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As a novel hydrogen sulfide-modulated agent, S-propargyl-L-cysteine (SPRC) is proven to be a potent cardioprotective candidate. Bioavailability and pharmacokinetics of SPRC (20 mg/kg) in beagle dogs after oral and intravenous administrations were investigated in this study. Plasma concentrations of SPRC were measured by a LC-MS/MS method. Intravenous administration of SPRC (single dose) to beagle dogs gave a mean plasma half-life of 14.7 h, mean clearance of 0.4 ml min⁻¹ kg⁻¹ and mean apparent volume of distribution of 0.56 L/kg. Single oral administration was completely, fast absorbed (T(max)= 0.33 ± 0.20 h) with a mean absolute availability of 112% and mean plasma half-life of 16.5 h. Multiple oral administration (once daily for 10 consecutive days) of SPRC to dogs resulted in steady state plasma drug concentration being reached after seven doses and didn't cause obvious accumulation. No significant difference was found between the single and multiple pharmacokinetic parameters.

A simple, fast and sensitive mixed-mode reversed-phase and cation-exchange HPLC-MS/MS method for the quantification of S-propargyl-cysteine (SPRC), a novel cardioprotective agent, has been developed and validated for preclinical studies. Chromatographic separation of SPRC and its internal standard (IS) was performed using a commercial analytical column which contained both C18 bonded silica particles and sulfonic acid cation-exchange particles. The optimized mobile phase was composed of acetonitrile/ammonium acetate buffer (10mM, pH 4): 30/70 (v/v). Quantification was conducted by multiple reaction monitoring (MRM) of the transitions of m/z 160.0 → 143.0 for SPRC and 178.1 → 160.9 for S-butyl-cysteine (IS). The assay utilized methanol to achieve a simple and fast deproteinization. The lower limit of quantification (LLOQ) was 0.6 μg/mL (diluted with 50-fold of methanol) using 20 μL rat plasma. The assay was linear over a range from 0.6 to 159 μg/mL, with intra- and inter-batch accuracy (as relative error) less than ± 5% and precision (as relative standard deviation) less than 10%. Using the validated assay, the pharmacokinetic properties of SPRC in rats were investigated. SPRC exhibits linear pharmacokinetics after oral or intravenous administration in rats. The bioavailability after oral administration at 25, 75, and 225 mg/kg was 96.6%, 97.0%, and 94.7%, respectively., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Leonurine, an alkaloid typically found in Herba leonuri, is known to have both antioxidant and cardioprotective properties. In the present study, we investigated the cardioprotective mechanism of leonurine the in vivo rat model of chronic myocardial ischemia and in vitro H9c2 cardiac myocyte model of oxidative stress. Myocardial ischemia was induced by ligating the left anterior descending coronary artery. Rats were divided into sham, myocardial ischemia+saline, and myocardial ischemia+leonurine (15 mg/kg/day). Cardiac function was recorded by catheterization. Apoptosis-related factor vascular endothelial growth factor (VEGF), survivin, Bcl-2 and Bax and pro-survival signaling pathways Akt, hypoxia inducible factor (HIF)-1α were measured by Western blotting or RT-PCR. Our results showed leonurine significantly improved myocardial function as evidenced by the decreased left ventricle end-diastolic pressure and the increased +dP/dt. Interestingly, leonurine increased the phosphorylation of Akt, the protein and gene expression of Bcl-2, but it reduced the protein and gene expression of Bax in vivo. Meanwhile leonurine significantly increased Akt phosphorylation in a concentration-dependent manner in H9c2 cardiac myocyte induced by oxidative stress in vitro, which was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Furthermore, leonurine not only increased the expression of HIF-1α but also the expression of survivin and VEGF. The results of present study demonstrated, for the first time that leonurine has potent anti-apoptotic effects after chronic myocardial ischemia mediated by activating the PI3K/Akt signaling pathway. Angiogenic mechanisms may be partially responsible for such an effect, which needs to be studied further., (Copyright © 2010 Elsevier B.V. All rights reserved.)

3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (ZYZ451) was found to be an excellent cardio-protective agent in the previous research in our lab. However, its potent therapeutic effects on myocardial infarction and the underlying mechanism remain elusive. In the present study, we demonstrate that ZYZ451 protects neonatal rat ventricular cardiomyocytes (NRVCs) from hypoxia-induced apoptosis via increasing manganese-containing superoxide dismutase (MnSOD) activity and inhibiting mitochondrial reactive oxidative species (mitoROS) production. MnSOD knockdown impairs the anti-apoptotic effects of ZYZ451. We report here for the first time that signal transducer and activator of transcription 3 (STAT3), an important nuclear transcriptional factor also identified in mitochondria, co-localizes with MnSOD and interacts with it, as determined by using methods of co-immunofluorescence and co-immunoprecipitation. Knockdown of STAT3 rather than inhibition of STAT3 phosphorylation results in a significant reduction in MnSOD activity. Furthermore, interaction between MnSOD and STAT3 is diminished in STAT3 deficient H 9 C 2 cells. Its novel subcellular localization and interaction with MnSOD suggest that STAT3 may be involved in regulation of MnSOD activity beyond its transcriptional potential. Consistent with the results in vitro, ZYZ451 reduces myocardial infarct size as well as cardiomyocytes apoptosis, inhibits lactate dehydrogenase (LDH) and malondialchehyche (MDA) release, and restores MnSOD activity in peri-infarct hearts. These benefits appear to be attributed to the enhanced interaction between STAT3 and MnSOD. These findings shed a light on a new role of STAT3 in oxidative stress and suggest that ZYZ451 is likely an effective cardio-protective agent. [ABSTRACT FROM AUTHOR]

