Alogliptin, a dipeptidyl peptidase-4 inhibitor, regulates the atrial arrhythmogenic substrate in rabbits.

Abstract

BACKGROUND:

Dipeptidyl peptidase-4 (DPP-4) inhibitors were recently reported to have cardioprotective effects via amelioration of ventricular function. However, the role of DPP-4 inhibition in atrial remodeling, especially of the arrhythmogenic substrate, remains unclear.

OBJECTIVE:

We investigated the effects of a DPP-4 inhibitor, alogliptin, on atrial fibrillation (AF) in a rabbit model of heart failure caused by ventricular tachypacing (VTP).

METHODS:

Rabbits subjected to VTP at 380 bpm for 1 or 3 weeks, with or without alogliptin treatment, were assessed using echocardiography, electrophysiology, histology, and immunoblotting and compared with nonpaced animals.

RESULTS:

VTP rabbits exhibited increased duration of atrial burst pacing-induced AF, whereas administration of alogliptin shortened this duration by 73%. The extent of atrial fibrosis after VTP was reduced by 39% in the alogliptin-treated group. VTP rabbits treated with alogliptin displayed a 1.6-fold increase in left atrial myocardial capillary density compared with nontreated rabbits. A 2-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation was observed in the left atrium of alogliptin-treated rabbits compared with nontreated rabbits. Moreover, a nitric oxide synthase inhibitor (N(ω)-nitro-l-arginine methyl ester) blocked the beneficial effects of alogliptin on AF duration, fibrosis, and capillary density.

CONCLUSION:

Alogliptin shortened the duration of AF caused by VTP-induced fibrotic atrial tissue by augmenting atrial angiogenesis and activating eNOS. Our findings suggest that DPP-4 inhibitors may be useful in the prevention of heart failure-induced AF.

• Authors: Toshihiko Yamamoto, Masayuki Shimano, Yasuya Inden, Mikito Takefuji, Satoshi Yanagisawa, Naoki Yoshida, Yukiomi Tsuji, Makoto Hirai, Toyoaki Murohara
• Journal: Heart rhythm (Heart Rhythm) Vol. 12 Issue 6 Pg. 1362-9 (Jun 2015) ISSN: 1556-3871 [Electronic] United States
• PMID: 25757661 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Piperidines
• Uracil
• Nitric Oxide Synthase
• Nitric Oxide Synthase Type III
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
• alogliptin
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Atrial Fibrillation (physiopathology, prevention & control)
• Blotting, Western
• Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (antagonists & inhibitors)
• Echocardiography
• Electrophysiology
• Endothelium (enzymology)
• Enzyme-Linked Immunosorbent Assay
• Fibrosis (pathology)
• Fluorescent Antibody Technique
• Heart Atria (enzymology, pathology)
• Heart Failure (prevention & control)
• Male
• NG-Nitroarginine Methyl Ester (pharmacology)
• Neovascularization, Physiologic (drug effects)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Phosphorylation
• Piperidines (antagonists & inhibitors, pharmacology)
• Rabbits
• Tachycardia, Ventricular (complications)
• Uracil (analogs & derivatives, antagonists & inhibitors, pharmacology)