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

Peter J. Hanley, Markus Mickel *, Monika Löffler †, Ulrich Brandt ‡ and Jürgen Daut

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 µM) 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 µM) or pinacidil (100 µM) 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 (-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.

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