title: Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway.
abstract: The objective of the present study was to investigate whether pretreatment with single low loading dose of tongxinluo (TXL), a traditional Chinese medicine, 1 h before myocardial ischemia could attenuate no-reflow and ischemia-reperfusion injury by regulating endothelial nitric oxide synthase (eNOS) via the PKA pathway. In a 90-min ischemia and 3-h reperfusion model, minipigs were randomly assigned to the following groups: sham, control, TXL (0.05 g/kg, gavaged 1 h before ischemia), TXL + H-89 (a PKA inhibitor, intravenously infused at a dose of 1.0 μg·kg(-1)·min(-1) 30 min before ischemia), and TXL + N(ω)-nitro-L-arginine (L-NNA; an eNOS inhibitor, intravenously administered at a dose of 10 mg/kg 30 min before ischemia). TXL decreased creatine kinase (CK) activity (P < 0.05) and reduced the no-reflow area from 48.6% to 9.5% and infarct size from 78.5% to 59.2% (P < 0.05), whereas these effects of TXL were partially abolished by H-89 and completely reversed by L-NNA. TXL elevated PKA activity and the expression of PKA, Thr(198) phosphorylated PKA, Ser(1179) phosphorylated eNOS, and Ser(635) phosphorylated eNOS in the ischemic myocardium. H-89 repressed the TXL-induced enhancement of PKA activity and phosphorylation of eNOS at Ser(635), and L-NNA counteracted the phosphorylation of eNOS at Ser(1179) and Ser(635) without an apparent influence on PKA activity. In conclusion, pretreatment with a single low loading dose of TXL 1 h before ischemia reduces myocardial no-reflow and ischemia-reperfusion injury by upregulating the phosphorylation of eNOS at Ser(1179) and Ser(635), and this effect is partially mediated by the PKA pathway.
authors.affiliation: Department of Cardiology, Fuwai Hospital and Cardiovascular Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Li
authors.forename: Yue-Jin
authors.initials: YJ
authors.lastname: Yang
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.forename: Chen
authors.initials: C
authors.lastname: Jin
authors.forename: Feng-Huan
authors.initials: FH
authors.lastname: Hu
authors.forename: Jing-Lin
authors.initials: JL
authors.lastname: Zhao
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhang
authors.forename: Yu-Tong
authors.initials: YT
authors.lastname: Cheng
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qian
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Wang
authors.forename: Bao-Jie
authors.initials: BJ
authors.lastname: Zhang
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000097:blood; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D007546:Isoquinolines / Q000494:pharmacology; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature
chemical_list: D004365:Drugs, Chinese Herbal; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C513941:tongxinluo; D052250:Nitric Oxide Synthase Type III; D017868:Cyclic AMP-Dependent Protein Kinases; D003402:Creatine Kinase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide