International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H₂S Levels: H₂S Donors and H₂S Biosynthesis Inhibitors

Abstract

Over the last decade, hydrogen sulfide (HS) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, HS is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. HS levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of HS, either based on HS donation or inhibition of HS biosynthesis. HS donation can be achieved through the inhalation of HS gas and/or the parenteral or enteral administration of so-called fast-releasing HS donors (salts of HS such as NaHS and NaS) or slow-releasing HS donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated HS release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with HS-donating groups (the most advanced compound in clinical trials is ATB-346, an HS-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of HS synthesis, there are now several small molecule compounds targeting each of the three HS-producing enzymes cystathionine--synthase (CBS), cystathionine--lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous HS production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known HS donors and HS biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.

Extended hypoxia‐mediated H2S production provides for long‐term oxygen sensing

“…In no instance was H 2 S production completely inhibited. This could be attributed to poor absorption by cells or lack of inhibitor specificity . It is also possible that H 2 S may be produced by one or several other “unconventional” pathways that are unaffected by these inhibitors and are independent of Cys.…”

Possible role of hydrogen sulfide as an endogenous relaxation factor in the rat bladder and prostate

“…In addition, intravesically instilled NaHS at 1 mM increased the frequency of micturition and reduced voiding volume in Sprague‐Dawley rats, while GYY4137, a slow‐releasing H 2 S donor, at a submicromolar order prolonged ICI and tended to reduce MVP in Wistar rats in this study. In general, responses induced by gasotransmitters are highly dependent on the dose, the physiological response at lower doses and the toxic effect at higher doses, and fatal effects of H 2 S occur at approximately 0.1% (=29 mM) . Therefore, NaHS‐induced contraction in vitro and in vivo might indicate a toxic effect of H 2 S on the bladder.…”

“…A limitation of this study is that effects of H 2 S biosynthesis inhibition or H 2 S scavenging on bladder and prostate contractility were not investigated. Some compounds are reported to inhibit CBS, CSE, or MPST, and in human urothelium, carbachol‐induced enhancement of H 2 S production was attenuated by a “CBS inhibitor.” However, these compounds have limitations, low potency and non‐selectivity . In addition, to our knowledge, there is nor report demonstrating selective H 2 S scavengers.…”

“…After a 30 min‐washout period, prostate strips were pre‐treated with propranolol (1 × 10 −6 M) to prevent β‐adrenoceptor‐mediated relaxation. The relaxation response to NaHS (a rapid‐releasing H 2 S donor: 1 × 10 −9 to 3 × 10 −4 M) was measured cumulatively in bladder strips pre‐contracted by carbachol (1 × 10 −5 M) and prostate strips pre‐contracted by noradrenaline (1 × 10 −5 M). NaHS solutions were quickly prepared before use.…”

“…Cystometry was performed under urethane anesthesia (0.8 g/kg, ip) according to previous reports . Saline was intravesically instilled (2.4 mL/h) in all animals until 4‐5 voidings were detected, and then ether GYY4137 (a slow‐releasing H 2 S donor: 10 −8 , 10 −7 , and 10 −6 M in saline) or vehicle (3.3 × 10 −5 % N , N ‐dimethylformamide/saline) was instilled (2.4 mL/h). In the GYY4137‐treated group, after detecting 4‐5 voidings, the dose was increased in turn, and a total of 12‐15 voidings were recorded after starting GYY4137 instillation.…”