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Journal of Ocular Pharmacology and Therapeutics logoLink to Journal of Ocular Pharmacology and Therapeutics
. 2018 Mar 1;34(1-2):61–69. doi: 10.1089/jop.2017.0077

Regulation of Aqueous Humor Dynamics by Hydrogen Sulfide: Potential Role in Glaucoma Pharmacotherapy

Sunny E Ohia 1,✉, Jenaye Robinson 1, Leah Mitchell 1, Kalu K Ngele 2, Segewkal Heruye 3, Catherine A Opere 3, Ya Fatou Njie-Mbye 1
PMCID: PMC5963637  PMID: 29215951

Abstract

Hydrogen sulfide (H2S) is a gaseous transmitter with well-known biological actions in a wide variety of tissues and organs. The potential involvement of this gas in physiological and pathological processes in the eye has led to several in vitro, ex vivo, and in vivo studies to understand its pharmacological role in some mammalian species. Evidence from literature demonstrates that 4 enzymes responsible for the biosynthesis of this gas (cystathionine β-synthase, CBS; cystathionine γ-lyase, CSE; 3-mercaptopyruvate sulfurtransferase, 3MST; and d-amino acid oxidase) are present in the cornea, iris, ciliary body, lens, and retina. Studies of the pharmacological actions of H2S (using several compounds as fast- and slow-releasing gas donors) on anterior uveal tissues reveal an effect on sympathetic neurotransmission and the ability of the gas to relax precontracted iris and ocular vascular smooth muscles, responses that were blocked by inhibitors of CSE, CBS, and KATP channels. In the retina, there is evidence that H2S can inhibit excitatory amino acid neurotransmission and can also protect this tissue from a wide variety of insults. Furthermore, exogenous application of H2S-releasing compounds was reported to increase aqueous humor outflow facility in an ex vivo model of the porcine ocular anterior segment and lowered intraocular pressure (IOP) in both normotensive and glaucomatous rabbits. Taken together, the finding that H2S-releasing compounds can lower IOP and can serve a neuroprotective role in the retina suggests that H2S prodrugs could be used as tools or therapeutic agents in diseases such as glaucoma.

Keywords: : hydrogen sulfide, neurotransmitters, neuroprotection, aqueous humor dynamics

Introduction

For centuries Hydrogen sulfide (H2S), was known as a toxic gas with deleterious consequences for the environment and animals. In animal models, acute exposure to high concentrations of H2S was reported to alter neuronal activity through an action on calcium channels.1,2 In humans, victims of H2S poisoning have problems with coordination, memory loss, and other psychiatric disorders.2 Warenycia et al.3 found that exposure of rats to H2S by inhalation or through intraperitoneal injections of the H2S releasing compound, sodium hydrosulfide (NaHS), caused a dose-dependent increase in the concentration of this gas in the brain. Interestingly, these workers measured basal levels of H2S in both rat and postmortem human brains suggesting an endogenous source of this gas in mammals.3,4 Although enzymes involved in the metabolism of H2S in mammalian tissues were characterized earlier,5,6 it was assumed that this gas was a by-product of metabolic pathways or a marker of activities of some enzymes. The possible role of H2S as an endogenous neuromodulator was first described by Abe and Kimura.7 These investigators found that H2S can facilitate long-term potentiation by enhancing the activity of N-methyl-d-aspartate (NMDA) receptors and that cystathionine β-synthase (CBS) can synthesize this gas in the brain.7 It was subsequently reported by Snyder and colleagues8 that a H2S produced its biological action by adding sulfur to cysteine residues of target proteins, a process known as sulfhydration.8,9

