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Chronic inhibition of phosphodiesterase 5 with tadalafil affords cardioprotection in a mouse model of metabolic syndrome: role of nitric oxide.
Molecular and Cellular Biochemistry ( IF 3.5 ) Pub Date : 2020-03-11 , DOI: 10.1007/s11010-020-03710-0
Saisudha Koka 1, 2 , Lei Xi 1 , Rakesh C Kukreja 1, 3
Affiliation  

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb-lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.

中文翻译:


用他达拉非长期抑制磷酸二酯酶 5 可在代谢综合征小鼠模型中提供心脏保护作用:一氧化氮的作用。



代谢综合征 (MetS) 患者通常表现出全身内皮和心脏功能障碍,并伴有一氧化氮 (NO) 产生和/或生物利用度降低。由于磷酸二酯酶 5 (PDE5) 抑制剂恢复 NO 信号传导,我们假设用长效 PDE5 抑制剂他达拉非长期治疗可能会提高 C57BL/6NCrl-Leprdb-lb 中缺血/再灌注 (I/R) 损伤后的血浆 NO 水平并减少心功能障碍/Crl 具有 MetS 表型的小鼠。成年雄性 MetS 小鼠随机接受载体溶剂或他达拉非(1 mg/kg,腹腔注射),持续 28 天,C57BL/6NCrl 小鼠作为健康野生型对照。 28天后,通过超声心动图评估心脏功能,并分离出一部分小鼠的心脏,并在离体Langendorff模式下进行30分钟的整体缺血,然后进行60分钟的再灌注(I/R)。与野生型对照相比,MetS 小鼠的体重、血脂和血糖水平升高。他达拉非治疗后,MetS 的血脂异常得到改善。尽管 MetS 小鼠的左心室 (LV) 收缩功能改变很小,但二尖瓣流入早期与晚期充盈峰值速度比的降低表明存在显着的舒张功能障碍,而他达拉非治疗显着改善了这一情况。与野生型对照相比,MetS 小鼠的缺血后心功能、心率和冠状动脉血流显着下降,但通过他达拉非治疗后得以保留。缺血再灌注后,心肌梗塞面积显着缩小,这与接受他达拉非治疗的 MetS 小鼠血浆硝酸盐和亚硝酸盐水平升高有关。 总之,他达拉非具有显着的心脏保护作用,如改善左心室舒张功能、血脂状况以及缺血再灌注后梗死面积的减少。他达拉非治疗增强了一氧化氮的产生,这可能有助于心脏保护作用。
更新日期:2020-04-22
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