Chinese Natural Compound Decreases Pacemaking of Rabbit Cardiac Sinoatrial Cells by Targeting Second Messenger Regulation of F-channels

Overview

Journal Elife

Specialty Biology

Date 2022 Mar 22

PMID 35315774

Authors

Chiara Piantoni

Manuel Paina

David Molla

Sheng Liu

Giorgia Bertoli

Hongmei Jiang

Yanyan Wang

Yi Wang

Dario DiFrancesco

Andrea Barbuti

Annalisa Bucchi

Mirko Baruscotti

Affiliations

Soon will be listed here.

Abstract

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 I 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 I to pacemaker rate during high metabolic demand and sympathetic stimulation.

Citing Articles

Pacemaker Channels and the Chronotropic Response in Health and Disease.

Hennis K, Piantoni C, Biel M, Fenske S, Wahl-Schott C Circ Res. 2024; 134(10):1348-1378.

PMID: 38723033 PMC: 11081487. DOI: 10.1161/CIRCRESAHA.123.323250.

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