Upregulation of liver inducible nitric oxide synthase following thyroid hormone preconditioning: suppression by N-acetylcysteine.
3,3-5-L-Triiodothyronine (T(3)) exerts significant protection against ischemia-reperfusion (IR) liver injury in rats. Considering that the underlying mechanisms are unknown, the aim of this study was to assess the involvement of inducible nitric oxide synthase (iNOS) expression and oxidative stress in T(3) preconditioning (PC). Male Sprague-Dawley rats given a single dose of 0.1 mg of T(3)/kg were subjected to 1-hour ischemia followed by 20 hours reperfusion, in groups of animals pretreated with 0.5 g of N-acetylcysteine (NAC)/kg 0.5-hour prior to T3 or with the respective control vehicles. At the end of the reperfusion period, liver samples were taken for analysis of iNOS mRNA levels (RT-PCR), liver NOS activity, and hepatic histology. T(3) protected against hepatic IR injury, with 119% enhancement in liver iNOS mRNA/18S rRNA ratios (p<0.05) and 12.7-fold increase (p<0.05) in NOS activity in T(3)-treated animals subjected to IR over values in control-sham operated rats, with a net 7.7-fold enhancement (p<0.05) in the net effect of T(3) on liver iNOS expression and a net enhancement of 0.58 units in NOS activity, changes that were abolished by NAC treatment before T(3). It is concluded that T(3)-induced liver PC is associated with upregulation of iNOS expression as a protective mechanisms against IR injury, which is achieved through development of transient and reversible oxidative stress.
Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile. vfernand@med.uchile.cl
Virginia
V
Fernández
Gladys
G
Tapia
Patricia
P
Varela
Pamela
P
Cornejo
Luis A
LA
Videla
D000111:Acetylcysteine; D000818:Animals; D016166:Free Radical Scavengers; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D014284:Triiodothyronine / Q000494:pharmacology*; D015854:Up-Regulation
D016166:Free Radical Scavengers; D012333:RNA, Messenger; D014284:Triiodothyronine; D052247:Nitric Oxide Synthase Type II; D000111:Acetylcysteine