REDUCTION OF PROGRESSIVE BURN INJURY BY USING NEW NONSELECTIVE ENDOTHELIN-A AND ENDOTHELIN-B RECEPTOR ANTAGONIST, TAK-044 - AN EXPERIMENTAL-STUDY IN RATS

Endothelins are well-known vasoconstrictor peptides produced by vascul ar endothelial cells that hale been reported to have a fundamental rol e in regulation of the systemic blood circulation. Plasma levels of en dothelins are increased by burn injury, which also causes thrombosis a nd occlusion of vessels in the dermis as well as a vascular response i n the adjacent uninjured dermis. Diminished blood flow leads to progre ssive ischemia and necrosis of the dermis beneath and around the burn (zone of stasis). If blood flow could be restored in this zone, second ary tissue damage would be minimized. In this study we examined the ef fects of a new nonselective endothelin receptor antagonist, TAK-044 (T akeda Chemical Industries, Ltd., Osaka, Japan), on burn trauma in rats . Fifty male Sprague-Dawley rats weighing an average of 450 gm were bu rned with a brass probe that produced a row of three burns 10 x 30 mm in size and two intervening unburned areas 5 x 30 mm in size. Rats wer e divided into five groups of 10 animals. Four groups received 0.01, 0 .1, 1, or 10 mg/kg of TAK-044 via the dorsal vein of the penis immedia tely after burn trauma, while the control group received the same volu me of saline. Skin blood flow was measured with a laser-Doppler flow-m eter, and the development of edema and the area of necrotic tissue als o were determined. Inhibition of endothelin activity be TAK-044 after burn injury improved microvascular perfusion in the zone of stasis and prevented the progression of tissue damage in this zone. This support s the role of endothelins in the progression of burn injury in the zon e of stasis. TAK-044 was most effective in preventing progressive burn damage at a dose of 1 mg/kg. The extent of necrosis and edema was red uced significantly, and blood now in the zone of stasis was increased in the treated rats.