Cardiac Gap Junction Channels Are Upregulated by Metoprolol: An Unexpected Effect of Beta-Blockers

Salameh, Aida; Blanke, Katja; Dhein, Stefan; Janoušek, Jan

doi:10.1159/000276982

Cited by 12 publications

(9 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antifibrillatory effect of melatonin may be mainly attributed to its ability to prevent connexin‐43 lateralization. Moreover, other antiarrhythmic agents, such as metoprolol, lead to a lower degree of lateralization and lower transverse conduction velocity . Furthermore, our results indicated that melatonin receptor activation is necessary to prevent connexin‐43 lateralization and arrhythmias that require reentry to persist.…”

Section: Discussionmentioning

confidence: 70%

Melatonin receptor activation protects against low potassium‐induced ventricular fibrillation by preserving action potentials and connexin‐43 topology in isolated rat hearts

Prado

Beňová

Diez

et al. 2019

Journal of Pineal Research

View full text Add to dashboard Cite

Hypokalemia prolongs the QRS and QT intervals, deteriorates intercellular coupling, and increases the risk for arrhythmia. Melatonin preserves gap junctions and shortens action potential as potential antiarrhythmic mechanisms, but its properties under hypokalemia remain unknown. We hypothesized that melatonin protects against low potassium-induced arrhythmias through the activation of its receptors, resulting in action potential shortening and connexin-43 preservation. After stabilization in Krebs-Henseleit solution (4.5 mEq/L K + ), isolated hearts from Wistar rats underwent perfusion with low-potassium (1 mEq/L) solution and melatonin (100 μmol/L), a melatonin receptor blocker (luzindole, 5 μmol/L), melatonin + luzindole or vehicle. The primary endpoint of the study was the prevention of ventricular fibrillation.Electrocardiography was used, and epicardial action potentials and heart function were measured and analyzed. The ventricular expression, dephosphorylation, and distribution of connexin-43 were examined. Melatonin reduced the incidence of low potassium-induced ventricular fibrillation from 100% to 59%, delayed the occurrence of ventricular fibrillation and induced a faster recovery of sinus rhythm during potassium restitution. Melatonin prevented QRS widening, action potential activation delay, and the prolongation of action potential duration at 50% of repolarization. Other ECG and action potential parameters, the left ventricular developed pressure, and nonsustained ventricular arrhythmias did not differ among groups. Melatonin prevented connexin-43 dephosphorylation and its abnormal topology (lateralization). Luzindole abrogated the protective effects of melatonin on electrophysiological properties and connexin-43 misdistribution. Our results indicate that melatonin receptor activation protects against low potassium-induced ventricular fibrillation, shortens action potential duration, preserves ventricular electrical activation, and prevents acute changes in connexin-43 distribution. All of these properties make melatonin a remarkable antifibrillatory agent. K E Y W O R D Saction potential, arrhythmias, connexin-43, hypokalemia, melatonin, QRS

show abstract

Section: Discussionmentioning

confidence: 70%

Melatonin receptor activation protects against low potassium‐induced ventricular fibrillation by preserving action potentials and connexin‐43 topology in isolated rat hearts

Prado

Beňová

Diez

et al. 2019

Journal of Pineal Research

View full text Add to dashboard Cite

show abstract

“…These results also indicate that metoprolol can reduce the number of contraction in a given time, possibly reflecting an improved contraction force; they may represent some of the beneficial factors contributing to the protective effects on DCM iPSC-CMs. In addition, metoprolol treatment on cultured neonatal rat CMs have been shown to upregulate protein levels of cardiac gap junction channels (47), allowing a better connection and communication between cells. Altogether, these may exert beneficial effects on the DCM iPSC-CMs observed in our study.…”

