title: Cardioprotective effects and pharmacokinetic properties of a controlled release formulation of a novel hydrogen sulfide donor in rats with acute myocardial infarction.
abstract: We previously reported that S-propargyl-cysteine (SPRC) exerts cardioprotective effects by elevating H2S levels via the CSE/H2S pathway. In the present study, we investigated the cardioprotective effects and pharmacokinetic properties of a controlled release formulation of SPRC (CR-SPRC) in an in vivo rat model of myocardial infarction (MI). Rats were randomly assigned to seven groups that were pre-treated with CR-SPRC daily for 7 days prior to ligation of the left anterior descending coronary artery to induce MI. Cardiac function and infarct size were determined after MI, and we examined the activity of antioxidant enzymes, expression of anti-inflammation proteins and hydrogen sulfide levels. Mixed-mode, reversed-phase and cation-exchange HPLC-MS/MS were used to compare the pharmacokinetic properties of CR-SPRC and SPRC. CR-SPRC significantly reduced infarct size and creatine kinase (CK) and lactate dehydrogenase (LDH) leakage and it preserved cardiac function during MI. CR-SPRC displayed antioxidant properties, preserving glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) levels whereas reducing malondialdehyde (MDA) levels. Moreover, CR-SPRC significantly reduced the protein levels of inflammatory biomarkers (phospho-NF-κB p65/NF-κB p65, TNF-α) and increased cystathionine-γ-lyase (CSE) and Iκ-Bα protein levels. CR-SPRC had better pharmacokinetic properties than SPRC, with a reduced concentration peak (Cmax), prolonged time to reach peak concentration (Tmax), prolonged mean residence time (MRTinf) and increased AUC0-t. CR-SPRC showed protective effects against MI via the CSE/H2S pathway and demonstrated better cardioprotective effects than SPRC by prolonging the release of endogenous H2S.
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, Shanghai, China.
authors.forename: Ba Hieu
authors.initials: BH
authors.lastname: Tran
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, Shanghai, China.
authors.forename: Chengrong
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, Shanghai, China.
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, Shanghai, China.
authors.forename: Shizhou
authors.initials: S
authors.lastname: Lin
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, Shanghai, China.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
authors.forename: Shujun
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, Shanghai, China School of Pharmacy & Institutes of Biomedical Sciences, Fudan University, Shanghai, Shanghai, China zhuyz@fudan.edu.cn.
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D003402:Creatine Kinase / Q000097:blood; D003545:Cysteine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004562:Electrocardiography; D005978:Glutathione / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000008:administration & dosage* / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002316:Cardiotonic Agents; D003692:Delayed-Action Preparations; C556437:S-propargylcysteine; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D003402:Creatine Kinase; D005978:Glutathione; D003545:Cysteine; D006862:Hydrogen Sulfide
keywords: acute myocardial infarction; anti-inflammation; antioxidant; cardioprotection; hydrogen sulfide