Beyond H₂S and NO Interplay: Hydrogen Sulfide and Nitroprusside React Directly to Give Nitroxyl (HNO). A New Pharmacological Source of HNO

Abstract

Hydrogen sulfide (H2S) has been increasingly recognized as an important signaling molecule that regulates both blood pressure and neuronal activity. Attention has been drawn to its interactions with another gasotransmitter, nitric oxide (NO). Here, we provide evidence that the physiological effects observed upon the application of sodium nitroprusside (SNP) and H2S can be ascribed to the generation of nitroxyl (HNO), which is a direct product of the reaction between SNP and H2S, not a consequence of released NO subsequently reacting with H2S. Intracellular HNO formation has been confirmed, and the subsequent release of calcitonin gene-related peptide from a mouse heart has been demonstrated. Unlike with other thiols, SNP reacts with H2S in the same way as rhodanese, i.e., the cyanide transforms into a thiocyanate. These findings shed new light on how H2S is understood to interact with nitroprusside. Additionally, they offer a new and convenient pharmacological source of HNO for therapeutic purposes.

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

“…2B,C). These results are in accordance with the observation that the NO donor SNP prevented H2S-induced relaxation of rat uterus, an effect that was attributed to the generation of nitroxyl (HNO) [20]. Recently, it was reported that relaxation effects of neutral and anionic forms of sulfide (H2S/HS -) differ in quality and the inhibition of uterine contractility might be a consequence of the specific actions of HSin relation to its negative charge [19].…”

“…The mechanisms of contraction and relaxation between uterus and aorta differ. It was reported that SNP prevented H2S induced relaxation of rat uterus, and this effect was attributed to the generation of nitroxyl (HNO) [20]. From the different sensitivities of rat uterus and aorta to NO [25], it was suggested that an activation of sGC, a key mechanism for vasorelaxation in many non-uterine smooth muscle such as aortic tissue, may not be involved in uterine relaxation [35].…”

“…Products of this H2S/NO interaction appear to have pronounced biological effects; however the nature of the reaction intermediates is currently unclear and many inconsistencies remain; for example, H2S donors were found to either potentiate or attenuate relaxation effect of NO donors in isolated aortic rings in vitro [15,16], or result in complete loss of vasodepressor activity in anesthetized rats [16]. H2S was shown to relax uterus from pregnant [17,18] and non-pregnant rats [19], and sodium nitroprusside (SNP) prevented H2S induced relaxation of rat uterus [20]. Thionitrous acid (HSNO) has been proposed to represent an important carrier of bioactivity of the interaction of S-nitrosothiols with H2S [10], but the evidence provided appears to be inconsistent with the known chemical properties of HSNO.…”

Protective effects of exogenous and endogenous hydrogen sulfide in mast cell-mediated pruritus and cutaneous acute inflammation in mice

“…Interestingly, Ali and co-workers [43] demonstrated that low concentration of H2S or spontaneous H2S donors reversed histamine, but not isoprenaline-induced vasodilatation, possibly via a direct chemical reaction between H2S and NO, which may lead to the formation of a nitrosothiol [44] or even nitroxyl species (NO-/HNO) [45] of poor vasorelaxant activities.…”

Hydrogen sulfide as an oxygen sensor

“…HSNO/SNO -is reported to be further metabolized to NO + , NO, and NO -with a variety of distinct stimulatory functions, and since it can diffuse freely across membranes, it may facilitate transnitrosation of proteins (40). SNP appears to be a poor choice of an NO donor, as it directly reacts with H 2 S and produces HNO and although this is a source of HNO, the chemistry does not appear to be similar to H 2 S/NO interactions in biological systems (38). HSNO/SNO -can further react with additional H 2 S and form H 2 S 2 (40).…”