H2S : REVOLUTIONARY SCIENTIFIC MIRACLE AS A GASOTRANSMITTER AT MAXIMUM POTENTIAL IF USED WISELY

ABOUT AUTHORS:
Krishna J. Kathawala¹*, Gaurav L. Ninama¹, Ankitkumar Y. Parikh¹, Krupali V. Upadhyay^2
1A. R. College of Pharmacy & G. H. Patel Institute of Pharmacy B/H. B & B Polytechnic College, Vallabh Vidyanagar - 388 120, Gujarat, India.
²Shree Satsangi Saketdham “Ram Ashram” group of Institution, At. & Post. Vadasma, Tal. & Dist. Mehsana, Gujarat – 382708, India.
*krishna.kathawala@gmail.com

ABSTRACT
Nitric oxide (NO) and Carbon monoxide (CO) are the reputed neurotransmitters involved in the regulation of vascular tone. H₂S, which synthesized from L-cysteine, can play more vital role as Gasotransmitters compare to NO and CO. H₂S have a role as a stimulator of ATP-sensitive potassium channels (KATP-channels) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic β-cells. H₂S also minimize the toxic effect by reacting with reactive oxygen and/or nitrogen species and attenuating their physiological functions. H₂S have a unique feature of not to stimulate soluble guanylate-cyclase like other Gasotransmitters. H₂S plays a critical role in the regulation of vascular tone, neurotransmission, insulin secretion, and myocardial contractility. Recent studies showed that, in various animal models of arterial and pulmonary hypertension, Alzheimer’s disease, gastric mucosal injury and liver cirrhosis had H₂S deficiency which defines the significance of H₂S. Exogenous H₂S alleviates myocardial dysfunction associated with the ischemia/reperfusion injury with reducing the damage of gastric mucosa generated by anti-inflammatory drugs. H₂S had also some drawbacks like every coin has two sides. Excessive production of H₂S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states. Preclinical evidence is provided to show that H₂S releasing derivatives of several NSAIDs, including Diclofenac and Indomethacin indeed represent excellent gastrointestinal safety and are more potent than the parent drugs as anti inflammatory agents. Derivatives of anti-inflammatory drugs other than NSAIDs (e.g. mesalamine) have also been shown to be significantly improved over the parent drug in many respects. So, H₂S can be Revolutionary scientific miracle as a gasotransmitters  at maximum potential if the drawbacks are minimize by cutting edge solution.

REFERENCE ID: PHARMATUTOR-ART-1917

INTRODUCTION
It was a great surprise for scientific community when the endothelium-derived relaxing factor (EDRF) was identified as nitric oxide (NO), a simple inorganic molecule, because all hormones, mediators and neurotransmitters known before were organic compounds [1].

Now there is no doubt that NO plays important regulatory roles in almost all tissues. Soon thereafter, the second inorganic gaseous compound, carbon monoxide (CO), was recognized as an endogenously produced mediator and neurotransmitter. CO is synthesized during the catabolism of heme to biliverdin by heme-oxygenase (HO) [2, 3].

Interestingly, NO and CO share at least one common mechanism of action, i.e. they stimulate soluble guanylate cyclase and increase intracellular CGMP concentration, although CO is a much weaker activator than NO. Recent studies indicate that another “toxic gas”, hydrogen sulfide (H₂S), is also produced in substantial amounts by mammalian tissues and exerts many physiological effects suggesting its potential role as a regulatory mediator. H₂S, the colorless gas with a strong odour of rotten eggs, was known for decades only as a toxic environmental pollutant. The main mechanism of its toxicity is a potent inhibition of mitochondrial cytochrome-c-oxidase. In fact, H₂Sis a more potent inhibitor of mitochondrial respiration than cyanide. Although endogenous hydrogen sulfide was found in the brain at the end of 1980, it was initially suggested to be an artifact since sulfide concentration rapidly increases postmortem in mammalian tissues and may be easily released from so called “sulfane sulfur” (compounds containing sulfur atoms bound only to other sulfur atoms) during tissue preparation [5].  That H₂Smay operate as an endogenous neurotransmitter was first suggested a decade ago by Abe and Kimura, who described the enzymatic mechanism of H₂Sproduction in the brain, its biological effects at physiological concentrations, and its specific cellular targets [6]. Now H₂Sis increasingly recognized as a member of a growing family of “gasotransmitters”, together with its two counterparts, NO and CO [5].

