Cardioprotection in ischemic rat hearts with the SH-containing angiotensin-converting enzyme inhibitor zofenopril: possible involvement of the ATP-sensitive potassium channel.
Cardioprotection in ischemic rat hearts with the SH-containing angiotensin-converting enzyme inhibitor zofenopril: possible involvement of the ATP-sensitive potassium channel.
复制标题
含 SH 的血管紧张素转换酶抑制剂佐芬普利对缺血大鼠心脏的心脏保护作用：可能涉及 ATP 敏感的钾通道。
DOI：
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发表时间：
1993
影响因子：
3.5
通讯作者：
G. Grover
中科院分区：
文献类型：
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作者：
C. Sargent;P. Sleph;S. Dzwonczyk;Mark A. Smith;D. Normandin;M. Antonaccio;G. Grover
含 SH 的血管紧张素转换酶 (ACE) 抑制剂佐芬普利和卡托普利已被证明可以独立于 ACE 抑制而保护缺血心肌。佐芬普利 (30-100 microM) 增强再灌注收缩功能并减少乳酸脱氢酶释放。佐芬普利的心脏保护活性在离体的全身缺血大鼠心脏中具有立体选择性（佐芬普利的 S、S、R 立体异构体无活性）。使用两种结构不同的 KATP 阻滞剂（1 µM 格列本脲和 100 µM 5-羟基癸酸钠）研究了 ATP 敏感钾通道 (KATP) 激活的作用。两种 KATP 阻滞剂均消除了 100 µM 佐芬普利的心脏保护活性。含 SH 的化合物 n-乙酰半胱氨酸 (300 µM) 的心脏保护作用也被格列本脲逆转，这进一步证明 ACE 抑制并不是先决条件。等辐射分析表明，佐芬普利和 KATP 开启剂 Cromakalim 共同治疗可在缺血心肌中产生超加性反应。 KB 分析表明，在佐芬普利存在下，格列本脲是一种非竞争性拮抗剂，而在克罗卡林存在下，格列本脲是一种竞争性拮抗剂。据报道，佐芬普利通过内皮依赖性成分引起主动脉平滑肌环松弛。格列本脲和 5-羟基癸酸钠均使这种松弛向右移动。平滑肌中佐芬普利和克罗卡林的等辐射线分析也证明了超加性反应。这些结果首次证明了含 SH 的化合物佐芬普利和 n-乙酰半胱氨酸的心脏保护作用与 KATP 之间的联系。该活性似乎是受体介导的事件，其发生方式不同于传统的 KATP 开启剂（例如 Cromakalim）。
The SH-containing angiotensin-converting enzyme (ACE) inhibitors zofenopril and captopril have been shown to protect the ischemic myocardium independently of ACE inhibition. Zofenopril (30-100 microM) enhanced reperfusion contractile function and reduced lactate dehydrogenase release. The cardioprotective activity of zofenopril was stereoselective in isolated globally ischemic rat hearts (S, S,R stereoisomer of zofenopril was inactive). The role of ATP-sensitive potassium channel (KATP) activation was investigated using two structurally different KATP blockers, 1 microM glyburide and 100 microM sodium 5-hydroxydecanoate. The cardioprotective activity of 100 microM zofenopril was abolished by both KATP blockers. Cardioprotection with the SH-containing compound n-acetyl cysteine (300 microM) was also reversed by glyburide, further demonstrating that ACE inhibition is not a prerequisite. Isobolographic analysis demonstrated that cotreatment with zofenopril and the KATP opener cromakalim resulted in a super-additive response in the ischemic myocardium. KB analysis demonstrated glyburide was a noncompetitive antagonist in the presence of zofenopril and a competitive antagonist in the presence of cromakalim. Zofenopril has been reported to cause relaxation in aortic smooth muscle rings via an endothelium-dependent component. This relaxation was shifted to the right by both glyburide and sodium 5-hydroxydecanoate. Isobolographic analysis of zofenopril and cromakalim in smooth muscle also demonstrated a super-additive response. These results demonstrate for the first time a link between the cardioprotective effects of the SH-containing compounds zofenopril and n-acetyl cysteine and the KATP. The activity appears to be a receptor-mediated event which occurs in a manner different from classical KATP openers such as cromakalim.