Hemodynamic and Metabolic Effects of Hydrogen Sulfide During Porcine Ischemia/Reperfusion Injury

Abstract

In awake spontaneously breathing mice, inhaling gaseous hydrogen sulfide (H2S) produced a "suspended animation-like" metabolic status with hypothermia and reduced O2 demand, thus protecting from lethal hypoxia. Murine models may be questioned, however, because due to their large surface area/mass ratio, rodents can rapidly drop their core temperature. Therefore, we investigated whether intravenous H2S (Na2S, sodium sulfide) would induce a comparable metabolic response in anesthetized and mechanically ventilated pigs. Because H2S was reported to improve heart function after myocardial ischemia, we also investigated whether sulfide would influence the noradrenaline responsiveness during reperfusion after aortic occlusion. After 2 h of i.v. sulfide (0.2 mg.kg followed by 2 mg.kg.per h; n=8) or vehicle (n=8), animals underwent 30 minutes of aortic occlusion with nitroglycerine, esmolol, and adenosine-5'-triphosphate adjusted to maintain MAP at 80% to 120% of baseline. During reperfusion, noradrenaline was titrated to keep MAP greater than or equal to 80% of this level. Sulfide reduced heart rate and cardiac output without affecting stroke volume, markedly decreased the time and dose of noradrenaline required to maintain hemodynamic targets, and caused a drop in core temperature concomitant with lower O2 uptake and CO2 production. Although arterial PCO2 and acid-base status were comparable, arterial PO2 was lower in the sulfide group at the end of the experiment. Sulfide attenuated the reperfusion-related hyperlactatemia, although glycemia was higher at the end of the experiment. The parameters of inflammation and oxidative stress did not differ. Intravenous sulfide allowed reducing energy expenditure in an anesthetized large-animal model and improved the noradrenaline responsiveness during reperfusion after aortic occlusion. Investigations are warranted, hence, whether it may also protect other organs after I/R injury.

The role of gasotransmitters NO, H2S and CO in myocardial ischaemia/reperfusion injury and cardioprotection by preconditioning, postconditioning and remote conditioning

“…In anaesthetized and mechanically ventilated pigs subjected to ischaemia/reperfusion, Na2S reduced the heart rate and the cardiac output without affecting stroke volume (Simon et al, 2008). In animals with co-morbidities, administration of Na2S beginning 24 h or 7 days before myocardial ischaemia significantly decreased infarct size in db/db diabetic mice.…”

“…No change in oxidative stress. Simon et al (2008) In vivo (mice) NaHS-PostC Dose dependent reduction of I/R. Anti-inflammatory properties, preservation of mitochondrial function Elrod et al (2007) In vivo (rat) model of haemorrhage-induced I/R NaHS PostC Shock and I/R induced a decrease in MAP, lactic acidosis and ex vivo vascular hyporeactivity, which were attenuated by NaHS Decrease in both pro-inflammatory cytokines and iNOS expression and an up-regulation of the Akt/eNOS pathway Issa et al (2013) In vivo (pigs) NaHS-PostC Reduction of infarct size Anti-inflammatory effects Sodha et al (2009) In vivo (pigs) NaHS-PostC Reduction of infarct size Markers of apoptosis and autophagy anti-apoptotic effects Osipov et al (2009) db/db diabetic mice (Na2S) PC Decreased myocardial injury Impair aspects of Nrf2 signalling Peake et al (2013) against reoxygenation damage was assessed.…”

“…Typical characteristics of isoprenaline-induced myocardial injury were abolished by NaHS administration as shown by reduction in elevated thiobarbituric acid reactive substances and normalization of GSH, glutathione peroxidase, SOD and catalase activity. Furthermore, a decrease in TNF-α expression and an improvement of myocardial architecture was also observed and the inhibition of NOS abolished the H2S-induced cardioprotection in mice (Sojitra et al, 2012).S-allylcysteine (SAC), which is an organosulphurcontaining compound derived from garlic, mediated cardioprotection via a H2S-related pathway in rats and significantly lowered mortality and reduced infarct size, whereas protein expression studies revealed that SAC up-regulated CSE expression (Chuah et al, 2007).In anaesthetized and mechanically ventilated pigs subjected to ischaemia/reperfusion, Na2S reduced the heart rate and the cardiac output without affecting stroke volume (Simon et al, 2008). In animals with co-morbidities, administration of Na2S beginning 24 h or 7 days before myocardial ischaemia significantly decreased infarct size in db/db diabetic mice.…”

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…Commercial Na 2 S, on the other hand, is considerably purer but in in vitro experiments, still generates H 2 S too quickly to be physiologically equivalent. Nonetheless, as a therapeutic tool, pharmaceutical-grade Na 2 S shows great potential and has been successfully used to prevent and treat myocardial infarction, ischemia-reperfusion injury and endotoxic shock [112,113]. It is Table 2 By sharp contrast, no effect was observed with mesalamine or ADT-OH treatment alone, suggesting protective effects in addition to H 2 S release [111] Male Wistar rats: Carageenan-induced hindpaw edema The study concluded that the additional anti-inflammatory effect of S-diclofenac was due to H 2 S release [134] Male Wistar rats: Trinitrobenzene sulfonic acid-induced colitis [125] Male Swiss albino mice: Cecal ligation and puncture-induced sepsis PPT-A gene expression and substance P levels whereas NaSH increased substance P levels and lung injury [71] Balb/C mice: Acute pancreatitis and associated lung inflammation induced by cerulein…”

Is Pharmacological, H2S-induced ‘Suspended Animation’ Feasible in the ICU?

“…In larger species (swine, sheep), various authors failed to confi rm any H 2 S-related reduction in metabolic activity at all, regardless of whether inhalation of gaseous H 2 S or injection of sulfi de salts were studied [19]- [22]. Moreover, in sheep, Derwall et al [23] demonstrated that during administration of gaseous H 2 S via an extracorporeal, veno-arterial membrane oxygenator to avoid any airway mucosa damage related to the gas inhalation [24], [25], whole body O 2 uptake, CO 2 production, and cardiac output remained within the physiological range. At the highest doses administered (300 ppm), H 2 S did not aff ect calorimetric energy expenditure either, but caused pulmonary vasoconstriction associated with arterial hypotension and metabolic acidosis [23].…”