However, much less is known about the physiological role of H2S than about either NO or CO. H2S can be produced from L-cysteine by pyridoxal-5-phosphate dependent enzymes, including cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) [7].

BIOSYNTHESIS OF H₂S:
H₂Sis produced at significant amounts in most tissues. The highest rate of production was noted in the brain, cardiovascular system liver and kidney [8]. The only substrate for the generation of endogenous L-cysteine is a sulfurcontaining amino acid derived from alimentary sources, synthesized from L-methionine through the so-called “trans-sulfuration pathway” with Homocysteine (HCY) as an intermediate, or liberated from endogenous proteins ( Fig.1) [5] .

Fig.1 Homocysteine Trans-sulfuration pathway [5]

There are two major pathways of Cysteine metabolism:
1) Oxidation of thionyl (-SH) group
2) Desulfhydration

REGULATION OF H₂S -PRODUCING ENZYMES:
In the brain, electrical stimulation and excitatory neurotransmitter, glutamate, rapidly increase cystathionine-β-synthase activity in Ca2+/calmodulin-dependent manner [9].

Both N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4 isoxazole propionate (AMPA) glutamate receptors are involved in this effect. Sadenosyl methionine (SAM), an intermediate product of methionine metabolism and a major donor of methyl groups (Fig.1) are an allosteric activator of cystathionine-β- synthase. Sex hormones seem to regulate brain H₂Ssince cystathionine-β-synthase activity and H₂Slevel are higher in male than in female mice and castration of male mice decreases H₂Sformation [10].

A nitric oxide donor, sodium nitroprusside, increases the activity of brain cystathionine-β-synthase in vitro; however, this effect is NO-independent and results from chemical modification of the enzyme’s cysteine groups [11].

In contrast, NO itself may bind to and inactivate the cystathionine-β-synthase. Interestingly, CO is a much more potent cystathionine-β-synthase inhibitor than NO and it is suggested that cystathionine-β-synthase may be one of the molecular targets for CO in the brain. [12, 13]

In homogenates of the rat aorta, NO donors acutely increase Cystathionine-γ -lyase dependent H₂Sgeneration in a cGMP-dependent manner. Moreover, prolonged incubation of cultured vascular smooth muscle cells in the presence of NO donors increases cystathionine-γ-lyase mRNA and protein levels. The physiological significance of NO in the regulation of H₂Sproduction is also supported by the observation that circulating. H₂Slevel as well as cystathionine-γ-lyase gene expression and enzymatic activity in the cardiovascular system are reduced in rats chronically treated with NO-synthase inhibitor. Thus, NO is probably a physiological regulator of H₂Sproduction in the cardiovascular system. [5]

CATABOLISM OF H₂S:
Catabolism of H₂Sis less recognized and most data were obtained by using exogenous H₂S, thus these studies have important toxicological but not necessarily physiological implications. H₂Sis rapidly oxidized, mainly in mitochondria, initially to thiosulfate which is further converted to sulfite and sulfate (Fig. 2). Oxidation of H₂Sto thiosulfate is probably a nonenzymatic process associated with mitochondrial respiratory electron transport, although superoxide dismutase may also catalyze this reaction. [5]

Fig 2.  Catabolism of H₂S[5]

(1) Mitochondrial oxidation, (2) Cytosolic methylation, (3) Binding to hemoglobin.

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THE PHYSIOLOGIC SOURCE OF H₂S:
H₂S is produced from sulfur-containing amino acids, methionine, cysteine and cystine, catalyzed by 2 different enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). [14]

These enzymes are abundantly expressed in various organs: CBS is mainly expressed in the brain, peripheral nervous system, liver and kidney, whereas CSE is mostly found in liver, vascular and nonvascular smooth cells. Moreover, small intestine and stomach express low amounts of CSE. [14]

A second source of H2S is the intestinal flora. Erythrocytes are a third source of H₂S where H₂S is produced from organic polysulfides in a glutathione-dependent manner. Thus, there is ample local production of H₂S enzymatically in arterial vessels both from smooth vascular cells in the arterial walls and nonenzymatically from red blood cells. The enzymatic generation of H₂S may be directly regulated by a number of hormones and other signaling molecules. [14]

The activity of CBS is directly inhibited by two different gaseous signal molecules, NO and CO, and stimulated by bacterial endotoxins. Also glucocorticoids appear to regulate CBS and CSE activity. [14]

