Machha Ajay, Achike Francis I, Mohd Mustafa Ali, Mustafa Mohd Rais
Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia.
Eur J Pharmacol. 2007 Jun 22;565(1-3):144-50. doi: 10.1016/j.ejphar.2007.03.009. Epub 2007 Mar 19.
Acute exposure to the flavonoid baicalein inhibited endothelium-dependent relaxation in physiological arteries, although the mechanisms are not fully understood. We investigated the effect of baicalein on vascular tone in Wistar-Kyoto (WKY) rat isolated aortic rings in the presence and absence of oxidative stress to further determine the underlying mechanisms. Exposure to baicalein (10 microM) completely abolished endothelium-dependent relaxation induced by acetylcholine and attenuated significantly the endothelium-independent relaxation induced by sodium nitroprusside. Baicalein, similar to Nomega-nitro-L-arginine methyl ester (L-NAME, 10 microM), potentiated significantly the contractile response of aortic rings to alpha1-adrenoceptor agonist phenylephrine. In the presence of L-NAME the baicalein effect on phenylphrine contraction or acetylcholine relaxation was unaltered, suggesting that these effects of baicalein are (like L-NAME effect) endothelial nitric oxide synthase (eNOS)/endothelium-derived nitric oxide-dependent. Inhibition of cyclooxygenase activity with indomethacin (10 microM) or scavenging of superoxide anions with superoxide dismutase (150 units/ml), but not scavenging of hydrogen peroxide with catalase (800 units/ml), enhanced significantly by an essentially similar extent the relaxation to acetylcholine in baicalein-pretreated aortic rings. Relaxant effect to acetylcholine was significantly attenuated in control aortic rings, but was completely abolished in baicalein-pretreated aortic rings in the presence of reduced form of beta-nicotinamide adenine di-nucleotide (beta-NADH, 300 microM). Baicalein blocked beta-NADH (300 microM)-induced transient contractions, suggesting that baicalein may have inhibited activity of NADH/NADPH-oxidase. Baicalein did not alter the failure of acetylcholine to induce relaxation in the presence of pyrogallol (300 microM). In summary, acute exposure to baicalein impairs eNOS/endothelium-derived nitric oxide-mediated vascular tone in rat aortas through the inhibition of endothelium-derived nitric oxide bioavailability coupled to reduced bioactivity of endothelium-derived nitric oxide and to cyclooxygenase-mediated release of superoxide anions.
急性暴露于黄酮类化合物黄芩素会抑制生理状态下动脉的内皮依赖性舒张，尽管其机制尚未完全明确。我们研究了在有或无氧化应激的情况下，黄芩素对Wistar-Kyoto（WKY）大鼠离体主动脉环血管张力的影响，以进一步确定其潜在机制。暴露于黄芩素（10微摩尔）完全消除了乙酰胆碱诱导的内皮依赖性舒张，并显著减弱了硝普钠诱导的非内皮依赖性舒张。黄芩素与Nω-硝基-L-精氨酸甲酯（L-NAME，10微摩尔）类似，显著增强了主动脉环对α1-肾上腺素能受体激动剂去氧肾上腺素的收缩反应。在存在L-NAME的情况下，黄芩素对去氧肾上腺素收缩或乙酰胆碱舒张的作用未改变，这表明黄芩素的这些作用（如L-NAME的作用）是内皮型一氧化氮合酶（eNOS）/内皮源性一氧化氮依赖性的。用吲哚美辛（10微摩尔）抑制环氧化酶活性或用超氧化物歧化酶（150单位/毫升）清除超氧阴离子，但用过氧化氢酶（800单位/毫升）清除过氧化氢，均能在黄芩素预处理的主动脉环中以基本相似的程度显著增强对乙酰胆碱的舒张作用。在对照主动脉环中，对乙酰胆碱的舒张作用显著减弱，但在存在还原型β-烟酰胺腺嘌呤二核苷酸（β-NADH，300微摩尔）的情况下，在黄芩素预处理的主动脉环中完全消除。黄芩素阻断了β-NADH（300微摩尔）诱导的短暂收缩，表明黄芩素可能抑制了NADH/NADPH氧化酶的活性。在存在邻苯三酚（300微摩尔）的情况下，黄芩素并未改变乙酰胆碱无法诱导舒张的情况。总之，急性暴露于黄芩素会通过抑制内皮源性一氧化氮的生物利用度，同时降低内皮源性一氧化氮的生物活性以及环氧化酶介导的超氧阴离子释放，损害大鼠主动脉中eNOS/内皮源性一氧化氮介导的血管张力。
