Stimulation of brain nicotinic acetylcholine receptors activates adrenomedullary outflow via brain inducible NO synthase‐mediated S‐nitrosylation

다국어 초록 (Multilingual Abstract)

We have demonstrated that i.c.v.‐administered (±)‐epibatidine, a nicotinic ACh receptor (nAChR) agonist, induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla with dihydro‐β‐erythroidin (an α4β2 nAChR antagonist)‐sensitive brain mechanisms. Here, we examined central mechanisms for the (±)‐epibatidine‐induced responses, focusing on brain NOS and NO‐mediated mechanisms, soluble GC (sGC) and protein S‐nitrosylation (a posttranslational modification of protein cysteine thiol groups), in urethane‐anaesthetized (1.0 g·kg−1, i.p.) male Wistar rats.
(±)‐Epibatidine was i.c.v. treated after i.c.v. pretreatment with each inhibitor described below. Then, plasma catecholamines were measured electrochemically after HPLC. Immunoreactivity of S‐nitrosylated cysteine (SNO‐Cys) in α4 nAChR subunit (α4)‐positive spinally projecting neurones in the rat hypothalamic paraventricular nucleus (PVN, a regulatory centre of adrenomedullary outflow) after i.c.v. (±)‐epibatidine administration was also investigated.
(±)‐Epibatidine‐induced elevation of plasma catecholamines was significantly attenuated by L‐NAME (non‐selective NOS inhibitor), carboxy‐PTIO (NO scavenger), BYK191023 [selective inducible NOS (iNOS) inhibitor] and dithiothreitol (thiol‐reducing reagent), but not by 3‐bromo‐7‐nitroindazole (selective neuronal NOS inhibitor) or ODQ (sGC inhibitor). (±)‐Epibatidine increased the number of spinally projecting PVN neurones with α4‐ and SNO‐Cys‐immunoreactivities, and this increment was reduced by BYK191023.
Stimulation of brain nAChRs can induce elevation of plasma catecholamines through brain iNOS‐derived NO‐mediated protein S‐nitrosylation in rats. Therefore, brain nAChRs (at least α4β2 subtype) and NO might be useful targets for alleviation of catecholamines overflow induced by smoking.