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: Meijuan Xu, Haiping Hao, Lifeng Jiang, Yidan Wei, Fang Zhou, Jianguo Sun, Jingwei Zhang, Hui Ji, Guangji Wang, Wenzheng Ju, Ping Li
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 44 Issue 7 Pg. 878-87 (07 2016) ISSN: 1521-009X [Electronic] United States
• PMID: 27149899 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Cardiotonic Agents
• Drugs, Chinese Herbal
• Eicosanoids
• Isoenzymes
• Cytochrome P-450 Enzyme System
• 14,15-episulfide eicosatrienoic acid
• L-Lactate Dehydrogenase
• Creatine Kinase, MB Form
• 8,11,14-Eicosatrienoic Acid

Topics

• 8,11,14-Eicosatrienoic Acid (analogs & derivatives, pharmacology)
• Animals
• Cardiotonic Agents (pharmacology)
• Cell Line
• Creatine Kinase, MB Form (blood)
• Cytochrome P-450 Enzyme System (metabolism)
• Cytoprotection
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal (pharmacology)
• Eicosanoids (blood)
• Isoenzymes
• L-Lactate Dehydrogenase (blood)
• Male
• Myocardial Reperfusion Injury (blood, pathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Rats, Sprague-Dawley
• Up-Regulation