Abstract
The important role of nitric oxide (NO) in the regulation of vascular tone has been well studied. By contrast, the vascular significance of another gaseous mediator, hydrogen sulphide (H2S), is still poorly understood. A study published in this issue of the British Journal of Pharmacology now provides evidence that in addition to the vasorelaxant effects of H2S reported in vitro, low concentrations of H2S also cause arterial vasoconstriction, reverse NO-mediated vasorelaxation and cause an NO-dependent pressor effect in vivo. This commentary discusses the implications and questions raised by these results.
Keywords: hydrogen sulphide, vasorelaxation, vasoconstriction, nitric oxide, vasculature, blood pressure, nitrosothiol
Hydrogen sulphide (H2S) is endogenously generated from cysteine in a reaction catalysed (in the vasculature) by cystathionine β-synthase. Unlike the endogenous gas nitric oxide (NO), the physiological relevance of H2S is unclear, although under much investigation. In a continuation of recently published work showing that H2S reacts chemically with NO to produce an as-yet unidentified nitrosothiol in vitro (Whiteman et al., 2006), Ali et al. (2006) now report the physiological consequences of such an interaction. In the present study, low, physiologically relevant (ca. 50 μM in rat and human plasma) concentrations of H2S cause endothelium-dependent, CuSO4-sensitive (CuSO4 converts nitrosothiols to nitrites and nitrates) arterial vasoconstriction, suggested to be owing to quenching of NO. Furthermore, H2S reversed NO-mediated vasorelaxation to acetylcholine and histamine in a CuSO4-sensitive manner. The conclusion drawn from these data is that formation of a nitrosothiol compound terminates the biological activity of NO.
To date, H2S has been shown to cause vasorelaxation of rat isolated aortae (Zhao et al., 2001), albeit at relatively high concentrations (EC50 125 μM) which appear to be more consistent with the levels of H2S stimulated by situations such as sepsis, shock and inflammation (levels of 150 μM plasma H2S have been reported in humans with septic shock, Li et al., 2005). The vasorelaxant effects of H2S in vitro are largely thought to be owing to activation of potassium channels (Zhao et al., 2001; Cheng et al., 2004). Consistent with the current literature, the present authors (Ali et al., 2006) show that high concentrations of H2S (200–1600 μM) cause KATP channel-mediated vasorelaxation; however, at low concentrations (10–100 μM), they find a vasoconstrictor effect of H2S. It is of note that other studies of H2S in the vasculature have not revealed a vasoconstrictor response to H2S in these concentration ranges (Zhao et al., 2001; Cheng et al., 2004). Additional studies are therefore required to establish whether this newly reported effect of H2S is potentially a species, strain and/or vascular bed-sensitive response. Indeed, Dombkowski et al. (2005) report that H2S causes both vasorelaxation and vasoconstriction in different arteries from a range of vertebrates including shark, hagfish, sea lamprey, toad, alligator, duck and rat. These authors suggest that H2S is a versatile vasoregulatory molecule that can be used to suit both organ-specific and species-specific requirements.
The major question raised from these interesting data is: what are the physiological or pathophysiological consequences of such a reaction? As both NO and H2S are increased by sepsis and inflammation, an initial suggestion might be that the reaction of the two compounds might act as a braking mechanism to prevent exaggerated vasodilatation and large decreases in peripheral resistance. Thus, are the cardiovascular responses to sepsis enhanced if we block H2S production? Does administration of H2S reverse the depressor response to sepsis? Data presented by Ali et al. (2006) would certainly suggest that H2S could be beneficial by quenching the effects of NO under these conditions. However, conversely, in a rat model of haemorrhagic shock, inhibitors of H2S biosynthesis were found to partially restore blood pressure (Mok et al., 2004). Furthermore, in lipopolysaccharide (LPS) models of sepsis, it has been reported that pretreatment with H2S significantly inhibits the LPS-induced increase in inducible NO synthase expression (with additional decreases in nuclear factor-kappa B, Oh et al., 2006), and vice versa, that the NO donor nitroflurbiprofen, downregulates the biosynthesis of H2S (Anuar et al., 2006). Therefore the pro- versus anti-inflammatory actions of H2S are far from understood.
The authors of the present study found that slow infusion of a low dose of H2S (10 μmol kg−1) caused a small, NO-dependent pressor effect in anaesthetized rats, but high doses (25 μmol kg−1) caused a depressor effect. Previously, a depressor effect of infused H2S has been reported in anaesthetized rats (3–14 μmol kg−1, Zhao et al., 2001). Clearly, the effects of H2S are of potential significance in terms of therapeutic manipulation of blood pressure, and therefore it would be of interest to know what might be the cardiovascular effects of both chronic inhibition/administration of H2S. As cardiovascular disease is often associated with dysfunctions of NO, are there also dysfunctions of the H2S system? And what are the effects of H2S manipulation in these conditions? Preliminary evidence suggests that H2S may be decreased in patients with coronary heart disease, hypertension and those who smoke (Jiang et al., 2005). Interestingly, this is to a level (to ∼25 vs 50 μmol/l H2S) at which the present authors would suggest H2S terminates the biological activity of NO. Does this cause the reduced bioavailability of NO often observed with these patients, or does this exaggerate a pre-existing problem?
The authors of the present study suggest that nitrosothiols are formed from H2S and NO (terminating NO activity), but it is not suggested what subsequently happens to these compounds. Allen and Piantadosi (2006) describe a process whereby NO is actually protected as a nitrosothiol bound to haemoglobin in red blood cells such that O2-dependent allosteric modulation of haemoglobin releases the NO to cause local vasodilatation. Similarly, Chvanov et al. (2006) have shown that NO can be released from nitrosothiols in a calcium-dependent manner upon acetylcholine stimulation in isolated pancreatic acinar cells. Thus in some circumstances, NO can be re-released from nitrosothiols, which warrants further investigation in the context of the present data. Perhaps the ‘physiological' role of H2S lies in its ability to store and quickly release (independent of enzymatic activity) NO via nitrosothiols?
In conclusion, there appear to be distinct vascular actions of H2S in the rat aorta at low (vasoconstriction and pressor effects) and high concentrations (vasorelaxation and depressor effects), with interactions and cardiovascular consequences between H2S and NO. The roles of H2S, NO and nitrosothiols in both normal physiology and pathophysiology appear intriguing and complex, and the present study by Ali et al. (2006) opens many new lines of research for both NO and H2S.
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