Section: Discussionmentioning

confidence: 99%

Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated Cardiomyopathy

et al. 2012

View full text Add to dashboard Cite

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy, characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. DCM is the most common diagnosis leading to heart transplantation and places a significant burden on healthcare worldwide. The advent of induced pluripotent stem cells (iPSCs) offers an exceptional opportunity for creating disease-specific models, investigating underlying mechanisms, and optimizing therapy. Here we generated cardiomyocytes (CMs) from iPSCs derived from patients of a DCM family carrying a point mutation (R173W) in the gene encoding sarcomeric protein cardiac troponin T. Compared to the control healthy individuals in the same family cohort, DCM iPSC-CMs exhibited altered Ca2+ handling, decreased contractility, and abnormal sarcomeric α-actinin distribution. When stimulated with β-adrenergic agonist, DCM iPSC-CMs showed characteristics of failure such as reduced beating rates, compromised contraction, and significantly more cells with abnormal sarcomeric α-actinin distribution. β-adrenergic blocker treatment and over-expression of sarcoplasmic reticulum Ca2+ ATPase (Serca2a) improved DCM iPSC-CMs function. Our study demonstrated that human DCM iPSC-CMs recapitulated to some extent the disease phenotypes morphologically and functionally, and thus can serve as a useful platform for exploring molecular and cellular mechanisms and optimizing treatment of this particular disease.

show abstract

“…We previously found that α‐ and β‐adrenoceptor stimulation up‐regulated the expression of Cx43 (Salameh et al ., 2006, 2008; Rojas Gomez et al ., 2008) and mechanical stretch enhanced the expression of Cx43 and altered Cx43 localization (Salameh et al ., 2010a). Moreover, in a cell culture study, we have found enhanced Cx43 expression in cells treated with metoprolol (Salameh et al ., 2010b). Thus, we proposed the hypothesis that β‐adrenoceptor antagonists may have an effect on connexin expression and/or on connexin localization.…”

Section: Introductionmentioning

confidence: 90%

Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation

Dhein

Rothe

Busch

et al. 2011

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEWe investigated the influence of metoprolol on gap junction proteins connexin43 (Cx43) and connexin40 (Cx40) in atrial tissue from patients with/without atrial fibrillation (AF). EXPERIMENTAL APPROACHLeft atrial tissue samples from 160 patients with AF or sinus rhythm (SR) with or without metoprolol (mean daily dose: 65.2 Ϯ 9.1 mg·day -1 ) were analysed for Cx43 and Cx40 by Western blot and immunohistology. Transverse and longitudinal conduction velocities were determined by 64 multi-electrode mapping. KEY RESULTSBoth Cx43 and Cx40 expression were significantly increased in patients with AF versus SR. Cx43-expression in AF was significantly higher in patients receiving metoprolol, while Cx40 expression was unaffected by metoprolol treatment. In AF, the ratio of lateral/polar expression of Cx43 and Cx40 was enhanced due to increased expression at the sides of the cells (lateral) and a loss at the cell poles. This AF-induced increase in lateral/polar expression of Cx43, but not of Cx40, was significantly antagonized by metoprolol treatment. Functionally, in AF patients, transverse conduction velocity in atrial samples was significantly enhanced and this change was also significantly antagonized by metoprolol. CONCLUSIONS AND IMPLICATIONSAF induced enhanced lateral expression of Cx43 and Cx40 together with enhanced transverse conduction velocity in left atrial tissue. Alterations in localization of Cx43 and conduction changes were both antagonized by metoprolol, showing that pharmacological modulation of gap junction remodelling seems, in principle, possible. This finding may open new approaches to the development of anti-arrythmic drugs. AbbreviationsAF, atrial fibrillation; CHD, coronary heart disease; Cx40, connexin40; Cx43, connexin43; EF, ejection fraction; FITC, Fluorescein isothiocyanate; GAPDH, glyceraldehyde-3-phosphate-dehydrogenase; LM, length of the plasma membrane; MVD, mitral valve disease; PLM, length of the immunofluorescence-positive membrane; SR, sinus rhythm; TBS, Tris-buffered saline; V(L), longitudinal conduction velocity; V(T), transverse conduction velocity BJP British Journal of Pharmacology

show abstract

Cardiac Gap Junction Channels Are Upregulated by Metoprolol: An Unexpected Effect of Beta-Blockers

Cited by 12 publications

References 47 publications

Melatonin receptor activation protects against low potassium‐induced ventricular fibrillation by preserving action potentials and connexin‐43 topology in isolated rat hearts

Melatonin receptor activation protects against low potassium‐induced ventricular fibrillation by preserving action potentials and connexin‐43 topology in isolated rat hearts

Patient-Specific Induced Pluripotent Stem Cells as a Model for Familial Dilated Cardiomyopathy

Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation

Contact Info

Product

Resources

About