Role of kinins in the cardioprotective effect of preconditioning: study of myocardial ischemia/reperfusion injury in B2 kinin receptor knockout mice and kininogen-deficient rats.
Role of kinins in the cardioprotective effect of preconditioning: study of myocardial ischemia/reperfusion injury in B2 kinin receptor knockout mice and kininogen-deficient rats.
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DOI：
10.1161/01.hyp.30.3.735
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发表时间：
1997-09
期刊：
影响因子：
8.3
通讯作者：
X. P. Yang;Yun-he Liu;G. Scicli;C. Webb;O. Carretero
中科院分区：
文献类型：
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作者：
X. P. Yang;Yun-he Liu;G. Scicli;C. Webb;O. Carretero
作用于B2受体的激动素可能参与了预适应对心肌缺血/再灌注损伤的保护作用。我们测试的假设是，在缺乏B2激肽受体编码基因的小鼠(B2基因敲除小鼠；B2-KO)以及缺乏高分子量激肽原(HMW)的大鼠(布朗挪威Katholiek大鼠；BNK)中，预适应的心脏保护作用减弱或取消。以129SvEvTac(SV129)小鼠和棕色挪威大鼠(BN)为对照。我们证实BNK大鼠的血浆HMW激肽原水平比BN大鼠低100倍，比Spraogue-Dawley大鼠低140倍(分别为1814+/-253和2397+/-302 ng/mL，P<；0.01)。每种小鼠分为(1)对照组(无预适应)，(2)1个周期的预适应(3分钟结扎，5分钟再灌流)，(3)3个周期的预适应。每种品系的大鼠分为(1)对照组和(2)三个周期的预适应。所有动物接受30分钟的缺血和120分钟的再灌流。SV129对照组的脑梗塞面积/危险面积(IS/AR)为55.6+/-4.6%。一次和三次预适应使IS/AR分别降低到38.6+/-3.2%和31.1+/-2.3%(与对照组相比，P<；0.05和P<；0.01)。而B2-KO小鼠则无此保护作用：对照组IS/AR为54.8+/-2.9%，1个周期为58.5+/-3.6%，3个周期为58.5+/-3.4%。无预适应的BN大鼠，IS/AR为84.7+/-3.9%，预适应后降至61.6+/-3.4%(P<；0.01)。在BNK大鼠中，对照组IS/AR为87.1+/-4.8%，预适应组为84.3+/-4.1%。预适应也能预防BN大鼠的再灌注性心律失常，但不能预防BNK大鼠的再灌注性心律失常。在物种内，不同菌株之间的危险区域、平均血压和心率相似。我们得出的结论是：(1)预适应保护小鼠和大鼠的心脏免受缺血/再灌注损伤；(2)前激肽释放酶激活，继而从高分子激肽原产生激动素，可能有助于预适应的效果；(3)完整的激肽释放酶-激动素系统对于预适应的心脏保护作用是必要的。
Kinins acting on the B2 receptor appear to be involved in the cardioprotective effect of preconditioning on myocardial ischemia/reperfusion injury. We tested the hypothesis that in mice lacking the gene encoding for the B2 kinin receptor (B2 knockout mice; B2-KO) as well as in rats deficient in high-molecular-weight (HMW) kininogen (Brown Norway Katholiek rats; BNK), the cardioprotective effect of preconditioning is diminished or abolished. 129SvEvTac (SV129) mice and Brown Norway rats (BN) served as controls. We confirmed that plasma HMW kininogen in BNK rats was 100-fold lower than in BN and 140-fold lower than in Sprague-Dawley rats (33+/-4 versus 1814+/-253 and 2397+/-302 ng/mL, P<.01). Each strain of mice was divided into (1) controls (without preconditioning); (2) one cycle of preconditioning (3 minutes ligation and 5 minutes reperfusion); and (3) three cycles of preconditioning. Each strain of rats was divided into (1) controls; and (2) three cycles of preconditioning. All animals were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In SV129 controls, the ratio of infarct size to risk area (IS/AR) was 55.6+/-4.6%. One and three cycles of preconditioning reduced IS/AR to 38.6+/-3.2% and 31.1+/-2.3%, respectively (P<.05 and P<.01 versus control). This protective effect was absent in B2-KO mice: IS/AR was 54.8+/-2.9% in controls, 58.5+/-3.6% with one cycle of preconditioning, and 58.5+/-3.4% with three cycles. In BN rats without preconditioning, IS/AR was 84.7+/-3.9%; preconditioning reduced it to 61.6+/-3.4% (P<.01). In BNK rats, IS/AR was 87.1+/-4.8% in controls and 84.3+/-4.1% with preconditioning. Preconditioning also prevented reperfusion arrhythmias in BN but not BNK rats. Within species, risk area, mean blood pressure, and heart rate were similar between strains. We concluded that (1) preconditioning protects the heart against ischemia/reperfusion injury in mice and rats; (2) activation of prekallikrein, which in turn generates kinins from HMW kininogen, may contribute to the effect of preconditioning; and (3) an intact kallikrein-kinin system is necessary for the cardioprotective effect of preconditioning.