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Inhibition of endogenous nitric oxide production influences ovine hindlimb metabolism independently of insulin concentrations¹

J. J. Cottrell^*,, R. D. Warner^*,, M. B. McDonagh and F. R. Dunshea^,,2

^* Victoria University, Werribee, Australia; and Department of Primary Industries, Werribee, Australia; and and Institute of Land and Food Resources, University of Melbourne, Australia

² Correspondence: Victorian Institute of Animal Science, 600 Sneydes Rd., Werribee 3030, Australia (phone: +61 3 9742 0438; fax: +61 3 9742 0400; e-mail: frank.dunshea{at}nre.vic.gov.au).

The hindlimb arteriovenous difference (AVD) model was used to determine whether 30 mg/kg of the nitric oxide synthase (NOS) inhibitor L-N^G-nitroarginine methyl ester (hydrochloride; L-NAME) inhibited ovine NO synthesis and influenced muscle metabolism. Eight Border Leicester x Merino cross lambs (50 to 55 kg BW) were infused with saline (control) or saline containing L-NAME via an indwelling jugular vein catheter in a balanced randomized crossover design with 3 d between treatments. The abdominal aorta and deep femoral vein were catheterized for assessment of AVD of hind limb metabolism. Arterial hematocrit and insulin concentration and both arterial and venous concentrations of nitrate/nitrite (NO_x), glucose, lactate, NEFA, and urea were determined. Infusion of L-NAME decreased arterial NO_x concentrations (P = 0.049), indicating inhibition of systemic NO synthesis. Treatment had no effect on arterial (3.5 vs. 3.6 ± 0.19 mmol/L for control and L-NAME lambs, respectively; P = 0.39) or venous (3.3 vs. 3.4 ± 0.16 mmol/L, P = 0.55) plasma glucose concentrations or on glucose AVD (0.19 vs. 0.27 ± 0.065 mmol/L, P = 0.20). There was an interaction (P = 0.038) between time and treatment, such that L-NAME initially increased the AVD of glucose (up to 180 m) divergent from control lambs. The response was then decreased before a possible inflection beyond 240 min. Infusion of L-NAME increased hindlimb venous NEFA (222 vs. 272 ± 13.2 µmol/L, P = 0.007) and NEFA AVD (79.4 vs. –13.3 ± 31.5 µmol/L, P = 0.018). These metabolic changes were independent of plasma insulin concentrations, which were not affected by L-NAME infusion (25.3 vs. 27.8 ± 3.62 mU/L, P = 0.85). The increase in hindlimb lipolysis after L-NAME infusion does not seem to be due to increased lipolysis of plasma triacylglycerol because circulating arterial (155 vs. 142 ± 20.8 µmol/L, P = 0.58), venous (154 vs. 140 ± 20.5 µmol/L, P = 0.50), and AVD (1.0 vs. 2.9 ± 3.17 µmol/L, P = 0.38) triacylglycerol concentrations were unaffected by L-NAME infusion. In conclusion, these data indicate that infusion of 30 mg of L-NAME/kg inhibits NO synthesis, which in turn influences fat and carbohydrate metabolism in the ovine hindlimb independently of plasma insulin concentrations.

Key Words: Glucose • Insulin • L-N^G-Nitroarginine Methyl Ester (Hydrochloride) • Nitric Oxide • Nonesterified Fatty Acids • Ovine