Effects of H 2 S-donor ascorbic acid derivative and ischemia/reperfusion-induced injury in isolated rat hearts

• Published in: European journal of pharmaceutical sciences 2024-04, Vol.195, p.106721
• Main Authors: Tánczos, Bence, Vass, Virág, Szabó, Erzsébet, Lovas, Miklós, Kattoub, Rasha Ghanem, Bereczki, Ilona, Borbás, Anikó, Herczegh, Pál, Tósaki, Árpád
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Antioxidants - pharmacology; Ascorbic Acid - pharmacology; Ascorbic Acid - therapeutic use; Hydrogen Sulfide - metabolism; Hydrogen Sulfide - pharmacology; Hydrogen Sulfide - therapeutic use; Ischemia; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - metabolism; Rats; Rats, Wistar; Reperfusion; Water
• ISSN: 1879-0720
• DOI: 10.1016/j.ejps.2024.106721

Hydrogen sulfide (H S), a gasotransmitter, plays a crucial role in vasorelaxation, anti-inflammatory processes and mitigating myocardial ischemia/reperfusion-induced injury by regulating various signaling processes. We designed a water soluble H S-releasing ascorbic acid derivative, BM-164, to combine the beneficial cardiovascular and anti-inflammatory effects of H S with the excellent water solubility and antioxidant properties of ascorbic acid. DPPH antioxidant assay revealed that the antioxidant activity of BM-164 in the presence of a myocardial tissue homogenate (extract) increased continuously over the 120 min test interval due to the continuous release of H S from BM-164. The cytotoxicity of BM-164 was tested by MTT assay on H9c2 cells, which resulted in no cytotoxic effect at concentrations of 10 to 30 μM. The possible beneficial effects of BM-164 (30 µM) was examined in isolated 'Langendorff' rat hearts. The incidence of ventricular fibrillation (VF) was significantly reduced from its control value of 79 % to 31 % in the BM-164 treated group, and the infarct size was also diminished from the control value of 28 % to 14 % in the BM-164 treated group. However, coronary flow (CF) and heart rate (HR) values in the BM-164 treated group did not show significantly different levels in comparison with the drug-free control, although a non-significant recovery in both CF and HR was observed at each time point. We attempted to reveal the mechanism of action of BM-164, focusing on the processes of autophagy and apoptosis. The expression of key autophagic and apoptotic markers in isolated rat hearts were detected by Western blot analysis. All the examined autophagy-related proteins showed increased expression levels in the BM-164 treated group in comparison to the drug-free control and/or ascorbic acid treated groups, while the changes in the expression of apoptotic markers were not obvious. In conclusion, the designed water soluble H S releasing ascorbic acid derivative, BM-164, showed better cardiac protection against ischemia/reperfusion-induced injury compared to the untreated and ascorbic acid treated hearts, respectively.