3′,4′-Dihydroxyflavonol improves post-ischaemic coronary endothelial function following 7 days reperfusion in sheep

Abstract

3′,4′-dihydroxyflavonol (DiOHF) is a potent antioxidant that reduces infarct size following myocardial ischaemia-reperfusion. Since oxidative stress induced by myocardial ischaemia-reperfusion impairs endothelium-dependent vasodilatation, we investigated whether DiOHF preserved coronary endothelial function following ischemia-reperfusion. One week after surgery conscious, instrumented sheep were subjected to 1 h of myocardial ischaemia followed by 7 days reperfusion. Immediately before reperfusion, sheep were injected with DiOHF (2 mg/kg iv, n = 4) or vehicle (dimethyl sulphoxide, n = 4). Coronary vascular responses to the endothelium-dependent vasodilator acetylcholine (ACh, 0.05-10.0 μg/kg/min iv), sodium nitroprusside and phenylephrine were determined. After ischaemia-reperfusion, dP/dtmax decreased from 1511 ± 93 to 1094 ± 53 mmHg/s, P < 0.05) at 24 h in the vehicle group, but by 7 days had returned towards baseline (1347 ± 91 mm Hg/s). DiOHF prevented the fall in dP/dtmax. Coronary conductance (CC) was increased (+ 34 ± 4%) by 10 μg/kg ACh given before ischaemia, but this vasodilatation was significantly reduced after 24 h and 7 days of reperfusion (+ 7 ± 2%, + 15 ± 2%, respectively, both P < 0.05). DiOHF partially preserved the coronary vasodilator response to ACh after 24 h reperfusion (basal 37 ± 7%, 24 h 18 ± 5%), and after 7 days reperfusion the response had recovered (31 ± 7%). DiOHF significantly decreased infarct size, expressed as a percentage of area-at-risk, by 40% after 7 days reperfusion (vehicle 80 ± 7%, DiOHF 46 ± 11%, P < 0.05). A single administration of DiOHF, during ischaemia and just prior to reperfusion, reduced infarct size, preserved ventricular contractility and caused a sustained protection against coronary endothelial dysfunction, with all these beneficial actions being preserved for 7 days reperfusion. © 2009 Elsevier B.V. All rights reserved.