The discovery of enzymes responsible for the biosynthesis of this gas from cysteine and homocysteine and the presence of transsulfuration pathways in mammals supports a biological role for H2S as a multifunctional signaling molecule with important regulatory roles in processes such as learning and memory, modulation of synaptic activities, inflammation, and in the maintenance of vascular tone.10 Furthermore, H2S has been shown to protect various organs and tissues such as heart, kidney, brain, and retina from ischemic, hypoxic, oxidative, and hyperglycemic insults.11–15 Recently, H2S was hypothesized to play a major role in aging and aging-related pathologies16,17 and was reported to play a role in erectile responses to NaHS and Na2S.18 There is evidence that H2S can utilize different signal transduction pathways in eliciting its physiological and pharmacological actions. For example, H2S-releasing compounds have been reported to relax vascular smooth muscle by stimulating ATP-sensitive K+ channels (KATP); they can promote angiogenesis and vascular remodeling through phosphatidylinositol 3-kinase/Akt/surviving axis in endothelial cells; they can stimulate long-term synaptic potentiation by enhancing the activity of NMDA receptors through the cyclic AMP/protein kinase A pathway; and they can downregulate pro-inflammatory genes involved in cardiac ischemic/reperfusion injury by preventing the translocation of nuclear factor-κB.19–21 In addition to KATP channels, H2S-releasing compounds have been reported to interact with calcium channels, chloride channels, sodium channels, transient receptor ankyrin 1(TRPA1), and transient receptor vanilloid channels.22–24

Apart from H2S, hydrogen polysulfide (H2Sn) compounds that contain a higher concentration of sulfur atoms than H2S have been reported to act as potential signaling molecules with pharmacological activity at TRPA1 channels,25,26 regulation of the activity of a tumor suppressor, phosphatase, and tensin homolog,27 facilitation of the translocation of Nrf2 to the nucleus for upregulation of transcription of antioxidant genes,28 and in the relaxation of vascular smooth muscle by an action on protein kinase G1α.29 It appears that the ability of H2Sn to modify these processes is based on their possession of 2 sensitive cysteine residues at active sites (either of which can be sulfureted by H2Sn) to generate a cysteine disulfide bond by reacting with each other.30 It is pertinent to note that the potential pharmacological actions of H2Sn in ocular tissues are yet to be determined.

Biosynthesis of Hydrogen Sulfide

The biosynthesis of H2S occurs through 4 major pathways involving amino acids: 3 from l-cysteine and 1 from d-cysteine.30 The two pyridoxal-5′-phosphate-dependent enzymes found in the cytosol, cystathionine β-synthase (CBS), and cystathionine γ-lyase (CSE) convert l-cysteine, along with l-homocysteine into H2S.6,7,31,32 A third enzyme cysteine aminotransferase converts l-cysteine, along with α-ketoglutarate to 3-mercaptopyruvate, which is then further metabolized by 3-mercaptopyruvate sulfur transferase (3MST) to H2S in the presence of thioredoxin.6,33–38 A fourth enzyme, d-amino acid oxidase (DAO) converts d-cysteine to achiral 3-mercaptopyruvate, which is then metabolized to H2S by 3MST.39,40 3MST is found in the mitochondria, whereas DAO is present in peroxisomes.41 The regulation of H2S concentrations in mammalian tissues appears to depend upon the balance between its production and clearance.42–44

In the eye, the 4 enzymes responsible for the biosynthesis of H2S (CBS, CSE, 3MST, and DAO) have been localized in tissues such as the cornea, iris, ciliary body, lens, and retina.11,45–53 The reported expression of CBS and CSE enzymes in ocular tissues46,47 correlated with the endogenous production of H2S in these tissues.54 Kulkarni et al.54 found that inhibitors of CBS (propargylglycine) and CSE (aminooxyacetic acid) attenuated, while the activator of CBS (S-adenosyl-l-methionine) enhanced endogenous production of H2S in the retina. In summary, the presence of the 4 enzymes of the transsulfuration pathway in the eyes suggests that H2S may play a vital role in the pathophysiology of ocular diseases.

