KATP channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart

被引:284
作者
Hanley, PJ
Mickel, M
Löffler, M
Brandt, U
Daut, J
机构
[1] Univ Marburg, Inst Normale & Pathol Physiol, D-35037 Marburg, Germany
[2] Fachbereich Chem, D-35032 Marburg, Germany
[3] Inst Physiol Chem, Marburg, Germany
[4] Univ Frankfurt, Fachbereich Med, Inst Biochem 1, D-6000 Frankfurt, Germany
来源
JOURNAL OF PHYSIOLOGY-LONDON | 2002年 / 542卷 / 03期
关键词
D O I
10.1113/jphysiol.2002.023960
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Diazoxide and 5-hydroxydecanoate (5-HD; C10:0) are reputed to target specifically mitochondrial ATP-sensitive K+ (K-ATP) channels. Here we describe K-ATP channel-independent targets of diazoxide and 5-HD in the heart. Using submitochondrial particles isolated from pig heart, we found that diazoxide (10-100 mum) dose-dependently decreased succinate oxidation without affecting NADH oxidation. Pinacidil, a non-selective K-ATP channel opener, did not inhibit succinate oxidation. However, it selectively inhibited NADH oxidation. These direct inhibitory effects of diazoxide and pinacidil cannot be explained by activation of mitochondrial K-ATP channels. Furthermore, application of either diazoxide (100 mum) or pinacidil (100 mum) did not decrease mitochondrial membrane potential, assessed using TMRE (tetramethylrhodamine ethyl ester), in isolated guinea-pig ventricular myocytes. We also tested whether 5-HD, a medium-chain fatty acid derivative which blocks diazoxide-induced cardioprotection, was 'activated' via acyl-CoA synthetase (EC 6.2.1.3), an enzyme present both on the outer mitochondrial membrane and in the matrix. Using analytical HPLC and electrospray ionisation mass spectrometry, we showed that 5-HD-CoA (5-hydroxydecanoyl-CoA) is indeed synthesized from 5-HD and CoA via acyl-CoA synthetase. Thus, 5-HD-CoA may be the active form of 5-HD, serving as substrate for (or inhibiting) acyl-CoA dehydrogenase (beta-oxidation) and/or exerting some other cellular action. In conclusion, we have identified K-ATP channel-independent targets of 5-HD, diazoxide and pinacidil. Our findings question the assumption that sensitivity to diazoxide and 5-HD implies involvement of mitochondrial K-ATP channels. We propose that pharmacological preconditioning may be reelated to partial inhibition of respiratory chain complexes.
引用
收藏
页码:735 / 741
页数:7
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