Inhibition of angiotensin II action protects rat steatotic livers against ischemia-reperfusion injury

Araní Casillas-Ramirez, Mohammed Amine-Zaouali, Marta Massip-Salcedo, Susagna Padrissa-Altés, María Bintanel-Morcillo, Fernando Ramalho, Anna Serafín, Antoni Rimola, Vicente Arroyo, Juan Rodés, Joan Roselló-Catafau, Carmen Peralta

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    OBJECTIVE: We examined whether pharmacologic strategies blocking angiotensin II actions protect steatotic livers against ischemia-reperfusion (I/R) injury. The effects of ischemic preconditioning (PC) on angiotensin II were also evaluated. DESIGN: Randomized and controlled animal study. SETTING: Experimental laboratory. SUBJECTS: Zucker rats. INTERVENTIONS: The following experimental groups were studied: I/R, ischemia-reperfusion + angiotensin-converting enzyme inhibitor (I/R+ACE inhibitor), ischemia-reperfusion + angiotensin II type I receptor antagonist (I/R+AT1R antagonist), ischemia-reperfusion + angiotensin II type II receptor antagonist (I/R+AT2R antagonist), and PC (5 mins of ischemia + 10 mins of reperfusion before I/R). In some of these groups, the action of bradykinin (BK) and/or peroxisome-proliferator-activated receptor-γ (PPARγ) was altered pharmacologically. MEASUREMENTS AND MAIN RESULTS: I/R+ACE inhibitor, I/R+AT1R antagonist, and I/R+AT2R antagonist reduced hepatic injury in steatotic livers compared with the I/R group. PC reduced angiotensin II generation and hepatic injury in steatotic livers in comparison to I/R group. Our results revealed that I/R+ACE inhibitor, I/R+AT1R antagonist, I/R+AT2R antagonist, and PC increased BK compared with the I/R group. In addition, the effects of PC on BK and hepatic injury were abolished when angiotensin II was administered. Furthermore, administration of BK receptor antagonists to the I/R+ACE inhibitor, I/R+AT1R antagonist, I/R+AT2R antagonist, and PC groups resulted in hepatic injury similar to the I/R group, indicating that the benefits of ACE inhibitor, AT1R antagonist, AT2R antagonist, and PC were abolished when the action of BK was inhibited. Experiments aimed at investigating why BK was protective in steatotic livers indicated that BK acts as a positive regulator of PPARγ. If PPARγ action was inhibited, BK did not protect steatotic livers against hepatic injury. CONCLUSIONS: Pharmacologic blockers of angiotensin II action (ACE inhibitors, AT1R antagonists, and AT2R antagonists) and PC, which reduced angiotensin II generation, increased BK generation in steatotic livers after I/R. This in turn increased PPARγ and protected this type of liver against I/R injury. © 2008 Lippincott Williams & Wilkins, Inc.
    Original languageEnglish
    Pages (from-to)1256-1266
    JournalCritical Care Medicine
    Issue number4
    Publication statusPublished - 1 Jan 2008


    • Angiotensin II
    • Bradykinin
    • Interleukin
    • Ischemia
    • Ischemic preconditioning
    • Steatotic liver


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