Suspended Animation-like State Research Articles

Extreme Physiology Extreme Tolerance to Hypoxia, Hypercapnia, and Pain in the Naked Mole-Rat

Challenging environmental conditions can drive the evolution of extreme physiological traits. The naked mole-rat has evolved to survive and thrive in a low oxygen, high carbon dioxide environment that would be deadly to humans and most other mammals. The naked mole-rat’s lifestyle is unusual in that this species combines subterranean living and living in large, social groups of up to 300 + individuals. Many respiring animals in a closed environment can lead to depletion of oxygen (hypoxia) and accumulation of carbon dioxide (hypercapnia). Naked mole-rats display a variety of physiological traits that negate the adverse effects of living in this atmosphere. For hypoxia tolerance, naked mole-rats have a low resting metabolism, high affinity hemoglobin, intrinsic brain tolerance, the ability to use fructose for anaerobic glycolysis, and the ability to enter a low energy, suspended animation-like state. For hypercapnia tolerance, these animals have a mutation in a voltage gated sodium channel that effectively eliminates neuronal responses to tissue acidosis. In other mammals, acidosis from exposure to high concentrations of carbon dioxide induces pain and pulmonary edema. Understanding these mechanisms of extreme physiology is not only inherently interesting, but it may lead to biomedical breakthroughs in research on heart attacks, strokes, and pain pathologies.

African Naked Mole-Rats Demonstrate Extreme Tolerance to Hypoxia and Hypercapnia.

Naked mole-rats are extremely tolerant to low concentrations of oxygen (hypoxia) and high concentrations of carbon dioxide (hypercapnia), which is consistent with the environment that they inhabit. Naked mole-rats combine subterranean living with living in very densely populated colonies where oxygen becomes depleted and carbon dioxide accumulates. In the laboratory, naked mole-rats fully recover from 5h exposure to 5% O2 and 5h exposure to 80% CO2, whereas both conditions are rapidly lethal to similarly sized laboratory mice. During anoxia (0% O2) naked mole-rats enter a suspended animation-like state and switch from aerobic metabolism of glucose to anaerobic metabolism of fructose. Additional fascinating characteristics include that naked mole-rats show intrinsic brain tolerance to anoxia; a complete lack of hypoxia-induced and CO2-induced pulmonary edema; and reduced aversion to high concentrations of CO2 and acidic fumes. Here we outline a constellation of physiological and molecular adaptations that correlate with the naked mole-rat's hypoxic/hypercapnic tolerance and which offer potential targets for ameliorating pathological conditions in humans, such as the damage caused during cerebral ischemia.

Outcome after hydrogen sulphide intoxication

AimHydrogen sulphide (H2S) intoxication in man is frequently associated with a fatal outcome. In small animal models hydrogen sulphide has demonstrated profound protection against hypoxia. No reports that focus on a potential protective effect in humans have been published. MethodsThe frequency and outcome of a large cohort of hydrogen sulphide intoxications is described. ResultsFrom 1980 until 2013, 35 accidents totalling 56 victims occurred of whom at least 24 (43%) survived. Of the 8 patients with documented cardiopulmonary resuscitation on the scene, 6 (75%) survived. In some of these cases with good outcome the exposure time to very high hydrogen sulphide levels before extraction and resuscitation was more than 45min. ConclusionManure related hydrogen sulphide intoxication is associated with a high mortality, although in some cases, recovery appears to be far more favourable than the initial presentation would suggest. Possibly protection from hypoxic injury due to induction of a suspended animation-like state by hydrogen sulphide may be responsible.

PL13 Saying NO to H2S

Hydrogen sulfide (H 2 S) emerged recently as an important signaling molecule involved in regulation of blood pressure and neuronal activity. Additionally, H 2 S and its donors possess huge pharmacological potential to prevent ischemia–reperfusion injuries and, as it has been speculated, to induce suspended animation-like state in small animals. However, the real (bio) chemical events behind all these observed phenomena remained elusive. In this talk, physiological effects of H 2 S in context of its interaction with another physiological gassotransmitter, nitric oxide (NO), and its metabolites (peroxynitrite, S-nitrosothiols, nitrite) will be addressed, providing the evidence for the existence of a strong cross-talk of these molecules. Applying state-of-the art analytical techniques, as the products of these reactions, we identify thionitric (HSNO 2 ) and thionitrous acid (HSNO) as well as nitroxyl (HNO), and show on cellular level that they too serve as important signaling molecules. Finally on the animal level we prove our chemistry and show that H 2 S-induced vasodilatory effects are directly NO dependent, identifying therefore completely new signaling cascade for systemic neurovascular control.

