Cardioprotective effects and pharmacokinetic properties of a controlled release formulation of a novel hydrogen sulfide donor in rats with acute myocardial infarction.

Ba Hieu Tran,Shujun Wang,Qiuyan Zhang,Xu Liu,Hongrui Liu,Shizhou Lin,Chengrong Huang,Yi Zhun Zhu

doi:10.1042/bsr20140185

Ba Hieu Tran, Shujun Wang + Show 6 more

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https://doi.org/10.1042/bsr20140185

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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.

Highlights

Despite some recent improvements in diagnosis and treatment, cardiovascular diseases remain the leading cause of death worldwide and myocardial infarction (MI) is among the most prevalent ischemic heart diseases
Mortality was significantly lower in the controlled release formulation of SPRC (CR-SPRC) and SPRC groups than in the MI group (9.1 % and 13.6 % compared with 40.9 %, P < 0.05, respectively)
Mortality was significantly lower in the CR-SPRC group than in the PAG group (9.1 % compared with 36.4 % P < 0.05)

Summary

Introduction

Despite some recent improvements in diagnosis and treatment, cardiovascular diseases remain the leading cause of death worldwide and myocardial infarction (MI) is among the most prevalent ischemic heart diseases. Extensive evidence has established the importance of oxidative stress and inflammation in the pathogenesis of MI. MI initiates oxidative stress and an intense inflammatory response that promotes myocardial apoptosis, cell death, ventricular remodelling and cardiac dysfunction [1,2,3]. Antioxidative and anti-inflammatory responses may be vital for preventing apoptosis, salvaging the myocardium, preserving heart function and reversing cardiac remodelling.

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