Blocking cardiac ATP-sensitive K+ channels reduces hydroxyl radicals caused by potassium chloride-induced depolarization in the rat myocardium.
The current study examined whether opening of the ATP-sensitive K(+) (K(ATP)) channel can induce hydroxyl free radical (OH) generation, as detected by increases in nonenzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels in the rat myocardium. When KCl (4-140mM) was administered to rat myocardium through microdialysis probe, the level of 2,3-DHBA increased gradually in a potassium ion concentration ([K(+)](o))-dependent manner. The [K(+)](o) for half-maximal effect of the level of 2,3-DHBA production (ED(50)) was 67.9microM. The maximum attainable concentration of the level of 2,3-DHBA (E(max)) was 0.171microM. Induction of glibenclamide (10microM) decreased OH formation. The half-maximal inhibitory effect (IC(50)) for glibenclamide against the [K(+)](o) (70mM)-evoked increase in 2,3-DHBA was 9.2microM. 5-Hydroxydecanoate (5-HD, 100microM), another K(ATP) channel antagonist, also decreased [K(+)](o)-induced OH formation. The IC(50) for 5-HD against the [K(+)](o) (70mM)-evoked increase in 2,3-DHBA was 107.2microM. The heart was subjected to myocardial ischemia for 15min by occlusion of left anterior descending coronary artery (LAD). When the heart was reperfused, the normal elevation of 2,3-DHBA in the heart dialysate was not observed in animals pretreated with glibenclamide (10microM) or 5-HD (100microM). These results suggest that opening of cardiac K(ATP) channels by depolarization evokes OH generation.
Obata
Toshio
T
Department of Analytical Chemistry, School of Pharmaceutical Sciences, Ohu University, Koriyama, Fukushima 963-8611, Japan. t-obata@pha.ohu-u.ac.jp
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D003652:Decanoic Acids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D003652:Decanoic Acids; D006880:Hydroxy Acids; D062385:Hydroxybenzoates; D015221:Potassium Channels; D017665:Hydroxyl Radical; C052853:5-hydroxydecanoic acid; D011189:Potassium Chloride; C009135:2,3-dihydroxybenzoic acid; D000255:Adenosine Triphosphate; D005905:Glyburide