Pharmacological Actions of Hydrogen Sulfide in Ocular Tissues

Due to the inherent difficulties of working with H2S as a gas, the pharmacological actions of H2S are studied using donor molecules or gas-releasing compounds, which include inorganic sulfide salts, synthetic organic slow-releasing H2S donors, H2S-releasing nonsteroidal anti-inflammatory drugs, cysteine analogs, nucleoside phosphorothioates, and plant-derived polysulfide contained in garlic.55,56

Anterior uveal tissues

Experimental studies on the pharmacological actions of H2S (using several compounds as fast- and slow-releasing gas donors) on the anterior uvea (Table 1) have focused on the regulation of sympathetic neurotransmission and their direct effects on iris muscle tone. Furthermore, the pharmacological effects of H2S-releasing compounds have also been studied on aqueous humor (AH) outflow facility in a porcine anterior segment model, ex vivo. Since the autonomic nervous system plays an important role in the regulation of AH dynamics,57 Kulkarni et al.58 studied the pharmacological actions of H2S (using sodium hydrosulfide, NaHS, and Na2S as donors) on sympathetic neurotransmission in the anterior uvea.58,59 In porcine isolated iris-ciliary bodies, release of radiolabeled norepinephrine ([3H]NE) triggered by electrical field stimulation was reduced by both NaHS and Na2S in a concentration-dependent manner.58 The inhibitors of CSE (propargylglycine) and CBS (aminooxyacetic acid) antagonized the inhibitory action of the H2S donors on NE release. Furthermore, both H2S donors elicited a concentration-dependent decrease in NE and epinephrine content in the iris-ciliary bodies. Kulkarni et al.58 concluded that H2S donors can block sympathetic neurotransmission in the porcine anterior uvea, an action that was dependent, at least in part, on the intramural biosynthesis of this gas and a direct action of H2S on neurotransmitter pools.58 Recently, Salvi et al.59 investigated the pharmacological actions of different sources of H2S on sympathetic neurotransmission in the bovine isolated iris-ciliary bodies: ACS67, a hybrid of latanoprost and a H2S donating moiety; l-cysteine, a substrate for endogenous production of H2S; and GYY4137, a slow donor of H2S. All 3 donors caused a concentration-dependent attenuation of [3H]NE release evoked by electrical field stimulation, a response that was antagonized by an inhibitor of CBS, aminooxyacetic acid, and glibenclamide (a KATP channel blocker). Interestingly, flurbiprofen (a cyclooxygenase inhibitor) enhanced the inhibitory effect of ACS67 and l-cysteine on stimulated NE release. Taken together, Salvi et al.59 concluded that the ability of H2S donors to reduce sympathetic neurotransmission in bovine anterior uvea was partially dependent upon the intramural production of this gas and prostanoids and was mediated by an action on KATP channels. It is pertinent to note that reduced sympathetic neurotransmission in the anterior uvea could have an indirect action on vascular tone and blood flow to ciliary body. Indeed, there is evidence of a relationship between the activity level of sympathetic nerves, choroidal blood flow, and intraocular pressure (IOP) in experimental animals.60–63 Furthermore, autonomic regulation of blood vessels of the ciliary body and ciliary epithelium has been reported to play a major role in the formation of AH, while such regulatory process in the trabecular meshwork and episcleral blood vessels is associated with AH outflow.57 Clearly, the finding that H2S-releasing compounds can alter sympathetic neurotransmission indicates that this gas is capable of eliciting an indirect action on AH dynamics.

Table 1.

Anterior Uvea

Tissue Pharmacological effect Mechanism of action References
Iris-ciliary body Inhibition of sympathetic neurotransmission in bovine and porcine iris-ciliary bodies (NaHS, Na2S, ACS67, GYY4137) Endogenous biosynthesis of H2S; biosynthesis of prostaglandins; activation of KATP channels. 58,59
  Decrease in norepinephrine and epinephrine content in porcine iris-ciliary bodies (Na2S, NaHS) Endogenous biosynthesis of H2S 58
Iris Relaxation of induced tone in porcine irides (NaHS, Na2S, l-cysteine) Endogenous biosynthesis of H2S; biosynthesis of prostaglandins; activation of KATP channels. 60,61
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A summary of the pharmacological effects and potential mechanism/s of action of hydrogen sulfide-releasing compounds in the anterior uvea.

