title: Pharmacologic inhibition of the renin-angiotensin system did not attenuate hepatic toxicity induced by carbon tetrachloride in rats.
abstract: The renin-angiotensin system (RAS) subserves vital physiological functions and also implicated in certain pathological states. Modulation of this system has been proposed in recent studies to be a promising strategy in treating liver fibrosis. We investigated the effect of the pharmacologic inhibition of RAS with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in CCl(4)-induced liver injury with a view to ascertaining the chemopreventive benefit. Fifty-six Wistar albino rats were divided into eight experimental groups of seven rats/group. Groups 1-4 received normal saline (10 ml/kg), enalapril (0.6 mg/kg), losartan (1.4 mg/kg) and CCl(4) (80 mg/kg), respectively. Groups 5-8 were pretreated with enalapril (0.3 mg/kg), enalapril (0.6 mg/kg), losartan (0.7 mg/kg) and losartan (1.4 mg/kg) 1 hour before CCl(4) administration. Experiment lasted 11 days and dosing was via oral route. Rats were killed 24 hours after the last treatment. Serum activities of alkaline phosphatase, aspartate and alanine aminotransferases increased significantly (p < 0.05) by 46.0%, 90.6% and 122.3%, respectively, with severe hepatic centrilobular necrosis, fatty infiltration and increase in liver weight (p < 0.05) in the CCl(4)-treated rats. Enalapril (0.6 mg/kg) and losartan (1.4 mg/kg) significantly (p < 0.05) increased aspartate aminotransferase activity by 37.0% and 94.7% and produced mild centrilobular and periportal hepatic necrosis, respectively, with enalapril significantly (p < 0.05) increasing liver weight. Serum total cholesterol, triglyceride, albumin and total protein did not change significantly in these rats. Also, glutathione, malondialdehyde and uric acid levels were not significantly altered. Enalapril and losartan failed to attenuate liver injury associated with CCl(4) treatment. Although both drugs did not significantly alter serum biochemistry in the CCl(4)-treated rats, they however produced slight elevations in biomarkers of liver function and appear to worsen liver histopathology. Overall, the chemopreventive benefits of RAS inhibitors in liver disease remain doubtful and should be used with caution during hepatic dysfunction.
authors.affiliation: Department of Chemical Sciences, Redeemer's University, Ogun State, Nigeria. m_ekor@yahoo.com
authors.forename: Martins
authors.initials: M
authors.lastname: Ekor
authors.forename: Adesina O
authors.initials: AO
authors.lastname: Odewabi
authors.forename: Oluwafemi E
authors.initials: OE
authors.lastname: Kale
authors.forename: Kolawole S
authors.initials: KS
authors.lastname: Oritogun
authors.forename: Omolola A
authors.initials: OA
authors.lastname: Adesanoye
authors.forename: Titilayo O
authors.initials: TO
authors.lastname: Bamidele
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy*; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008315:Malondialdehyde / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D008315:Malondialdehyde; D004656:Enalapril; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D005978:Glutathione; D019808:Losartan