To review previous work and present additional evidence characterizing the I1-imidazoline receptor and its role in cellular signaling, central cardiovascular control, and the treatment of
metabolic syndromes. Second-generation centrally-acting
antihypertensives inhibit sympathetic activity mainly via
imidazoline receptors, whereas first-generation agents act via alpha2-adrenergic receptors. The I1 subtype of
imidazoline receptor resides in the plasma membrane and binds central
antihypertensives with high affinity.
METHODS AND RESULTS: Radioligand binding assays have characterized I1-imidazoline sites in the brainstem site of action for these agents in the rostral ventrolateral medulla. Binding affinity at I1-imidazoline sites, but not at other classes of
imidazoline binding sites, correlates closely with the potency of central
antihypertensive agents in animals and in human clinical trials. The
antihypertensive action of systemic
moxonidine is eliminated by the I1/alpha2-antagonist
efaroxan, but not by selective blockade of alpha2-adrenergic receptors. Until now, the cell signaling pathway coupled to I1-imidazoline receptors was unknown. Using a model system lacking alpha2-adrenergic receptors (PC12
pheochromocytoma cells) we have found that
moxonidine acts as an agonist at the cell level and I1-imidazoline receptor activation leads to the production of the second messenger
diacylglycerol, most likely through direct activation of
phosphatidylcholine-selective
phospholipase C. The obese spontaneously hypertensive rat (SHR; SHROB strain) shows many of the abnormalities that cluster in human syndrome X, including elevations in blood pressure, serum
lipids and
insulin. SHROB and their lean SHR littermates were treated with
moxonidine at 8 mg/kg per day. SHROB and SHR treated with
moxonidine showed not only lowered blood pressure but also improved
glucose tolerance and facilitated insulin secretion in response to a
glucose load. Because alpha2-adrenergic agonists impair
glucose tolerance, I1-imidazoline receptors may contribute to the multiple beneficial effects of
moxonidine treatment.
CONCLUSION: