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

1 Department of Molecular Physiology and Biophysics, 2 Diabetes Research and Training Center, and 3 Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee Submitted 22 March 2007 ; accepted in final form 20 January 2008 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·kg –1 ·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 µg·kg –1 ·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. N G -nitro- L -arginine methyl ester; 3-morpholynosydnonimine; dog Address for reprint requests and other correspondence: M. C. Moore, 702 Light Hall, Dept. of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-0615 (e-mail: genie.moore{at}vanderbilt.edu )