Rotigaptide (ZP123) Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs

Hennan, James K.; Swillo, Robert E.; Morgan, Gwen A.; Keith, James C.; Schaub, Robert G.; Smith, Robert P.; Feldman, Hal S.; Haugan, Ketil; Kantrowitz, Joel; Wang, Phil J.; Abu-Qare, Aqel W.; Butera, John; Larsen, Bjarne Due; Crandall, David L.

doi:10.1124/jpet.105.096933

Cited by 78 publications

(79 citation statements)

References 36 publications

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“…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). 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).…”

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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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%

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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“…bolus of Rotigaptide 10 min before reperfusion and different concentrations throughout reperfusion (1 ng/kg bolus+10 ng/kg/h infusion, 10 ng/kg bolus+100 ng/kg/h and 100 ng/kg bolus+1000 ng/kg/h and 1000 ng/ kg bolus+10 ng/kg/h). In this study, IS reduction was dose-dependent [12]. More recently, danegaptide a mimetic of the connexin 43 targeting peptide Rotigaptide also demonstrated cardioprotective capacity in an in vivo model [20].…”

Section: Discussionmentioning

confidence: 68%

“…Rotigaptide reduces infarct size in experimental models of myocardial ischemia-reperfusion injury [10][11][12] Rotigaptide has been demonstrated to prevent dephosphorylation of Cx43 during ischemic stress [13]. Sarcolemmal Cx43 contributes to…”

Section: Introductionmentioning

confidence: 99%

Effects of Rotigaptide and RIC on Ischemia Reperfusion Injury in the In Vitro Rabbit Heart

Salman¹,

Johnsen²,

Tr³

et al. 2017

Cardiovasc Pharm Open Access

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Background: Remote Ischemic Preconditioning (rIPC) and the antiarrhythmic peptide analogue, Rotigaptide (ZP123), protects against myocardial ischemia-reperfusion injury through potentially similar mechanisms. We aimed to study whether the cardioprotective effects of Rotigaptide and rIPC interacts. Methods:We used male New Zealand White rabbit hearts mounted in a Langendorff system and exposed to 30 min of global no-flow ischemia and 120 min of reperfusion. A total of 48 rabbits were randomized into 6 groups: control (n=6), Rotigaptide (1 µM) before (n=9) or after (n=9) ischemia, rIPC (n=7), rIPC+Rotigaptide before (n=9) or after (n=8) ischemia. rIPC was induced by four cycles of 5-min ischemia and reperfusion on the left hind limb achieved by intermittent tourniquet occlusion. Primary endpoint was infarct size measured by tetrazolium staining.Results: rIPC reduced infarct size compared to controls. Rotigaptide alone did not affect infarct size irrespective of administration before ischemia or during reperfusion. The combination of rIPC and Rotigaptide before ischemia reduced infarct size, whereas the effect of rIPC was abrogated by Rotigaptide when administered during reperfusion. No significant changes in hemodynamic recovery were observed when compared to control group. Conclusion:In contrast to in vivo rIPC, in vitro Rotigaptide did not yield cardioprotection in our rabbit model, but Rotigaptide attenuated the effect of rIPC. These findings indicate that modification of myocardial gap junction is involved in cardioprotection by rIPC.

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“…The commonly used concentration of rotigaptide is 50 -250 nM. [109]. In contrast with AAP10, danegaptide decreased the dye uptake in C6 cells stably transfected with Cx43 [108].…”

Section: Rotigaptide (Zp123 Gap-486)mentioning

confidence: 99%

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

Szentmiklósi¹,

Szentandrássy²,

Hegyi³

et al. 2014

CPD

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The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling.Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR.Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

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Rotigaptide (ZP123) Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs

Abstract: The antiarrhythmic and cardioprotective effect of increasing gap junction intercellular communication during ischemia/ reperfusion injury has not been studied.

Cited by 78 publications

References 36 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

Effects of Rotigaptide and RIC on Ischemia Reperfusion Injury in the In Vitro Rabbit Heart

Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?

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Rotigaptide (ZP123) Prevents Spontaneous Ventricular Arrhythmias and Reduces Infarct Size During Myocardial Ischemia/Reperfusion Injury in Open-Chest Dogs

Abstract: The antiarrhythmic and cardioprotective effect of increasing gap junction intercellular communication during ischemia/ reperfusion injury has not been studied.

Cited by 78 publications

References 36 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

Effects of Rotigaptide and RIC on Ischemia Reperfusion Injury in the In Vitro Rabbit Heart

Chemistry, Physiology, and Pharmacology of &#946;.-Adrenergic Mechanisms in the Heart. Why are .&#946;-Blocker Antiarrhythmics Superior?

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Chemistry, Physiology, and Pharmacology of β.-Adrenergic Mechanisms in the Heart. Why are .β-Blocker Antiarrhythmics Superior?