title: ZP123 reduces energy required for defibrillation by preventing connexin43 remodeling during prolonged ventricular fibrillation in swine.
abstract: In ventricular fibrillation, the uncoupling of gap junctions slows conduction velocity and increases action-potential dispersion, which slows and diminishes defibrillation. We studied how the peptide ZP123, a gap-junction enhancer, might lower defibrillation-energy requirements during ventricular fibrillation in live pigs. We randomly assigned 33 pigs into 3 groups: ZP123 (receiving a 1-µg/kg bolus and 10 µg/kg/hr of ZP123), control (receiving saline solution), and sham (undergoing a sham operation). After a 30-min administration of agents, ventricular fibrillation was induced and left untreated for 8 min. Biphasic defibrillation of 50 J was increased by 50-J increments as necessary. Defibrillation-energy requirements were defined as the lowest energy required to achieve defibrillation. Electrocardiographic values were obtained before and after the administration of agents. Western blot and immunofluorescence analyses were performed on ventricular myocardial samples. All but one pig survived. The ZP123 treatment did not alter electrocardiographic variables. In the ZP123 group, the average required defibrillation energy was lower than that in the control group (327.28±269.6 vs 610±192.64 J; P=0.015), and the cumulative percentage of successful defibrillation at upper energy levels was higher (P<0.05). Supraventricular rhythm occurred more often in the ZP123 group than in the control group (72.7% vs 50%, P=0.042). Western-blot and immunofluorescence results showed that ZP123 did not alter the total amount of connexin43 but did prevent its dephosphorylation. We conclude that ZP123 can reduce defibrillation-energy requirements by preventing connexin43 remodeling during prolonged ventricular fibrillation.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Public Health, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, People's Republic of China.
authors.forename: Shao-lei
authors.initials: SL
authors.lastname: Yi
authors.forename: Jing-quan
authors.initials: JQ
authors.lastname: Zhong
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Guo-ying
authors.initials: GY
authors.lastname: Su
authors.forename: Jing-sha
authors.initials: JS
authors.lastname: Li
authors.forename: Hong-zhen
authors.initials: HZ
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D004554:Electric Countershock / Q000379:methods*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D013552:Swine; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000628:therapy*; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D018031:Connexin 43; D009842:Oligopeptides; C477643:rotigaptide
keywords: Anti-arrhythmia agents/administration & dosage/therapeutic use; arrhythmias, cardiac/prevention & control; connexin 43/analysis/metabolism; gap junctions/drug effects/metabolism/physiology; models, cardiovascular; phosphorylation/drug effects; swine; treatment outcome; ventricular fibrillation/therapy