内皮素-1可通过蛋白激酶C和ATP敏感性钾通道减少离体大鼠心脏的梗死面积。

Endothelin-1 can reduce infarct size through protein kinase C and KATP channels in the isolated rat heart.

作者信息

Bugge E, Ytrehus K

机构信息

Department of Medical Physiology, University of Tromsø, Norway.

出版信息

Cardiovasc Res. 1996 Nov;32(5):920-9.

PMID:8944823

Abstract

OBJECTIVE

Protection from ischaemic preconditioning (IP) is dependent on activation of protein kinase C (PKC), and preconditionings protection can be mimicked by stimulation of various membrane receptors which are known to activate PKC. It is well known that KATP channel activation is cardioprotective. We tested the hypothesis that preischaemic treatment with endothelin-1 (ET-1) can protect against infarction by a PKC-dependent mechanism and by activating KATP channels.

METHODS

Buffer-perfused isolated rat hearts were subjected to 30 min regional ischaemia and 120 min reperfusion. Risk zone was determined by fluorescent particles, and infarct size by TTC staining.

RESULTS

Treatment with ET-1 in a dose of 1 nM prior to ischaemia significantly reduced infarct size in % of the risk zone compared to the control group (infarct size: 14.1 +/- 2.6 vs. 41.9 +/- 3.4%), while ET-1 0.1 nM did not protect (infarct size: 40.9 +/- 3%). AS the protective dose of ET-1 resulted in a significant reduction of coronary flow, a control group with a similar preischaemic flow-reduction was included (infarct size: 48.1 +/- 4.2%). Both the nonselective ETA/ETB receptor antagonist bosentan (1 microM) and the ET(A)-receptor-selective antagonist BQ 123 (2 microM) abolished protection from ET-1 (infarct size: 43.3 +/- 3.5 and 41.3 +/- 3.3%, respectively), as did the PKC inhibitor chelerythrine (2 microM) (infarct size: 41.1 +/- 5.2%) and the KATP blocker 5-hydroxydecanoate (infarct size: 41.7 +/- 2.9%). None of the ET receptor antagonists bosentan and BQ-123 influenced infarct size alone (infarct size: 42.7 +/- 2.5 and 41.3 +/- 3.3%, respectively). IP, similarly to ET-1, reduced infarct size (infarct size: 6.1 +/- 1.4%), but the nonselective ET receptor antagonist bosentan did not interfere with preconditioning's protection (infarct size: 13.2 +/- 4.3%).

CONCLUSIONS

ET-1 treatment prior to ischaemia can protect against infarction via ETA receptors by a PKC-dependent mechanism and by activating KATP channels, but ET does not mediate IP in the isolated rat heart.

摘要

目的

缺血预处理（IP）的保护作用依赖于蛋白激酶C（PKC）的激活，并且预处理的保护作用可通过刺激各种已知能激活PKC的膜受体来模拟。众所周知，ATP敏感性钾通道（KATP通道）的激活具有心脏保护作用。我们检验了以下假设：缺血前用内皮素-1（ET-1）治疗可通过PKC依赖机制并激活KATP通道来预防梗死。

方法

用缓冲液灌注分离的大鼠心脏，使其经历30分钟的局部缺血和120分钟的再灌注。通过荧光颗粒确定危险区，通过TTC染色确定梗死面积。

结果

与对照组相比，缺血前给予1 nM剂量的ET-1可显著降低梗死面积占危险区的百分比（梗死面积：14.1±2.6%对41.9±3.4%），而0.1 nM的ET-1则无保护作用（梗死面积：40.9±3%）。由于ET-1的保护剂量导致冠状动脉血流量显著减少，因此纳入了一个缺血前血流量减少情况相似的对照组（梗死面积：48.1±4.2%）。非选择性ETA/ETB受体拮抗剂波生坦（1 μM）和ETA受体选择性拮抗剂BQ 123（2 μM）均消除了ET-1的保护作用（梗死面积分别为：43.3±3.5%和41.3±3.3%），PKC抑制剂白屈菜红碱（2 μM）（梗死面积：41.1±5.2%）和KATP阻滞剂5-羟基癸酸（梗死面积：41.7±2.9%）也有同样效果。ET受体拮抗剂波生坦和BQ-123单独使用均不影响梗死面积（梗死面积分别为：42.7±2.5%和41.3±3.3%）。与ET-1类似，IP也可减小梗死面积（梗死面积：6.1±1.4%），但非选择性ET受体拮抗剂波生坦并不干扰预处理的保护作用（梗死面积：13.2±4.3%）。