Perera, Ruwan K. and Fischer, Thomas H. and Wagner, Michael and Dewenter, Matthias and Vettel, Christiane and Bork, Nadja I. and Maier, Lars S. and Conti, Marco and Wess, Juergen and El-Armouche, Ali and Hasenfuss, Gerd and Nikolaev, Viacheslav O. (2017) Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4. SCIENTIFIC REPORTS, 7: 15222. ISSN 2045-2322,
Full text not available from this repository. (Request a copy)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 Forster 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 M-2- or M-1/3-muscarinic receptor knockout mice, atropine increased cAMP levels that were pre-elevated with the beta-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 M-2 or M(1/3-)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HUMAN ATRIAL MYOCARDIUM; MUSCARINIC RECEPTORS; KNOCKOUT MICE; INTACT-CELLS; HEART; ACETYLCHOLINE; PATHOPHYSIOLOGY; ARRHYTHMIAS; RESPONSES; SYSTEM; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:19 |
| Last Modified: | 25 Feb 2019 15:03 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1856 |
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