A possible direct action of H2S donors on isolated porcine iris smooth muscle was studied by Monjok et al.64 and Ohia et al.65 In the presence of tone induced by muscarinic receptor stimulation, both NaHS and Na2S elicited a concentration-dependent relaxation porcine isolated irides, a response that was blocked by inhibitors of CSE (propargylglycine and β-cyanoalanine) and CBS (aminooxyacetic acid and hydroxylamine) and a blocker to KATP channels (glibenclamide) but enhanced by S-adenosylmethionine, an activator of CBS.64 These workers also found that while endogenously generated prostanoids were involved in the inhibitory action of H2S donors, nitric oxide (NO) was not a mediator of this response. Monjok et al.64 concluded that relaxations induced by H2S donors in porcine irides were partially due to intramural generation of the gas and by an effect on KATP channels. In a related study, the pharmacological actions of l-cysteine, a substrate for the biosynthesis of H2S was examined under the presence of tone induced by muscarinic receptor activation in porcine irides.65 l-Cysteine produced a concentration-related relaxation of tone that was inhibited by aminooxyacetic acid, propargylglycine, and glibenclamide but enhanced by flurbiprofen, a cyclooxygenase inhibitor, indicating that the response induced by the H2S substrate was dependent upon the endogenous biosynthesis of this gas and prostanoids. Furthermore, the relaxation elicited by l-cysteine was mediated by KATP channels.65 While the observed direct pharmacological actions of H2S-releasing compounds on iris muscle tone are interesting, its relevance in regulation of AH dynamics is unclear and merits further investigation.

A study to investigate the possible direct pharmacological effects of H2S-releasing compounds on pathways involved in AH outflow was reported in an ex vivo model. The pharmacological actions of H2S-releasing compounds on AH dynamics in whole animals are discussed in the appropriate section below (Pharmacological Actions of Hydrogen Sulfide on AH Dynamics). To determine whether H2S donors can alter AH dynamics, Robinson et al.66 studied the pharmacological actions of NaHS and the H2S substrate, l-cysteine, on AH outflow facility on porcine ocular anterior segment model, ex vivo. Both compounds elicited a concentration-dependent increase in AH outflow facility, an effect that was antagonized by aminooxyacetic acid, glibenclamide, and SQ22536 (an inhibitor of adenylyl cyclase). Morphological studies of the effect of l-cysteine on the architecture of the trabecular meshwork did not reveal any significant anatomical changes compared to controls. These findings led Robinson et al.66 to conclude that the stimulatory effects of these compounds on AH outflow facility are mediated, at least in part, by endogenously produced H2S, KATP channels, and adenylyl cyclase. Interestingly, the observation that increases in AH outflow facility induced by NaHS and l-cysteine can be blocked by an inhibitor of adenylyl cyclase is noteworthy based on the fact that this nucleotide has been implicated in the overall regulation of AH dynamics.67 The perfused ocular anterior segment model preserves the architecture of the outflow pathway and has been used extensively in ex vivo studies of the pharmacological actions of drugs on AH dynamics.68–70 Clearly, the increase in outflow facility induced by H2S-releasing compounds suggests that an effect on conventional outflow channels could underlie, at least in part, a mechanism of IOP-lowering action of this gas in mammals.

