ADAPTATION TO CHRONIC HYPOXIA

幼兔从出生起就缺氧增加了对 离体心抗缺血与年龄匹配的常氧组的比较 控制。我们确定这种耐受性的提高是否归因于 内源性一氧化氮产生的变化。要测试 假设，兔(n=8只/组)从出生起就在常氧环境中饲养 或低氧环境7-10天，心脏灌流 碳酸氢盐缓冲液。一氧化氮供体S-亚硝基谷胱甘肽 或一氧化氮合酶抑制剂NG-硝基-L精氨酸(L-NAME) 在30分钟的全局缺血期之前添加了15分钟，然后 再灌流35min。GSnO(10微摩尔/L)提高了回收率 正常氧合心脏的左心室发展压未达到 与低氧心脏不同，但对心脏的恢复没有影响 在缺氧的心脏中产生了压力。L-姓名(200微摩尔/L) 完全消除慢性低氧的心脏保护作用 但对常氧心脏无保护作用。至 确定改变的一氧化氮合酶(NOS)基因表达 与增加对缺血原始性一氧化氮合酶的耐受性有关 (NOS3)和诱导型一氧化氮合酶(NOS2)转录本水平通过 北方分析。出生时低氧通过增加NOS3的表达 常氧值的238%归一化为内部对照时， α-微管蛋白。NOS2在常氧和低氧心脏中均未检测到。 低氧心脏和心脏释放亚硝酸盐、硝酸盐和cGMP 组织中cGMP含量高于常氧心脏。这些数据表明 未成熟心脏从出生起就缺氧会增加其表达 结构性一氧化氮合酶，增加对 缺血症。

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.