ADAPTATION TO CHRONIC HYPOXIA

未成熟家兔出生时缺氧可增加对 与年龄匹配的常氧对照相比， 对照 我们确定这种耐受性的增加是否是由于 内源性一氧化氮产生的改变。 测试 假设，家兔（n=8/组）从出生起在含氧量正常的 或低氧环境中7-10天， 碳酸氢盐缓冲液。 一氧化氮供体S-亚硝基谷胱甘肽（GSNO） 或一氧化氮合酶抑制剂NG-硝基-L-精氨酸（L-NAME）， 在30分钟的全身缺血期之前15分钟添加，随后 再灌注35 min。 GSNO（10 μ mol/L）可增加 正常氧含量心脏的左心室发展压力值 与缺氧心脏不同，但对恢复 在缺氧的心脏中产生了压力。 L-NAME（200微摩尔/L） 完全消除了慢性缺氧的心脏保护作用 但对含氧量正常的心脏没有保护作用。 到 确定一氧化氮合酶（NOS）基因表达的改变 与缺血耐受性增加相关 通过以下方法测定诱导型一氧化氮合酶（NOS 3）和诱导型一氧化氮合酶（NOS 2）转录水平： 北方分析。 出生时缺氧可增加NOS 3的表达， 标准化至内部对照时，为含氧量正常值的238%， α-微管蛋白 NOS 2在常氧和缺氧心脏中均未发现。 缺氧心脏释放亚硝酸盐、硝酸盐和cGMP， 组织cGMP高于含氧量正常的心脏。 这些数据表明 在未成熟的心脏中，出生时的缺氧会增加 组成型一氧化氮合酶，其增加对 缺血

Hypoxia from birth in immature rabbits increases the tolerance of isolated hearts to ischemia compared with age-matched normoxic controls. We determined if this increased tolerance was due to alterations in endogenous nitric oxide production. To test the hypothesis, rabbits (n=8/group) were raised from birth in a normoxic or hypoxic environment for 7-10 days and the hearts perfused with bicarbonate buffer. A nitric oxide donor S-nitrosoglutathione (GSNO) or a nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NAME) was added 15 min prior to a global ischemic period of 30 min, followed by 35 min reperfusion. GSNO (10 micromole/L) increased the recovery of left ventricular developed pressure in normoxic hearts to values not different from hypoxic hearts but had no effect on recovery of developed pressure in hypoxic hearts. L-NAME (200 micromole/L) completely abolished the cardioprotective effect of chronic hypoxia but had no effect on cardioprotection in normoxic hearts. To determine if altered nitric oxide synthase (NOS) gene expression correlated with increased tolerance to ischemia constitutive NOS (NOS3) and inducible NOS (NOS2) transcripts levels were determined by Northern analysis. Hypoxia from birth increased NOS3 expression by 238% of normoxic values when normalized to the internal control, alpha-tubulin. NOS2 was not found in normoxic or hypoxic hearts. Release of nitrite, nitrate, and cGMP from hypoxic hearts as well as tissue cGMP was greater than in normoxic hearts. These data indicate that hypoxia from birth in immature hearts elevates expression of constitutive nitric oxice synthase which increases tolerance to ischemia.