title: Cardiotonic Pill Reduces Myocardial Ischemia-Reperfusion Injury via Increasing EET Concentrations in Rats.
abstract: Accumulating data suggest that epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid, both cytochrome P450 (P450) enzyme metabolites of arachidonic acid (AA), play important roles in cardiovascular diseases. For many years, the cardiotonic pill (CP), an herbal preparation derived from Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Borneolum Syntheticum, has been widely used in China for the treatment of coronary artery disease. However, its pharmacological mechanism has not been well elucidated. The purpose of this study was to investigate the chronic effects of the CP on myocardial ischemia-reperfusion injury (MIRI) and AA P450 enzyme metabolism in rats (in vivo) and H9c2 cells (in vitro). The results showed that CP dose dependently (10, 20, and 40 mg/kg/d; 7 days) mitigated MIRI in rats. The plasma concentrations of EETs in CP-treated ischemia-reperfusion (I/R) rats (40 mg/kg/d; 7 days) were significantly higher (P < 0.05) than those in controls. Cardiac Cyp1b1, Cyp2b1, Cyp2e1, Cyp2j3, and Cyp4f6 were significantly induced (P < 0.05); CYP2J and CYP2C11 proteins were upregulated (P < 0.05); and AA-epoxygenases activity was significantly increased (P < 0.05) after CP (40 mg/kg/d; 7 days) administration in rats. In H9c2 cells, the CP also increased (P < 0.05) the EET concentrations and showed protection in hypoxia-reoxygenation (H/R) cells. However, an antagonist of EETs, 14,15-epoxyeicosa-5(Z)-enoic acid, displayed a dose-dependent depression of the CP's protective effects in H/R cells. In conclusion, upregulation of cardiac epoxygenases after multiple doses of the CP-leading to elevated concentrations of cardioprotective EETs after myocardial I/R-may be the underlying mechanism, at least in part, for the CP's cardioprotective effect in rats.
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Meijuan
authors.initials: M
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Lifeng
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Yidan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Fang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Jianguo
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Jingwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.).
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.) liping2004@126.com ju_njxmj@126.com.
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Ju
authors.affiliation: State Key Laboratory of Natural Medicines (M.X., H.H., L.J., Y.W., H.J., P.L.) and Key Laboratory of Drug Metabolism and Pharmacokinetics (H.H., F.Z., J.S., J.Z., G.W.), China Pharmaceutical University, Nanjing, China; and Department of Clinical Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China (M.X., W.J.) liping2004@126.com ju_njxmj@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D052279:Creatine Kinase, MB Form / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D015777:Eicosanoids / Q000097:blood*; D007527:Isoenzymes; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D002316:Cardiotonic Agents; D004365:Drugs, Chinese Herbal; D015777:Eicosanoids; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; C067407:14,15-episulfide eicosatrienoic acid; D007770:L-Lactate Dehydrogenase; D052279:Creatine Kinase, MB Form; D015126:8,11,14-Eicosatrienoic Acid