Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels
Tongmai Yangxin (TMYX) is a complex compound of the Traditional Chinese Medicine (TCM) used to treat several cardiac rhythm disorders; however, no information regarding its mechanism of action is available. In this study we provide a detailed characterization of the effects of TMYX on the electrical...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75119 |
| _version_ | 1828166704562176000 |
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| author | Chiara Piantoni Manuel Paina David Molla Sheng Liu Giorgia Bertoli Hongmei Jiang Yanyan Wang Yi Wang Yi Wang Dario DiFrancesco Andrea Barbuti Annalisa Bucchi Mirko Baruscotti |
| author_facet | Chiara Piantoni Manuel Paina David Molla Sheng Liu Giorgia Bertoli Hongmei Jiang Yanyan Wang Yi Wang Yi Wang Dario DiFrancesco Andrea Barbuti Annalisa Bucchi Mirko Baruscotti |
| author_sort | Chiara Piantoni |
| collection | DOAJ |
| description | Tongmai Yangxin (TMYX) is a complex compound of the Traditional Chinese Medicine (TCM) used to treat several cardiac rhythm disorders; however, no information regarding its mechanism of action is available. In this study we provide a detailed characterization of the effects of TMYX on the electrical activity of pacemaker cells and unravel its mechanism of action. Single-cell electrophysiology revealed that TMYX elicits a reversible and dose-dependent (2/6 mg/ml) slowing of spontaneous action potentials rate (−20.8/–50.2%) by a selective reduction of the diastolic phase (−50.1/–76.0%). This action is mediated by a negative shift of the If activation curve (−6.7/–11.9 mV) and is caused by a reduction of the cyclic adenosine monophosphate (cAMP)-induced stimulation of pacemaker channels. We provide evidence that TMYX acts by directly antagonizing the cAMP-induced allosteric modulation of the pacemaker channels. Noticeably, this mechanism functionally resembles the pharmacological actions of muscarinic stimulation or β-blockers, but it does not require generalized changes in cytoplasmic cAMP levels thus ensuring a selective action on rate. In agreement with a competitive inhibition mechanism, TMYX exerts its maximal antagonistic action at submaximal cAMP concentrations and then progressively becomes less effective thus ensuring a full contribution of If to pacemaker rate during high metabolic demand and sympathetic stimulation. |
| first_indexed | 2024-04-12T02:05:38Z |
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| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:05:38Z |
| publishDate | 2022-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5a4c42db53c340f6bcf8c080de7fbe1a2022-12-22T03:52:32ZengeLife Sciences Publications LtdeLife2050-084X2022-03-011110.7554/eLife.75119Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channelsChiara Piantoni0https://orcid.org/0000-0002-3621-8402Manuel Paina1https://orcid.org/0000-0001-9250-9303David Molla2https://orcid.org/0000-0003-4355-4508Sheng Liu3https://orcid.org/0000-0001-8160-5762Giorgia Bertoli4https://orcid.org/0000-0001-5352-253XHongmei Jiang5https://orcid.org/0000-0001-5117-5212Yanyan Wang6https://orcid.org/0000-0003-4859-4963Yi Wang7https://orcid.org/0000-0002-3676-9183Yi Wang8https://orcid.org/0000-0001-5098-6750Dario DiFrancesco9https://orcid.org/0000-0002-7322-1790Andrea Barbuti10https://orcid.org/0000-0002-4521-4913Annalisa Bucchi11https://orcid.org/0000-0002-5303-4242Mirko Baruscotti12https://orcid.org/0000-0002-6155-8388Department of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Tianjin, ChinaDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Physiology and Pathophysiology, School of Basic Medical Science, Tianjin Medical University, Tianjin, ChinaSchool of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, ChinaInstitute of Traditional Chinese Medicine Tianjin University of Traditional Chinese Medicine, Tianjin, ChinaDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyDepartment of Biosciences, The Cell Physiology Lab and “Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata”, Università degli Studi di Milano, Milano, ItalyTongmai Yangxin (TMYX) is a complex compound of the Traditional Chinese Medicine (TCM) used to treat several cardiac rhythm disorders; however, no information regarding its mechanism of action is available. In this study we provide a detailed characterization of the effects of TMYX on the electrical activity of pacemaker cells and unravel its mechanism of action. Single-cell electrophysiology revealed that TMYX elicits a reversible and dose-dependent (2/6 mg/ml) slowing of spontaneous action potentials rate (−20.8/–50.2%) by a selective reduction of the diastolic phase (−50.1/–76.0%). This action is mediated by a negative shift of the If activation curve (−6.7/–11.9 mV) and is caused by a reduction of the cyclic adenosine monophosphate (cAMP)-induced stimulation of pacemaker channels. We provide evidence that TMYX acts by directly antagonizing the cAMP-induced allosteric modulation of the pacemaker channels. Noticeably, this mechanism functionally resembles the pharmacological actions of muscarinic stimulation or β-blockers, but it does not require generalized changes in cytoplasmic cAMP levels thus ensuring a selective action on rate. In agreement with a competitive inhibition mechanism, TMYX exerts its maximal antagonistic action at submaximal cAMP concentrations and then progressively becomes less effective thus ensuring a full contribution of If to pacemaker rate during high metabolic demand and sympathetic stimulation.https://elifesciences.org/articles/75119pacemaker currentsinoatrial nodeTMYXpure bradycardic agentscAMP antagonismHCN channels |
| spellingShingle | Chiara Piantoni Manuel Paina David Molla Sheng Liu Giorgia Bertoli Hongmei Jiang Yanyan Wang Yi Wang Yi Wang Dario DiFrancesco Andrea Barbuti Annalisa Bucchi Mirko Baruscotti Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels eLife pacemaker current sinoatrial node TMYX pure bradycardic agents cAMP antagonism HCN channels |
| title | Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels |
| title_full | Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels |
| title_fullStr | Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels |
| title_full_unstemmed | Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels |
| title_short | Chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f-channels |
| title_sort | chinese natural compound decreases pacemaking of rabbit cardiac sinoatrial cells by targeting second messenger regulation of f channels |
| topic | pacemaker current sinoatrial node TMYX pure bradycardic agents cAMP antagonism HCN channels |
| url | https://elifesciences.org/articles/75119 |
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