Ocular vasculature

In the eye, the pharmacological actions of H2S (using several compounds as fast- and slow-releasing gas donors) have been reported in the posterior ciliary artery, the ophthalmic artery, and the retinal artery (Table 2). Ocular blood flow has been shown to be regulated directly through autonomic influences on the vasculature of the optic nerve head, choroid, ciliary body, and iris, as well as through indirect autonomic influences on retinal blood flow.57 The first biological activity ascribed to H2S was its relaxant action on the vasculature.71 After publication of the report by Hosoki et al.,71 other workers have provided evidence for the involvement of this gas in the pathophysiology of vascular smooth muscles and the endothelium.72–74 In the eye, Chitnis et al.75 were the first investigators to describe the pharmacological actions of H2S donors on vascular tone in the bovine isolated long posterior ciliary artery.75 Both NaHS (a fast-releasing H2S donor) and GYY4137 (a slow-releasing H2S donor) caused a concentration-dependent relaxation of phenylephrine-induced tone in the long posterior ciliary artery. Relaxations elicited by GYY4137 were blocked by aminooxyacetic acid, propargylglycine, and glibenclamide but enhanced by flurbiprofen suggesting that endogenously produced H2S, prostanoids, and KATP channels were involved in the observed response. Chitnis et al.75 also reported that N(ω)-nitro-l-arginine methyl ester (L-NAME) had no effect on relaxations evoked by GYY4137 indicating that NO did not mediate responses of the bovine long posterior ciliary artery to the slow-releasing H2S donor. In the rabbit isolated ophthalmic artery, Salomone et al.76 found that carbon monoxide and NO can synergize to induce relaxations of phenylephrine-induced tone and that H2S released by GYY4137 counteracted the effects produced by endogenous NO. It is pertinent to note that the concentrations of GYY4137 utilized by Salomone et al.76 in their studies with the rabbit ophthalmic artery were higher than those reported to elicit relaxations of the bovine long posterior ciliary artery.75 In a subsequent study, Kulkarni-Chitnis et al.77 examined the pharmacological actions of 2 novel slow-releasing H2S donors, (4-methoxyphenyl)pyrrolidin-1-ylphosphinodithioc acid (AP67) and (4-methoxyphenyl)piperidin-1-ylphosphinodithioc acid (AP72), on bovine isolated long posterior ciliary arteries.77 Both AP67 and AP72 caused a concentration-related relaxation of phenylephrine-induced tone, a response that was blocked by aminooxyacetic acid, propargylglycine, L-NAME, glibenclamide, and flurbiprofen (AP67 only). Kulkarni-Chitnis et al.77 concluded that the inhibitory action of novel slow-releasing H2S donors on isolated bovine long posterior ciliary arteries was dependent upon the endogenous production of H2S and that it could involve products of the NO pathways and activity of KATP channels. It is of interest to note that in comparison with AP67 and AP72, GYY4137 did not interact with the NO pathway indicating that differences exist in the mechanism of action of these compounds on vascular tone in the bovine long posterior ciliary arteries. In bovine retinal arteries, Takir et al.78 found that relaxations of PGF2α- and potassium-induced tone elicited by NaHS were blocked by inhibitors of voltage-dependent potassium channels and inwardly rectifying potassium channels suggesting that H2S could play a major role in the regulation of retinal arterial tone through an action on these channels. In endothelin precontracted porcine retinal arterioles, Winther et al.79 demonstrated that both GYY4137 and NaHS evoked concentration-dependent relaxations that were consistent with reports from other investigators.75,78 Interestingly, inhibitors of H2S biosynthetic enzymes, aminooxyacetic acid and propargylglycine, enhanced the endothelin contractions, a response that was more pronounced in hypoxic (1% O2) conditions. These findings led Winther et al.79 to conclude that the presence of perivascular retina and hypoxia reduces arteriolar vasoconstriction and that endogenously produced H2S plays an important role in the regulation of arteriolar tone.79 Apart from ocular vasculature, the ability of H2S donors to relax other vascular beds has been well documented.74,80,81 The observed ability of H2S-releasing compounds in altering vascular tone in posterior ciliary, ophthalmic, and retinal arteries is of pharmacological importance because of the role of these blood vessels in the regulation of AH dynamics and other visual processes in the eye.57

Table 2.

Ocular Vasculature

Tissue Pharmacological effect Mechanism of action References
Posterior ciliary artery Relaxation of induced tone in bovine posterior ciliary arteries (NaHS, GYY4137, AP67, AP72) Endogenous biosynthesis of H2S; biosynthesis of prostaglandins; activation of KATP channels; NO synthesis (AP67 and AP72) 68,70
Relaxation of induced tone in porcine retinal arteries (NaHS and GYY4137) Endogenous biosynthesis of H2S 72
Ophthalmic artery Reversal of NO mediated relaxation of induced tone in rabbit ophthalmic artery (GYY4137)   69
Retinal artery Relaxation of induced tone in bovine retinal arteries (NaHS) Activation of voltage-dependent potassium channels (Kv); activation of inwardly rectifying potassium channels (Kir) 71
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A summary of the pharmacological effects and potential mechanism/s of action of hydrogen sulfide-releasing compounds on the ocular vasculature.

