a number of gases are produced endogenously in humans and have roles in the pathology of various diseases . among these gases , nitric oxide ( no ) and carbon monoxide ( co ) have vital roles in the physiology of the body . since the last decade
, hydrogen sulfide ( h2s ) has captured the interest of scientists because of its significant role in different systems of the body .
h2s has been known as a toxic gas with rotten egg smell for more than 300 years . as a toxicant ,
some studies have also reported the toxic effects of h2s on the central nervous system ( cns ) and respiratory system .
h2s is endogenously produced from two sulfur - containing amino acids l - cysteine and l - methionine by the two enzymes cystathionine  lyse ( cse ) and cystathionine  synthase ( cbs ) as shown in figure 1a and b. recently , a third enzyme , namely , 3-mercaptopyruvate sulfur transferase ( 3mst ) , along with cysteine aminotransferase ( cat ) , which is similar to aspartate amino transferase , has been shown to produce h2s in brain .
3mst is produced by schematic chain reaction from 3-mercaptopyruvate which is also produced by cat from cysteine and -ketoglutarate[figure 1 ] . 
 
( a - c ) the schematic presentation of h2s production in the mammalians body by involving three different pathways both the enzymes cse and cbs are present in mammalian cells and tissues .
previously , cse has been reported to be responsible for the production of h2s in the cardiovascular system ( cvs ) and kidneys , whereas cbs performs the same function in cns .
few studies have supported that cse is dominant in cvs , whereas cbs is dominant in cns .
both cbs and cse have been reported to be present in the kidneys , predominantly in predominantly cortical thymoma .
however , the mechanism of its production still remains unclear ; whether or not the production of h2s is induced by cse or cbs .
expression of both enzymes in the kidneys can lead us to conclude about the production of h2s by both enzymes .
the third enzyme , 3mst , is responsible for h2s production and has also been reported to be present in endothelial cells in the thoracic aorta .
recent studies have shown that greater than 90% of the total h2s is produced in the brain by 3mst .
based on the literature , different enzymes are involved in the production of h2s in different parts of body ; for example , h2s is predominantly produced in the heart by cse , both cbs and cse in the kidneys , and 3mst in the brain by .
dl - propargylglycine ( dl - pag ) is an inhibitor of cse , whereas aminooxyacetic acid is an inhibitor of cbs .
both inhibitors are nonselective and may be responsible for the inhibition of other enzymes . some selective inhibitors can elaborate the mechanisms of h2s . some mechanisms for long - term control production of h2s are coming to light .
long - term regulation of h2s seems to be dependent on s - adenosyl - l  methionine , which activates cbs and ultimately leads to the production of h2s[figure 1c ] .
the endogenous concentration of circulating h2s is 50160 m in rats , bovines , and humans .
h2s hyperpolarizes the membranes of localized cells , modulates the neuronal excitability , relaxes the smooth muscles , and controls cell apoptosis or proliferation . in one study , normal concentration of h2s in wistar kyoto ( wky ) rats was measured at 10 m ; however , other studies have demonstrated that the plasma level of h2s is 50 m
. the tissue level of h2s has been thought to be higher than its plasma level .
for example , the physiological concentration of h2s in the brain has been documented at 50160 m .
the h2s level decreased below the normal level in the body if coronary heart disease spontaneously hypertensive rats ( shrs ) ; however , the level increased in diabetes and circulatory shock . in carrageenan - induced inflammation model , concentration is increased .
increase in the concentration of h2s has also been observed in acute pancreatitis , hemorrhagic shock , and in endotoxin shock .
the vasorelaxant effect of h2s has been proven , which shows that h2s relaxes the isolated aorta at a concentration as low as 18 m and 60 m if pretreated with 20 mm kcl or phe .
a number of gases are produced endogenously in humans and have roles in the pathology of various diseases . among these gases , nitric oxide ( no ) and carbon monoxide ( co ) have vital roles in the physiology of the body . since the last decade
, hydrogen sulfide ( h2s ) has captured the interest of scientists because of its significant role in different systems of the body .
h2s has been known as a toxic gas with rotten egg smell for more than 300 years . as a toxicant ,
some studies have also reported the toxic effects of h2s on the central nervous system ( cns ) and respiratory system .
h2s is endogenously produced from two sulfur - containing amino acids l - cysteine and l - methionine by the two enzymes cystathionine  lyse ( cse ) and cystathionine  synthase ( cbs ) as shown in figure 1a and b. recently , a third enzyme , namely , 3-mercaptopyruvate sulfur transferase ( 3mst ) , along with cysteine aminotransferase ( cat ) , which is similar to aspartate amino transferase , has been shown to produce h2s in brain .
