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Hydrogen sulfide (H 2 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 2 S-releasing ascorbic acid derivative, BM-164, to combine the beneficial cardiovascular and anti-inflammatory effects of H 2 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 2 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 2 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., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hydrogen sulfide (H 2 S) plays an important role in cardiac protection by regulating various redox signalings associated with myocardial ischemia/reperfusion (I/R) induced injury. The goal of the present investigations is the synthesis of a newly designed H 2 S-releasing ibuprofen derivative, BM-88, and its pharmacological characterization regarding the cardioprotective effects in isolated rat hearts. Cytotoxicity of BM-88 was also estimated in H9c2 cells. H 2 S-release was measured by an H 2 S sensor from the coronary perfusate. Increasing concentrations of BM-88 (1.0 to 20.0 µM) were tested in vitro studies. Preadministration of 10 µM BM-88 significantly reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from its drug-free control value of 92% to 12%. However, no clear dose dependent reduction in the incidence of reperfusion-induced VF was observed while different concentrations of BM-88 were used. It was also found that 10 µM BM-88 provided a substantial protection and significantly reduced the infarct size in the ischemic/reperfused myocardium. However, this cardiac protection was not reflected in any significant changes in coronary flow and heart rates. The results support the fact that H 2 S release plays an important role mitigating reperfusion-induced cardiac damage., Competing Interests: Declaration of Competing Interest All the authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

The gasotransmitter hydrogen sulfide (H 2 S) is involved in the regulation of the vascular tone and an impairment of its endogenous production may play a role in hypertension. Thus, the administration of exogenous H 2 S may be a possible novel and effective strategy to control blood pressure. Some natural and synthetic sulfur compounds are suitable H 2 S-donors, exhibiting long-lasting H 2 S release; however, novel H 2 S-releasing agents are needed to improve the pharmacological armamentarium for the treatment of cardiovascular diseases. For this purpose, N-phenylthiourea (PTU) and N,N'-diphenylthiourea (DPTU) compounds have been investigated as potential H 2 S-donors. The thioureas showed long-lasting H 2 S donation in cell free environment and in human aortic smooth muscle cells (HASMCs). In HASMCs, DPTU caused membrane hyperpolarization, mediated by activation of K ATP and Kv7 potassium channels. The thiourea derivatives promoted vasodilation in rat aortic rings, which was abolished by K ATP and Kv7 blockers. The vasorelaxing effects were also observed in angiotensin II-constricted coronary vessels. In conclusion, thiourea represents an original H 2 S-donor functional group, which releases H 2 S with slow and long lasting kinetic, and promotes typical H 2 S-mediated vascular effects. Such a moiety will be extremely useful for developing original cardiovascular drugs and new chemical tools for investigating the pharmacological roles of H 2 S., (Copyright © 2020 Elsevier Ltd. All rights reserved.)