Successful induction of deep hypothermia by isoflurane anesthesia and cooling in a non-hibernator, the rat

The aim of the present study was to establish a novel method for inducing deep hypothermia in rats. Cooling rats anesthetized with isoflurane caused a time-dependent decrease in rectal temperature, but cardiac arrest occurred before their body temperature reached 20 °C when isoflurane inhalation was continued during the cooling process. Stopping inhalation of isoflurane when the rectal temperature reached 22.5 °C successfully induced deep hypothermia, although stopping the inhalation at 27.5 °C resulted in spontaneous recovery of rectal temperature. The hypothermic condition was able to be maintained for up to 6 h. A large number of c-Fos-positive cells were detected in the hypothalamus during hypothermia. Both the maintenance of and recovery from hypothermia caused organ injury, but the damage was transient and recovered within 1 week. These findings indicate that the established procedure is appropriate for inducing deep hypothermia without accompanying serious organ injury in rats.

Mild Hypothermia Attenuates Intercellular Adhesion Molecule-1 Induction via Activation of Extracellular Signal-Regulated Kinase-1/2 in a Focal Cerebral Ischemia Model

Intercellular adhesion molecule-1 (ICAM-1) in cerebral vascular endothelium induced by ischemic insult triggers leukocyte infiltration and inflammatory reaction. We investigated the mechanism of hypothermic suppression of ICAM-1 in a model of focal cerebral ischemia. Rats underwent 2 hours of middle cerebral artery occlusion and were kept at 37°C or 33°C during occlusion and rewarmed to normal temperature immediately after reperfusion. Under hypothermic condition, robust activation of extracellular signal-regulated kinase-1/2 (ERK1/2) was observed in vascular endothelium of ischemic brain. Hypothermic suppression of ICAM-1 was reversed by ERK1/2 inhibition. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in ischemic vessel was attenuated by hypothermia. STAT3 inhibitor suppressed ICAM-1 production induced by stroke. ERK1/2 inhibition enhanced phosphorylation and DNA binding activity of STAT3 in hypothermic condition. In this study, we demonstrated that hypothermic suppression of ICAM-1 induction is mediated by enhanced ERK1/2 activation and subsequent attenuation of STAT3 action.

Central A1-receptor activation associated with onset of torpor protects the heart against low temperature in the Syrian hamster

Body temperature drops dramatically during hibernation, but the heart retains the ability to contract and is resistant to induction of arrhythmia. Although adaptive changes in the heart prior to hibernation may be involved in the cold-resistant property, it remains unclear whether these changes are sufficient for maintaining cardiac pulsatility under an extreme hypothermic condition. We forcibly induced hypothermia in Syrian hamsters by pentobarbital anesthesia combined with cooling of the animals. This allows reproduction of a hypothermic condition in the absence of possible hibernation-specific reactions. Unlike hypothermia in natural hibernation, the forced induction of hypothermia caused atrioventricular block. Furthermore, J-waves, which are typically observed during hypothermia in nonhibernators, were recorded on an ECG. The origin of the J-wave seemed to be related to irreversible injury of the myocardium, because J-waves remained after recovery of body temperature. An abnormal ECG was also found when hypothermia was induced in hamsters that were well adapted to a cold and darkened environment or hamsters that had already experienced hibernation. These results suggest that acclimatization prior to hibernation does not have a crucial effect at least on acquisition of cardiac resistance to low temperature. In contrast, an abnormal ECG was not observed in the case of hypothermia induced by central administration of an adenosine A1-receptor agonist and subsequent cooling, confirming the importance of the adenosine system for inducing hibernation. Our results suggest that some specific mechanisms, which may be driven by a central adenosine system, operate for maintaining the proper cardiac pulsatility under extreme hypothermia.