Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin.
We examined the effects of inhibiting nitric oxide synthase with Nomega-nitro-l-arginine-methyl ester (l-NAME) on total hindlimb blood flow, muscle microvascular recruitment, and hindlimb glucose uptake during euglycemic hyperinsulinemia in vivo in the rat. We used two independent methods to measure microvascular perfusion. In one group of animals, microvascular recruitment was measured using the metabolism of exogenously infused 1-methylxanthine (1-MX), and in a second group contrast-enhanced ultrasound (CEU) was used. Limb glucose uptake was measured by arterial-venous concentration differences after 2 h of insulin infusion. Saline alone did not alter femoral artery flow, glucose uptake, or 1-MX metabolism. Insulin (10 mU.min-1.kg-1) significantly increased hindlimb total blood flow (0.69 +/- 0.02 to 1.22 +/- 0.11 ml/min, P < 0.05), glucose uptake (0.27 +/- 0.05 to 0.95 +/- 0.08 micromol/min, P < 0.05), 1-MX uptake (5.0 +/- 0.5 to 8.5 +/- 1.0 nmol/min, P < 0.05), and skeletal muscle microvascular volume measured by CEU (10.0 +/- 1.6 to 15.0 +/- 1.2 video intensity units, P < 0.05). Addition of l-NAME to insulin completely blocked the effect of insulin on both total limb flow and microvascular recruitment (measured using either 1-MX or CEU) and blunted glucose uptake by 40% (P < 0.05). We conclude that insulin specifically recruits flow to the microvasculture in skeletal muscle via a nitric oxide-dependent pathway and that this may be important to insulin's overall action to regulate glucose disposal.
Vincent
M A
MA
Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Barrett
E J
EJ
Lindner
J R
JR
Clark
M G
MG
Rattigan
S
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D014465:Ultrasonics; D014463:Ultrasonography; D014970:Xanthines / Q000493:pharmacokinetics
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D014970:Xanthines; C053085:1-methylxanthine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D005947:Glucose; D019331:NG-Nitroarginine Methyl Ester