CHRONIC HYPOXIA AND RESISTANCE TO MYOCARDIAL ISCHEMIA

该提案的总体目标是改善接受先天性心脏缺陷修复手术的儿童的心脏保护。大多数接受心脏手术的婴儿表现出不同程度的紫绀性心脏病，其中心肌长期灌注缺氧血液。为探讨慢性缺氧适应和抗心肌缺血的机制，我们建立了一种非手术性慢性缺氧家兔模型。蛋白激酶和一氧化氮合酶之间的关系以及它们是否激活肌膜或线粒体K/ATP通道以在慢性缺氧心脏中提供心脏保护尚不清楚。我们假设慢性缺氧激活蛋白激酶信号转导通路，导致一氧化氮合酶的激活，从而通过激活肌膜和线粒体K/ATP通道来提供心脏保护。我们建议在缺氧和常氧环境中出生的兔子的离体心脏和离体肌细胞以及接受先天性心脏缺陷手术修复的紫绀和无紫绀婴儿的右心房组织中测试这一假设。我们将确定：（1）在正常氧和慢性缺氧的未成熟兔的离体心脏以及患有紫绀和非紫绀心脏缺陷的婴儿的人心脏中，蛋白激酶是否参与慢性缺氧适应和缺血抵抗的机制，（2）慢性缺氧控制一氧化氮合酶产生一氧化氮和对随后缺血的抵抗的机制，以及（3）蛋白激酶和一氧化氮合酶介导肌膜和线粒体K/ATP通道活性的机制，以及环GMP在控制慢性缺氧诱导的心肌缺血抵抗中的作用。这些研究的结果应该增强我们对未成熟心脏适应慢性缺氧所产生的心脏保护机制的理解，并可能导致制定新的策略来保护接受先天性出生缺陷手术修复的儿童的心脏。

The overall objective of this proposal is to improve cardioprotection in children undergoing surgery for repair of congenital heart defects. The majority of infants undergoing cardiac surgery exhibit varying degrees of cyanotic heart disease where the myocardium is chronically perfused with hypoxic blood. To investigate mechanisms of adaptation to chronic hypoxia and resistance to myocardial ischemia a non-surgical rabbit model of chronic hypoxia from birth has been developed. The relationship between protein kinases and nitric oxide synthase and whether they activate sarcolemmal or mitochondrial K/ATP channels to confer cardioprotection in chronically hypoxic hearts is unknown. We hypothesize that chronic hypoxia activates protein kinase signal transduction pathways leading to activation of nitric oxide synthase which confers cardioprotection by activation of sarcolemmal and mitochondrial K/ATP channels. We propose to test this hypothesis in isolated hearts and isolated myocytes from rabbits raised from birth in hypoxic and normoxic environments and in right atrial tissue from cyanotic and acyanotic infants undergoing surgical repair of congenital heart defects. We shall determine (1) whether protein kinases participate in the mechanism of adaptation to chronic hypoxia and resistance to ischemia in isolated hearts from normoxic and chronically hypoxic immature rabbits and in human hearts from infants with cyanotic and acyanotic heart defect, (2) the mechanisms by which chronic hypoxia controls nitric oxide production from nitric oxide synthase and resistance to subsequent ischemia and (3) the mechanisms by which protein kinases and nitric oxide synthase mediate the activity of the sarcolemmal and mitochondrial K/ATP channels and the involvement of cyclic GMP in controlling resistance to myocardial ischemia induced by chronic hypoxia. The findings from these studies should enhance our understanding of the cardioprotective mechanisms resulting from adaptation to chronic hypoxia in the immature heart and may lead to the development of new strategies to protect hearts of children undergoing surgical repair for congenital birth defects.