NO, nitric oxide.

Retina

The pharmacological effects of H2S (using several compounds as fast- and slow-releasing gas donors) in the retina have been studied with emphasis on its potential neuroprotective role in this tissue (Table 3). In published reports, effects of H2S-releasing compounds were examined on excitatory amino acid neurotransmission and under conditions of ischemia, oxidative stress, and glutamate excitotoxicity. In 2009, Opere et al.82 studied the pharmacological actions of H2S donors, NaHS and Na2S, on excitatory amino acid transmission [using [3H]d-aspartate as a marker for glutamate] in isolated, superfused bovine and porcine neural retinae. Both H2S donors caused a concentration-dependent inhibition of evoked [3H]d-aspartate release from bovine and porcine tissues, a response that was blocked by propargylglycine indicating a role for endogenously produced H2S in the regulation of amino acid transmission in neural retina from both species.82 Since an increase in retinal glutamate concentrations has been linked to excitotoxicity,83,84 the ability of H2S to reduce glutamate release suggests a potential neuroprotective action of this gas in the retina.23 In both isolated bovine and porcine neural retinae85 and rat retinal pigment epithelial cells (RPE-J),86 NaHS, Na2S, and l-cysteine enhanced cyclic AMP production through mechanisms that were dependent upon the intramural biosynthesis of H2S and an action on KATP channels. In a rat model of ischemia/reperfusion injury, Biermann et al.87 showed that preconditioning of animals with inhalational H2S decreased the death of retinal ganglion cells and reduced caspase-3 activity while elevating HSP-90 expression indicating that the gas mediates antiapoptotic/neuroprotective actions. H2S donors have also been reported to protect the mouse retina from light-induced degeneration through an action on calcium homeostasis.11,88 In rats, Sakamoto et al.,89 showed that NaHS inhibited NMDA induced oxidative damage in the retina affirming a neuroprotective role for H2S in this model. In summary, it appears that H2S can protect the retina from a wide variety of insults, an action that may play an important role in the pathophysiology of ocular diseases such as diabetic retinopathy90and glaucoma.91 A potential neuroprotective action of H2S has also been described in some diseases of the central nervous system such as Stroke, Alzheimer's disease, and Parkinson's Disease.92,93

Table 3.

Retina

Pharmacological effect Mechanism of action References
Inhibition of excitatory amino acid transmission in bovine and porcine neural retina (NaHS, Na2S) Endogenous biosynthesis of H2S 75
Neuroprotection against ischemia, ocular hypertension, oxidative stress, and glutamate excitotoxicity in retinal tissues (ACS, ADTOH, NaHS) Decrease in caspase-3 activity; increase Hsp 90 expression; regulation of calcium homeostasis; ROS scavenging; increase in glutathione production 11,78,81,82,84,91
Increase cyclic AMP production in isolated bovine and porcine neural retinae and rat retinal pigment epithelial cells (NaHS, Na2S, l-cysteine) Endogenous biosynthesis of H2S; activation of KATP channels 79,80
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A summary of the pharmacological effects and potential mechanism/s of action of hydrogen sulfide-releasing compounds in the retina.

