Attenuation of Myocardial Ischemia-Reperfusion Injury by Trimetazidine Derivatives Functionalized with Antioxidant Properties

Abstract

Trimetazidine (TMZ), an anti-ischemic metabolic drug, is used to treat chest pain (angina pectoris). We hypothesized that derivatives of TMZ with antioxidant functions may improve the cardiac dysfunction caused by ischemia-reperfusion (I/R) above that observed with TMZ alone. Isolated rat hearts perfused with Krebs-Henseleit buffer according to the Langendorff method were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Trimetazidine, TMZ-NH (TMZ modified with a pyrroline moiety), or TMZ-⌽NH (TMZ-NH with a phenyl substitute) were infused (50 M) for 1 min before the onset of ischemia. Untreated (control) hearts at the end of 45 min of reperfusion showed a significant decrease in the recovery of coronary flow (42%), left ventricular-developed pressure (22%), and rate-pressure product (25%) compared with preischemic baseline values. The I/R hearts also showed markedly increased lactate dehydrogenase and creatine kinase activities in the coronary effluent, significant myocardial infarction (46% of risk area), and activation of Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. Pretreatment of hearts with TMZ-NH or TMZ-⌽NH significantly enhanced the recovery of heart function and decreased infarct size. The I/R-induced activation of Akt was further enhanced by TMZ-⌽NH. The present study demonstrated that TMZ-NH and TMZ-⌽NH significantly protected hearts against I/R-mediated cardiac dysfunction and injury. The protective effect of the TMZ derivatives could be due to the combined effects of antioxidant and anti-ischemic activities as well as enhanced pro-survival Akt activity.

Cardioprotection by HO-4038, a novel verapamil derivative, targeted against ischemia and reperfusion-mediated acute myocardial infarction

“…Some earlier studies have shown that H-2693, a compound containing a secondary amine nitroxide precursor, and HO-3070, a free-radical scavenging compound, enhanced the I/R-induced activation of Akt and protected the hearts from I/R injury (50,51). Our observations are also consistent with a recent study from our laboratory that demonstrated the protective effect of nitroxide-precursor derivatives of trimetazidine against I/R-induced damage through the involvement of Akt activity (25). The results of the present study showed that HO-4038 significantly enhanced the expression of prosurvival Akt and Bcl-2, thereby conferring myocardial protection.…”

“…The improved cardiac functions could be due to the availability of HO-4038 in the myocardium during I/R injury and scavenging free radicals generated during early minutes of reperfusion. We had previously reported the cardioprotective properties of several antiarrhythmic compounds with pyrroline modifications against I/R-induced damage and contractile dysfunction without compromising their individual properties (25,29,49). HO-4038-administered hearts also showed a significant decrease in infarct size compared with untreated or verapamiltreated hearts.…”

Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression

“…As a result, TMZ attenuates the adverse effects of free fatty acid-associated oxidative stress (Gambert et al, 2006), lessens oxygen demand by decreasing oxygen consumption (Monteiro et al, 2004), and improves mitochondrial metabolism and cardiac performance during ischemia (Kantor et al, 2000). At the cellular level, TMZ preserves ATP production, reduces the generation of oxygen free radicals (Maupoil et al, 1990;Gambert et al, 2006;Kutala et al, 2006), and reduces intracellular acidosis and calcium overload (Kantor et al, 2000). TMZ has been shown to protect hearts from ischemia-induced electrical dysfunction leading to ventricular fibrillation (Vaillant et al, 2008), ischemia-reperfusion-induced damage to mitochondrial respiration (Guarnieri and Muscari, 1993), and ischemia-reperfusion injury by decreasing myocardial lactate content early at reperfusion (Pantos et al, 2005).…”

Pharmacogenomics and end-organ susceptibility to injury in the perioperative period

“…Upon reperfusion, oxygen interacts with the damaged mitochondrial respiratory chain to produce a burst of reactive oxygen species leading to ischemia/reperfusion (I/R) injury [24]. I/R induces translocation of d-protein kinase C (dPKC; the redox sensitive PKC isoform) to cardiac mitochondria, preventing pyruvate dehydrogenase reactivation (via phosphorylation of the aE1 subunit of pyruvate dehydrogenase [PDH] via PDH kinase 2) [25].…”