Regulation of Heart Function by Endogenous Gaseous Mediators—Crosstalk Between Nitric Oxide and Hydrogen Sulfide

Abstract

Both nitric oxide (NO) and hydrogen sulfide (H(2)S) are two important gaseous mediators regulating heart function. The present study examined the interaction between these two biological gases and its role in the heart. We found that l-arginine, a substrate of NO synthase, decreased the amplitudes of myocyte contraction and electrically induced calcium transients. Sodium hydrogen sulfide (an H(2)S donor), which alone had minor effect, reversed the negative inotropic effects of l-arginine. The effect of l-arginine + sodium hydrogen sulfide was abolished by three thiols (l-cysteine, N-acetyl-cysteine, and glutathione), suggesting that the effect of H(2)S + NO is thiol sensitive. The stimulatory effect on heart contractility was also induced by GYY4137, a slow-releasing H(2)S donor, when used together with sodium nitroprusside, an NO-releasing donor. More importantly, enzymatic generation of H(2)S from recombinant cystathionine-γ-lyase protein also interacted with endogenous NO generated from l-arginine to stimulate heart contraction. In summary, our data suggest that endogenous NO may interact with H(2)S to produce a new biological mediator that produces positive inotropic effect. The crosstalk between H(2)S and NO also suggests an intriguing potential for the endogenous formation of a thiol-sensitive molecule, which may be of physiological significance in the heart.

Key bioactive reaction products of the NO/H 2 S interaction are S/N-hybrid species, polysulfides, and nitroxyl

“…The recent surge of interest in this chemistry in the biological community (13)(14)(15) was triggered by a growing appreciation that NO and sulfide exert similar and often interdependent biological actions within the cardiovascular system and elsewhere (NO/H 2 S "cross-talk") (16,17), resulting in mutual attenuation or potentiation of their responses. This crosstalk is possibly mediated by chemical interactions (18)(19)(20), but much of the older chemical work seems to have been forgotten. Recently, low concentrations of sulfide were shown to quench NO-mediated vascular responses through formation of an uncharacterized "nitrosothiol" (RSNO) (18)(19)(20), assumed to be thionitrous acid (HSNO) (13)(14)(15).…”

“…This crosstalk is possibly mediated by chemical interactions (18)(19)(20), but much of the older chemical work seems to have been forgotten. Recently, low concentrations of sulfide were shown to quench NO-mediated vascular responses through formation of an uncharacterized "nitrosothiol" (RSNO) (18)(19)(20), assumed to be thionitrous acid (HSNO) (13)(14)(15).…”

Low molecular thiols, pH and O2 modulate H2S-induced S-nitrosoglutathione decomposition – •NO release

“…• NO and H 2 S signaling pathways (Stamler 1994;Ellis et al 2000;Gaston et al 2006;Duan and Chen 2007;Li et al 2009;Yong et al 2010;Yong et al 2011;Kasparek et al 2012). For instance, thiols such as Cys, NAC and GSH have been reported to influence the • NO-H 2 S effects on myocyte contraction (Yong et al 2010(Yong et al , 2011.…”

“…For instance, thiols such as Cys, NAC and GSH have been reported to influence the • NO-H 2 S effects on myocyte contraction (Yong et al 2010(Yong et al , 2011. Although these authors suggested that the mutual effect of H 2 S and…”

GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

“…Finally, this report demonstrated that chronic treatment of rats with GYY4137 resulted in a lowering of blood pressure both in normotensive and, to a greater extent, in spontaneously hypertensive rats (Li et al, 2008). The effect of GYY4137 on cardiac motility has yet to be determined but one report did indicate that this H 2 S donor (like NaHS) could reduce the negative inotropic effect of NO (Yong et al, 2011). It should be noted whilst chronic treatment with GYY4137, using a dose regimen which reduced blood pressure for a period of several days, caused no apparent deleterious side effects in this study, a full screen for possible toxic side effects of GYY4137 has yet to be reported.…”