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In Vivo Cardioprotection by N-Acetylcysteine and Isosorbide 5-Mononitrate in a Rat Model of Ischemia-Reperfusion

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Abstract

Aims: We evaluated the effect of N-acetylcysteine (NAC, infused i.v.), isosorbide 5-mononitrate (IS5MN, by gavage), or their combination on cardiac injury in an in vivo rat model of 30-min ischemia followed by 24 hours or 7 days of reperfusion.

Results: When administered immediately prior to reperfusion with continuous infusion for 24 h, the combination of NAC + IS5MN reduced infarct size (29 ± 6 vs. 59 ± 4% area-at-risk, p < 0.01) and the infiltration of polymorphonuclear leukocytes (226 ± 15 vs. 315 ± 18 cells mm−2 of area-at-risk, p = 0.002) and monocytes/macrophages (118 ± 8 vs. 194 ± 22 cells mm−2, p = 0.012), compared to vehicle. NAC or IS5MN alone did not reduce infarct size at 24 hours of reperfusion. The same dose regimen of NAC and IS5MN did not reduce infarct size with permanent ischemia for 24 hours not followed by reperfusion. After 7 days of reperfusion (3 days of treatment with NAC + IS5MN or vehicle and 4 days of wash-out), infarct size was similar in the vehicle and NAC + IS5MN groups, but LV end-diastolic pressure and diastolic LV chamber wall stress were significantly lower in the animals treated with NAC + IS5MN (5 ± 1 mmHg and 62 ± 7 dyne mm−2, respectively) compared to vehicle (9 ± 1 mmHg and 123 ± 18 dyne mm−2, p < 0.05).

Conclusion: We demonstrate in a rat model of cardiac ischemia-reperfusion treated with NAC and IS5MN, according to a regimen that mimicked a clinical situation (drugs started at time of reperfusion), that the short-term benefit seen after 24 h of reperfusion (51% reduction of infarct size) is maintained after one week, possibly through modulation of the inflammatory response to cardiac injury.

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Authors and Affiliations

  1. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano

    Laura Calvillo, Serge Masson, Monica Salio, Loredana Pollicino, Noeleen De Angelis, Fabio Fiordaliso & Antonio Bai

  2. Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano

    Pietro Ghezzi

  3. Zambon Group SpA, Bresso, Italy

    Francesco Santangelo

  4. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri”, Milano

    Roberto Latini

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  1. Laura Calvillo
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Calvillo, L., Masson, S., Salio, M. et al. In Vivo Cardioprotection by N-Acetylcysteine and Isosorbide 5-Mononitrate in a Rat Model of Ischemia-Reperfusion. Cardiovasc Drugs Ther 17, 199–208 (2003). https://doi.org/10.1023/A:1026182404805

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