Abstract: Leonurine possesses cardioprotective effects in myocardial ischemia due to its anti-apoptotic properties. However, the process to isolate and purify leonurine is difficult, because of its low content in the Herb Leonuri and its impurity. Moreover, the high dosage used indicates low potency of leonurine. To overcome these defects, we had synthesized a novel twin drug of leonurine, 3,5-dimethoxy-4-(3-(2-carbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (compound 2). In this paper, we focused on investigating the cardioprotective effect and underlying mechanisms of compound 2. Our data showed that cell viability was significantly increased in a dose-dependent manner and the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were also significantly attenuated in the compound 2-treated group. In addition, we observed the cardioprotective effects by Hoechst 33258 nucleus staining, JC-1 staining, Annexin V-FITC/PI staining and transmission electron microscopy. Compound 2 inhibited apoptosis by reducing the ratio of Bcl-2/Bax, decreasing cleaved-caspase-3 expression and enhancing the phosphorylation of Akt. Furthermore, the phosphorylation effect of compound 2 was reversed by LY294002 the phosphatidylinositol-3-kinase (PI3K) inhibitor from happening. We concluded that compound 2 played a cardioprotective role in hypoxia-induced primary cardiac myocytes apoptosis partly via modulating the PI3K/Akt pathway at a 10-fold lower concentration than leonurine. [Copyright &y& Elsevier]

Background: Heart failure (HF) is one of the most serious health issues in both developed and developing countries that causes millions of people suffering. In recent years, as a significant endogenous gasotransmitter, hydrogen sulfide has been reported to play vital roles on cardiovascular system. S-Propargyl-cysteine (SPRC), a novel endogenous hydrogen sulfide donor, is proved to mediate the formation of hydrogen sulfide to inhibit myocardial apoptosis and reduce oxidative stress to protect against acute myocardial ischemia. In order to produce more stable and sustaining hydrogen sulfide, we modified the dosage form to get SPRC controlled release formulation (SPRC (RS)). In this work, we elucidated the possible cardioprotective effects of this formulation on HF rats and investigated the involved mechanisms on apoptosis and oxidation. Methods: Left coronary artery was occluded to induce HF model of rat. The survival rats were then divided into 7 groups (Sham, Model, SPRC, SPRC (RS), SPRC (RS)+PAG, PAG and Digoxin) after 24h and treated with drugs for 6weeks. Echocardiographic indexes including LV, LVID, LVPW, LVAW, EF and FS were recorded to determine the cardiac function. TTC staining was performed to determine the infarct size. Plasmatic level of hydrogen sulfide was detected by modified sulfide electrode. The enzymatic activities of SOD, CK, CAT and GSH were determined by colorimetry. The proteins extracted from myocardial tissues were determined by Western blot. Results: The cardioprotective effects of SPRC (RS) on HF rats were confirmed by significant reduction of infarct size and improvement of cardiac function, with better effects than normal SPRC. LVAW, LVPW, FS and EF were elevated in SPRC (RS)-treated group compared with model group, while LV and LVID decreased. SPRC (RS) modulated antioxidant defenses in HF rats by preserving plasmatic levels of GSH, CAT and SOD and reducing CK leakage from cells. In addition, SPRC (RS) was shown to increase protein expression of Bcl-2 and decrease protein expression of Bax, caspase-3 and caspase-9 in infarct area to protect against myocardial apoptosis. Furthermore, SPRC (RS) promoted protein expression of CSE, then elevated plasmatic concentration of hydrogen sulfide. These effects of SPRC (RS) could be abolished by PAG, an inhibitor of CSE. Conclusion: All experiment data indicated the SPRC controlled release formulation played a cardioprotective role on chronic heart failure after myocardial infarction, which was confirmed by improved cardiac function, decreased myocardial apoptosis and preserved oxidative stress. Endogenous hydrogen sulfide was partly involved in these protective effects of SPRC (RS). More important, SPRC (RS) exerted better effects than normal SPRC from all sides, that providing a new perspective on hydrogen sulfide-mediated drug therapy. [Copyright &y& Elsevier]