Insulin resistance after hypertension induced by the nitric oxide synthesis inhibitor L-NMMA in rats

Abstract

To explore the relationship between insulin resistance and hypertension, we examined whether acute induction of hypertension can engender insulin resistance. For this purpose we measured rates of insulin-mediated glucose uptake in awake unstressed rats with the euglycemic hyperinsulinemic (12 microns.kg-1.min-1) clamp technique during infusions of saline alone or after induction of hypertension by bolus administration of NG-monomethyl-L-arginine (L-NMMA, 30 and 15 mg/kg), a competitive inhibitor of nitric oxide synthase. Arterial pressure was approximately 20% greater with L-NMMA bolus than with saline alone. Isotopically determined steady-state rates of glucose uptake were 36 +/- 1 mg.kg-1.min-1 during saline alone and 26 +/- 2 and 19 +/- 1 mg.kg-1.min-1 with low- and high-dose L-NMMA (P < 0.001 vs. saline), respectively. To rule out that insulin resistance induced by L-NMMA was adrenergically mediated, clamp studies were repeated with alpha- and beta-blockade. Rates of glucose uptake remained approximately 20% below those observed with saline alone (P < 0.001). A significant inverse correlation was observed between the height of the blood pressure and the rate of glucose uptake (r = 0.32, P = 0.04). In conclusion, acute induction of hypertension with L-NMMA can cause marked insulin resistance. We postulate that reduced skeletal muscle perfusion and/or sympathetic nervous system activation may contribute to insulin resistance induced by L-NMMA.

Nitric Oxide Increases Glucose Uptake Through a Mechanism That Is Distinct From the Insulin and Contraction Pathways in Rat Skeletal Muscle

“…The administration of L-NMMA in vivo results in the development of marked insulin resistance (9,12,13) cemia (13), suggesting an important role for NO in muscle glucose metabolism. Interestingly, these effects of NOS inhibition on insulin-mediated glucose uptake in vivo are not observed when isolated skeletal muscles are incubated with NOS inhibitors and insulin in vitro (6,8,9,35).…”

“…Part of the mechanism by which insulin increases glucose transport in vivo involves enhanced blood flow and glucose delivery to the muscle, a process mediated by the release of NO from the endothelium (9)(10)(11). The acute administration of the NOS inhibitors N G -monomethyl-L-arginine (L-NMMA) or N G -nitro-L-arginine methyl ester (L-NAME) results in the development of marked insulin resistance, hypertension, and/or hyperglycemia (9,12,13). NOS blockade decreases blood flow to skeletal muscle and impairs insulinmediated glucose disposal during a hyperinsulinemic-euglycemic clamp in vivo (9,12).…”

“…The acute administration of the NOS inhibitors N G -monomethyl-L-arginine (L-NMMA) or N G -nitro-L-arginine methyl ester (L-NAME) results in the development of marked insulin resistance, hypertension, and/or hyperglycemia (9,12,13). NOS blockade decreases blood flow to skeletal muscle and impairs insulinmediated glucose disposal during a hyperinsulinemic-euglycemic clamp in vivo (9,12). In contrast to the effects of NOS inhibition in vivo, NOS inhibitors fail to affect insulin-stimulated glucose transport in isolated muscles incubated using in vitro preparations (6,8,9); this suggests that hemodynamic factors are needed to fully amplify the increase in insulinstimulated glucose transport in skeletal muscle.…”

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

“…Recent studies in itro with NO donors have provided evidence that this gaseous signalling molecule stimulates glucose transport, glycolysis and glucose oxidation in skeletal muscle [8]. Inhibition of NOS, which forms NO, decreases basal glucose transport in itro [15] and causes insulin resistance in i o [26], although this latter effect is disputed [27]. NO activates the soluble form of guanylate cyclase [11].…”

“…In addition, skeletal muscles isolated from exercise-trained rats have increased sensitivity to insulin [40] and increased expression of NOS [17]. Conversely, treatment of rats in i o with the NOS inhibitor N G -nitro--arginine methyl ester resulted in insulin resistance (and hypertension) [26]. Furthermore the present study has shown that insulin-resistant obese Zucker rat skeletal muscle seems to possess multiple defects in the NO\cGMP pathway (both NOS and activation of the soluble guanylate cyclase by NO seem impaired).…”