In:
The Journal of Physiology, Wiley, Vol. 542, No. 3 ( 2002-08), p. 735-741
Abstract:
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 μ m ) 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 μ m ) or pinacidil (100 μ m ) 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 (β‐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.
Type of Medium:
Online Resource
ISSN:
0022-3751
,
1469-7793
DOI:
10.1113/jphysiol.2002.023960
Language:
English
Publisher:
Wiley
Publication Date:
2002
detail.hit.zdb_id:
1475290-6
SSG:
12
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