MECHANISM OF ACTION OF H2S:
H₂Sis a strong reducing agent. Therefore, it has been suggested that some of its effects may be mediated by protection of protein thiol groups from oxidation.[5] However, all studies performed indicate that effects of H₂Sapplied at physiological concentration are not reproduced or only partially mimicked by thiolprotecting agents, suggesting that this is not a major mechanism of H₂Saction.[5]

In many systems, the effect of H₂Sis mediated by ATP-sensitive potassium channels (KATP-channels). This conclusion is mostly based on the observation that many effects of H₂Sare mimicked by KATP-channel openers such as pinacidil or diazoxide and abolished by their inhibitors (sulfonylurea derivatives) such as glibenclamide. Only in few studies the stimulatory effect of H₂Son KATP-channel was demonstrated directly by measuring KATP-channel current by the Patch-clamp Method. [15, 16] The precise mechanism through which H₂Sstimulates KATP-channels is not clear. [5]

H₂Sis a highly reactive molecule and may easily react with other compounds, especially with reactive oxygen and nitrogen species. It has been demonstrated that

H₂Sreacts with at least four different reactive oxygen species: superoxide radical anion (O₂-), hydrogen peroxide (H₂O₂), peroxynitrite (ONOO–) and hypochlorite (ClO–). All of them are physiologically relevant reactive oxygen species or reactive nitrogen species. Superoxide anion (O^{2 -}) is produced by NADPH-oxidase present in phagocytes as well as by the related nonphagocytic NADP-oxidases expressed in many cell types, in particular in the cardiovascular system and the kidney. [5]

H₂O₂ is produced from O^{2 –} in the reaction catalyzed by superoxide dismutase. Peroxynitrite (ONOO–) is the product of spontaneous reaction between superoxide and NO, whereas hypochlorite (ClO–) is produced from H₂O₂by neutrophil myeloperoxidase (MPO). All these compounds are highly reactive and their interaction with H₂S results in the protection of proteins and lipids from reactive oxygen species or reactive nitrogen species mediated damage. Significance of H₂S reaction with O2 – is ambiguous since the product, sulfite may have toxic and antioxidant properties, most likely depending on its concentration. H₂S also reacts with NO to form a nitrosothiol compound with yet undefined chemical structure. [5]

Interestingly, in contrast to other nitrosothiols (R-S-NO) which are considered to be a reservoir of NO and often mimic its activity, the nitrosothiol originating from H₂S and NO is inactive. It has been suggested that H₂S may scavenge the excess of NO produced in the inflammatory state, but may also limit the availability of NO continuously produced at physiological concentrations. Additional mechanism through which H₂S may exert antioxidant effect involves stimulation of cysteine transport to the cells and enhancement of glutathione synthesis. Moreover, H₂S has been demonstrated to stimulate heme oxygenase expression and CO production, and to have bidirectional effects on the extracellular-signal-regulated kinases (ERK) and inducible NO-synthase. It is unclear if these effects are primary or result from the stimulation of other targets such as KATP-channels. [5]

NERVOUS SYSTEM:
In 1996 Abe and Kimura, first demonstrated high expression of cystathionine-β-synthase in the rat hippocampus and cerebellum and H₂S production by brain homogenates in vitro. [5]

H₂S generation in the brain was blocked by cystathionine-β-synthase but not cystathionine-γ-lyase inhibitors and was markedly reduced in cystathionine-β- synthase deficient mice. [11] The endogenous H₂S by CBS in the brain indicates it hasphysiological functions in the CNS. N-methyl-D-aspartate (NMDA) receptors may beone of its targets. The activation of NMDA receptors is required for the induction ofhippocampal long-term potentiation (LTP), a synaptic model of learning andmemory. Because of the relatively high concentration of endogenous H₂S in thebrain, the physiological concentration of H₂S facilitates the induction of LTP byenhancing NMDA receptor-induced currents. This activation could be blocked by anadenylyl-cyclase specific inhibitor, indicating that the modulation of NMDAreceptors by H₂S is induced by the enhancement of cAMP production. This functionranked H₂S as a neuromodulator in the brain. Another study showed that H₂S couldincrease intracellular Ca2+ and induce Ca2+ waves in neighboring astrocytes.