3mst is produced by schematic chain reaction from 3-mercaptopyruvate which is also produced by cat from cysteine and -ketoglutarate[figure 1 ] . 
 
( a - c ) the schematic presentation of h2s production in the mammalians body by involving three different pathways both the enzymes cse and cbs are present in mammalian cells and tissues .
previously , cse has been reported to be responsible for the production of h2s in the cardiovascular system ( cvs ) and kidneys , whereas cbs performs the same function in cns .
few studies have supported that cse is dominant in cvs , whereas cbs is dominant in cns .
both cbs and cse have been reported to be present in the kidneys , predominantly in predominantly cortical thymoma .
however , the mechanism of its production still remains unclear ; whether or not the production of h2s is induced by cse or cbs .
expression of both enzymes in the kidneys can lead us to conclude about the production of h2s by both enzymes .
the third enzyme , 3mst , is responsible for h2s production and has also been reported to be present in endothelial cells in the thoracic aorta .
recent studies have shown that greater than 90% of the total h2s is produced in the brain by 3mst .
based on the literature , different enzymes are involved in the production of h2s in different parts of body ; for example , h2s is predominantly produced in the heart by cse , both cbs and cse in the kidneys , and 3mst in the brain by .
dl - propargylglycine ( dl - pag ) is an inhibitor of cse , whereas aminooxyacetic acid is an inhibitor of cbs .
both inhibitors are nonselective and may be responsible for the inhibition of other enzymes . some selective inhibitors can elaborate the mechanisms of h2s . some mechanisms for long - term control production of h2s are coming to light .
long - term regulation of h2s seems to be dependent on s - adenosyl - l  methionine , which activates cbs and ultimately leads to the production of h2s[figure 1c ] .
the endogenous concentration of circulating h2s is 50160 m in rats , bovines , and humans .
h2s hyperpolarizes the membranes of localized cells , modulates the neuronal excitability , relaxes the smooth muscles , and controls cell apoptosis or proliferation . in one study , normal concentration of h2s in wistar kyoto ( wky ) rats was measured at 10 m ; however , other studies have demonstrated that the plasma level of h2s is 50 m
. the tissue level of h2s has been thought to be higher than its plasma level .
for example , the physiological concentration of h2s in the brain has been documented at 50160 m .
the h2s level decreased below the normal level in the body if coronary heart disease spontaneously hypertensive rats ( shrs ) ; however , the level increased in diabetes and circulatory shock . in carrageenan - induced inflammation model , concentration is increased .
increase in the concentration of h2s has also been observed in acute pancreatitis , hemorrhagic shock , and in endotoxin shock .
the vasorelaxant effect of h2s has been proven , which shows that h2s relaxes the isolated aorta at a concentration as low as 18 m and 60 m if pretreated with 20 mm kcl or phe .
the role of h2s seems to be partially solved by evaluating different mechanisms ; however , researchers have shifted their interest to other gaseous transmitters , such as no and carbon monoxide .
studying the role of h2s in hypertension chronologically , we were first informed that h2s produces vasorelaxation on rat aortic tissue in vitro . in succeeding research , the vasorelaxant effect of h2s
has been attributed to the opening of the atp - sensitive potassium ( katp ) channel ; this effect was mimicked by pinacidil ( a katp channel agonist ) and antagonized by glibenclamide ( a katp channel antagonist ) .
blood pressure reduction by intravenous ( iv ) bolus injection of h2s was 1230 mm of hg .
the study under discussion revealed that aortic rings were relaxed by 63%  2.2% at a dose of 180 m , if pretreated with phe .
the vasorelaxation of h2s was partially dependent on endothelium and mostly through direct effects on the smooth muscle cells . to further exclude the involvement of no ,
the vasorelaxant effects of h2s are not blocked by 1h-(1,2,4)oxadiazolo[4,3-a ] quinoxalin-1-one ( odq ) ( an inhibitor of guanylyl cyclase ) .
the katp channel mechanism was confirmed by inducing contractions in the aortic tissue through treating the tissue with low k ( 20 mm ) and high k ( 100 mm ) ; vasorelaxation produced by h2s on aortic tissues was observed when pretreated with low k ( 20 mm ) and high k ( 100 mm ) .
the maximum vasorelaxation produced by h2s was 90%  8.2% and 19%  3.9% when pretreated with low k ( 20 mm ) and high k ( 100 mm ) , respectively .
