Effects of radical scavengers, TA248 and TA276, on stunned myocardium in dogs: involvement of K ATP channels.
TA248 (7-(beta-D-glucopyranosyloxy)-4-hydroxy-3-octyloxy-2H-1-benzopyran-2-one) and TA276 (sodium 7-hydroxy-3-octyloxy-2H-1-benzopyran-2-one-4-oxide) were newly developed as radical scavengers. In vitro, TA276 scavenged both superoxide anions (. O(2)(-)) and hydroxyl radicals (. OH). TA248 also trapped. O(2)(-), but had less activity on. OH. In vivo, left ventricular contractile functions were determined in pentobarbital-anesthetized open-chest dogs. A regional portion of the left ventricular wall was made ischemic for 20 min by ligating the left anterior descending coronary artery and then reperfused for 60 min. TA248 (3 mg/kg) and TA276 (3 mg/kg) injected i.v. 10 min before occlusion significantly improved myocardial stunning that is contractile dysfunction observed after reperfusion following brief ischemia. Glibenclamide (1 mg/kg) injected i.v. 20 min before occlusion significantly worsened the myocardial stunning. Pretreatment with glibenclamide completely abolished the beneficial effect of TA276 on myocardial stunning, whereas it only partially attenuated that of TA248, showing some improvement even in the presence of glibenclamide. Because of the incomplete scavenging activity of TA248, residual. OH may play some roles in improvement of myocardial stunning with TA248 in the presence of glibenclamide. We speculate that the. OH may eject glibenclamide from its binding site on K(ATP) channels, leading to opening of the channels.
Kosugi
Tetsuro
T
Department of Pharmacology, Hokkaido College of Pharmacy, Otaru, Japan. ichiharal@hokuyakudai.ac.jp
Satoh
Kumi
K
Kaneta
Shigeru
S
Aoki
Yasuo
Y
Takagaki
Hidetsugu
H
Ichihara
Kazuo
K
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004285:Dogs; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015221:Potassium Channels / Q000378:metabolism*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects
D001578:Benzopyrans; D016166:Free Radical Scavengers; D015221:Potassium Channels; C414784:TA248; C414783:TA276; D000255:Adenosine Triphosphate; D005905:Glyburide; D004121:Dimethyl Sulfoxide