KR-31466, a benzopyranylindol analog, attenuates hypoxic injury through mitochondrial K(ATP) channel and protein kinase C activation in heart-derived H9c2 cells.

Abstract

In the present study, we investigated whether a novel benzopyranylindol analogue, KR-31466 (KR466) (1-[(2S,3R,4S)-3,4-dihydro-2-dimethoxymethyl-3-hydroxy-2-methyl-6-nitro-2H-1-benzopyran-4-yl]-1H-indole-2-carboxylic acid ethyl ester) can attenuate hypoxic injury in heart-derived H9c2 cells and, if so, whether the protective effect of KR466 is mediated through mitochondrial ATP-sensitive potassium (mtK(ATP)) opening. The treatment of H9c2 cells with KR466 (3 - 30 microM) significantly reduced hypoxia-induced cell death in a concentration-dependent manner, as shown by lactate dehydrogenase release and propidium iodide-uptake. In addition, KR466 (10 microM) significantly reduced the increase in hypoxia-induced TUNEL-positive cells, suggesting its anti-apoptotic potential in H9c2 cells. The protective effects of KR466 were abolished by 5-hydroxydecanoate, a specific blocker of the mtK(ATP) channel, suggesting the involvement of the mtK(ATP) channel in the protective effect of KR466. A specific inhibitor of protein kinase C (PKC), chelerythrine (3 microM), significantly attenuated the protective effect of KR466 against hypoxia-induced cardiac cell death. In conclusion, our results suggest that KR466 can protect H9c2 cells from hypoxia-induced death through mtK(ATP) channel opening and PKC activation.

• Authors: Yi-Sook Jung, Yoon Seok Jung, Mi-Young Kim, Min Hwa Kim, Sunkyung Lee, Kyu Yang Yi, Sung Eun Yoo, Soo Hwan Lee, Eun Joo Baik, Chang-Hyun Moon, Joon Pil Cho
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 92 Issue 1 Pg. 13-8 (May 2003) ISSN: 1347-8613 [Print] Japan
• PMID: 12832850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzopyrans
• Indicators and Reagents
• Indoles
• KR-31466
• Membrane Proteins
• Potassium Channels
• Protective Agents
• mitochondrial K(ATP) channel
• Propidium
• L-Lactate Dehydrogenase
• Protein Kinase C

Topics

• Animals
• Benzopyrans (pharmacology)
• Cell Hypoxia (drug effects)
• Cell Line
• Enzyme Activation
• In Situ Nick-End Labeling
• Indicators and Reagents
• Indoles (pharmacology)
• L-Lactate Dehydrogenase (metabolism)
• Membrane Proteins (metabolism)
• Myocardium (cytology, metabolism)
• Potassium Channels
• Propidium (metabolism)
• Protective Agents (pharmacology)
• Protein Kinase C (metabolism)
• Rats