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


METHODS
Randomized and controlled animal study.


METHODS
Experimental laboratory.


METHODS
Zucker rats.


METHODS
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-gamma (PPARgamma) was altered pharmacologically.


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 PPARgamma. If PPARgamma 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 PPARgamma and protected this type of liver against I/R injury.
Casillas-Ramirez
Araní
A
Unitat de Transplantament de fetge i viabilitat de l'empelt, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain.
Amine-Zaouali
Mohammed
M
Massip-Salcedo
Marta
M
Padrissa-Altés
Susagna
S
Bintanel-Morcillo
María
M
Ramalho
Fernando
F
Serafín
Anna
A
Rimola
Antoni
A
Arroyo
Vicente
V
Rodés
Juan
J
Roselló-Catafau
Joan
J
Peralta
Carmen
C
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000627:therapeutic use*; D005234:Fatty Liver / Q000378:metabolism*; D016753:Interleukin-10 / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II; D016753:Interleukin-10; D001920:Bradykinin