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

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• 作者：Yumiko Toyohira ; Tatsuhiko Kubo ; Miyabi Watanabe ; Yasuhito Uezono ; Susumu Ueno ; Koji Shinkai ; Masato Tsutsui ; Futoshi Izumi and Nobuyuki Yanagihara
• 关键词：Adrenal medullary cells ; Ca2+ influx ; Catecholamine ; Nicotinic acetylcholine receptors ; Pimobendan ; Secretion ; Synthesis ; Tyrosine hydroxylase
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2005
• 出版时间：February 2005
• 年：2005
• 卷：371
• 期：2
• 页码：107-113
• 全文大小：178 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Neurosciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1912

文摘

Pimobendan, a Ca2+ 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 (IC₅₀=29.5 M) 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 Ca2+ channels. Pimobendan also inhibited carbachol-induced influx of 22Na+ (IC₅₀=25.9 M) and 45Ca2+ (IC₅₀=26.0 M), but not veratridine-induced 22Na+ influx or high K+-induced 45Ca2+ 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 14C-catecholamine synthesis (IC₅₀=5.3 and 4.9 M) from [14C] tyrosine [but not from l-3, 4-dihydroxyphenyl [3-14C] alanine ([14C]DOPA)], as well as tyrosine hydroxylase activity (IC₅₀=3.8 and 4.3 M). These findings suggest that pimobendan inhibits carbachol-induced catecholamines secretion and synthesis through suppression of nicotinic acetylcholine receptors.