In vivo cardioprotection by N-acetylcysteine and isosorbide 5-mononitrate in a rat model of ischemia-reperfusion.
OBJECTIVE
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).


CONCLUSIONS
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.
Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche Mario Negri, Milano.
Laura
L
Calvillo
Serge
S
Masson
Monica
M
Salio
Loredana
L
Pollicino
Noeleen
N
De Angelis
Fabio
F
Fiordaliso
Antonio
A
Bai
Pietro
P
Ghezzi
Francesco
F
Santangelo
Roberto
R
Latini
D000111:Acetylcysteine / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004359:Drug Therapy, Combination; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008297:Male; D009000:Monocytes / Q000473:pathology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D009504:Neutrophils / Q000473:pathology; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate; D000111:Acetylcysteine