Cardioprotective effects of bms-180448, a prototype mitokatp channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury

Lee, Ju Han; Jung, In-Sang; Lee, Sunghun; Yang, Min-Kyu; Hwang, Jin Soo; Lee, Hak-Dong; Cho, Yu-Sun; Song, Min-Jin; Yi, Kyu Yang; Yoo, Sung‐Eun; Kwon, Suk-Hyung; Lee, Chang‐Soo; Shin, Hyung-Jin

doi:10.1007/bf02977659

Cited by 12 publications

(4 citation statements)

References 28 publications

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“…Each of these changes reduces the likelihood that PTP will open. Interestingly, inhibition of MCU facilitates post reperfusion recovery (Unitt et al, 1999) while activation of mitochondrial K + -ATP channels promotes cardioprotection (Lee et al, 2007). …”

Section: Mitochondrial Channels As Therapeutic Targetsmentioning

confidence: 99%

The therapeutic potential of mitochondrial channels in cancer, ischemia–reperfusion injury, and neurodegeneration

2012

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Mitochondria communicate with the rest of the cell through channels located in their inner and outer membranes. Most of the time, the message is encoded by the flow of anions and cations e.g., through VDAC and PTP, respectively. However, proteins are also both imported and exported across the mitochondrial membranes e.g, through TOM and MAC, respectively. Transport through mitochondrial channels is exquisitely regulated and controls a myriad of processes; from energy production to cell death. Here, we examine the role of some of the mitochondrial channels involved in neurodegeneration, ischemia-reperfusion injury and cancer in the context of their potential as therapeutic targets.

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Section: Mitochondrial Channels As Therapeutic Targetsmentioning

confidence: 99%

The therapeutic potential of mitochondrial channels in cancer, ischemia–reperfusion injury, and neurodegeneration

2012

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“…In the isolated rat heart model of ischemia and reperfusion-induced heart injury, KR-31762, given 10 min before the onset of global ischemia and reperfusion, exerted significant cardioprotective effects, as evidenced by dose-dependent recovery of heart function parameters including LVDP, LVEDP and left ventricular DP at 30-min reperfusion, a significant increase in TTC during global ischemia, and a significant decrease in LDH release during 30-min reperfusion. These cardioprotective effects of KR-31762 appear to be equipotent to those of BMS-180448, as compared with the results from the literature adopting the similar experimental protocols in isolated rat heart (Lee et al, 2007) and anesthetized ferrets (Gomoll et al, 1997). Cardioprotective effect of KR-31762 appears to be mediated via its direct effect on myocardium rather than via coronary dilatation, since KR-31762 exerted slight concentrationindependent increase in coronary flow 10 min after adding drug and no significant change in coronary flow at 30-min reperfusion compared with vehicle group.…”

Section: Discussionmentioning

confidence: 53%

KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury

et al. 2008

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The cardioprotective effects of KR-31762, a newly synthesized K+(ATP) opener, were evaluated in rat models of ischemia/reperfusion (I/R) heart injury. In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, KR-31762 (3 and 10 microM) significantly increased the left ventricular developed pressure (LVDP) and double product (heart rate x LVDP) after 30-min reperfusion in a concentration-dependent manner, while decreasing the left ventricular end-diastolic pressure (LVEDP). KR-31762 also significantly increased the time to contracture (TTC) during ischemic period (20.0, 22.4 and 26.4 min for control, 3 and 10 microM, respectively), while decreasing the release of lactate dehydrogenase (LDH) from the heart during 30 min reperfusion (30.4, 14.3 and 19.7 U/g heart weight, respectively). All these parameters except LDH release were reversed by glyburide (1 microM), a nonselective blocker of K+(ATP) channel, but not by 5-hydroxydecanoate, a selective blocker of mitoK+(ATP) channel. In anesthetized rats subjected to 45-min occlusion of left anterior descending coronary artery followed by 90-min reperfusion, KR-31762 significantly decreased the infarct size (60.8, 40.5 and 37.8% for control, 0.3 and 1.0 mg/kg, iv, respectively). KR-31762 slightly relaxed the isolated rat aorta precontracted with methoxamine (IC(50): 23.5 microM). These results suggest that KR-31762 exerts potent cardioprotective effects through the opening of sarcolemmal K(ATP) channel in rat hearts with the minimal vasorelaxant effects.

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“…These results suggest that the mitoK Ca channel is not regulated by PI3-K. On the other hand, it is unclear whether activation of the PI3-K /Akt pathway modulates the opening of mitoK ATP channels. Interestingly, Lee et al have reported that BMS-180448, a prototype mitoK ATP -channel opener, produces a cardioprotective effect without the phosphorylation of Akt (35). Contrary to this report, a recent study by Ahmad et al has demonstrated that cardioprotection by mitoK ATP -channel activation is dependent on Akt translocation from the cytosol to mitochondria (36).…”

Section: Mitochondrial Kmentioning

confidence: 65%

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection

et al. 2009

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Mitochondrial ATP-sensitive K + (mitoK ATP ) and Ca 2+ -activated K + (mitoK Ca ) channels exist in cardiac myocytes, and they play key roles in cardioprotection. We have recently reported that K + influx through mitoK ATP or mitoK Ca channels occurs independently of each other and confers cardioprotection in a similar manner. Activation of mitoK ATP channel is augmented by protein kinase C (PKC), whereas mitoK Ca channel is activated by protein kinase A (PKA). However, phosphatidylinositol 3-kinase (PI3-K) is linked to neither mitoK ATP nor mitoK Ca channels. We have demonstrated that bioactive substances modulate the opening of mitoK ATP channels via a PKC-dependent pathway or opening of mitoK Ca channels via a PKA-dependent pathway and thereby protecting the heart from ischemia/reperfusion injury. Several endogenous substances such as adenosine and bradykinin can reduce infarct size by activation of mitoK ATP channels in a PKC-dependent manner. Adrenomedullin, a potent vasodilator peptide, potentiates the opening of mitoK Ca channels by PKA activation. Treatment with adrenomedullin prior to ischemia results in the reduction of infarct size via a PKA-mediated activation of mitoK Ca channels. Thus, some endogenous substances confer cardioprotection via PKA-or PKC-mediated activation of mitoK ATP or mitoK Ca channels.

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Cardioprotective effects of bms-180448, a prototype mitokatp channel opener, and the role of salvage kinases, in the rat model of global ischemia and reperfusion heart injury

Cited by 12 publications

References 28 publications

The therapeutic potential of mitochondrial channels in cancer, ischemia–reperfusion injury, and neurodegeneration

The therapeutic potential of mitochondrial channels in cancer, ischemia–reperfusion injury, and neurodegeneration

KR-31762, a novel KATP channel opener, exerts cardioprotective effects by opening SarcKATP channels in rat models of ischemia/reperfusion-induced heart injury

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection

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