Therefore, H₂S may mediate signals between neurons and glia and regulate synaptic activity by modulating the activity of both neurons and glia. In addition to its role in signal transduction, H₂S can protect neuron cells from oxidative stress, not only by increasing the levels of antioxidant glutathione, but also by activating the K+ATP channels and Cl– channels. [17]In human cultured neuron cells, H₂S could inhibit peroxynitrite (ONOO–), whichis an important mediator of human neurodegenerative disease, inducing tyrosinenitration, antiproteinase inactivation, cell toxicity, intracellular protein oxidation, and protein nitration. This antioxidant action of H₂S suggests it functions as an endogenous ONOO– scavenger. Oxidative stress is responsible for neuronal damage and degenerates in brain disorders. These observations suggest that H₂S may act as a neuroprotectant against oxidative stress. The concentration of H₂S in the brainchanges with CNS diseases. [17]

H₂S may regulate not only neurocytic but also astrocytic function. Both H₂S and NaHS increase intracellular Ca2+ in primary cultures of rat brain astrocytes, which is achieved largely by Ca2+ influx from the extracellular space and to a lesser extent by its release from the intracellular stores. [18] Unlike in neurons, H₂S production in astrocytes is driven by the cystathionine-γ-lyase and its effect on Ca2+ influx is mediated by cAMP and protein kinase-A. [19]

H₂S may also have some effects in the peripheral nervous system. In particular, accumulating body of evidence suggests that H₂S stimulates the capsaicin-sensitive sensory nerves and evokes the release of tachykinins such as substance P (SP) and neurokinin-A. H₂S induces a concentration-dependent contraction of the rat urinary bladder detrusor muscle. [20] However, this is not a direct effect on the muscle because it was abolished by the combination of neurokinin NK1 and NK2 receptor antagonists as well as by desensitizing afferent sensory nerves by high-dose capsaicin. [5]

The specific mechanism through which H₂S elicits this response is unclear; however, it is abolished by ruthenium red– a nonspecific blocker of transient receptor potential vanilloid receptor-1 (TRPV-1) calcium channel. TRPV-1 is a nonselective cation channel which serves as a nonspecific receptor of sensory terminals for various noxious physical and chemical stimuli. These data suggest that H₂S may stimulate TRPV-1 or a related ion channel in the sensory nerve endings. In addition, Sadenosyl- methionine (SAM) attenuated stress-induced increase in plasma glucocorticoids suggesting that H₂S may be a negative regulator of hypothalamopituitary- adrenal axis. [5]

CARDIOVASCULAR SYSTEM:
While cystathionine-β-synthase is a major H₂S -generating enzyme in the brain, H₂S in the cardiovascular system is mainly produced by cystathionine-γ-lyase. [21] The presence of H₂S-producing enzyme and endogenous level of H₂Sincardiovascular system shows that it has a role in the functioning of cardiovascularsystem. CSE expression and activity are found in rat portal vein and thoracic aorta.Expression levels of CSE mRNA varies in different types of vascular tissues, withintensity rank of pulmonary artery > aorta > tail artery > esenteric artery. The CBSdoes not have major role in H₂Sproduction in cardiovascular system. [22]

Immunohistochemical studies and reverse transcription-polymerase chain reaction revealed that cystathionine-γ-lyase is expressed in vascular smooth muscle but not in endothelial cells. One study reported cystathionine-β-synthase expression in human umbilical vein endothelial cells; however, these cells were cultured for 14 days in the presence of high concentration of homocysteine, which could up-regulate this enzyme. Nevertheless, this study suggests that cystathionine-β-synthase may be induced in cardiovascular tissue under certain conditions. [5]

H2S can be produced enzymatically in vascular tissues and relaxes vascular smooth muscles both in vivo and in vitro. This vasorelaxant effect is most probably caused by opening vascular smooth muscle cells KATP-channels which leads to membrane hyperpolarization. [23]

Therefore, H₂Smay reduce extracellular Ca2+ entry and relax vascular tissues. The vasorelaxation induced by H₂Scan be attenuated by the removal of the endothelium, since H₂Smay facilitate the release of vasorelaxant factors from the endothelium, including NO and the endothelium-derived relaxing factor. As opposed to NO and CO, H₂S-induced vasorelaxation is not mediated by the cGMP signaling pathway. This indicates that H₂S is a novel endogenous gaseous modulator of vascular contractility. [17]

Fig3. Physiological actions of Hydrogen sulfide (H₂S)

