Understanding the cardioprotective effects of flavonols: discovery of relaxant flavonols without antioxidant activity.
3',4'-Dihydroxyflavonol (DiOHF) is a cardioprotective flavonol that can reduce injury after myocardial ischemia and reperfusion and thus is a promising small molecule for the treatment of cardiovascular disease. Like all vasoactive flavonols reported to date, DiOHF is both relaxant and antioxidant, hindering investigation of the relative contribution of each activity for the prevention of reperfusion injury. This study investigates structure-activity relationships of variations at the 3' and 4' positions of the B ring of DiOHF and vasorelaxant and antioxidant activities. Relaxation of rat isolated aortic rings precontracted with KCl revealed that the most active flavonols were those with a 4'-hydroxyl group, with the opening of potassium channels as a possible contributing mechanism. For the antioxidant activity, with the exception of DiOHF, none of the flavonols investigated were able to significantly scavenge superoxide radical, and none of the three most potent vasorelaxant flavonols could prevent oxidant-induced endothelial dysfunction. The discovery of single-acting vasorelaxant flavonols without antioxidant activity, in particular 4'-hydroxy-3'-methoxyflavonol, will assist in investigating the mechanism of flavonol-induced cardioprotection.
Qin
Cheng Xue
CX
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Chen
Xingqiang
X
Hughes
Richard A
RA
Williams
Spencer J
SJ
Woodman
Owen L
OL
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D044948:Flavonols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
D000975:Antioxidants; D002316:Cardiotonic Agents; D044948:Flavonols; D016166:Free Radical Scavengers; D016877:Oxidants; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D011189:Potassium Chloride