Kasten T P, Settle S L, Misko T P, Riley D P, Weiss R H, Currie M G, Nickols G A
Monsanto Corporate Research, St. Louis, Missouri 63167.
Proc Soc Exp Biol Med. 1995 Feb;208(2):170-7. doi: 10.3181/00379727-208-43848.
Nitric oxide (NO) produced by the vascular endothelium is an endogenous contributor to the regulation of vascular relaxation and the maintenance of blood pressure. The effective half-life of NO and the relaxation of aortic rings by NO is enhanced by a reduction in the concentration of superoxide radicals with superoxide dismutase (SOD). In the current study, SC52608, a newly synthesized SOD mimic with a manganese core, was tested for its ability to potentiate the activity of NO both in vitro and in vivo. SC52608 relaxation of rat aortic segments was endothelium dependent as well as concentration dependent. The maximum relaxation following KCl contraction was 44% with 300 microM SC52608. Cyclic GMP concentrations in the segments were increased 1.6- and 3.2-fold with 5 and 300 microM SC52608, respectively. N-monomethyl-I-arginine pretreatment of aortic rings abolished the relaxation and cyclic GMP accumulation mediated by SC52608. In a smooth muscle cell reporter system of nitric oxide synthase activity, SC52608 potentiated the increase in cyclic GMP elicited by NO in a concentration-dependent manner with a maximum increase of 5.2-fold at 100 microM. Injection of SC52608 into conscious, restrained rats resulted in a dose-dependent decrease of blood pressure. Therefore, the data suggest that SC52608 potentiates the actions of nitric oxide on vascular tone, cyclic GMP, and blood pressure by enhancing the half-life of NO through a mechanism that mimics the action of SOD.
血管内皮产生的一氧化氮（NO）是调节血管舒张和维持血压的内源性物质。超氧化物歧化酶（SOD）可降低超氧阴离子自由基的浓度，从而延长NO的有效半衰期并增强NO对主动脉环的舒张作用。在本研究中，对一种新合成的、以锰为核心的SOD模拟物SC52608在体外和体内增强NO活性的能力进行了测试。SC52608对大鼠主动脉段的舒张作用依赖于内皮且具有浓度依赖性。在300μM SC52608作用下，KCl收缩后最大舒张率为44%。5μM和300μM SC52608分别使主动脉段中环鸟苷酸（cGMP）浓度增加1.6倍和3.2倍。用N-单甲基-L-精氨酸预处理主动脉环可消除SC52608介导的舒张作用和cGMP积累。在一氧化氮合酶活性的平滑肌细胞报告系统中，SC52608以浓度依赖的方式增强NO引起的cGMP增加，在100μM时最大增加5.2倍。给清醒、束缚状态的大鼠注射SC52608可导致血压呈剂量依赖性下降。因此，数据表明SC52608通过模拟SOD的作用机制延长NO的半衰期，从而增强一氧化氮对血管张力、cGMP和血压的作用。
