文章基本信息

标题：Effects of Tetrahydrobiopterin Combined with Nebivolol on Cardiac Diastolic Function in SHRs
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作者：Zhengyi Zhang ; Changhong Lu ; Ying Meng 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：2019
卷号：42
期号：7
页码：1102-1111
DOI：10.1248/bpb.b18-00691
出版社：The Pharmaceutical Society of Japan
摘要：This study aimed to evaluate the effects of combined use of tetrahydrobiopterin (BH4) and nebivolol on cardiac diastolic dysfunction in spontaneously hypertensive rats (SHRs). Twelve-week-old male SHRs were treated with BH4, nebivolol, or a combination of both. Left ventricle function was evaluated, and reactive oxygen species (ROS) production (including dihydroethidium (DHE) and 3-nitrotyrosine (3-NT)), nitric oxide synthase (NOS) activity and the level of NO in myocardial tissue were determined. The expression levels of endothelial NOS (eNOS), phospholamban (PLN), sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), β3-adrenoceptor, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) were assayed. Treatment with BH4, nebivolol, or both reversed the noninvasive indexes of diastolic function, including E/E′ and E′/A′, and the invasive indexes, including time constant of isovolumic left ventricle (LV) relaxation (tau), −d P /d t min, −d P /d t min/LV systolic pressure (LVSP), and LV end-diastolic pressure (LVEDP) in SHRs. mRNA and protein expression levels of eNOS dimer, phosphorylated PLN, SERCA2a, cGMP, and PKG in the myocardium of treated SHRs were significantly up-regulated compared with those in control rats ( p < 0.05 or p < 0.01). The expression levels of 3-NT and DHE were reduced in all treated groups ( p < 0.05 or p < 0.01). Notably, combined use of BH4 and nebivolol had better cardioprotective effects than monotherapies. BH4 or nebivolol has a protective effect on diastolic dysfunction in SHRs, and BH4 combined with nebivolol may exert a synergistically cardioprotective effect through activation of β3-adrenoceptor and the NO/cGMP/PKG signaling pathway.
关键词：tetrahydrobiopterin;nebivolol;diastolic function;endothelial nitric oxide synthase;cyclic guanosine monophosphate