title: Hepatic portal venous delivery of a nitric oxide synthase inhibitor enhances net hepatic glucose uptake.
abstract: Hepatic portal venous infusion of nitric oxide synthase (NOS) inhibitors causes muscle insulin resistance, but the effects on hepatic glucose disposition are unknown. Conscious dogs underwent a hyperinsulinemic (4-fold basal) hyperglycemic (hepatic glucose load 2-fold basal) clamp, with assessment of liver metabolism by arteriovenous difference methods. After 90 min (P1), dogs were divided into two groups: control (receiving intraportal saline infusion; n = 8) and LN [receiving N(G)-nitro-L-arginine methyl ester (L-NAME), a nonspecific NOS inhibitor; n = 11] intraportally at 0.3 mg x kg(-1) x min(-1) for 90 min (P2). During the final 60 min of study (P3), L-NAME was discontinued, and five LN dogs received the NO donor SIN-1 intraportally at 6 mug x kg(-1) x min(-1) while six received saline (LN/SIN-1 and LN/SAL, respectively). Net hepatic fractional glucose extraction (NHFE) in control dogs was 0.034 +/- 0.016, 0.039 +/- 0.015, and 0.056 +/- 0.019 during P1, P2, and P3, respectively. NHFE in LN was 0.045 +/- 0.009 and 0.111 +/- 0.007 during P1 and P2, respectively (P < 0.05 vs. control during P2), and 0.087 +/- 0.009 and 0.122 +/- 0.016 (P < 0.05) during P3 in LN/SIN-1 and LN/SAL, respectively. During P2, arterial glucose was 204 +/- 5 vs. 138 +/- 11 mg/dl (P < 0.05) in LN vs. control to compensate for L-NAME's effect on blood flow. Therefore, another group (LNlow; n = 4) was studied in the same manner as LN/SAL, except that arterial glucose was clamped at the same concentrations as in control. NHFE in LNlow was 0.052 +/- 0.008, 0.093 +/- 0.023, and 0.122 +/- 0.021 during P1, P2, and P3, respectively (P < 0.05 vs. control during P2 and P3), with no significant difference in glucose infusion rates. Thus, NOS inhibition enhanced NHFE, an effect partially reversed by SIN-1.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA. genie.moore@vanderbilt.edu
authors.forename: Mary Courtney
authors.initials: MC
authors.lastname: Moore
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Dicostanzo
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.forename: Tiffany D
authors.initials: TD
authors.lastname: Rodewald
authors.forename: Doss W
authors.initials: DW
authors.lastname: Neal
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Williams
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism; D002404:Catheterization; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D005990:Glycerol / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D006946:Hyperinsulinism / Q000188:drug therapy / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011169:Portal Vein; D019518:Postprandial Period / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D009569:Nitric Oxide; D019344:Lactic Acid; C002385:linsidomine; D002244:Carbon; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D005990:Glycerol; D019331:NG-Nitroarginine Methyl Ester