The Antiarrhythmic Peptide Analog ZP123 Prevents Atrial Conduction Slowing During Metabolic Stress

Haugan, Ketil; Olsen, Karsten; Hartvig, Line; Petersen, Jørgen S.; Holstein‐Rathlou, Niels‐Henrik; Hennan, James K.; Nielsen, Morten Schak

doi:10.1111/j.1540-8167.2005.40687.x

Cited by 64 publications

(69 citation statements)

References 25 publications

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“…In addition, ZP123 reduced the incidents of spontaneous ventricular arrhythmias of ischemic origin and size of infarct scars (Hennan et al 2006). It was suggested that these effects resulted from enhancement of intercellular communication, and it was shown that ZP123 does not affect the normal functioning myocardium but is protective during acidosis and metabolic stress (Eloff et al 2003, Haugan et al 2005). Thus, a new class of antiarrhythmic peptides that act on gap junctional communication may emerge.…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

“…Several reports show that antiarrhythmic properties of the peptide AAP10 and its analogue ZP123, which is more resistant to proteolytic degradation in the digestive tract, are determined by decreased dispersion of activation and increased velocity of impulse conduction in the heart (Haugan et al 2005). In addition, ZP123 reduced the incidents of spontaneous ventricular arrhythmias of ischemic origin and size of infarct scars (Hennan et al 2006).…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

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Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Kreuzberg

Willecke

Bukauskas

2006

Trends in Cardiovascular Medicine

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In mouse heart, four connexins (Cxs), Cx30.2, Cx40, Cx43, and Cx45, form gap junction (GJ) channels for electric and metabolic cell-to-cell signaling. Extent and pattern of Cx isoform expression together with cytoarchitecture and excitability of cells determine the velocity of excitation spread in different regions of the heart. In the SA node, cell-cell coupling is mediated by Cx30.2 and Cx45, which form lowconductance (approximately 9 and 32 pS, respectively) GJ channels. In contrast, the working cardiomyocytes of atria and ventricles express mainly Cx40 and Cx43, which form GJ channels of high conductance (approximately 180 and 115 pS, respectively) that facilitate the fast conduction necessary for efficient mechanical contraction. In the AV node, cell-cell coupling is mediated by abundantly expressed Cx30.2 and Cx45 and Cx40, which is expressed to a lesser extent. Cx30.2 and Cx45 may determine higher intercellular resistance and slower conduction in the SA-and AV-nodal regions than in the ventricular conduction system or the atrial and ventricular working myocardium. Cx30.2 and its putative human ortholog, Cx31.9, under physiologic conditions form unapposed hemichannels in nonjunctional plasma membrane; these hemichannels have a conductance of approximately 20 pS and are permeable to cationic dyes up to approximately 400 Da in molecular mass. Genetic ablation of Cxs confirmed that Cx40 and Cx43 are important in determining the high conduction velocities in atria and ventricles, whereas the deletion of the Cx30.2 complementary DNA led to accelerated conduction in the AV node and reduced the Wenckebach period. We suggest that these effects are caused by (1) a dominant-negative effect of Cx30.2 on junctional conductance via formation of low-conductance homotypic and heterotypic GJ channels, and (2) open Cx30.2 hemichannels in non-junctional membranes, which shorten the space constant and depolarize the excitable membrane.In the mammalian heart, gap junction (GJ) channels mediate electric and metabolic communication between cardiac myocytes, thereby allowing cardiac impulse propagation and coordinated contraction of the chambers. Gap junction channels, which connect the cytosplasms of two adjacent cells and enable the diffusion of molecules up to approximately 1 kDa molecular mass, are composed of two hemichannels or connexons (Kumar and Gilula 1996). Each hemichannel consists of six connexin (Cx) protein subunits that are encoded by a multigene family comprising at least 20 members in the mouse and human genome (Söhl and Willecke 2004). Different Cxs coexpressed in the same tissue can form homotypic (same Cx isotype in both hemichannels), heterotypic (two Cx isotypes form cell-cell

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Section: Conclusion and Open Questionsmentioning

confidence: 99%

Section: Conclusion and Open Questionsmentioning

confidence: 99%

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Kreuzberg

Willecke

Bukauskas

2006

Trends in Cardiovascular Medicine

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“…25 The compound shows very low affinity for a wide range of ion channels and receptors and does not affect heterologously expressed HERG current. 22 The mechanisms by which rotigaptide alters connexin function are unclear. Rotigaptide may improve connexin function by protein kinase C-mediated phosphorylation.…”

