The I-1-imidazoline receptor: From binding site to therapeutic target in cardiovascular disease

Objective To review previous work and present additional evidence characterizing the I-1-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 alpha(2)-adrenergic receptors, The I-1 subtype of imidazoline receptor resides in the plasma membrane and binds central antihypertensives with high affinity. Methods and results Radioligand binding assays have characterized I-1-imidazoline sites in the brainstem site of action for these agents in the rostral ventrolateral medulla, Binding affinity at I-1-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 I-1/alpha(2)-antagonist efaroxan, but not by selective blockade of alpha(2)-adrenergic receptors, Until now, the cell signaling pathway coupled to I-1-imidazoline receptors was unknown, Using a model system lacking alpha(2)-adrenergic receptors (PC12 pheochromocytoma cells) we have found that moxonidine acts as an agonist at the cell level and I-1-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 alpha(2)-adrenergic agonists impair glucose tolerance, I-1-imidazoline receptors may contribute to the multiple beneficial effects of moxonidine treatment. Conclusion The I-1-imidazoline receptor is a specific high-affinity binding site corresponding to a functional cell-surface receptor mediating the antihypertensive actions of moxonidine and other second-generation centrally-acting agents, and may play a role in countering insulin resistance in an animal model of metabolic syndrome X.