GASTROINTESTINAL SYSTEM:
Both CSE and CBS are expressed in the gastric mucosa and endogenous H₂S seems to be a protective factor against mucosal injury. Both acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the expression of CSE gene and H₂S production in the gastric mucosa. NaHS prevents the reduction of mucosal blood flow induced in rats by ASA (Amino salicylic acid) and NSAIDs (Non-steroidal anti-inflammatory drugs). [5]

In addition, NaHS reduces NSAIDs-induced adherence of leukocytes to vascular endothelium and mucosal leukocyte infiltration assessed as MPO activity, normalizes increased expression of TNF-α and intracellular adhesion molecule-1 (ICAM-1), and improves prostaglandin E2 synthesis impaired by these agent. Moreover, NaHS attenuates histological lesions of the gastric mucosa. [5] Several studies have demonstrated that H2S reduces spontaneous or acetylcholineinduced contractility of the ileum in various animal species. In addition, NaHS administered intraperitoneally relaxes the rat colon in vivo. In contrast to the relaxing effect on rabbit or guinea-pig ileum observed in vitro, the effect on colon contractility was abolished by glibenclamide. CBS and CSE were immunohistochemically detected in guinea pig and human colonic submucosal and myenteric nerve plexuses. [5]

Serosal application of NaHS or L-cysteine stimulated luminal chloride secretion by guinea pig and human colonic tissues. This effect was blocked by tetrodotoxin, desensitization of afferent nerves with capsaicin, or TRPV1 antagonist, capsazepine. In addition, secretory effect of NaHS was not observed in cultured colonic epithelial cells.

Taken together, these data indicate that H₂S is generated in the enteric nervous system and indirectly stimulates mucosal secretion by acting on TRPV1-containing sensory nerve endings which then send collaterals to the mucosa or to submucosal secretomotor neurons. Thus, H2S is involved in the regulation of gut motility and secretory function. [5]

Recently, Distrutti has demonstrated that NaHS dose-dependently ameliorates visceral nociception evoked in the rat by colorectal distension (CRD). This effect could not be attributed to colonic relaxation since the latter was observed only at the highest NaHS dose. Rather, antinociceptive effect might be associated with the direct impact on neurotransmission since NaHS attenuated the CRD-induced increase in c-Fos gene expression in the spinal cord. [5]

Fig. 4 A schematic representation of the pharmacological effects of H₂S. [24]

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CLINICAL CONDITIONS IN WHICH H₂S MAY PLAY A PART:

1. ARTERIAL HYPERTENSION:
As H₂S induces vasorelaxation, one may ask whether its deficiency contributes to the pathogenesis of arterial hypertension. Several data suggest that this may indeed be the case, at least in some animal models. [25]

First, plasma H₂S concentration as well as aortic cystathionine-γ-lyase mRNA expression and enzymatic activity are lowers in spontaneously hypertensive rats than in control Wistar-Kyoto rats. In addition, chronic administration of NaHS lowers blood pressure in SHR but not in normotensive rats. [25]

Administration of cystathionine-γ-lyase inhibitor, propargylglycine (PAG), decreases plasma H₂S concentration and aortic H₂S production and elevates blood pressure in normotensive rats but not in spontaneously hypertensive rats, indicating that vascular H₂S is involved in the regulation of vascular tone under baseline conditions, and that H₂S generating system is suppressed in the hypertensive strain. [26]

H₂S deficiency, decreased cystathionine-γ-lyase activity and gene expression, and hypotensive effect of an exogenous H₂S donor have also been demonstrated in experimental hypertension induced by chronic inhibition of NO-synthase. Future studies have to address the question whether vascular H₂S is involved in human hypertension.

2. ATHEROSCLEROSIS:
Both NO and CO produced in the arterial wall inhibit atherogenesis through their anti-inflammatory, antiplatelet, and antiproliferative activities. Therefore, the question arises if H₂S is also involved in atherogenesis. In vivo, administration of NaHS attenuates vascular remodeling in spontaneously hypertensive rats, hypoxiainduced pulmonary hypertension, and in hypertension induced by chronic NOS blockade. [25, 26]

These data suggest that H₂S may have some direct effects on the vascular wall. Indeed, H₂S suppresses endothelin-induced proliferation of rat aortic smooth muscle cells by down-regulating nitogen activated protein kinases. [27] In addition, H₂S induces apoptosis of human aortic smooth muscle cells. Thus, H₂S might reduce the growth of atherosclerotic lesions. The other effect of H₂S relevant to atherogenesis is its influence on vascular inflammatory reaction, which plays an important role in plaque destabilization and rupture. [5]

