Contrasting effects of HMR1098 on arrhythmogenicity in a Langendorff-perfused phase-2 myocardial infarction rabbit model.

Abstract

BACKGROUND:

The stability of dynamic factors has been reported to play a role in the antiarrhythmic actions of adenosine triphosphate (ATP)-sensitive potassium channel (KATP) opener in phase-2 myocardial infarction (MI) hearts. In the situation of the downregulation of KATP, the effects of KATP blocker (HMR1098) on the dynamic factors and electrophysiological changes during phase-2 MI remain unclear.

METHODS:

Dual voltage and intracellular Ca(2+) (Cai) optical mapping was performed in nine Langendorff-perfused hearts 4-5 hours after coronary artery ligation and five control hearts. Electrophysiology studies, including action potential duration (APD) restitution, conduction velocity (CV), inducibility of ventricular fibrillation (VF), VF dominant frequency, APD and Cai alternans, and Cai decay, were performed. The same protocol was repeated in the presence of HMR1098 (10 μm) after the baseline studies.

RESULTS:

HMR1098 significantly prolonged APD and effective refractory period to prevent sustained VF in five of nine MI hearts and two of five control hearts compared to none at baseline in both groups. On the other hand, HMR1098 steepened APD restitution slope to enhance spatially concordant alternans in both groups. In the phase-2 MI group, HMR1098 steepened CV restitution slope and enhanced spatially discordant alternans (SDA), which might account for a decreased pacing threshold of VF induction during HMR1098 infusion in phase-2 MI hearts.

CONCLUSIONS:

In phase-2 MI hearts, HMR1098 has contrasting effects on arrhythmogenesis, suppressing reentry and VF persistence but facilitating VF inducibility. The mechanism is the intensified induction of SDA because of the steepened APD and CV restitution slopes.

• Authors: Hui-Ling Lee, Cheng-Hui Lu, Po-Cheng Chang, Chung-Chuan Chou, Hung-Ta Wo, Ming-Shien Wen
• Journal: Pacing and clinical electrophysiology : PACE (Pacing Clin Electrophysiol) Vol. 37 Issue 8 Pg. 1058-66 (Aug 2014) ISSN: 1540-8159 [Electronic] United States
• PMID: 24645834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 Wiley Periodicals, Inc.

Chemical References

• Glucuronides
• HMR 1098 glucuronide
• Sulfonamides

Topics

• Action Potentials (drug effects)
• Animals
• Disease Models, Animal
• Electrophysiological Phenomena (drug effects)
• Glucuronides (pharmacology)
• Heart (drug effects, physiopathology)
• Myocardial Infarction (complications, physiopathology)
• Rabbits
• Sulfonamides (pharmacology)
• Ventricular Fibrillation (etiology)