Abstract
We examined glucose metabolism after I1-imidazoline (I1R) and α2-adrenergic receptor (α2AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I1R/α2AR agonists moxonidine and rilmenidine or the α2AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (α2AR) efaroxan (I1R/α2AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I1R). 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 I1R agonists (moxonidine, 32 ± 5%; rilmenidine, 24 ± 7%) but elevated by guanabenz (71 ± 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 ± 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 α2AR 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 α2AR, whereas I1R may reduce glucagon and increase insulin, particularly after a glucose load.
Footnotes
-
This study was supported by Grant HL44514 from the National Institutes of Health and by a grant from Solvay Pharmaceuticals (Hannover, Germany).
-
DOI: 10.1124/jpet.103.050468.
-
ABBREVIATIONS: α2AR, α2-adrenergic receptor; I1R, I1-imidazoline receptor; SHROB, spontaneously hypertensive obese rat; SHR, spontaneously hypertensive rat; OGTT, oral glucose tolerance test; ANOVA, analysis of variance; REMANOVA, analysis of variance with repeated measures; AUC, area under the curve; AGN 192403, 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane.
- Received February 13, 2003.
- Accepted May 13, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|