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 alpha(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 alpha(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 alpha(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, alpha(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.