دورية أكاديمية
Blockers of Hyperpolarization-activated Cyclic Nucleotide-gated channels exhibit antimuscarinic properties in human atrial cardiomyocytes
| العنوان: | Blockers of Hyperpolarization-activated Cyclic Nucleotide-gated channels exhibit antimuscarinic properties in human atrial cardiomyocytes |
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| المؤلفون: | Gencarelli, M, Laurino, A, Balducci, V, Spinelli, V, Cameli, M, Pecori, R, Vistoli, G, Matucci, R, Cerbai, E, Sartiani, L |
| المصدر: | Cardiovascular Research ; volume 118, issue Supplement_1 ; ISSN 0008-6363 1755-3245 |
| بيانات النشر: | Oxford University Press (OUP) |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Physiology (medical), Cardiology and Cardiovascular Medicine, Physiology |
| الوصف: | Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): M.I.U.R. PRIN 2017 to E.C and ECRF to L.S. Introduction Ivabradine (Iva), Zatebradine (Zat) and ZD7288 (ZD) are blockers of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels, which play definite electrophysiological functions in cardiac pacemakers, working cardiomyocytes, peripheral and central neurons [1]. Among them, Iva is in clinical use as bradycardic agent for uncontrolled angina and heart failure with reduced ejection fraction. Accumulating evidence suggests Iva may have a more complex pharmacological profile, including targets different from HCN channels [2, 3]. Reports on experimental atrial fibrillation, detrusor contraction and bladder overactivity [4] led us to hypothesize that muscarinic receptors (mAChRs) may represent still unexplored targets of Iva and analogues. Present study was designed to identify the effect of Iva on acetylcholine-gated inward-rectifier K+-current (IKACh), the main effector of atrial mAChRs, and to assess whether Iva and analogues interact directly with human atrial and recombinant mAChRs. Methods Patch-clamp recordings were performed on human atrial myocytes (hAMs) isolated from atrial appendages of patients in sinus rhythm. Competition and kinetic radioligand binding assays were performed on hAM preparations and on mAChR(1,2,3) expressed in heterologous systems. Results Patch-clamp recordings on hAMs demonstrated Iva is able to suppress IKAch similarly to atropine, thus suggesting a functional antagonism of Iva on atrial mAChRs. Competition binding assays on hAM membranes revealed Iva, Zat and ZD bind to mAChRs with affinity values close to those of muscarinic ligands carbachol (Cch) and gallamine (Gal). Competition binding assays on recombinant mAChR(1,2,3), which are functionally relevant in hAMs, showed all blockers are ligands for each single mAChR type with affinity values close to those of CCh and Gal. Finally, using dissociation ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1093/cvr/cvac066.078 |
| الإتاحة: | https://doi.org/10.1093/cvr/cvac066.078Test https://academic.oup.com/cardiovascres/article-pdf/118/Supplement_1/cvac066.078/44155115/cvac066.078.pdfTest |
| حقوق: | https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_modelTest |
| رقم الانضمام: | edsbas.AAC39ADA |
| قاعدة البيانات: | BASE |
| DOI: | 10.1093/cvr/cvac066.078 |
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