Inhibition of the renin-angiotensin system attenuates the development of liver fibrosis and oxidative stress in rats.
1. The present study was designed to investigate the potential antifibrotic and anti-oxidant effects of lisinopril, fosinopril and losartan in an experimental rat model of liver injury using carbon tetrachloride (CCl(4)). 2. First, the potential hepatoprotective dose of each drug was screened against CCl(4)-induced acute hepatotoxicity. Then, we chose the minimum hepatoprotective dose of each drug to further investigate the mechanisms involved in the hepatoprotection using a chronic model of hepatotoxicity induced by CCl(4). 3. Liver function was assessed in addition to histopathological examination. Furthermore, oxidative stress markers (reduced glutathione (GSH) and lipid peroxides levels) and markers of fibrosis (hydroxyproline content and liver fibrosis area) were assessed. 4. It was found that treatment of animals with different drugs concomitantly with CCl(4) significantly counteracted the changes in liver function induced by CCl(4) (except fosinopril). In addition, the drugs ameliorated the histopathological changes induced by CCl(4). All drugs significantly counteracted lipid peroxidation and GSH depletion (except fosinopril) compared with the CCl(4)-intoxicated group. Moreover, the drugs studied significantly reduced liver hydroxyproline levels and the area of fibrosis compared with the CCl(4)-intoxicated group. 5. In conclusion, the present study provides evidence for the hepatoprotective effect of lisinopril, fosinopril and losartan. Both lisinopril and losartan was found to have better hepatoprotective potential than fosinopril against CCl(4)-induced hepatotoxicity. These hepatoprotective effects can be explained on the basis of anti-oxidant and antifibrotic mechanisms, mainly enhancement of GSH and reduction of lipid peroxidation and fibrosis.
El-Demerdash
Ebtehal
E
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. ebtehal_dm@yahoo.com
Salam
Omar M Abdel
OM
El-Batran
Seham A
SA
Abdallah
Heba M I
HM
Shaffie
Nermeen M
NM
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D002251:Carbon Tetrachloride; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017328:Fosinopril / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D017706:Lisinopril / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008111:Liver Function Tests; D019808:Losartan / Q000494:pharmacology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D000975:Antioxidants; D002251:Carbon Tetrachloride; D017706:Lisinopril; D005978:Glutathione; D019808:Losartan; D017328:Fosinopril; D006909:Hydroxyproline