Mitochondrial uncoupling agents trigger ventricular fibrillation in isolated rat hearts

Area of Science:

• Cardiovascular Research
• Mitochondrial Physiology
• Cardiac Electrophysiology

Background:

• Sudden cardiac death from ventricular fibrillation (VF) is a significant mortality cause.
• Understanding VF triggers during myocardial ischemia is crucial for developing effective treatments.

Purpose of the Study:

• Investigate the role of mitochondrial dysfunction in VF development during ischemia.
• Examine the involvement of oxidative phosphorylation, mitochondrial ATP-sensitive K+ channels, and permeability transition pores in VF.

Main Methods:

• Utilized mitochondrial uncoupling agents (carbonyl cyanide m-chlorophenylhydrazone, 2,4-dinitrophenol) and channel blockers (5-hydroxydecanoate, cyclosporine A) in isolated rat hearts.
• Induced regional ischemia and monitored VF incidence, QT interval, and tissue ATP content.

Main Results:

• Uncoupling agents induced VF in 100% of hearts before ischemia by shortening the QT interval.
• Neither cyclosporine A nor 5-hydroxydecanoate prevented VF during ischemia.
• Uncoupling agents reduced tissue ATP and, with glibenclamide/glimepiride, delayed VF onset.

Conclusions:

• Mitochondrial uncoupling agents trigger VF via ATP depletion and subsequent sarcolemmal ATP-sensitive K+ current activation.
• VF during ischemia in this model does not involve mitochondrial ATP-sensitive K+ channel or permeability transition pore activation.