Mercanoglu G, Safran N, Ahishali B B, Uzun H, Yalcin A, Mercanoglu F
Department of Pharmacology, Biruni University, Faculty of Pharmacy, Istanbul, Turkey.
Eur Rev Med Pharmacol Sci. 2015 Dec;19(24):4872-89.
After MI pathological LV remodeling is one of the major causes of death. We previously showed the NO mediated beneficial effects of nebivolol in rat MI model, in this study we aimed to evaluate the NOS related mechanisms in this phenomenon.
Rats were divided into four groups: sham operated (sham-control), MI-induced (MI-control), immediate nebivolol loaded (MI-neb1), orally nebivolol treated (MI-neb2). MI was induced by the ligation of the LAD. Loading dose of nebivolol (0.1 mg/kg) was administrated i.v. during reperfusion and continuation dose was administrated orally (2 mg/kg) by gastric gavages once daily. NOS related mechanisms were assessed either in acute (2nd day) and sub-acute (28th day) period of MI by histologic, hemodynamic and biologic studies.
Compared to MI-control rats, physiological functions of LV (LVEDP, Δ±dp/dt) were prevented in both nebivolol treated groups. Improvements in anatomical parameters (LEV, HW, LVW/HW) were consistent with functional improvement too. Moreover, oxidative (characterized by decreased MDA and increased SOD levels) and nitrosative (characterized by decreased ONOO- levels) damage were limited in these groups. Compared to MI-control rats, most marked change was seen in the nNOS labelling in the nebivolol treated groups. The decrease in iNOS labelling was also prominent in these groups too.
NOS mediated mechanisms of nebivolol can be summarized as: 1) diminishing iNOS expression together with restoration of MI induced eNOS activation both in vascular bed and myocytes at the acute period of MI, and 2) prevention of deterioration in nNOS expression in myocardial cells at the sub-acute period of MI.
心肌梗死后病理性左心室重构是主要死亡原因之一。我们之前在大鼠心肌梗死模型中证明了奈必洛尔通过一氧化氮介导的有益作用，在本研究中，我们旨在评估这一现象中与一氧化氮合酶相关的机制。
将大鼠分为四组：假手术组（假手术对照）、心肌梗死诱导组（心肌梗死对照）、即刻负荷奈必洛尔组（心肌梗死 - 奈必洛尔1）、口服奈必洛尔治疗组（心肌梗死 - 奈必洛尔2）。通过结扎左冠状动脉前降支诱导心肌梗死。在再灌注期间静脉注射奈必洛尔负荷剂量（0.1mg/kg），并通过胃管每日口服一次持续剂量（2mg/kg）。通过组织学、血流动力学和生物学研究在心肌梗死的急性期（第2天）和亚急性期（第28天）评估与一氧化氮合酶相关的机制。
与心肌梗死对照大鼠相比，两个奈必洛尔治疗组的左心室生理功能（左心室舒张末期压力、±dp/dt）均得到改善。解剖学参数（左心室舒张末期内径、心脏重量、左心室重量/心脏重量）的改善也与功能改善一致。此外，这些组中氧化损伤（以丙二醛水平降低和超氧化物歧化酶水平升高为特征）和亚硝化损伤（以过氧亚硝基阴离子水平降低为特征）受到限制。与心肌梗死对照大鼠相比，奈必洛尔治疗组中最明显的变化见于神经元型一氧化氮合酶标记。诱导型一氧化氮合酶标记的减少在这些组中也很突出。
奈必洛尔的一氧化氮合酶介导机制可总结为：1）在心肌梗死急性期，在血管床和心肌细胞中减少诱导型一氧化氮合酶表达并恢复心肌梗死诱导的内皮型一氧化氮合酶激活；2）在心肌梗死亚急性期防止心肌细胞中神经元型一氧化氮合酶表达恶化。