hydrogen sulfide produces more relaxation with low k ( 20 mm ) because of k conductance .
the k channel opener effect was further verified using 10 mm tetraethylammonium and 100 nm of charybdotoxin or 100 nm iberiotoxin ( specific inhibitors of kca channel ) , completely inhibiting h2s - induced relaxation . in upcoming years
, the vasorelaxation produced by h2s was proven to be through a different mechanism than that of no and co. furthermore , the vasorelaxation effect on the vascular tissue by no is reduced when pretreated with h2s .
this study also suggests that an additive response can be achieved using no and h2s .
a study elaborated that the cardioprotective action of h2s mediated by katp channel opening is caused by the physiological production of h2s in the heart .
this study has proven the negative inotropic effects of h2s both in vivo and in vitro , and concluded that h2s can effectively prevent hypertension in rats when induced by l - n - nitro arginine methyl ester . nitric oxide and
deficiency in no and co has been proven to contribute to the pathogenesis of hypertension .
h2s has also been reported to play the same role in hypertension because of similar biological activities . in subsequent studies , the level of h2s in the plasma and its production rate in seriously hypertensive rats ( shr ) was lower than that in wky rats . therefore , cse is a specific enzyme for h2s production in the thoracic aorta and its decreased activity in hypertension may lead to less production of h2s , resulting in decreased circulating level of h2s .
the above - mentioned theory proposes that less activity and decreased transcription of cse results in decreased circulating aortic h2s level and that vasoconstriction is a dominant phenomenon over vasorelaxant one .
sodium hydrogen sulfide ( nahs ) has been selected as an exogenous source ofh2s because of to four reasons .
( 1 ) na dissociates from hs in a nahs solution , then hs associates with h and produces h2s , regardless if the h2s solution was prepared by bubbling h2s gas or dissolving nahs . in physiological saline ,
about one - third of h2s exists in the undissociated form ( h2s ) , and the remaining two - thirds is hs - at equilibrium with h2s .
( 2 ) nahs enables a more accurate and reproducible measurement of h2s concentrations in a solution than by bubbling h2s gas . ( 3 ) the influence of 1 mm or less sodium ion on the physiological experiments is negligible .
( 4 ) nahs at concentrations used in the current study does not change the ph of the medium .
the results of one study suggest that upregulation of h2s results in the reduction of sbp in the shr + nahs group ( 158.13  12.52
mm vs. 183.57  11.8 mm of hg ) . a study demonstrated that an iv bolus injection of h2s at 2.8 mol / kg and 14 mol / kg body weight results in a decrease in the mean arterial blood pressure of rats by 12.5  2.1 mmhg and 29.8  7.6 mmhg , respectively .
therefore , the physiological concentration of h2s is responsible for maintaining the mean arterial blood pressure .
however , the expression of cse activity decreases with the onset of disease . based on the findings , the finding that the physiological concentration of h2s is responsible for the normal function of cvs is a matter of great interest .
diseases like hypertension occur when the concentration of h2s decreases ; however , the opposite occurs in hemorrhagic shock . in a study , induction of hemorrhagic shock results in a prolonged decrease in the mean arterial pressure ( map ) and heart rate ( hr ) .
however , data suggest that vasoconstriction is responsible for a hemorrhagic shock because of vasopressin , noradrenaline , and angiotensin ii .
a reasonable number of previous studies have shown that excessive formation of inducible nitric oxide synthase ( inos ) in hypotension is responsible for hemorrhagic shock ; thus , the concentration of h2s increases in the induction of hemorrhagic shock .
treatment with inhibitors of h2s - producing enzymes cse and dl - pag , a suicidal inhibitor , resulted in the rapid and partial restoration of map and hr .
previously , glibenclamide ( a k channel blocker ) has been proven to perform the same partial but equally effective function after hemorrhagic shock in a rat .
a comparative study was conducted to compare the effect of h2s with pag and -cyano - l - alanine , a reversible inhibitor of cse , on the blood pressure of rats subjected to hemorrhagic shock .
after many years of earning good repute among researchers , h2s research started to intermingle with each other .
two different schools of thought exist between interchangeable production of h2s and no . in 1997
, a study has proven that a low concentration of h2s increases the relaxation of smooth muscles by 13-folds .
this study also explained that low concentration ( 30 m ) of h2s enhances the vasodilator effect of no .
therefore , a synergistic response between h2s and no can be the therapeutic outcome in hypertension .
this study further elaborated that no - induced vasorelaxation is specifically for h2s , but no can not potentiate the vasorelaxant effect of h2s .
