The I1-imidazoline-binding site is a functional receptor mediating vasodepression via the ventral medulla.

Abstract

I1-imidazoline-binding sites fulfill all essential criteria for identification as receptors, including specificity of binding, association with physiological functions, appropriate anatomic and cellular and subcellular localization, and specific cell signaling pathways. Moreover, binding affinities correlate with functional drug responses. The evidence linking I1 receptors to vasodepression includes expression in RVLM and consistent correlations between vasodepressor potency in humans and animals and I1 binding affinity. Some I1 agonists are antagonists at alpha 2-adrenergic receptors (alpha 2AR), and these elicit vasodepression in RVLM. Potent alpha 2-agonists with phenylethylamine or guanidine structures are inactive in RVLM, yet highly effective in nucleus of the solitary tract, a region with well-defined alpha 2-mediated vasodepressor responses. Selective I1 agonists are used clinically to lower blood pressure with minimal alpha 2-mediated sedation. Moreover, when microinjected into the RVLM only antagonists active at I1 receptors can block the vasodepressor action of either local or systemic imidazolines. RVLM alpha 2-blockade has no effect. Some reports appear to conflict with the I1 receptor hypothesis; but these reports often make incorrect assumptions regarding drug specificity, overlook systemic effects of alpha 2-antagonists, or inappropriately analyze data. Blockade of gamma-aminobutyric acid (GABA) receptors blocks the vasodepressor action of imidazolines, implying a multisynaptic pathway. Thus imidazolines act via I1 receptors in RVLM to lower blood pressure, although alpha 2AR are also important, especially in NTS.