Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with Nω-nitro-L-arginine methyl ester (L-NAME)

Abstract

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.

Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake

“…Our findings are in accord with the observation that, in the presence of glucose and amino acids, treatment of isolated hepatocytes with the NO donor S-nitroso-Nacetylpenicillamine reduced glycogen synthesis in a dosedependent manner, due to inhibition of glycogen synthase phosphatase (36). Additionally, treatment of lean rats with L-NAME for 4 wk resulted in greater insulin sensitivity, increased hepatic glycogen content, and increased insulin-stimulated phosphorylation of protein kinase B/Akt and glycogen synthase kinase-3 in liver, consistent with enhanced hepatic insulin signaling (38). Moreover, during a hyperinsulinemic hyperglycemic clamp concomitant with portal glucose infusion, intraportal infusion of SIN-1 significantly reduced net hepatic carbon retention in the dog (2).…”

“…The increase in NHGU was accompanied by an increase in hepatic carbon retention (glycogen storage) and may reflect an enhancement of hepatic insulin signaling in the presence of L-NAME (38).…”

Rationale for phosphodiesterase 5 inhibitor use post-radical prostatectomy: experimental and clinical review

“…First, the fact that general inhibition of the activity of all NOS isoforms, and hence nitric oxide production, by prolonged sustained administration of N(G)-nitro-L-arginine methyl ester to rats, leads to considerable fibrotic degeneration in organs such as the heart, liver and kidney, independent of hemodynamic factors that may contribute to this process. [21][22][23][24][25] Second, specific genetic blockade of iNOS in the iNOS knockout mice leads to exacerbation of experimental fibrosis of the kidney and liver, 26,27 and the chronic inhibition of iNOS activity in rats by N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) intensifies aging-related fibrosis of the arterial wall and of the experimentally induced Peyronie's disease-like fibrotic plaque in the penis. 28,29 Third, administration of iNOS cDNA in the latter model reduces the fibrotic plaque.…”

Angiotensin II or epinephrine hemodynamic and metabolic responses in the liver of L-NAME induced hypertension and spontaneous hypertensive rats

“…Treatment with L-NAME did not affect fasting glucose levels but reduced significantly insulin levels in blood and increased insulin sensitivity of rats[43]. Gouveia et al[44] described increased glycemia and insulinemia values for fasted or fed SHRs.…”

“…Tarsitano et al[43] described how prolonged treatment (2-8 wk) with NO synthase inhibitor enhanced hepatic glycogen levels. In our study, as the treatment with L-NAME was only for 10 d, the amount of liver glycogen was similar to the WIS group.…”