Pharmacological Actions of Hydrogen Sulfide on AH Dynamics

Despite the evidence presented above that H2S-releasing compounds can elicit pharmacological effects on various ocular tissues, there are few reports in literature about the ability of H2S-releasing compounds to alter AH dynamics in whole animals (Table 4). Latanoprost, an ester prodrug of PGF2α, has been used for the treatment of glaucoma for more than a decade.94,95 In 2009, Perrino et al.96 reported that ACS67, a H2S-releasing derivative of latanoprost, caused a time-dependent decrease in IOP in glaucomatous pigmented rabbits that was significantly higher than those elicited by latanoprost. Interestingly, these investigators observed that while latanoprost failed to lower IOP in glaucomatous albino rabbits, ACS was effective in reducing IOP by the fourth hour after treatment.96 The increased IOP lowering action of ACS67 was accompanied by a significant increase in glutathione levels in the AH of ACS67-treated rabbits compared to their latanoprost counterparts. Perrino et al.96 then concluded that addition of the H2S releasing moiety enhanced the therapeutic potential of ACS67 and that its ability to affect glutathione levels suggests a potential neuroprotective action of this compound in their animal glaucoma model. In a preliminary report, NaHS was found to lower IOP in normotensive albino rabbits indicating that on its own, H2S can alter AH dynamics.97 In a recent study, Salvi et al.98 compared the IOP lowering activity of GYY4137 with those produced by l-cysteine and ACS67 in normotensive male albino rabbits. All 3 H2S-producing compounds lowered IOP and also caused significant contralateral effects in vehicle-treated control eyes. Salvi et al.98 found that GYY4137 displayed a profile of response that showed a slow onset and a prolonged duration of action compared with l-cysteine and ACS67, a fact that is consistent with its chemical nature as a slow-releasing gas donor. In a new model of chronic ocular hypertension in rats that simulates glaucoma, Huang et al.99 studied the involvement of H2S in both the IOP response and retinal ganglion cell (RGC) survival. These workers showed that retinal H2S levels were markedly decreased when retinal protein expressions of CBS, CSE, and 3MST were downregulated.99 Furthermore, the decrease in retinal H2S concentrations and loss of RGCs were both reversed by prior intraperitoneal injection of animals with NaHS 3 days before the induction of chronic ocular hypertension. Huang et al.99 then concluded that H2S had a protective action against RGC death in a chronic ocular hypertension model, suggesting a role for this gas in retinal neuroprotection. In summary, H2S-releasing compounds are effective in lowering IOP and exerting a neuroprotective action in animal models of glaucoma. Further studies are, therefore, needed to determine if these compounds can elicit the ocular hypotensive action response in primates or humans.

Table 4.

Aqueous Humor Dynamics

Pharmacological effect Mechanism of action References
Time-dependent decrease in IOP in glaucomatous rabbits (ACS67) ? 91
Time- and dose-dependent decrease in IOP in normotensive rabbits (NaHS, l-cysteine, ACS67, and GYY4137) ? 93
Dose-dependent increase in aqueous humor outflow facility (NaHS and l-cysteine) Endogenous biosynthesis of H2S; activation of KATP channels; activation of adenylyl cyclase. 62
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A summary of the pharmacological effects and potential mechanism/s of action of hydrogen sulfide-releasing compounds in the retina.

IOP, intraocular pressure.

Hydrogen Sulfide-Releasing Compounds and Glaucoma Pharmacotherapy

Evidence from the literature discussed above demonstrates that H2S-releasing compounds exert pharmacological action on ocular tissues involved in the regulation of AH dynamics and IOP in experimental animals. Furthermore, these compounds have been reported to have neuroprotective actions in both nonocular and ocular tissues, an additional attribute that may prove useful in the pharmacotherapy of glaucoma. As gaseous molecules, H2S and NO share common traits such as free diffusion across cell membranes and an endogenous enzymatic biosynthetic pathway that can be regulated at several levels. Furthermore, both gases can modulate many physiological processes in the central and peripheral nervous systems.100 In both nonocular and ocular blood vessels, there are reports of interaction between H2S and NO in the regulation of vascular tone.76,101,102 In preclinical and clinical studies, the NO-donating latanoprost has been shown to lower IOP more effectively than latanoprost alone.103,104 The observation that a H2S-releasing derivative of latanoprost can lower IOP in rabbits91 strongly suggests that such a formulation may also find utility in the treatment of glaucoma in humans. Consequently, it is feasible to speculate that a new generation of compounds could be developed whose mechanism of action is associated with the H2S metabolic pathway. Indeed, there is a new focus on the development of H2S prodrugs that can be classified into: plant-derived natural products; hydrolysis-based H2S compounds, and controlled-release compounds.105 It is possible that these H2S prodrugs could serve as tools or therapeutic agents for the therapy of some cardiovascular and neurological diseases of which glaucoma can be added to the list.

Author Disclosure Statement

No competing financial interests exist.

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