Abstract P301: Investigation of the Mechanism of the Cardioprotective Effects of Flavonols in Langendorff Perfused Rat Hearts
We investigated the mechanism(s) of flavonol-induced cardioprotection using a flavonol which inhibits calcium utilization and has antioxidant activity 3’,4’-dihydroxylflavonol, a flavonol which only affects calcium activity 4’-OH-3’-OCH3 flavonol and a water-soluble flavonol with selective antioxidant activity DiOHF-6-succinamic acid in rat isolated hearts. Hearts were perfused with physiological solution using a Langendorff apparatus and subjected to global, no-flow 20-min ischaemia followed by 30-min reperfusion. Hearts (n = 6–8 per group) were randomly treated with vehicle (0.05% DMSO), DiOHF, 4’-OH-3’-OCH3 flavonol or DiOHF-6-succinamic acid (all 10 µM). Flavonols were included in the perfusate for 10 min before ischaemia and during the entire duration of reperfusion. In vehicle treated hearts, LV+dP/dt was significantly reduced at the end of reperfusion (60±8% decrease in LV+dP/dt) compared to the pre-ischaemic level. Furthermore, LDH release (895±121 U/L) was significantly elevated during reperfusion compared to shams (70±10 U/L) and total eNOS expression was significantly lower in vehicle-treated hearts. In comparison, DiOHF treatment significantly improved LV function upon reperfusion (35±6% reduction in LV+dP/dt), significantly decreased the level of LDH (265±66 U/L) and preserved total eNOS expression. Hearts treated with the antioxidant DiOHF-6-succinamic acid had a similar preservation of contractility, resulting in a 36±5% reduction in LV+dP/dt, and a significantly lower release of LDH (388±57 U/L) and preserved total eNOS expression. In contrast, hearts treated with 4’-OH-3’-OCH3 showed similar impairment of contractility to the vehicle group. DiOHF-6-succinamic acid also exerted cardioprotection when given only during reperfusion but not when administered only prior to ischaemia. This study demonstrated that flavonol-induced cardioprotection relies on the antioxidant activity and is mainly exerted during the reperfusion phase. The water-soluble DiOHF-6-succinamic acid with selective antioxidant activity may lead to the development of a new cardioprotective agent effective when applied at reperfusion and therefore appropriate for clinical use.
- © 2011 by American Heart Association, Inc.