Section: Relation To Previous Observations On the Effects Of Antiarrhmentioning

confidence: 99%

“…19,20 Rotigaptide also has been reported to attenuate gap junction closure during experimental acidosis 21 and prevent atrial conduction slowing during metabolic stress. 22 Given the occurrence of connexin abnormalities and their potential pathophysiological role in AF, gap junction coupling promoters like rotigaptide might be useful for AF therapy. The present study was designed to assess the efficacy and electrophysiological actions of rotigaptide in 3 clinically relevant experimental AF-promoting paradigms: atrial tachycardia remodeling, CHF, and acute atrial ischemia.…”

Section: Clinical Perspective P 318mentioning

confidence: 99%

Model-Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs

et al. 2007

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Background-Abnormal intercellular communication caused by connexin dysfunction may be involved in atrial fibrillation (AF). The present study assessed the effect of the gap junctional conduction-enhancing peptide rotigaptide on AF maintenance in substrates that result from congestive heart failure induced by 2-week ventricular tachypacing (240 bpm), atrial tachypacing (ATP; 400 bpm for 3 to 6 weeks), and isolated atrial myocardial ischemia. Methods and Results-Electrophysiological study and epicardial mapping were performed before and after rotigaptide administration in dogs with ATP and congestive heart failure, as well as in similarly instrumented sham dogs that were not tachypaced. For atrial myocardial ischemia, dogs administered rotigaptide before myocardial ischemia were compared with no-drug myocardial ischemia controls. ATP significantly shortened the atrial effective refractory period (Pϭ0.003) and increased AF duration (Pϭ0.008), with AF lasting Ͼ3 hours in all 6-week ATP animals. Rotigaptide increased conduction velocity in ATP dogs slightly but significantly (Pϭ0.04) and did not affect the effective refractory period, AF duration, or atrial vulnerability. In dogs with congestive heart failure, rotigaptide also slightly increased conduction velocity (Pϭ0.046) but failed to prevent AF promotion. Rotigaptide had no statistically significant effects in sham dogs. Myocardial ischemia alone increased AF duration and impaired conduction (based on conduction velocity across the ischemic border and indices of conduction heterogeneity). Rotigaptide prevented myocardial ischemiainduced conduction slowing and AF duration increases. Conclusions-Rotigaptide improves conduction in various AF models but suppresses AF only for the acute ischemia substrate. These results define the atrial antiarrhythmic profile of a mechanistically novel antiarrhythmic drug and suggest that gap junction dysfunction may be more important in ischemic AF than in ATP remodeling or congestive heart failure substrates. (Circulation. 2007;115:310-318.)

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“…Schematic view of a gap junction channel and its constituent component, the connexin, as a target of pharmacology (Salameh & Dhein, 2005. Two recent studies showed (Haugan et al 2005, Axelsen et al 2007(Haugan et al, 2005Axelsen et al, 2007) that an increase of gap junctional conductance by specific peptide, rotigaptide, can prevent atrial conduction slowing or re-entrant ventricular tachycardia in ischemic heart. Suppression of ischemia-induced dephosphorylation of connexin seems to be one of the mechanisms involved.…”

Section: Therapeutic Implications Of Gap Junction Remodeling After Mymentioning

confidence: 99%

Mechanisms of Postinfarction Electrophysiological Abnormality: Sympathetic Neural Remodeling, Electrical Remodeling and Gap Junction Remodeling

Zhong¹,

Li²,

Ke³

et al. 2012

Advances in Electrocardiograms - Clinical Applications

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The Antiarrhythmic Peptide Analog ZP123 Prevents Atrial Conduction Slowing During Metabolic Stress

Abstract: ZP123 has no effects on atrial conduction during physiological conditions, but it selectively prevents atrial conduction slowing during metabolic stress.

Cited by 64 publications

References 25 publications

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Connexin-Mediated Cardiac Impulse Propagation: Connexin 30.2 Slows Atrioventricular Conduction in Mouse Heart

Model-Dependent Effects of the Gap Junction Conduction–Enhancing Antiarrhythmic Peptide Rotigaptide (ZP123) on Experimental Atrial Fibrillation in Dogs

Mechanisms of Postinfarction Electrophysiological Abnormality: Sympathetic Neural Remodeling, Electrical Remodeling and Gap Junction Remodeling

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