Nikolaev, Viacheslav O.

[["dc.bibliographiccitation.artnumber","15222"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Perera, Ruwan K."],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Wagner, Michael"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Bork, Nadja I."],["dc.contributor.author","Maier, Lars S."],["dc.contributor.author","Conti, Marco"],["dc.contributor.author","Wess, Juergen"],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.date.accessioned","2018-04-23T11:48:02Z"],["dc.date.available","2018-04-23T11:48:02Z"],["dc.date.issued","2017"],["dc.description.abstract","Atropine is a clinically relevant anticholinergic drug, which blocks inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia. However, many cardiac effects of atropine cannot be adequately explained solely by its antagonism at muscarinic receptors. In isolated mouse ventricular cardiomyocytes expressing a Förster resonance energy transfer (FRET)-based cAMP biosensor, we confirmed that atropine inhibited acetylcholine-induced decreases in cAMP. Unexpectedly, even in the absence of acetylcholine, after G-protein inactivation with pertussis toxin or in myocytes from M2- or M1/3-muscarinic receptor knockout mice, atropine increased cAMP levels that were pre-elevated with the β-adrenergic agonist isoproterenol. Using the FRET approach and in vitro phosphodiesterase (PDE) activity assays, we show that atropine acts as an allosteric PDE type 4 (PDE4) inhibitor. In human atrial myocardium and in both intact wildtype and M2 or M1/3-receptor knockout mouse Langendorff hearts, atropine led to increased contractility and heart rates, respectively. In vivo, the atropine-dependent prolongation of heart rate increase was blunted in PDE4D but not in wildtype or PDE4B knockout mice. We propose that inhibition of PDE4 by atropine accounts, at least in part, for the induction of tachycardia and the arrhythmogenic potency of this drug."],["dc.identifier.doi","10.1038/s41598-017-15632-x"],["dc.identifier.gro","3142321"],["dc.identifier.pmid","29123207"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14861"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13454"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/194"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D01: Erholung aus der Herzinsuffizienz – Einfluss von Fibrose und Transkriptionssignatur"],["dc.relation.issn","2045-2322"],["dc.relation.workinggroup","RG El-Armouche"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG L. Maier (Experimentelle Kardiologie)"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e0167974"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","PLoS One"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Sprenger, Julia U."],["dc.contributor.author","Bork, Nadja I."],["dc.contributor.author","Herting, Jonas"],["dc.contributor.author","Fischer, Thomas H."],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.date.accessioned","2018-11-07T10:04:36Z"],["dc.date.available","2018-11-07T10:04:36Z"],["dc.date.issued","2016"],["dc.description.abstract","Calcium (Ca2+) and 3',5'-cyclic adenosine monophosphate (cAMP) play a critical role for cardiac excitation-contraction-coupling. Both second messengers are known to interact with each other, for example via Ca2+-dependent modulation of phosphodiesterase 1 (PDE1) and adenylyl cyclase 5/6 (AC 5/6) activities, which is supposed to occur especially at the local level in distinct subcellular microdomains. Currently, many studies analyze global and local cAMP signaling and its regulation in resting cardiomyocytes devoid of electrical stimulation. For example, Forster resonance energy transfer (FRET) microscopy is a popular approach for visualization of real time cAMP dynamics performed in resting cardiomyocytes to avoid potential contractility-related movement artifacts. However, it is unknown whether such data are comparable with the cell behavior under more physiologically relevant conditions during contraction. Here, we directly compare the cAMP-FRET responses to AC stimulation and PDE inhibition in resting vs. paced adult mouse ventricular cardiomyocytes for both cytosolic and subsarcolemmal microdomains. Interestingly, no significant differences in cAMP dynamics could be detected after beta-adrenergic (isoproterenol) stimulation, suggesting low impact of rapidly changing contractile Ca2+ concentrations on cytosolic cAMP levels associated with AC activation. However, the contribution of the calcium-dependent PDE1, but not of the Ca2+-insensitive PDE4, to the regulation of cAMP levels after forskolin stimulation was significantly increased. This increase could be mimicked by pretreatment of resting cells with Ca2+ elevating agents. Ca2+ imaging demonstrated significantly higher amplitudes of Ca2+ transients in forskolin than in isoproterenol stimulated cells, suggesting that forskolin stimulation might lead to stronger activation of PDE1. In conclusion, changes in intracellular Ca2+ during cardiomyocyte contraction dynamically interact with cAMP levels, especially after strong AC stimulation. The use of resting cells for FRET-based measurements of cAMP can be justified under beta-adrenergic stimulation, while the reliable analysis of PDE1 effects may require electric field stimulation."],["dc.identifier.doi","10.1371/journal.pone.0167974"],["dc.identifier.isi","000389580900066"],["dc.identifier.pmid","27930744"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/14002"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/38732"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/157"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","Najko"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A01: cAMP- und cGMP- Mikrodomänen bei Herzhypertrophie und Insuffizienz"],["dc.relation.issn","1932-6203"],["dc.relation.workinggroup","RG Nikolaev (Cardiovascular Research Center)"],["dc.relation.workinggroup","RG T. Fischer"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Interactions of Calcium Fluctuations during Cardiomyocyte Contraction with Real-Time cAMP Dynamics Detected by FRET"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]