Turan Nilufer, Csonka Csaba, Csont Tamás, Giricz Zoltán, Fodor Gabriella, Bencsik Péter, Gyöngyösi Mariann, Cakici Iclal, Ferdinandy Péter
Department of Pharmacology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
Cardiovasc Res. 2006 May 1;70(2):384-90. doi: 10.1016/j.cardiores.2005.12.012. Epub 2006 Jan 27.
3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase, has been shown to protect against ischemic injury in the brain and in the heart via a preconditioning-like effect; however, the cellular mechanism is not known. The aim of the present study was to investigate if 3-NP pretreatment reduces infarct size and if altered metabolism of nitric oxide and reactive oxygen species are involved.
Hearts were assigned into 3 groups: 3 intermittent cycles of 5 min no-flow ischemia separated by 5 min aerobic perfusion protocol were used to induce ischemic preconditioning as a positive control; a time-matched non-preconditioning group served as control; and 3-NP (20 mg/kg, i.p.) was injected 3 h before the perfusion protocol to induce pharmacological preconditioning. Hearts from all groups were then subjected to 30 min global ischemia followed by 120 min reperfusion.
Infarct size and lactate dehydrogenase release were significantly reduced after ischemia/reperfusion. While cardiac nitric oxide (NO) was increased, superoxide formation, nitrotyrosine level, and cardiac NADH oxidase and xanthine oxidase (XO) activities were markedly reduced by 3-NP administration. Cardiac activities of NO synthase and superoxide dismutase were not changed by 3-NP.
This is the first demonstration in the rat myocardium that 3-NP induces pharmacological preconditioning, thereby limiting infarct size, and that this effect is associated with increased NO bioavailability and reduced peroxynitrite formation due to inhibition of superoxide formation by XO and NADH oxidase.
3-硝基丙酸（3-NP）是琥珀酸脱氢酶的不可逆抑制剂，已被证明可通过类似预处理的作用保护大脑和心脏免受缺血性损伤；然而，其细胞机制尚不清楚。本研究的目的是探讨3-NP预处理是否能减小梗死面积，以及一氧化氮和活性氧代谢的改变是否与之有关。
将心脏分为3组：采用5分钟无血流缺血的3个间歇周期，中间间隔5分钟有氧灌注方案诱导缺血预处理作为阳性对照；一个时间匹配的非预处理组作为对照；在灌注方案前3小时注射3-NP（20mg/kg，腹腔注射）以诱导药物预处理。然后对所有组的心脏进行30分钟全心缺血，随后再灌注120分钟。
缺血/再灌注后梗死面积和乳酸脱氢酶释放显著降低。虽然心脏一氧化氮（NO）增加，但3-NP给药可使超氧化物形成、硝基酪氨酸水平以及心脏NADH氧化酶和黄嘌呤氧化酶（XO）活性显著降低。3-NP对心脏一氧化氮合酶和超氧化物歧化酶的活性没有影响。
这是首次在大鼠心肌中证明3-NP诱导药物预处理，从而限制梗死面积，并且这种作用与一氧化氮生物利用度增加以及由于XO和NADH氧化酶抑制超氧化物形成导致过氧亚硝酸盐形成减少有关。
