title: Endogenous ACh tonically stimulates ANP secretion in rat atria.
abstract: Exogenous acetylcholine (ACh) is known to stimulate atrial natriuretic peptide (ANP) secretion concomitantly with a decrease in atrial pulse pressure. However, the role of intrinsic ACh in the regulation of ANP secretion remains unknown. Recently, it was shown that nonneuronal and neuronal ACh is present in the cardiac atria. From this finding we hypothesize that endogenously released ACh is involved in the regulation of ANP secretion in an autocrine or paracrine manner in the atria. Experiments were performed in isolated beating rat atria. ANP was measured using radioimmunoassay. To increase the availability of the ACh in the extracellular space of the atrium, its degradation was inhibited with an inhibitor of acetylcholinesterase. Acetylcholinesterase inhibition with physostigmine increased ANP secretion concomitantly with a decrease in atrial dynamics in a concentration-dependent manner. Inhibitors of M2 muscarinic ACh receptor (mAChR), methoctramine, and ACh-activated K(+) (KACh(+)) channels, tertiapin-Q, abolished the physostigmine-induced changes. The effects were not observed in the atria from rats treated with pertussis toxin. Furthermore, the physostigmine-induced effects were attenuated by an inhibitor of high-affinity choline transporter, hemicholinium-3, which is a rate-limiting step of ACh synthesis. Inhibitors of the mAChR signaling pathway and ACh synthesis also attenuated the basal levels of ANP secretion and accentuated atrial dynamics. These findings suggest that endogenously released ACh tonically stimulates ANP secretion from atrial cardiomyocytes via activation of M2 mAChR-Gi/o-KACh(+) channel signaling. It is also suggested that the ACh-ANP signaling is implicated in cardiac physiology and pathophysiology.
authors.affiliation: Hanbang Body-fluid Research Center & College of Oriental Medicine, Wonkwang University, Iksan, Jeonbuk, Republic of Korea; and.
authors.forename: Hye Yoom
authors.initials: HY
authors.lastname: Kim
authors.forename: Kyung Woo
authors.initials: KW
authors.lastname: Cho
authors.forename: Dong Yuan
authors.initials: DY
authors.lastname: Xu
authors.forename: Dae Gill
authors.initials: DG
authors.lastname: Kang
authors.forename: Ho Sub
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D016275:Atrial Function; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000378:metabolism; D006439:Hemodynamics; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C075746:Slc6a8 protein, rat; D009320:Atrial Natriuretic Factor; D000109:Acetylcholine
keywords: ACh-evoked potassium channel; acetylcholine; atrial natriuretic peptide; hemicholinium-3; muscarinic acetylcholine receptor; pertussis toxin