Hypercholesterolemia blunts NO donor-induced late preconditioning against myocardial infarction in conscious rabbits

Abstract

Although NO donors have been shown to confer late preconditioning (PC) against myocardial ischemia/reperfusion injury in healthy rabbits, it is unknown whether concurrent systemic disorders affect NO donor-induced cardioprotection. Since many patients with coronary artery disease have hypercholesterolemia (HC), we examined the effect of this condition on late PC induced by the NO donor diethylenetriamine/nitric oxide (DETA/ NO). Chronically instrumented rabbits were fed a normal diet (normocholesterolemia, NC) or a diet enriched with 1% cholesterol (HC) for 4 weeks. Plasma cholesterol levels were significantly elevated and the arterial pressure response to the endothelium-dependent vasodilator bradykinin was blunted in cholesterol diet-fed rabbits. Conscious rabbits underwent a 30-minute coronary occlusion followed by 3 days of reperfusion. When NC rabbits were pretreated with DETA/NO (0.1 mg/kg, i. v. x 4, group II, n = 7) 24 hours before the 30-minute occlusion, infarct size was reduced by 52% (29.7 +/- 3.4% versus 62.4 +/- 4.0% of the region at risk in NC controls [group I, n = 5], P < 0.05), indicating that DETA/NO induced a late PC effect against myocardial infarction. In contrast, when HC rabbits were pretreated with the same dose of DETA/NO (group IV, n = 6), infarct size was not significantly reduced (61.0 +/- 5.7% versus 68.1 +/- 4.5% of the region at risk in HC [group III, n = 5], P = NS), suggesting that DETA/NO failed to induce a delayed cardioprotective effect. These data demonstrate, for the first time, that HC blunts NO donor-induced late PC against myocardial infarction, implying that the inhibitory effects of HC on ischemia-induced and NO donor-induced late PC are caused by disruption of biochemical pathways distal to the generation of NO that triggers these adaptations.

Fig. 1

Change in mean arterial pressure in response to a bolus i.v. injection of (A) 0.01, 0.10 or 1.0 μg/kg of the endothelium-dependent vasodilator bradykinin and (B) 1, 10, or 100 μg/kg of the endothelium-independent vasodilator nitroglycerin in rabbits (n = 6) at baseline (before cholesterol diet) and after 4 weeks on a 1% cholesterol diet (just prior to sacrifice). Data are means ± SEM

Fig. 2

Myocardial infarct size in groups I (n = 5, NC control group), II (n = 7, NC DETA/NO group), III (n = 5, HC control group), and IV (n = 6, HC DETA/NO group). Infarct size is expressed as a percentage of the region at risk of infarction. Open circles represent individual rabbits, whereas solid circles represent means ± SEM. NC normocholesterolemia; HC hypercholesterolemia. *P < 0.05 vs. group I (NC control group)

Fig. 3

Relationship between size of the region at risk and size of myocardial infarction. The figure illustrates both individual values and the regression lines obtained by linear regression analysis for the NC control group (group I, n = 5), the NC DETA/NO group (group II, n = 7), the HC control group (group III, n = 5), and the HC DETA/NO group (group IV, n = 6). In all groups, infarct size was positively and linearly related to risk region size. The linear regression equations were as follows: group I, y = 0.60 χ + 0.02 (r= 0.95); group II, y = 0.36 χ − 0.06 (r= 0.80); group III, y = 0.60 χ + 0.15 (r = 0.93); and group IV, y = 0.71 χ − 0.10 (r = 0.90). ANCOVA demonstrated that the regression line for the NC DETA/NO group was significantly different from that for the NC control group (P < 0.05), indicating that for any given risk region size, infarct size was smaller in the DETA/NO-pretreated NC rabbits compared with the vehicle-pretreated NC rabbits; in contrast, the line for the HC DETA/NO group was similar to those for the vehicle-pretreated HC rabbits and the NC control groups