| Summary: | Hydrogen sulfide (H2S) has relatively recently been added to a list of endogenously produced gaseous signalling molecules. Our understanding of the science of H2S has advanced rapidly in recent years as exemplified by the fact that within a mere 10 years a range of H2S releasing drugs have already been discovered and some indeed are entering clinical trials. However, the precise biological roles of endogenous H2S are not fully understood. In this respect, slow releasing H2S donors, such as GYY4137, have played a part in elucidating the complex roles of this gas in the body and are also beginning to show promise as possible therapeutics in inflammation - an area in which the function of H2S remains ambiguous. This thesis attempts to provide some additional clarity to the biological significance endogenous H2S. The first part of this work examines the release of endothelial cell derived H2S in vitro and the consequences of knocking out nitric oxide synthase on tissue H2S biosynthesis in mice. As part of this study, I show that the methods currently utilised to measure H2S are insufficiently sensitive/reliable to demonstrate the release of H2S synthesis from endothelial cells in vitro. In addition, data reported herein has demonstrated that knocking out endothelial cell nitric oxide synthase (eNOS) results in a presumably compensatory increase in tissue H2S synthesising activity associated with increased protein levels of the H2S synthesising enzyme, cystathionine-γ-lyase (CSE). The second part of this thesis examines the role of H2S in inflammation and provides further evidence for its anti-inflammatory activity both in vitro and in vivo. In addition, this thesis has shown the ‘added benefit’ of slow-releasing H2S donors (c.f. 3 conventional sulpide salt based donors) in that the H2S released from slow-releasing donors is sustained and does not instantaneously expose cells to potentially cytotoxic amounts of H2S. Identifying a need for additional slow releasing H2S donors attempts were made to examine the H2S releasing ability and antioxidant capacity of a library of additional compounds. As a result of this work, a novel compound, ZJ802 was shown to exhibit more potent antioxidant ability than the currently commercially available H2S donors and was further shown to exhibit anti-inflammatory activity both in vitro and in vivo. Overall, the roles of H2S in physiology are not clear. Current methods to detect H2S are flawed. Thus, the necessity for pharmacological tools, such as slow releasing H2S donors and selective H2S synthesising enzyme inhibitors, cannot be overemphasised. Whilst the possible use of H2S donors in the clinic has been raised there is still a need for more detailed preclinical, pharmacokinetic and long term drug safety and toxicological studies.
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