another study has proven that no is responsible for the upregulated production of h2s in rats in a dose - dependent manner ( 1100 m ) , as shown in the following figure .
this study claims that production of h2s by no is narrated by two mechanisms : ( 1 ) no increases cse activity , which ultimately leads to the production of h2s , and ( 2 ) no increases the activity of protein kinase , which is dependent on cyclic guanosine monophosphate , thereby increasing cse protein .
a growing body of evidence has proven that h2s as a cofactor is responsible for the generation of no from nitrite . in his previous studies in 2002 , documented the interaction between hydrogen sulfide and no resulting in the formation of the intermediate compound nitrosothiol , which releases no through hemolysis . in his next experimentation , proposed the mechanism of no production from sodium nitroprusside . in 2006 , has proven that the interaction between two gasotransmitters results in the formation of nitrosothiol and the release of only a small portion of no unless an antioxidant is involved .
these findings contradict those of other studies , which demonstrate that the interaction between no and h2s enhances vasodilatation . in the battle of the interchangeable production of h2s and no ,
another finding cropped up , supporting the claim that h2s is responsible for the direct inhibition of endothelial nitric oxide synthase ( enos ) .
this theory is born out of the result of the first school of thought , which proposed that no can potentiate the response of h2s , but no can do this .
has elaborated that h2s is responsible for the inhibition of enos , as well as inos and nnos .
they further strengthened the results of their study by explaining that h2s and tetrahydrobiopterin ( bh4 ) reverse the h2s inhibition of enos and nnos , but not inos .
a study in 2006 elaborated that the intermediate complex formed from the interaction between h2s and no has no vasorelaxant effect ; h2s was responsible for the regulation of no .
this study concluded that h2s inhibits the vasorelaxant effect of no . a decrease in h2s concentration results in over stimulation of  adrenoreceptor .
the h2s has also been reported to inhibit the l - type ca channels in cardiomyocyte , which leads to a decrease in contractility , thereby revealing the ca channel - blocking mechanism of h2s . in the same year
, h2s has been found to have the ability to block the angiotensin - converting enzyme and responsible for additive vasorelaxant response leading to the inhibition of angiotensin ii production , ultimately resulting in reduced degradation of bradykinin . in a related study in 2010 , reported that enos and neuronal nitric oxide synthase ( nos ) activation is important to produce a cardioprotective response .
the cardioprotective response of the nos family mentioned in is contrary to the results by .
another area of interest is the formation of the intermediate complex nitrosothiol , which is responsible for the vasorelaxant effect in the blood vessels through interaction between two gasotransmitters , h2s and no .
the presence of this intermediate molecule , nitrosothiol , has not been fully confirmed and has been considered as a possible molecule for the said action .
a previously mentioned study has stated that the intermediate molecule is nitrosothiol but has no vasorelaxant effect in vivo and in vitro .
another school of thought has reported that the interaction between no and h2s leads to the formation of the nitroxyl group ; nitroxyl has been reported to be involved in positive inotropic and vasodilation activities .
these results support the evidence that hno / no produce positive inotropic and lusitropic effects ( independent of -adrenergic stimulation ) in a failing heart .
most recently , a group of researchers studied the role of h2s in hypertension along with diabetes and emphasized that h2s improves the renal blood flow by reducing renal vasculature resistance through vasodilation .
the same group of researchers extended their study to investigate the role of h2s in cardiac protection in dihydroxycortisone acetate - induced hypertension and shr combined with diabetes .
in view of the above - mentioned literature review , many things remain to be explored and many questions still to be answered .
future studies must verify whether the intermediate molecule formed as a result of interaction between no and h2s is nitroxyl or nitrosthiol or both .
if both molecules are present ; then , which one is responsible for the vasorelaxant effect?concentration of h2s decreased in hypertension .
is it a cause or consequence of the disease?h2s acts by vasodilatation , so  blocking effect can be investigatedbh4 and h2s effects in hypertension can be studiedthe molecular mechanism of h2s can be studied using reverse transcription polymerase chain reactionsome selective inhibitors can be introduced to avoid inhibition of unwanted enzymesreleasers of h2s introduced as present releasers are inconsistent and have sustained - release property . 