Suspended animation-inducer hydrogen sulphide protects against organ injury during endotoxemia, but aggravates systemic inflammation

A suspended animation-like state induced by hydrogen sulphide (H2S) was shown before to protect lungs from ventilator-induced lung injury by reducing metabolism and inflammation. This beneficial effect of H2S seems promising, but the effects of H2S during prolonged infusion are unknown. We hypothesized that reducing metabolism in a rat model of LPS-induced systemic inflammation during 8 hours is more protective than during 4 hours.

Potential Applications of Hydrogen Sulfide-Induced Suspended Animation

A suspended animation-like state has been induced in rodents with the use of hydrogen sulfide, resulting in hypothermia with a concomitant reduction in metabolic rate. Also oxygen demand was reduced, thereby protecting against hypoxia. Several therapeutic applications of induction of a hibernation-like state have been suggested, including ischemia-reperfusion injury. More recently, hydrogen sulfide has been found to be protective in states of exaggerated inflammatory responses, such as acute lung injury. Possible mechanisms of this protective effect may include reduction of metabolism, as well as reduction of inflammation. In this manuscript, the methods of inducing a suspended animation-like state in experimental models using hydrogen sulfide are described. We discuss the effects of hydrogen sulfide-induced hypo-metabolism on hemodynamic, metabolic and inflammatory changes in animal models of various hypoxic and inflammatory diseases. In addition, potential therapeutic possibilities of hydrogen sulfide-induced hibernation are outlined.

Hydrogen sulfide: anti-inflammatory and cytoprotective effects

Pharmacological actions of gaseous biological mediator hydrogen sulfide (H2S) include vasodilatation, inhibition of mitochondrial respiration as well as induction of suspended animation-like state [1,2]. Its beneficial cellular actions include cytoprotection and anti-inflammatory effects [2].

Inhaled Hydrogen Sulfide

Breathing hydrogen sulfide (H2S) has been reported to induce a suspended animation-like state with hypothermia and a concomitant metabolic reduction in rodents. However, the impact of H2S breathing on cardiovascular function remains incompletely understood. In this study, the authors investigated the cardiovascular and metabolic effects of inhaled H2S in a murine model. The impact of breathing H2S on cardiovascular function was examined using telemetry and echocardiography in awake mice. The effects of breathing H2S on carbon dioxide production and oxygen consumption were measured at room temperature and in a warmed environment. Breathing H2S at 80 parts per million by volume at 27 degrees C ambient temperature for 6 h markedly reduced heart rate, core body temperature, respiratory rate, and physical activity, whereas blood pressure remained unchanged. Echocardiography demonstrated that H2S exposure decreased both heart rate and cardiac output but preserved stroke volume. Breathing H2S for 6 h at 35 degrees C ambient temperature (to prevent hypothermia) decreased heart rate, physical activity, respiratory rate, and cardiac output without altering stroke volume or body temperature. H2S breathing seems to induce bradycardia by depressing sinus node activity. Breathing H2S for 30 min decreased whole body oxygen consumption and carbon dioxide production at either 27 degrees or 35 degrees C ambient temperature. Both parameters returned to baseline levels within 10 min after the cessation of H2S breathing. Inhalation of H2S at either 27 degrees or 35 degrees C reversibly depresses cardiovascular function without changing blood pressure in mice. Breathing H2S also induces a rapidly reversible reduction of metabolic rate at either body temperature.

Effect of inhaled hydrogen sulfide on metabolic responses in anesthetized, paralyzed, and mechanically ventilated piglets*

Induced hypometabolism may improve the balance between oxygen delivery and consumption and may help sustain tissue viability in critically ill patients with low cardiac output state. Inhaled hydrogen sulfide (H2S) has been shown to induce a suspended animation-like state in mice with a 90% decrease in oxygen consumption. We conducted a preclinical study to explore the potential effect of H2S on metabolic rate in large mammals. Prospective study. Animal laboratory in a university hospital. Eleven anesthetized, paralyzed, and mechanical ventilated piglets (5.8 +/- 0.7 kg). The right carotid artery and superior vena cava were cannulated for arterial pressure monitoring and blood gas sampling. Seven piglets were sequentially exposed to 20, 40, 60, and 80 ppm of H2S over a period of 6 hrs (each level for 1.5 hrs) (H2S group), and additionally four piglets were exposed to air over the same period (control group). Ambient temperature was fixed at 22 degrees C throughout. Central body temperature, arterial pressure, and heart rate were continuously monitored. Oxygen consumption and carbon dioxide production were continuously measured using respiratory mass spectrometry. Cardiac output was calculated using the Fick principle. Central temperature and oxygen consumption significantly and linearly decreased over the H2S exposures (p < .0001 for both), the rates of which were significantly less compared with those in the control group (p < .01 for both). Mean arterial pressure increased significantly (p = .007), whereas heart rate (p = .14), cardiac output (p = .89), and lactate (p = .67) did not change significantly during H2S exposures in H2S group; all the variables decreased significantly in the control group (p < .01 for all), and p < .01 by comparison with H2S group except for lactate (p = .05). H2S does not appear to have hypometabolic effects in ambiently cooled large mammals and conversely appears to act as a hemodynamic and metabolic stimulant.

