Bukhari Ishfaq A, Almotrefi Abdulrahman A, Mohamed Osama Y, Al-Masri Abeer A, Sheikh Saeed A
Department of Pharmacology, College of Medicine, King Saud University P. O. BOX 2454, Riyadh, 11451, Saudi Arabia.
Department of Physiology, Cardiovascular Research Group, College of Medicine, King Saud University P. O. BOX 2454, Riyadh, 11451, Saudi Arabia.
Fundam Clin Pharmacol. 2018 Apr;32(2):141-146. doi: 10.1111/fcp.12342. Epub 2018 Jan 25.
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.
非诺贝特是一种过氧化物酶体增殖物激活受体（PPAR）-α激活剂，可降低甘油三酯，并影响细胞色素P-450（CYP-450）环氧合酶依赖性花生四烯酸（AA）代谢。CYP-450环氧合酶将AA代谢为环氧二十碳三烯酸（EETs）。EETs具有冠状动脉扩张以及心脏和肾脏保护特性。由于贝特类药物具有诱导CYP-450环氧合酶的特性，可导致内源性EET生成增加，因此它们具有类似的特性。在当前的研究中，非诺贝特（100mg/kg，口服）给药2周可减少离体大鼠心脏中缺血/再灌注（I/R）诱导的室性早搏（PVCs）、室性心动过速（VT）和室颤（VF）。非诺贝特对再灌注诱导的心律失常有明显抑制作用。再灌注诱导的VF发生率从对照载体处理动物的80%降至非诺贝特处理动物的33%（P<0.001）。PVCs也显著降低（P<0.01），从对照载体处理动物的223.2±51降至非诺贝特处理动物的136.8±22。再灌注诱导的VT总持续时间从对照载体处理动物的29.2±6.3秒降至非诺贝特处理动物的4.8±1.3秒，P<0.001。非诺贝特预处理对心率和灌注压力无显著影响。地尔硫䓬是一种临床使用的抗心律失常药物，在该模型中对I/R诱导的心律失常产生完全保护作用，将VF发生率从对照载体处理动物的80%降至地尔硫䓬处理心脏的10%。这些发现表明，非诺贝特可抑制遭受I/R诱导损伤的离体大鼠心脏中的心律失常。