3. MYOCARDIAL INJURY:
Myocardial cells contain large density of KATP-channels consisting of inwardly rectifying K+-channel and a sulfonylurea-receptor, SUR-2A. Multiple studies have documented a protective effect of KATP-channel activators in myocardial ischemiareperfusion injury. [28] Thus, it is of interest whether H₂S activates myocardial KATPchannel and, if so, what is its effect on myocardial ischemic injury. [5]

Geng, a scientist has investigated the role of H₂S in the “infarct-like” myocardial necrosis induced in the rat by isoproterenol. v concentrations in myocardium and plasma were by 60% lower in isoproterenol treated rats, which was associated with reduced myocardial CSE activity despite up-regulation of CSE gene expression. [5] Exogenous NaHS decreased the mortality rate of isoproterenol treated rats as well as significantly attenuated the isoproterenol-induced decrease in myocardial contractility and ameliorated myocyte necrosis. [5]

In the isolated perfused rat heart preparation, NaHS limited the size of infarction induced by left coronary artery ligation and this protective effect was abolished by KATP-channel blockers. [29]

4. PULMONARY HYPERTENSION:
In experimental pulmonary hypertension induced in the rat by a 3-week hypobaric hypoxia (hypoxic pulmonary hypertension, HPH), plasma H₂S concentration was reduced by about one third, which was accompanied by a twofold decrease in H₂S generation by lung homogenates, as well as by the reduced pulmonary CSE gene expression and enzymatic activity. [30]

5. INFLAMMATION:
Septic shock, which often accompanies sepsis induced by infection with Gramnegative bacteria, is characterized by generalized vasodilation and hypotension. Overproduction of NO and CO by cytokine-induced enzymes, inducible NO-synthase and heme oxygenase-1, respectively, contributes to this vasodilation. [31]   H₂S is also overproduced in vascular tissue of rats with experimental septic shock induced by coecal ligation and puncture, as well as in endotoxemic shock induced by lipopolysaccharide (LPS) administration. [32] In addition, H2S level negatively correlates with blood pressure and myocardial contractility, suggesting its pathogenic role in the hemodynamic collapse. One study has demonstrated that LPS-induced hypotension is attenuated by glibenclamide suggesting the involvement of abnormal activation of KATP-channels. [5, 33]

DIABETES MELLITUS:
Apart from vascular smooth muscle cells and cardio myocytes KATP-channels are abundantly expressed in insulin-secreting pancreatic β-cells. In contrast to vascular KATP channels which consist of sulfonylurea receptor-SUR2B, pancreatic KATP channel contains sulfonylurea receptor-SUR1.[34] Pancreatic KATP-channels play a major role in the regulation of insulin secretion. Indeed, increased concentration of glucose leads to the accumulation of ATP in the cell, blockade of KATP-channels, depolarization of plasma membrane, Ca2+ influx and insulin secretion. [34]

THERAPEUTIC APPROACHES:
Over the past 2 years, a number of independent groups have reported the beneficial effects of H₂Sor sulphide-donor compounds in animal models of disease.

H₂Sor H₂S-donor compounds exert beneficial effects in multiple models of disease. The mechanisms of action are multiple and range from inhibition of cellular metabolism (in the lethal hypoxia model) to vasodilatation, KATP-channel activation, up-regulation of anti-inflammatory genes and down-regulation of inflammatory genes (COX-2, FOS, IL-1β). H2S can inhibit the adhesion and activation of neutrophil granulocytes, and also has a slight inhibitory effect on platelet aggregation. [7] The relative contribution of these effects (as well as other, not yet identified protective mechanisms) to the pharmacological effects of H₂Sin various disease models are defined to be remain. [7]

As may be concluded from the data presented in Table-1, production of endogenous H₂Sis altered in many diseases, at least in experimental studies. In addition, both exogenous and endogenous H₂Shas been demonstrated to exert either

Protective or deleterious effect in much pathology. Thus, the question arises if pharmacological modulation of H₂Slevel could be of a potential therapeutic value. [7]

The emerging data on the biological effects of H₂Ssupport basic approaches forthe development of sulphide-based therapeutics. So, the level of H₂Smay be modulated by mainly four approaches:
(1) Administration of H₂S it-self or of currently available H₂S donors
(2) Generating new H₂S-releasing compounds
(3) Administration of specific CBS or CSE inhibitors
(4) Targeting H₂S production by currently used drugs

Table: 1 Effects of H₂S and its donors in animal models of disease: [7]

(1) Administration of H₂S it-self or of currently available H₂S donors:
Anti-inflammatory effects of H₂Sdonors have been used to investigate further the potential role of this mediator in modulating inflammatory reactions.

