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Abstract

Introduction: Oxidative stress plays a major role in the pathology of hemorrhagic shock (HS). Acute kidney injury, cerebral edema (induced by increased AQP4 and NKCC1 expression) and cerebral perfusion pressure (CPP) drop are associated with high morbidity and mortality in HS. There is evidence that vasopressin is preferable to lactated Ringer's (LR) in HS. We hypothesized that terlipressin (TLP) protects the kidneys (K) and brain (B) in HS. Methods: We studied 35 female pigs (20-30 kg) in groups: sham; shock (60% reduction in blood volume-mean arterial pressure [MAP] of 40 mmHg for 30 min); LR (post-shock LR given at 3× the volume of blood removed); and TLP (2 mg of TLP given post-shock). At 60 min post-treatment, we evaluated CPP (mmHg), MAP (mmHg) and serum creatinine (Creat, mg/dl) and at 120 min post-treatment, we evaluated 2-thiobarbituric acid reactive substances (TBARS, nmol/g) (in B and K), as well as immunoblotting for AQP2, NKCC2 and Bax (in K); and AQP4, NKCC1 and Bax (in B). Results: Data are mean±SEM. MAP was markedly lower in Shock and LR than in Sham and TLP (49 ± 4.8 and 55 ± 2.9 vs. 71 ± 2.1 and 63 ± 3.0, P < 0.05). TLP treatment completely inhibited the decrease of CPP observed in Shock and LR (59 ± 2.6 vs. 45 ± 4.4 and 47 ± 2.9, P < 0.05) and was similar to Sham (65 ± 1.6). The TBARSB level was higher in Shock and LR groups than in Sham group (264 ± 46 and 308 ± 96 vs. 34.7 ± 5.7, P < 0.05). Although significantly different from Shock and LR groups, the TBARSB level observed for the TLP group (137 ± 9.5) differed significantly from the Sham group. Serum levels of creat were higher in Shock, LR and TLP groups than in Sham group (1.5 ± 0.08, 1.0 ± 0.09 and 1.3 ± 0.07 vs. 0.9 ± 0.07, P < 0.05). The TBARSk level was higher in Shock, LR and TLP groups than in Sham group (106 ± 23, 163 ± 62 and 108 ± 31 vs. 28.5 ± 1.1, P < 0.05). Expression of BaxB was markedly higher in shock and LR groups than in Sham (190 ± 30% and 154 ± 16% vs. 97 ± 2.5%, P < 0.05). TLP treatment completely inhibited the upregulation of BaxB (102 ± 2.6%). Similar, expression of Baxk was markedly higher in shock and LR groups than in Sham group (139 ± 5.1% and 130 ± 10% vs. 99 ± 0.6%, P < 0.05). TLP treatment completely inhibited the upregulation of BaxB (97.5 ± 8.5%). AQP2 expression was comparable in Sham and TLP pigs (97 ± 3.0% and 107 ± 5.0%) and was significantly lower in Shock (22 ± 2.5%) and LR (43 ± 12%) compared to Sham and TLP groups ( P < 0.05). NKCC2 expression was lower in Shock and LR pigs than in Sham and TLP pigs (27.5 ± 4.8% and 50 ± 21% vs. 102 ± 1.7% and 92.5 ± 12.5%, P < 0.05). Shock-induced increases in AQP4 (217%) and NKCC1 (237%) were reversed by TLP but not by LR. Conclusions: TLP-related protection appears to depend on sodium/water transporter regulation and be attributable, in part, to inhibition of oxidant injury.