Abstract
Fenofibrate is a peroxisome proliferator‐activated receptor (PPAR)‐α activator that lowers triglycerides and influences cytochrome P‐450 (CYP‐450) epoxygenase‐dependent arachidonic acid (AA) metabolism. CYP‐450 epoxygenase metabolizes AA to epoxyeicosatrienoic acids (EETs). EETs have coronary dilating and cardiac and renal protective properties. Fibrates possess similar properties due to their CYP‐450 epoxygenase‐inducing properties that lead to increase in endogenous EET production. In the current investigations, fenofibrate (100 mg/kg, orally) for 2 weeks decreased ischemia‐/reperfusion (I/R)‐induced premature ventricular contractions (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF) in the isolated rat hearts. Fenofibrate caused marked inhibition of the reperfusion‐induced cardiac arrhythmias. The incidence of reperfusion‐induced VF decreased from 80% in the control vehicle‐treated animals to 33% in the fenofibrate‐treated animals (P < 0.001). PVCs were also significantly (P < 0.01) decreased from 223.2 ± 51 in control vehicle‐treated animals to 136.8 ± 22 in fenofibrate‐treated animals. Total duration of reperfusion‐induced VT decreased from 29.2 ± 6.3 s in control, vehicle‐treated animals to 4.8 ± 1.3 s in fenofibrate‐treated animals, P < 0.001. Heart rate and perfusion pressure were not significantly affected by fenofibrate pretreatment. Diltiazem, a clinically used anti‐arrhythmic agent, produced complete protection against I/R‐induced cardiac arrhythmias in this model reducing the incidence of VF from 80% in control, vehicle‐treated animals to 10% in diltiazem‐treated hearts. These findings indicate that fenofibrate suppresses arrhythmias in isolated rat hearts subjected to I/R‐induced injury.