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The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H 2 S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H 2 S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H 2 S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H 2 S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H 2 S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H 2 S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H 2 S levels and severity of COVID-19. Therefore, repurposing of H 2 S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc., (© 2020 The British Pharmacological Society.)

Background: The vascular endothelium represents a fundamental mechanical and biological barrier for the maintenance of vascular homeostasis along the entire vascular tree. Changes in its integrity are associated to several cardiovascular diseases, including hypertension, atherosclerosis, hyperhomocysteinemia, diabetes, all linked to the peculiar condition named endothelial dysfunction, which is referred to the loss of endothelial physiological functions, comprehending the regulation of vascular relaxation and/or cell redox balance, the inhibition of leukocyte infiltration and the production of NO. Among the endothelium-released vasoactive factors, in the last years hydrogen sulfide has been viewed as one of the main characters involved in the regulation of endothelium functionality, and many studies demonstrated that H2S behaves as a vasoprotective gasotransmitter in those cardiovascular diseases where endothelial dysfunction seems to be the central issue. Aim: The role of hydrogen sulfide in endothelial dysfunction-related cardiovascular diseases is discussed in this review. Key Scientific Concepts: Possible therapeutic approaches using molecules able to release H2S.

The vascular endothelium represents a fundamental mechanical and biological barrier for the maintenance of vascular homeostasis along the entire vascular tree. Changes in its integrity are associated to several cardiovascular diseases, including hypertension, atherosclerosis, hyperhomocysteinemia, diabetes, all linked to the peculiar condition named endothelial dysfunction, which is referred to the loss of endothelial physiological functions, comprehending the regulation of vascular relaxation and/or cell redox balance, the inhibition of leukocyte infiltration and the production of NO. Among the endothelium-released vasoactive factors, in the last years hydrogen sulfide has been viewed as one of the main characters involved in the regulation of endothelium functionality, and many studies demonstrated that H2S behaves as a vasoprotective gasotransmitter in those cardiovascular diseases where endothelial dysfunction seems to be the central issue. The role of hydrogen sulfide in endothelial dysfunction-related cardiovascular diseases is discussed in this review. Possible therapeutic approaches using molecules able to release H 2 S. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic caused by SARS‐Cov‐2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H2S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H2S‐releasing agents have been developed as potential therapeutic tools for diseases related with impaired H2S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H2S in modulating the inflammatory response and pro‐inflammatory cytokine cascade is well recognized, and the usefulness of some H2S‐donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H2S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H2S levels and severity of COVID‐19. Therefore, repurposing of H2S‐releasing drugs may be a potential therapeutic opportunity for treatment of COVID‐19. Linked Articles: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Preservation of vascular wall integrity against degenerative processes associated with ageing, fat-rich diet and metabolic diseases is a timely therapeutical challenge. The loss of endothelial function and integrity leads to cardiovascular diseases and multiorgan inflammation. The protective effects of the H2S-donor erucin, an isothiocyanate purified by Eruca sativa Mill. seeds, were evaluated on human endothelial and vascular smooth muscle cells. In particular, erucin actions were evaluated on cell viability, ROS, caspase 3/7, inflammatory markers levels and the endothelial hyperpermeability in an inflammatory model associated with high glucose concentrations (25 mM, HG). Erucin significantly prevented the HG-induced decrease in cell viability as well as the increase in ROS, caspase 3/7 activation, and TNF-α and IL-6 levels. Similarly, erucin suppressed COX-2 and NF-κB upregulation associated with HG exposure. Erucin also caused a significant inhibition of p22phox subunit expression in endothelial cells. In addition, erucin significantly prevented the HG-induced increase in endothelial permeability as also confirmed by the quantification of the specific markers VE-Cadherin and ZO-1. In conclusion, our results assess anti-inflammatory and antioxidant effects by erucin in vascular cells undergoing HG-induced inflammation and this protection parallels the preservation of endothelial barrier properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]