Effect of a novel thromboxane A2 synthetase inhibitor on ischemia-induced mitochondrial dysfunction in canine hearts.
This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)
Ogawa
T
T
2nd Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Hieda
N
N
Sugiyama
S
S
Toki
Y
Y
Ito
T
T
Ogawa
K
K
Satake
T
T
Ozawa
T
T
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003327:Coronary Disease / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008247:Lysosomes / Q000201:enzymology; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D013876:Thiophenes; C055806:RS 5186; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase