I1-imidazoline receptors. Definition, characterization, distribution, and transmembrane signaling.

Data were presented showing that I1-imidazoline sites show a unique ligand specificity that differs markedly from that of any of the alpha 2-adrenergic subtypes or the I2-imidazoline sites labeled by [3H]idazoxan. On the other hand, the ligand specificity of I1-imidazoline sites is maintained across mammalian species (cow, rat, dog, and human) and between different tissues and cell types. I1-Imidazoline sites can be further distinguished from I2 sites because the latter, unlike I1 sites, were not present in RVLM membranes from bovine brain stem. Furthermore, I1-imidazoline sites were modulated by guanine nucleotides with a specificity appropriate for a receptor coupled to G-protein and were mainly localized to plasma membranes. I1-Imidazoline sites show a unique pattern of distribution between diverse tissues and cell types and appear to be a neuroepithelial marker as well as being present in secretory cells of the pancreatic islets. The widespread distribution of I1-imidazoline sites implies that the functional significance of this putative receptor may have been underestimated. The signaling pathway associated with the I1-imidazoline receptor remains to be fully elucidated, but is likely that activation of phospholipase A2 leading to release of arachidonic acid and subsequent generation of prostaglandins plays a major role.

A novel mechanism of action for hypertension control: moxonidine as a selective I1-imidazoline agonist.

Sympathoadrenal inhibition by a direct action within the central nervous system is an advantageous route to blood pressure control. Stimulation of brain alpha 2-adrenergic receptors is one mechanism for sympathoadrenal suppression, but comes at the cost of nonspecific depression of CNS function, including sedation and decreased salivary flow. Evidence is accumulating for a second pathway for pharmacological control of sympathoadrenal outflow, mediated by a novel receptor specific for imidazolines. First-generation central antihypertensive agents, which are imidazolines such as clonidine, act primarily to stimulate these I1-imidazoline receptors in the rostral ventrolateral medulla oblongata (RVLM) to lower blood pressure, but have sufficient agonism at alpha 2-adrenergic receptors to produce side effects. Second-generation centrally acting antihypertensive agents, such as moxonidine and rilmenidine, are selective for I1 relative to alpha 2 receptors. The reduced alpha 2 potency of these agents correlates with reduced severity of side effects. In this study we further established the selectivity of moxonidine for I1-imidazoline sites by characterizing the direct interaction of [3H]moxonidine with these receptors in the RVLM and in adrenomedullary chromaffin cells. [3H]Moxonidine preferentially labeled I1-imidazoline sites relative to alpha 2-adrenergic sites, only a small portion of which were labeled in the RVLM. [3H]Moxonidine binding to I1-imidazoline sites was modulated by guanine nucleotides, implying that I1-imidazoline sites may be membrane receptors coupled to guanine nucleotide binding regulatory proteins (G proteins). Receptor autoradiography with [125I]p-iodoclonidine confirmed the presence of I1-imidazoline sites in the RVLM and other areas of the brainstem reticular formation. In contrast, alpha 2-adrenergic sites were mainly localized to the nucleus of the solitary tract. Moxonidine selectively displaced [125I]p-iodoclonidine binding from reticular areas, including the RVLM. In vivo studies in SHR rats confirmed the ability of moxonidine to normalize hypertension by an action within the RVLM and confirmed the correspondence of I1 binding affinity and antihypertensive efficacy. We also discuss prior literature on the cardiovascular pharmacology of imidazolines, reinterpreting previous studies that only considered alpha-adrenergic mechanisms.