 
future studies must verify whether the intermediate molecule formed as a result of interaction between no and h2s is nitroxyl or nitrosthiol or both .
if both molecules are present ; then , which one is responsible for the vasorelaxant effect ?
h2s acts by vasodilatation , so  blocking effect can be investigated bh4 and h2s effects in hypertension can be studied the molecular mechanism of h2s can be studied using reverse transcription polymerase chain reaction some selective inhibitors can be introduced to avoid inhibition of unwanted enzymes releasers of h2s introduced as present releasers are inconsistent and have sustained - release property .
in view of the above - mentioned literature review , many things remain to be explored and many questions still to be answered .
future studies must verify whether the intermediate molecule formed as a result of interaction between no and h2s is nitroxyl or nitrosthiol or both .
if both molecules are present ; then , which one is responsible for the vasorelaxant effect?concentration of h2s decreased in hypertension .
is it a cause or consequence of the disease?h2s acts by vasodilatation , so  blocking effect can be investigatedbh4 and h2s effects in hypertension can be studiedthe molecular mechanism of h2s can be studied using reverse transcription polymerase chain reactionsome selective inhibitors can be introduced to avoid inhibition of unwanted enzymesreleasers of h2s introduced as present releasers are inconsistent and have sustained - release property . 
 
future studies must verify whether the intermediate molecule formed as a result of interaction between no and h2s is nitroxyl or nitrosthiol or both .
if both molecules are present ; then , which one is responsible for the vasorelaxant effect ?
h2s acts by vasodilatation , so  blocking effect can be investigated bh4 and h2s effects in hypertension can be studied the molecular mechanism of h2s can be studied using reverse transcription polymerase chain reaction some selective inhibitors can be introduced to avoid inhibition of unwanted enzymes releasers of h2s introduced as present releasers are inconsistent and have sustained - release property .
in view of the above - mentioned literature review , many things remain to be explored and many questions still to be answered .
future studies must verify whether the intermediate molecule formed as a result of interaction between no and h2s is nitroxyl or nitrosthiol or both .
if both molecules are present ; then , which one is responsible for the vasorelaxant effect?concentration of h2s decreased in hypertension .
is it a cause or consequence of the disease?h2s acts by vasodilatation , so  blocking effect can be investigatedbh4 and h2s effects in hypertension can be studiedthe molecular mechanism of h2s can be studied using reverse transcription polymerase chain reactionsome selective inhibitors can be introduced to avoid inhibition of unwanted enzymesreleasers of h2s introduced as present releasers are inconsistent and have sustained - release property . 
 
future studies must verify whether the intermediate molecule formed as a result of interaction between no and h2s is nitroxyl or nitrosthiol or both .
if both molecules are present ; then , which one is responsible for the vasorelaxant effect ?
h2s acts by vasodilatation , so  blocking effect can be investigated bh4 and h2s effects in hypertension can be studied the molecular mechanism of h2s can be studied using reverse transcription polymerase chain reaction some selective inhibitors can be introduced to avoid inhibition of unwanted enzymes releasers of h2s introduced as present releasers are inconsistent and have sustained - release property .
 in the family of gas transmitters , hydrogen sulfide ( h2s ) is yet not adequately researched . 
 known for its rotten egg smell and adverse effects on the brain , lungs , and kidneys for more than 300 years , the vasorelaxant effects of h2s on blood vessel was first observed in 1997 . since then , research continued to explore the possible therapeutic effects of h2s in hypertension , inflammation , pancreatitis , different types of shock , diabetes , and heart failure . 
 however , a considerable amount of efforts are yet needed to elucidate the mechanisms involved in the therapeutic effects of h2s , such as nitric oxide - dependent or independent vasodilation in hypertension and regression of left ventricular hypertrophy . 
 more than a decade of good repute among researchers , h2s research has certain results that need to be clarified or reevaluated . 
 h2s produces its response by multiple modes of action , such as opening the atp - sensitive potassium channel , angiotensin - converting enzyme inhibition , and calcium channel blockade . 
 h2s is endogenously produced from two sulfur - containing amino acids l - cysteine and l - methionine by the two enzymes cystathionine  lyase and cystathionine  synthase . 
 recently , the third enzyme , 3-mercaptopyruvate sulfur transferase , along with cysteine aminotransferase , which is similar to aspartate aminotransferase , has been found to produce h2s in the brain . 
 the h2s has interested researchers , and a great deal of information is being generated every year . 
 this review aims to provide an update on the developments in the research of h2s in hypertension amid the ambiguity in defining the exact role of h2s in hypertension because of insufficient number of research results on this area . 
 this critical review on the role of h2s in hypertension will clarify the gray areas and highlight its future prospects . 
Introduction
History and Background of Hydrogen Sulfide
Role of Hydrogen Sulfide in Hypertension
None
Future Prospects