THE I-1-IMIDAZOLINE-BINDING SITE IS A FUNCTIONAL RECEPTOR MEDIATING VASODEPRESSION VIA THE VENTRAL MEDULLA

I-1-imidazoline-binding sites fulfill all essential criteria for ident ification as receptors, including specificity of binding, association with physiological functions, appropriate anatomic and cellular and su bcellular localization, and specific cell signaling pathways. Moreover , binding affinities correlate with functional drug responses. The evi dence linking I-1 receptors to vasodepression includes expression in R VLM and consistent correlations between vasodepressor potency in human s and animals and I-1 binding affinity. Some I-1 agonists are antagoni sts at alpha 2-adrenergic receptors (alpha 2AR), and these elicit vaso depression in RVLM. Potent alpha(2)-agonists with phenylethylamine of guanidine structures are inactive in RVLM, yet highly effective in nuc leus of the solitary tract, a region with well-defined alpha(2)-mediat ed vasodepressor responses, Selective I-1 agonists are used clinically to lower blood pressure with minimal alpha(2)-mediated sedation. More over, when microinjected into the RVLM only antagonists active at I-1 receptors can black the vasodepressor action of either local or system ic imidazolines. RVLM alpha(2)-blockade has no effect. Some reports ap pear to conflict with the I-1 receptor hypothesis; but these reports o ften make incorrect assumptions regarding drug specificity, overlook s ystemic effects of alpha(2)-antagonists, or inappropriately analyze da ta. Blockade of gamma-aminobutyric acid (GABA) receptors blocks the va sodepressor action of imidazolines, implying a multisynaptic pathway. Thus imidazolines act via I-1 receptors in RVLM to lower blood pressur e, although alpha(2)AR are also important, especially in NTS.