Tongxinluo reduces myocardial no-reflow and ischemia-reperfusion injury by stimulating the phosphorylation of eNOS via the PKA pathway.
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.
Li
Xiang-Dong
XD
Department of Cardiology, Fuwai Hospital and Cardiovascular Institute, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Yang
Yue-Jin
YJ
Geng
Yong-Jian
YJ
Jin
Chen
C
Hu
Feng-Huan
FH
Zhao
Jing-Lin
JL
Zhang
Hai-Tao
HT
Cheng
Yu-Tong
YT
Qian
Hai-Yan
HY
Wang
Lin-Lin
LL
Zhang
Bao-Jie
BJ
Wu
Yi-Ling
YL
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
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