There are mainly three H₂Sdonors:
1) Sodium hydrogen sulfide (NaHS)
2) Calcium sulfide (CaS)
3) Sodium sulfite (Na2S)

In rats, H2S donors were shown to suppress leukocyte adherence to the vascular endothelium induced by superfusion of mesenteric venules with a pro-inflammatory peptide, formyl-methionyl-leucyl-phenylalanine (fMLP). These inhibitory effects were reversed by glibenclamide, suggesting the Sodium hydrogen sulfide involvement of ATP-sensitive K+ channels (KATP-channels). [35]

(2) Generating new H₂S-releasing compounds:
Now-a-days, H₂S releasing derivatives of NSAIDS (Non-steroidal anti-inflammatory drugs) are synthesized. (Mainly synthesized by Antibe Therapeutics, Table-2) The H₂S-releasing NSAIDs are substantially better tolerated, in terms ofgastric damage, than the parent drugs. At single doses of more than five times theED50 for anti-inflammatory activity in the oedema model in rats, no gastric damagedetected with H₂S releasing derivatives of Diclofenac (ATB-337). [3

Fig. 5: Stucture of Diclofenac [NSAIDS] & H₂S-releasing diclofenac derivative (ATB-337) [5]

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Administration of specific CBS or CSE inhibitors:

Pharmacological inhibitors of H₂S biosynthesis include:
1) Propargylglycine (PAG)
2) β-cyanoalanin (BCA)

These compounds, although of low potency, of low selectivity and of limited cell membrane

Permeability has been used in several studies to test the biological effect of inhibition of endogenous sulphide production. [37, 38]

Fig. 6 Structures of PAG (dl-propylargylglycine ) and BCA (β-cyanoalanine) [7]

(a) PAG (dl-propylargylglycine)

(b) BCA (β-cyanoalanine)

(4) Targeting H₂S production by currently used drugs:
H₂Smay also be affected by currently used drugs or their derivatives. For example, L-arginine supplementation, primarily expected to augment NO formation, also corrects the impaired H₂Sproduction in high blood flow induced pulmonary hypertension. [5] But these drugs have less therapeutic potential. So, not widely used even in research. [5]

CONCLUSION:
Taken together, the data presented above strongly suggest that apart from NO and CO, H₂S is another inorganic gaseous mediator in the cardiovascular and nervous system. However, our current knowledge about its role in physiology and pathology is still fragmentary. Many effects of H₂S are controversial. For example, H₂S has been demonstrated to either stimulate or inhibit certain intracellular transduction pathways to stimulate or inhibit cell proliferation, to activate or block apoptosis, to be overproduced or deficient in myocardial ischemia, to be pro or anti-inflammatory in the model of edema, etc. Only few studies demonstrated alterations in H₂S level in human diseases and in most cases it was done indirectly by measuring H₂S -related compounds such as thiosulfate or sulfhemoglobin rather than H₂S itself. Given a potential role of H₂S in cardiovascular pathology, its level should be examined in patients with various risk factors of atherosclerosis such as arterial hypertension, hyperlipidemia, diabetes mellitus, etc. and the relationship between H₂S and the progression of atherosclerosis must be addressed in the progressive studies. Novel exciting aspects of the H₂S research continuously emerge. For example, given that H₂S is considering the important role of oxidative stress in many diseases such as atherosclerosis, arterial hypertension, Alzheimer’s disease, etc. H₂S-relatedpharmacological research is a rapidly emerging field, which is likely to yield anumber of therapeutic possibilities, and early stage drug candidates are now indevelopment. These features make H₂San ideal candidate to be explored inthe development of new anti-inflammatory drugs. The H₂Sreleasing derivatives exhibit excellent gastrointestinal safety and are more robust compare to the parent drugs as anti-inflammatory agents. H₂S-related future therapeutic avenues might also include genetic approaches due to safety aspect. So, H₂Scan be Revolutionary scientific miracle as a gasotransmitters  at maximum potential with safety precaution.

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