Effects of amlodipine and perindoprilate on the structure and function of mitochondria in ventricular cardiomyocytes during ischemia‐reperfusion in the pig

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.

Section: Discussionmentioning

confidence: 99%

Protective effect of fenofibrate against ischemia‐/reperfusion‐induced cardiac arrhythmias in isolated rat hearts

Bukhari

Almotrefi

Mohamed

et al. 2018

“…We chose a postconditioning approach as the therapeutic relevance of preconditioning [5] is limited by the unpredictability of sustained ischemia. We chose a postconditioning approach as the therapeutic relevance of preconditioning [5] is limited by the unpredictability of sustained ischemia.…”

Section: Experimental Designmentioning

confidence: 99%

“…Vascular interventions with arterial clamping trigger IR injury to cardiac [5] but also to skeletal muscles, involving inflammation, oxidative stress, and mitochondrial dysfunctions [6][7][8][9][10]. Interestingly, muscle mitochondrial dysfunction was recently shown to be associated with 5-year survival in patients with peripheral arterial disease, underlining its clinical significance [11].…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle ischemia–reperfusion injury and cyclosporine A in the aging rat

Pottecher

Kindo

Chamaraux-Tran

et al. 2016

Old patients exhibit muscle impairments and increased perioperative risk during vascular surgery procedures. Although aging generally impairs protective mechanisms, data are lacking concerning skeletal muscle in elderly. We tested whether cyclosporine A (CsA), which protects skeletal muscle from ischemia-reperfusion (IR) in young rats, might reduce skeletal muscle mitochondrial dysfunction and oxidative stress in aging rats submitted to hindlimb IR. Wistar rats aged 71-73 weeks were randomized to IR (3 h unilateral tourniquet application and 2 h reperfusion) or IR + CsA (10 mg/kg cyclosporine IV before reperfusion). Maximal oxidative capacity (VM ax ), acceptor control ratio (ACR), and relative contribution of the mitochondrial respiratory chain complexes II, III, IV (VS ucc ), and IV (VTMPD /Asc ), together with calcium retention capacity (CRC) a marker of apoptosis, and tissue reactive oxygen species (ROS) production were determined in gastrocnemius muscles from both hindlimbs. Compared to the nonischemic hindlimb, IR significantly reduced mitochondrial coupling, VMax (from 7.34 ± 1.50 to 2.87 ± 1.22 μMO2 /min/g; P < 0.05; -70%), and VS ucc (from 6.14 ± 1.07 to 3.82 ± 0.83 μMO2 /min/g; P < 0.05; -42%) but not VTMPD /Asc . IR also decreased the CRC from 15.58 ± 3.85 to 6.19 ± 0.86 μMCa(2+) /min/g; P < 0.05; -42%). These alterations were not corrected by CsA (-77%, -49%, and -32% after IR for VM ax, VS ucc , and CRC, respectively). Further, CsA significantly increased ROS production in both hindlimbs (P < 0.05; +73%). In old rats, hindlimb IR impairs skeletal muscle mitochondrial function and increases oxidative stress. Cyclosporine A did not show protective effects.

“…Earlier work of Japanese researchers had also demonstrated that pretreatment with CIL was more effective than AML in preventing oxidative stress markers and cell damage in murine model of retinal I/R injury [35]. Some recent work also observed significant antioxidant and mitochondrial protection by AML during I/R in cardiomyocytes of pigs [16].…”

Section: Discussionmentioning

confidence: 95%

“…Cilnidipine (CIL) is a new generation DHP CCB that has been demonstrated to inhibit both N‐type and L‐type Ca 2+ channels in various types of neurons and thus inhibits sympathomimetic activity in contrast to other DHP . Previous studies have demonstrated that AML exerted protective effect against hepatic , myocardial , and ovarian I/R injuries but to our knowledge, there is no available information yet on the protective effects by the dual L/N‐type CCB, CIL on hepatic I/R injury. The aim of this study, however, is to provide comparative information on the hepatoprotective effects of AML and CIL in murine model of hepatic I/R injury.…”

Section: Introductionmentioning

confidence: 99%

Comparative study of amlodipine vs. cilnidipine for the prevention of hepatic ischemia‐reperfusion injury in rat model

Fouda

Youssef

Eldin

2017

Ca signaling plays crucial role in ischemia and reperfusion (I/R) injury. Although blockade of L-type Ca channels by amlodipine (AML) has been shown to suppress hepatic I/R injury in several animal models, information is still needed regarding the hepatoprotective effects of the dual L/N-type Ca channel blockers, cilnidipine (CIL). We examined the effect of pretreatment with AML or CIL (100 μg/kg i.p.) 45 min before induction of 60 min of liver ischemia followed by reperfusion, on oxidative stress markers, liver enzymes, serum tumor necrosis factor-α, interleukin-1β, apoptosis markers, and nuclear factor KB after 6 and 24 h of hepatic reperfusion. Both drugs significantly ameliorated biochemical and histological markers of hepatic I/R injury, but protection with CIL was more significant at the 6-h time point where protection with AML outlasted that of CIL. Both drugs offered significant protection against hepatic I/R damage, but the protection with CIL seemed more potent but of shorter duration than that observed with AML possibly due to the shorter half-life of CIL.