Urinary trypsin inhibitor suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in forebrain ischemia/reperfusion rats.
OBJECTIVE
To investigate the effects of ulinastatin, a urinary trypsin inhibitor (UTI), on jugular venous superoxide radical (O₂⁻·) generation, oxidative stress, early inflammation, and endothelial activation in forebrain ischemia/reperfusion (FBI/R) rats.


METHODS
Fourteen Wistar rats were allocated to a control group (n = 7) and a UTI group (n = 7). Throughout the experiments, O₂⁻· in the jugular vein was measured by the produced current using a novel electrochemical O₂⁻· sensor. Forebrain ischemia was induced by occlusion of the bilateral common caroti darteries with hemorrhagic hypotension for 20 min, followed by reperfusion. In the UTI group, UTI (5 U/g) was administered intravenously immediately after reperfusion. At 60 min after reperfusion, plasma and brain were harvested, and malondialdehyde, high-mobility group box 1 (HMGB1) protein, and intercellular adhesion molecule-1 (ICAM-1) were measured.


RESULTS
O₂⁻· current increased gradually during forebrain ischemia in both groups. The current increased markedly in the control group immediately after reperfusion but was significantly attenuated in the UTI group after reperfusion. Brain and plasma malondialdehyde, HMGB1, and ICAM-1 were significantly attenuated in the UTI group compared with those in the control group, except for brain HMGB1, which was associated with the amount of O₂⁻· generated during FBI/R.


CONCLUSIONS
UTI suppressed jugular venous O₂⁻· generation, oxidative stress, early inflammation, and endothelial activation in FBI/R rats. Therefore, UTI might be a useful agent for the therapy of the cerebral ischemia/reperfusion pathophysiology.
Koga
Yasutaka
Y
Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, Japan.
Fujita
Motoki
M
Tsuruta
Ryosuke
R
Koda
Yoichi
Y
Nakahara
Takashi
T
Yagi
Takeshi
T
Aoki
Tetsuya
T
Kobayashi
Chihiro
C
Izumi
Tomonori
T
Kasaoka
Shunji
S
Yuasa
Makoto
M
Maekawa
Tsuyoshi
T
D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis / Q000379:methods; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects / Q000293:injuries; D006023:Glycoproteins / Q000187:drug effects / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016548:Prosencephalon / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D013481:Superoxides / Q000097:blood*; D014361:Trypsin Inhibitors / Q000494:pharmacology*
D006023:Glycoproteins; D014361:Trypsin Inhibitors; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D008315:Malondialdehyde; C028665:urinastatin