The Role of I1‐Imidazoline Receptors and a2‐Adrenergic Receptors in the Modulation of Glucose and Lipid Metabolism in the SHROB Model of Metabolic Syndrome X

: 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: I1-imidazoline and a2-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 a2-adrenergic receptors. Rilmenidine and moxonidine also lowered glucagon, an effect that was mediated solely by I1-imidazoline receptors since it was potentiated by a2-blockade, but eliminated in the presence of I1-antagonists. Lowering of triglyceride and cholesterol levels followed the same pattern as glucagon, implicating I1-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, a2-adrenergic receptors mediate an acute deterioration of glucose tolerance, whereas in contrast I1-imidazoline receptors appear to mediate the persistent long-term improvements in glucose tolerance. The therapeutic action of I1-imidazoline agonists may be primarily mediated through reduced glucagon secretion.