Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with N(omega)-nitro-L-arginine methyl ester (L-NAME).
Chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), beta-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT(1) receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.
Tarsitano
Christiane Aparecida Badin
CA
Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), CP 6111, 13083-970 Campinas, SP, Brazil.
Paffaro
Valdemar A
VA
Pauli
José Rodrigo
JR
da Silva
Gustavo Henrique
GH
Saad
Mario J
MJ
Salgado
Ione
I
da Cruz-Höfling
Maria Alice
MA
Hyslop
Stephen
S
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002908:Chronic Disease; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004656:Enalapril / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005215:Fasting / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D006984:Hypertrophy / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D009569:Nitric Oxide / Q000096:biosynthesis; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D004656:Enalapril; D006003:Glycogen; D003577:Cytochrome P-450 Enzyme System; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D007703:Peptidyl-Dipeptidase A; D005947:Glucose; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester