The use of aspirin in the secondary prevention of acute myocardial infarction is limited by its gastric side effects. NCX4016 (NO-aspirin) is a member of a new class of NO-NSAIDs that release nitric oxide (NO) and has reduced gastric side effects whilst maintaining the pharmacological profile of aspirin (Del Soldato et al.,1999). The release of NO may contribute to the cardioprotective effect of NCX4016 observed in normal animals (Rossoni et al. 2001, Wainwright et al., 2002). Since obesity is a major risk factor for the development of CV disease, the aim of the present study was to assess the effect of chronic administration of NCX4016, on the consequences of coronary artery occlusion in fatty Zucker rats.

Male lean (LZ; 300 ± 9 g) and fatty Zucker (FZ; 479 ± 12 g) rats (12-13 weeks) were pre-treated orally for 5 days with either (i) Vehicle (PEG₄₀₀,1 ml kg^-1, n= 10 LZ, n=9 FZ), (iii) aspirin (65.2 mg kg^-1, n=8 LZ, n=9 FZ), (iii) NCX4016 (60 mg kg^-1, n=9 LZ, n=10 FZ), or (iv) NCX4016 (120 mg kg^-1, n=10 LZ, n=9 FZ). One hour following the last oral dose dose, anaesthesia was induced by inhalation of isofluorane (3%) the right jugular vein was cannulated and inhalation anaesthetic reduced as a bolus dose of sodium pentobarbitone was administered (30 mg kg^-1 i.v.). Inhalation anaesthetic was then withdrawn and sodium pentobarbitone administered i.v. to achieve the required depth of anaesthesia. Rats were then prepared for coronary artery occlusion (CAO) as described previously (Clark et al., 1980). Following 15-min stabilisation, the rats were subjected to 30-min regional myocardial ischaemia, and 120-min reperfusion. Mean arterial blood pressure (MABP), heart rate (HR), and the number and incidence of arrhythmias were recorded via an ECG from standard (lead II) limb electrodes. At the end of reperfusion hearts were stained to determine area at risk (AAR) and infarct size. Data are expressed as mean ± s.e.mean and compared using ANOVA with Tukey's post-hoc test. The percentage incidence of ventricular tachycardia (VT), ventricular fibrillation (VF) and mortality was compared using Fischer's exact test.

None of the drug treatments significantly modified initial MABP or plasma glucose levels compared to vehicle treated in either lean (118 ± 4 mmHg, 5.5 ± 0.8 mM) or fatty Zucker rats (132 ± 3 mmHg, 10.6 ± 0.7 mM). None of the drug treatments significantly modified the incidence of VT, VF or mortality during ischaemia in either LZ or FZ. While aspirin (LZ 1206 ± 437, FZ 2290 ±824) and NCX4016 (60 mg kg^-1, LZ 1565 ± 312, FZ 2430 ± 562) had no effect on the total number of arrhythmias observed during ischaemia (LZ 2123 ± 567, FZ 2230 ± 443), NCX4016 (120 mg kg^-1) showed a tendency to reduce ventricular premature beats (VPB's) in both LZ (989 ± 179, P=0.0527) and FZ (1427 ± 457, P=0.09). In LZ rats infarct size was reduced by NCX4016 at both doses (60 mg kg^-1, 31 ± 1.7; 120 mg kg^-1, 31 ± 5.7 vs. 45 ± 9 % of AAR, P<0.05). In the FZ rats NCX4016 at the lower dose reduced infarct size (39 ± 4 vs. 58 ± 9%, P<0.05), while aspirin (36 ± 6%, P=0.07) and high dose NCX4016 (32 ± 9%, P=0.09) showed a tendency to reduce infarct size. These results demonstrate that NCX4016 can protect the heart from the consequences of ischaemia and reperfusion in a rat model of obesity.

Del Soldato et al., (1999). TIPS. 20, 319-323.
Clark et al., (1980). J. Pharmacol. Methods. 3(4), 357-368.
Rossoni et al., (2001). J. Pharmacol. Exp. Ther. 291(1), 380-387.
Wainwright et al., (2002). Br. J. Pharmacol. 135(8), 1882-1888.

SGB was supported by a studentship from NICOX S.A.