Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats

Abstract

Introduction Hydrogen sulfide (H 2 S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H 2 S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H 2 S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses. Methods Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 ± 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-κB (NF-κB), phosphorylated Inhibitor κB (P-IκB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O 2 - ) were also measured by electron paramagnetic resonance. Results At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 ± 32 versus 101 ± 17 mmHg, P < 0.05). CBF was better maintained in NaHS-treated rats (1.9 ± 1.6 versus 4.4 ± 1.9 ml/minute P < 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IκB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O 2 - release in both aorta and heart ( P < 0.05). Conclusions NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR).

Hydrogen sulfide attenuates calcification of vascular smooth muscle cells via KEAP1/NRF2/NQO1 activation

“…These results are in line with a previous observation showing that H 2 S/HSprotects against cellular aging via KEAP1/NRF2 signaling despite the absence of an effect on the expression of these proteins [42]. However, an upregulation of NRF2 upon sulfide treatment was reported in other studies [12,16].…”

Pharmacologic attenuation of the hyperdynamic response to supraceliac aortic clamping

“…Pharmacologic adjuncts have demonstrated significant promise in minimizing metabolic and resuscitative requirements after an ischemia-reperfusion injury in swine and murine models. 5,16,17 HS is a medication of this class and is thought to work by minimizing the activation of the systemic inflammatory cascade that occurs after ischemiareperfusion injuries and allows reduction in cytotoxic inflammatory mediators and the downregulation of Lselectin expression, causing a reduced neutrophil extravasation and tissue infiltration. 5,18 Within our own laboratory, we demonstrated that valproic acid minimized aortic endothelial cell injury and resuscitative requirements with this same model when administered at the time of crossclamp.…”

“…5,16,17 HS is a medication of this class and is thought to work by minimizing the activation of the systemic inflammatory cascade that occurs after ischemiareperfusion injuries and allows reduction in cytotoxic inflammatory mediators and the downregulation of Lselectin expression, causing a reduced neutrophil extravasation and tissue infiltration. 5,18 Within our own laboratory, we demonstrated that valproic acid minimized aortic endothelial cell injury and resuscitative requirements with this same model when administered at the time of crossclamp. 4 However, for these medications to enter clinical practice, preclinical studies are essential to analyze the effect and preclinical response to novel therapeutics.…”

“…Although HS has demonstrated great promise through protective histologic and cellular mechanisms by attenuating oxidative stress and decreasing cellular injury, clinical findings are needed to make it useful in human clinical practice. 5,6 Of particular interest, a murine model demonstrated HS produced a state of "suspended animation," decreased inflammation after traumatic injury, and improved survival from hemorrhage. 5,[7][8][9] Despite the promising results in the murine model, porcine models have not demonstrated the same efficacy in cardiac arrest or after a hemorrhagic event.…”

“…5,6 Of particular interest, a murine model demonstrated HS produced a state of "suspended animation," decreased inflammation after traumatic injury, and improved survival from hemorrhage. 5,[7][8][9] Despite the promising results in the murine model, porcine models have not demonstrated the same efficacy in cardiac arrest or after a hemorrhagic event. 10,11 However, HS may have more promising benefit after an ischemia-reperfusion injury because it has been reported to dampen the inflammatory cascade.…”