HYDROGEN SULPHIDE‐INDUCED HYPOTHERMIA ATTENUATES STRESS‐RELATED ULCERATION IN RATS

1. Hydrogen sulphide (H(2)S) acts as a gaseous cellular messenger and has recently been reported to induce a suspended animation-like state in mice. The aim of the present study was to investigate the protective role of H(2)S exposure in stress gastric ulcer. 2. In the present study, we used a rat model of water immersion and restraint stress (WRS) to induce the typical stress disease, namely stress gastric ulcer. Rats were treated with WRS for 4 h, with or without pre-exposure to H(2)S (160 p.p.m. H(2)S for 2.5 h). 3. In H(2)S-exposed rats, body temperature was significantly reduced by 2.5C (P < 0.01) and oxygen consumption was reduced by 37.1% (P < 0.01) compared with control rats. Plasma levels of H(2)S were increased by 20.8% (P < 0.01) following pre-exposure. Pre-exposure to H(2)S significantly reduced the gastric ulcer index, from 24 +/- 9 to 9 +/- 2 (P < 0.01), in WRS rats. In addition, WRS increased plasma levels of adrenocorticotropin (ACTH) and corticosterone 4.7- and 4.8-fold, respectively (both P < 0.01). Pre-exposure to H(2)S markedly suppressed plasma ACTH and corticosterone level by 34.4 and 53.2%, respectively (both P < 0.01), and reduced WRS-elevated myeloperoxidase (MPO) activity by 19%. In the present study, WRS increased gastric malondialdehyde and conjugated diene content by 42 and 68%, respectively (both P < 0.01), and H(2)S exposure reduced lipid peroxide production. Finally, H(2)S exposure inhibited the WRS-elevated expression of glucose-regulated protein 78 and caspase 12, markers of endoplasmic reticulum stress. 4. In conclusion, a low concentration of H(2)S may be a new pharmacological tool for induced hypothermia to prevent severe stress-induced diseases and multifarious trauma in the clinical setting.

SUSPENDED ANIMATION-LIKE STATE PROTECTS MICE FROM LETHAL HYPOXIA

Joseph Priestley observed the high burn rate of candles in pure oxygen and wondered if people would "live out too fast" if we were in the same environment. We hypothesize that sulfide, a natural reducer of oxygen that is made in many cell types, acts as a buffer to prevent unrestricted oxygen consumption. To test this, we administered sulfide in the form of hydrogen sulfide (H2S) to mice (Mus musculus). As we have previously shown, H2S decreases the metabolic rate of mice by approximately 90% and induces a suspended animation-like state. Mice cannot survive for longer than 20 min when exposed to 5% oxygen. However, if mice are first put into a suspended animation-like state by a 20-min pretreatment with H2S and then are exposed to low oxygen, they can survive for more than 6.5 h in 5% oxygen with no apparent detrimental effects. In addition, if mice are exposed to a 20-min pretreatment with H2S followed by 1 h at 5% oxygen, they can then survive for several hours at oxygen tensions as low as 3%. We hypothesize that prior exposure to H2S reduces oxygen demand, therefore making it possible for the mice to survive with low oxygen supply. These results suggest that H2S may be useful to prevent damage associated with hypoxia.

H 2 S Induces a Suspended Animation-Like State in Mice

Mammals normally maintain their core body temperature (CBT) despite changes in environmental temperature. Exceptions to this norm include suspended animation-like states such as hibernation, torpor, and estivation. These states are all characterized by marked decreases in metabolic rate, followed by a loss of homeothermic control in which the animal's CBT approaches that of the environment. We report that hydrogen sulfide can induce a suspended animation-like state in a nonhibernating species, the house mouse (Mus musculus). This state is readily reversible and does not appear to harm the animal. This suggests the possibility of inducing suspended animation-like states for medical applications.