title: 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.
authors.affiliation: Division of Cardiology, University of Louisville, Louisville, Kentucky 40292, USA.
authors.forename: Xian-Liang
authors.initials: XL
authors.lastname: Tang
authors.forename: Adam B
authors.initials: AB
authors.lastname: Stein
authors.forename: Gregg
authors.initials: G
authors.lastname: Shirk
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology; D001920:Bradykinin / Q000494:pharmacology; D002784:Cholesterol / Q000097:blood; D003243:Consciousness / Q000502:physiology*; D006339:Heart Rate / Q000187:drug effects; D006937:Hypercholesterolemia / Q000378:metabolism* / Q000473:pathology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D002784:Cholesterol; D001920:Bradykinin