The anti-anginal drug trimetazidine reduces neutrophil-mediated cardiac reperfusion injury.
Trimetazidine has no hemodynamic/antithrombotic actions. Hence, its anti-ischemic properties have been mostly attributed to its metabolic effects. However, this issue is not completely elucidated. We investigated whether inhibition of neutrophil activation may also contribute to its cardioprotective action. We first showed that trimetazidine inhibits neutrophil activation in vitro. We subsequently tested whether trimetazidine protects postischemic hearts from neutrophil-mediated injury. Four groups of rat hearts underwent 20 minutes of global ischemia: (1) controls, reperfused with neutrophil-enriched buffer for 5 minutes, followed by 40 minutes standard perfusate; (2) hearts from rats pretreated with trimetazidine for 1 week; (3) hearts in which 10 M trimetazidine was added to the perfusate, starting 5 minutes before ischemia and for the initial 15 minutes of reflow; (4) hearts from pretreated rats that also received trimetazidine in the perfusate. Postischemic impairment of contractile function was significantly attenuated by trimetazidine infusion (recovery of developed pressure: 68 +/- 7% versus 42 +/- 9% of baseline in controls; P < 0.05). Pretreatment alone was not effective, nor did it further improve the beneficial effects of infusion. Cardiac oxygen radical production at reflow (by electron paramagnetic resonance spectroscopy) was also reduced by trimetazidine, independently of direct scavenger effects. Thus, trimetazidine can protect postischemic hearts from neutrophil-mediated injury.
Tritto
Isabella
I
Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Wang
Penghai
P
Kuppusamy
Periannan
P
Giraldez
Roberto
R
Zweier
Jay L
JL
Ambrosio
Giuseppe
G
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008163:Luminescent Measurements / Q000379:methods; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014292:Trimetazidine / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009240:N-Formylmethionine Leucyl-Phenylalanine; D014969:Xanthine Oxidase; D014292:Trimetazidine