title: Selective blockade of nicotinic acetylcholine receptors by pimobendan, a drug for the treatment of heart failure: reduction of catecholamine secretion and synthesis in adrenal medullary cells.
abstract: Pimobendan, a Ca(2+) sensitizer, is used clinically in the treatment of chronic heart failure. Although chronic heart failure is associated with activation of the sympathetic nervous system, it remains unknown whether pimobendan affects the function of sympathetic neurons and the adrenal medulla. Here, we report the inhibitory effects of pimobendan on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. Pimobendan decreased the catecholamine secretion (IC(50)=29.5 microM) elicited by carbachol, an agonist at nicotinic acetylcholine receptors, but not that elicited by veratridine, an activator of voltage-dependent Na(+) channels, or by high K(+), an activator of voltage-dependent Ca(2+) channels. Pimobendan also inhibited carbachol-induced influx of (22)Na(+) (IC(50)=25.9 microM) and (45)Ca(2+) (IC(50)=26.0 microM), but not veratridine-induced (22)Na(+) influx or high K(+)-induced (45)Ca(2+) influx. The reduction of catecholamine secretion caused by pimobendan was not overcome by increasing the concentration of carbachol. UD-CG 212, an active metabolite of pimobendan, lowered carbachol-induced catecholamine secretion with a concentration/inhibition curve similar to that of pimobendan. In experiments in situ, pimobendan suppressed both basal and carbachol-stimulated (14)C-catecholamine synthesis (IC(50)=5.3 and 4.9 microM) from [(14)C] tyrosine [but not from L: -3, 4-dihydroxyphenyl [3-(14)C] alanine ([(14)C]DOPA)], as well as tyrosine hydroxylase activity (IC(50)=3.8 and 4.3 microM). These findings suggest that pimobendan inhibits carbachol-induced catecholamines secretion and synthesis through suppression of nicotinic acetylcholine receptors.
authors.affiliation: Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu 807-8555, Japan. toyohira@med.uoeh-u.ac.jp
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Toyohira
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kubo
authors.forename: Miyabi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.forename: Susumu
authors.initials: S
authors.lastname: Ueno
authors.forename: Koji
authors.initials: K
authors.lastname: Shinkai
authors.forename: Masato
authors.initials: M
authors.lastname: Tsutsui
authors.forename: Futoshi
authors.initials: F
authors.lastname: Izumi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yanagihara
mesh_terms: D000313:Adrenal Medulla / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002395:Catecholamines / Q000096:biosynthesis* / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004347:Drug Interactions; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology*
chemical_list: D002316:Cardiotonic Agents; D002395:Catecholamines; D018733:Nicotinic Antagonists; D011724:Pyridazines; C041648:pimobendan; D014701:Veratridine; D002217:Carbachol; D012964:Sodium; D002118:Calcium