title: Antioxidant activity contributes to flavonol cardioprotection during reperfusion of rat hearts.
abstract: The mechanism of flavonol-induced cardioprotection is unclear. We compared the protective actions of a flavonol that inhibits calcium utilization and has antioxidant activity, 3',4'-dihydroxyflavonol (DiOHF); a flavonol that affects only calcium activity, 4'-OH-3'-OCH(3)-flavonol (4'-OH-3'-OCH(3)F); and a water-soluble flavonol with selective antioxidant activity, DiOHF-6-succinamic acid (DiOHF-6-SA), in isolated, perfused rat hearts. Hearts were subjected to global ischemia for 20 min followed by 30 min reperfusion and were treated with vehicle (0.05% DMSO), DiOHF, 4'-OH-3'-OCH(3)F, or DiOHF-6-SA (all 10 μM, n=5-8 per group). Flavonols were infused for 10 min before ischemia and during reperfusion. In vehicle-treated hearts, left-ventricular (LV) +dP/dt was reduced by 60% at the end of reperfusion compared to the preischemic level. Lactate dehydrogenase (LDH) release was elevated and endothelial NO synthase (eNOS) expression was lower in vehicle-treated hearts compared to shams. In comparison, DiOHF treatment improved LV function upon reperfusion, decreased LDH, and preserved eNOS expression. The antioxidant DiOHF-6-SA also preserved contractility, reduced LDH, and preserved eNOS expression. In contrast, hearts treated with 4'-OH-3'-OCH(3)F showed a degree of contractile impairment similar to that of the vehicle group. DiOHF and DiOHF-6-SA also exerted cardioprotection when given only during reperfusion and not when administered only before ischemia. Flavonol-induced cardioprotection relies on antioxidant activity and is mainly exerted during reperfusion.
authors.affiliation: Department of Pharmacology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Cheng Xue
authors.initials: CX
authors.lastname: Qin
authors.forename: Spencer J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Owen L
authors.initials: OL
authors.lastname: Woodman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D044948:Flavonols / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D007261:Infusions, Intra-Arterial; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000096:biosynthesis; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000975:Antioxidants; D002316:Cardiotonic Agents; D044948:Flavonols; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D002118:Calcium