INHIBITION OF INSULIN-MEDIATED GLUCOSE-UPTAKE IN RAT HINDLIMB BY AN ALPHA-ADRENERGIC VASCULAR EFFECT

The vasoconstrictor norepinephrine, at high doses, inhibits oxygen upt ake (VO2) in the perfused hindlimb, possibly by opening vascular shunt s and reducing nutrient access. Thus, in the present study, the effect of norepinephrine on insulin-mediated glucose uptake (IMGU) was asses sed. Rat hindlimbs were perfused at constant flow with medium containi ng 8.3 mM glucose and a tracer amount of 2-deoxy-D-[1-H-3]glucose (2-D G) with and without 15 nM insulin, 10 mu M norepinephrine (NE), and co mbinations of the adrenergic blockers propranolol (Prop) and prazosin. Perfusions were also conducted at a lower dose of 1 mu M NE where VO2 is stimulated. NE (10 mu M) inhibited IMGU > 80%, and this inhibition , when measured by 2-DG uptake, was most pronounced in muscles rich in white fibers. The inhibitory effect of NE on IMGU comprised a beta-ad renergic component also partly evident at lower concentrations of NE ( i.e., 1 mu M) and an alpha-adrenergic component only evident at 10 mu M NE. In contrast to the results for the hindlimb, 10 mu M NE plus Pro p (alpha-adrenergic combination) had no significant effect on insulin- mediated 2-DG uptake by isolated incubated soleus or extensor digitoru m longus muscles. It is concluded that NE, at doses likely to occur at sympathetic vasoconstrictor synapses in muscle, impairs IMGU by a Vas cular effect to cause shunting and reduce access.