The Role of I₁-Imidazoline and α₂-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Abstract

We examined glucose metabolism after I 1 -imidazoline (I 1 R) and ␣ 2 -adrenergic receptor (␣ 2 AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I 1 R/␣ 2 AR agonists moxonidine and rilmenidine or the ␣ 2 AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (␣ 2 AR) efaroxan (I 1 R/␣ 2 AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I 1 R). Hyperglycemia induced by moxonidine, rilmenidine, and guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates. Glucagon was reduced by the I 1 R agonists (moxonidine, 32 Ϯ 5%; rilmenidine, 24 Ϯ 7%) but elevated by guanabenz (71 Ϯ 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 Ϯ 6%). AGN 193402 blocked the glucagon response without affecting hyperglycemia and hypoinsulinemia. Efaroxan blocked all responses to moxonidine. When SHROB rats were treated with moxonidine 15 min before an oral glucose tolerance test, the glucose area under the curve (AUC) was increased. Antagonizing the ␣ 2 AR component of moxonidine's action with rauwolscine improved glucose AUC 3-fold and facilitated the insulin secretory response and reduced glucagon secretion. Testing fasting glucose and insulin during 3 weeks of oral moxonidine revealed early hyperglycemia that later faded, and a progressive drop in fasting insulin. The acute hyperglycemia and hypoinsulinemia elicited by moxonidine and rilmenidine was mediated by ␣ 2 AR, whereas I 1 R may reduce glucagon and increase insulin, particularly after a glucose load.

Marked Insulin Resistance in Obese Spontaneously Hypertensive Rat Adipocytes Is Ameliorated by in Vivo but Not in Vitro Treatment with Moxonidine

“…Similar results have been obtained for another imidazoline agonist, rilmenidine (Penicaud et al, 1998;Velliquette and Ernsberger, 2003b; This study was supported by Grant HL44514 from the National Institutes of Health. It was submitted in partial fulfillment of the requirements for a doctorate in Nutrition from Case Western Reserve University School of Medicine.…”

“…Similar results have been obtained for another imidazoline agonist, rilmenidine (Penicaud et al, 1998;Velliquette and Ernsberger, 2003b;Anichkov et al, 2005). Moxonidine is a selective agonist at I 1 -imidazoline receptors, while also activating ␣ 2 -adrenergic receptors (Ernsberger et al, 1993).…”

“…Moxonidine is a selective agonist at I 1 -imidazoline receptors, while also activating ␣ 2 -adrenergic receptors (Ernsberger et al, 1993). Whereas both imidazoline and ␣ 2 -adrenergic receptors contribute to sympatholytic actions, only the imidazoline component improves glucose metabolism (Velliquette and Ernsberger, 2003b). Most studies have been carried out with chronic treatment, but acute improvements in glucose tolerance and insulin secretion can be detected under blockade of ␣ 2 -adrenergic receptors (Velliquette and Ernsberger, 2003b).…”

Effects of aglycone genistein in a rat experimental model of postmenopausal metabolic syndrome

“…Body weight results were expressed compared with food intake, by using the following formula: food intake (g)/body weight (g)!100. Oral glucose tolerance tests were carried out at the end of the treatment period as described previously (Ernsberger et al 1999b, Velliquette et al 2002, Velliquette & Ernsberger 2003. All rats were fasted for 18 h and administered a 50% glucose solution in water by gavages at a dose of 6 g/kg body weight.…”

Effect of anesthetics on gastric damage using two models of portal hypertension

“…It has been reported that activation of α2-adrenoceptor can increase, decrease or not change the levels of glucagon. Increased glucagon levels associated with decreased insulin levels may account for hyperglycemic effect of α2-adrenoceptor agonist [31,32] . In rats, xylazine increases urine flow rate by activating of the α2-adrenergic receptors in hypothalamic paraventricular nucleus which in turn decreases vasopressin release [33] .…”