硝酸甘油耐受性机制探讨及卡维地洛的预防作用

Prevention of nitroglycerin tolerance with carvedilol

目的 研究硝酸甘油 (NTG)连续应用耐受性的形成机制及卡维地洛对 NTG耐受性的预防作用。方法 大鼠 NTG 10 mg· kg- 1 皮下注射 ,每日 3次连用 6日引致耐受。测定耐受性形成前、后舌静脉注射 NTG对鼠尾容积的作用 ,作为硝酸甘油效应及耐受的指标 ,同时检测耐受性形成后有关组织的氧自由基 (· O2 - )、亚硝酸盐(NO2 - )、总硝酸盐 (NOX- )、超氧化物歧化酶 (SOD)活力和丙二醛 (MDA)。结果 大鼠连用 NTG后 ,再静注 NTG对鼠尾容积的增加作用明显减弱 ;主动脉和心脏组织及血浆中· O2- 和 NOX- 都明显升高 ,除血浆 NO2- 水平升高外其余组织 NO2 - 水平都明显降低 ;主动脉、肝脏和红细胞中的 MDA含量增高 ,SOD活力降低 ;卡维地洛能有效预防NTG连续应用耐受性的形成 ,完全或部分防止上述检测指标的变化。结论 NTG连续应用期间耐受性的形成与· O2- 水平升高引起一氧化氮 (NO)氧化灭活有关 ;卡维地洛通过抗氧化、清除· O2- 等作用而有效预防或减轻 NTG连用过程中耐受性的形成。

Objective To study the mechanism of development of tolerance to nitroglycerin(NTG)and the preventive effect of carvedilol on the tolerance.Methods\ Tolerance was induced by NTG 10mg·kg -1 sc 3 times a day for 6 days in rats.Tail volume as the effect of NTG was measured by plethysmometry and oxygen free radical(·O 2 -),nitrite(NO 2 -),total nitrate(NO x -),superoxide dismutase(SOD)activity,and malonaldehyde(MDA)in tissues were determined at the end of the experiment.Results\ The increase in tail volume by NTG iv was significantly attenuated after treatment with NTG sc for 6 days in rats.The ·O 2 - and NO x - in aorta,heart,and plasma were elevated.The NO 2 - in the tissues were reduced except plasma in which NO 2 - was increased.The MDA in aorta,liver and RBC were significantly increased.SOD activities were decreased.These changes were completely or partly prevented by carvedilol.Conclusion\ The development of NTG tolerance during the administration of NTG is related to the increase in oxygen free radical production.Carvedilol which can act as an antioxidant and an oxygen free radical scavenger prevents or attenuates the development of the tolerance.