TY - JOUR T1 - Are Angiotensin II Receptor Antagonists Useful Strategies in Steatotic and Nonsteatotic Livers in Conditions of Partial Hepatectomy under Ischemia-Reperfusion? JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 130 LP - 140 DO - 10.1124/jpet.108.147835 VL - 329 IS - 1 AU - Fernando S. Ramalho AU - Izabel Alfany-Fernandez AU - Araní Casillas-Ramirez AU - Marta Massip-Salcedo AU - Anna Serafín AU - Antoni Rimola AU - Vicente Arroyo AU - Juan Rodés AU - Joan Roselló-Catafau AU - Carmen Peralta Y1 - 2009/04/01 UR - http://jpet.aspetjournals.org/content/329/1/130.abstract N2 - We examined whether angiotensin (Ang) II receptor antagonists could be considered a therapeutic strategy in steatotic and nonsteatotic livers in conditions of partial hepatectomy under ischemia-reperfusion (I/R), which is commonly applied in clinical practice to reduce blood loss. We report that Ang II type I receptor (AT1R) antagonist, but not Ang II type II receptor (AT2R) antagonist, increased regeneration in nonsteatotic livers. In the presence of steatosis, both AT1R and AT2R antagonists increased liver regeneration. This effect was stronger when the two were combined. Neither of the Ang II receptor antagonists protected nonsteatotic livers against damage. Only the AT1R antagonist, through nitric oxide inhibition, reduced damage in steatotic livers. The combination of the AT1R and AT2R antagonists in steatotic livers conferred a similar degree of protection to AT1R antagonist alone. Herein, we show that p38 mitogen-activated protein kinase (p38) was a key mechanism in the regeneration induced by the Ang II receptor antagonists in both liver types because when this signaling pathway was inhibited, the beneficial effects of the Ang II receptor antagonists on liver regeneration disappeared, regardless of hepatocyte growth factor or transforming growth factor β-hepatic levels. In conclusion, in conditions of partial hepatectomy under I/R, the AT1R antagonist for nonsteatotic livers and the AT1R and AT2R antagonists for steatotic livers improved regeneration in the remnant liver through p38 activation. In addition, the combination of the AT1R and AT2R antagonists in steatotic livers led to stronger liver regeneration than either antagonists used separately and also provided the same protection against damage as that afforded by AT1R antagonist alone. The American Society for Pharmacology and Experimental Therapeutics ER -