title: Yohimbine promotes cardiac NE release and prevents LPS-induced cardiac dysfunction via blockade of presynaptic α2A-adrenergic receptor.
abstract: Myocardial depression is an important contributor to mortality in sepsis. We have recently demonstrated that α2-adrenoceptor (AR) antagonist, yohimbine (YHB), attenuates lipopolysaccharide (LPS)-induced myocardial depression. However, the mechanisms for this action of YHB are unclear. Here, we demonstrated that YHB decreased nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) levels in the myocardium and plasma, attenuated cardiac and hepatic dysfunction, but not kidney and lung injuries in endotoxemic mice. Immunohistochemical analysis revealed that cardiac α2A-AR was mostly located in sympathetic nerve presynaptic membrane; YHB decreased cardiac α2A-AR level and promoted cardiac norepinephrine (NE) release in endotoxemic mice. Reserpine that exhausted cardiac NE without markedly decreasing plasma NE level abrogated the inhibitory effects of YHB on cardiac TNF-α and iNOS expression as well as cardiac dysfunction, but not the suppressive effects of YHB on plasma TNF-α and NO elevation in LPS-challenged mice. Furthermore, both reserpine and YHB significantly inhibited LPS-induced myocardial apoptosis. α1-AR, β2-AR, but not β1-AR antagonists reversed the inhibitory effect of YHB on LPS-stimulated myocardial apoptosis. However, β1-AR antagonist attenuated LPS-caused cardiomyocyte apoptosis, partly abolished the protective effect of YHB on the left ventricular ejection fraction in endotoxemic mice. Altogether, these findings indicate that YHB attenuates LPS-induced cardiac dysfunction, at least in part, through blocking presynaptic α2A-AR and thus increasing cardiac NE release. YHB-elevated cardiac NE improves cardiac function via suppressing cardiac iNOS and TNF-α expression, activating β1-AR and inhibiting cardiomyocyte apoptosis through α1- and β2-AR in endotoxemic mice. However, cardiac β1-AR activation promotes LPS-induced cardiomyocyte apoptosis.
authors.affiliation: Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
authors.forename: Yiyang
authors.initials: Y
authors.lastname: Wang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Yu
authors.forename: Faqiang
authors.initials: F
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Hongmei
authors.initials: H
authors.lastname: Li
authors.forename: Xiuxiu
authors.initials: X
authors.lastname: Lv
authors.forename: Daxiang
authors.initials: D
authors.lastname: Lu
authors.forename: Huadong
authors.initials: H
authors.lastname: Wang
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000096:biosynthesis; D009638:Norepinephrine / Q000378:metabolism*; D009928:Organ Specificity; D017729:Presynaptic Terminals / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015016:Yohimbine / Q000494:pharmacology*
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D008070:Lipopolysaccharides; D018341:Receptors, Adrenergic, alpha-2; D014409:Tumor Necrosis Factor-alpha; D015016:Yohimbine; D009569:Nitric Oxide; D012110:Reserpine; D009638:Norepinephrine