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The Role of I 1 ‐Imidazoline Receptors and a 2 ‐Adrenergic Receptors in the Modulation of Glucose and Lipid Metabolism in the SHROB Model of Metabolic Syndrome X
Author(s) -
KOLETSKY RICHARD J.,
VELLIQUETTE RODNEY A.,
ERNSBERGER PAUL
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1304.031
Subject(s) - rilmenidine , moxonidine , imidazoline receptor , endocrinology , medicine , insulin resistance , receptor , chemistry , glucagon , metabolic syndrome , pharmacology , insulin , biology , diabetes mellitus , agonist
A bstract : Hypertension is commonly accompanied by obesity, hyperlipidemia, and insulin resistance in humans, a cluster of abnormalities known as metabolic syndrome X. With the notable exception of inhibitors of the renin‐angiotensin system, which have mildly beneficial effects on insulin resistance, most antihypertensive agents worsen one or more components of metabolic syndrome X. Second‐generation centrally acting antihypertensive agents such as rilmenidine and moxonidine have mixed effects on components of metabolic syndrome X, which might reflect in part actions on two different receptors: I 1 ‐imidazoline and a 2 ‐adrenergic. Using a rat model of metabolic syndrome X, we sought to separate the influence of these two receptors on glucose and lipid metabolism by using selective antagonists. Rilmenidine and moxonidine acutely raised glucose and lowered insulin, thereby further worsening glucose tolerance. These effects were entirely mediated by a 2 ‐adrenergic receptors. Rilmenidine and moxonidine also lowered glucagon, an effect that was mediated solely by I 1 ‐imidazoline receptors since it was potentiated by a 2 ‐blockade, but eliminated in the presence of I 1 ‐antagonists. Lowering of triglyceride and cholesterol levels followed the same pattern as glucagon, implicating I 1 ‐imidazoline receptors in lipid‐lowering actions. Chronic treatment with moxonidine reproduced the beneficial effects on glucagon and lipids while the acute hyperglycemic response did not persist. Thus, a 2 ‐adrenergic receptors mediate an acute deterioration of glucose tolerance, whereas in contrast I 1 ‐imidazoline receptors appear to mediate the persistent long‐term improvements in glucose tolerance. The therapeutic action of I 1 ‐imidazoline agonists may be primarily mediated through reduced glucagon secretion.