title: Rotigaptide (ZP123) improves atrial conduction slowing in chronic volume overload-induced dilated atria.
abstract: Chronic atrial dilation is associated with atrial conduction velocity slowing and an increased risk of developing atrial tachyarrhythmias. Rotigaptide (ZP123) is a selective gap junction modifier that increases cardiac gap junctional intercellular communication. We hypothesised that rotigaptide treatment would increase atrial conduction velocity and reduce the inducibility to atrial tachyarrhythmias in a model of chronic volume overload induced chronic atrial dilatation characterized by atrial conduction velocity slowing. Chronic volume overload was created in Japanese white rabbits by arterio-venous shunt formation. Atrial conduction velocity and atrial tachyarrhythmias inducibility were examined in Langendorff-perfused chronic volume overload hearts (n=12) using high-resolution optical mapping before and after treatment with rotigaptide. Moreover, expression levels of atrial gap junction proteins (connexin40 and connexin43) were examined in chronic volume overload hearts (n=6) and compared to sham-operated controls (n=6). Rotigaptide treatment significantly increased atrial conduction velocity in chronic volume overload hearts, however, rotigaptide did not decrease susceptibility to the induction of atrial tachyarrhythmias. Protein expressions of Cx40 and Cx43 were decreased by 32% and 72% (P<0.01), respectively, in chromic volume overload atria compared to control. To conclude, rotigaptide increased atrial conduction velocity in a rabbit model of chromic volume overload induced atrial conduction velocity slowing. The demonstrated effect of rotigaptide on atrial conduction velocity did not prevent atrial tachyarrhythmias inducibility. Whether rotigaptide may possess antiarrhythmic efficacy in other models of atrial fibrillation remains to be determined.
authors.affiliation: Zealand Pharma A/S, Smedeland 26B, Dk-2600 Glostrup, Denmark.
authors.forename: Ketil
authors.initials: K
authors.lastname: Haugan
authors.forename: Takuya
authors.initials: T
authors.lastname: Miyamoto
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
authors.forename: Isao
authors.initials: I
authors.lastname: Kubota
authors.forename: Jun
authors.initials: J
authors.lastname: Nakayama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimojo
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D001810:Blood Volume / Q000502:physiology; D015153:Blotting, Western; D018031:Connexin 43 / Q000096:biosynthesis; D017630:Connexins / Q000096:biosynthesis; D004452:Echocardiography; D004594:Electrophysiology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D000889:Anti-Arrhythmia Agents; D018031:Connexin 43; D017630:Connexins; D009842:Oligopeptides; D000097003:Gap Junction alpha-5 Protein; C477643:rotigaptide