95.5.1278.

DOI:10.1161/01.cir.95.5.1278

PMID:9054860

Abstract

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 (KATP) channel and whether increased KATP 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 degrees 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 KATP channel agonist (bimakalim) or a KATP 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 mumol/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 mumol/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 KATP channel. This increased KATP activity may be the result of increased intracellular concentrations of lactate.

摘要

背景

与年龄匹配的常氧兔相比，未成熟兔出生时的缺氧增加了离体心脏对缺血的耐受性。我们确定这种对缺血耐受性的增加是否归因于三磷酸腺苷敏感性钾（KATP）通道的改变，以及KATP通道激活增加是否与细胞内乳酸增加有关。

方法与结果

将未成熟兔离体心脏（7至10日龄）在Langendorff模式下于39℃用碳酸氢盐缓冲液恒压灌注。将充满盐水的乳胶球囊置于左、右心室内以测量心室内压。在18分钟全心缺血期前15分钟加入KATP通道激动剂（苄甲噻嗪）或KATP通道拮抗剂（格列本脲），随后再灌注35分钟。出生后在缺氧条件下饲养（吸入氧分数=FIO2=0.12）的兔子心室内压恢复明显增强。在常氧和缺氧心脏中，右心室比左心室对缺血更具耐受性。苄甲噻嗪（1μmol/L）使常氧心脏左心室内压恢复至与缺氧对照组无差异的水平（43±3%至67±5%），并使缺氧心脏的心室内压略有增加（67±5%至72±5%）。格列本脲（3μmol/L）消除了缺氧的心脏保护作用（67±5%至43±5%）。恒流研究表明，苄甲噻嗪和格列本脲的作用与其对冠状动脉血流的影响无关。与常氧对照心脏相比，缺氧心脏的心室乳酸和乳酸脱氢酶浓度升高。