Shingo Hagioka

Changes in nitric oxide production and cerebral blood flow before development of hyperbaric oxygen-induced seizures in rats

The predictive value of increase in cerebral blood flow (CBF) was examined to detect hyperbaric oxygen (HBO(2))-induced electrical discharge in artificially ventilated rats at three PaCO(2) levels under 5 atmospheric pressures. The possible involvement of NO production in the mechanism of the increase in CBF was also assessed by measurement of major NO metabolites (NO(2)(-) plus NO(3)(-)) using a microdialysis technique at the left parietal cortex during HBO(2) exposure. The onset times of electrical discharge, measured in the right frontal region, were significantly prolonged and shortened in the low PaCO(2) group (79+/-21 min) and high PaCO(2) group (27+/-7 min), respectively, compared to that in the normal PaCO(2) group (37+/-5 min). Increase in CBF (200% of the pre-exposure level) was observed in every animal and was sustained until the appearance of electrical discharge. The onset time of increase in CBF was closely related to that of electrical discharge (R(2)=0.987), and the durations of increase in CBF were almost identical (11-14 min in mean) regardless of the PaCO(2) level. The level of NO(2)(-) plus NO(3)(-) was unaffected by the initiation of HBO(2) exposure and simultaneously increased up to 246+/-59% of control level with the onset of increase in CBF. There was a close relationship between changes in CBF and levels of NO(2)(-) plus NO(3)(-) (R(2)=0.544). These results indicate that monitoring of CBF is useful for the prediction of electrical discharge in artificially ventilated rats regardless of their PaCO(2) levels and that the increase in NO production is related to the mechanism of increase in CBF.

Effects of 7-nitroindazole and N-nitro-l-arginine methyl ester on changes in cerebral blood flow and nitric oxide production preceding development of hyperbaric oxygen-induced seizures in rats

Hyperbaric oxygen (HBO(2)) exposure induces increases in cerebral blood flow (CBF) and extracellular concentrations of nitric oxide (NO) that precede the appearance of central nervous system toxicity, which may manifest as convulsions. To elucidate the origins of NO production during HBO(2) exposure, we examined the effects of the selective neuronal NO synthase (NOS) inhibitor, 7-nitroindazole (7-NI), and the non-selective NOS inhibitor, N-nitro-l-arginine methyl ester (l-NAME), on changes in CBF and NO metabolites (NO(x), nitrite and nitrate) using a laser Doppler flow probe and in vivo microdialysis techniques, respectively. Rats were anesthetized, artificially ventilated, and pressurized to 5 atmosphere absolute (ATA) with pure oxygen for 60 min. In rats treated with vehicle, CBF and NO(x) levels in the cortex increased to 201% and 239% of basal levels, respectively, before the onset of electrical discharges, measured by electroencephalogram. The increase in CBF and NO(x) was completely inhibited by 7-NI and l-NAME. Both drugs also inhibited the appearance of electrical discharges for 60 min. Dynamic changes in CBF and NO(x) were not significantly different between 7-NI and l-NAME. These findings suggest that neuronal NOS is the main mediator of NO production associated with increase in CBF leading to the appearance of electrical discharge during HBO(2) exposure.

Nasopharyngeal cooling selectively and rapidly decreases brain temperature and attenuates neuronal damage even if initiated at the onset of cardiopulmonary resuscitation in rats

ObjectiveTo determine the effectiveness of nasopharyngeal cooling for selective brain cooling and neuroprotection from ischemia. DesignProspective animal study. SettingExperimental laboratory in a university hospital. SubjectsMale Wistar rats (n = 28). InterventionsIn study 1, hippocampal temperature was decreased to 31°C under spontaneous circulation. In the nasopharyngeal cooling group, physiologic saline (5°C) was infused to the bilateral nasal cavities at the rate of 100 mL·min−1·kg weight−1. In the whole body cooling group, a fan and a water blanket (5°C) were used. In study 2, ischemia and resuscitation were performed in normothermic and nasopharyngeal cooling (initiated with resuscitation after 5 mins of ischemia and continued for 20 mins) groups. Measurements and Main ResultsThe hippocampal temperature was decreased to 31°C in 7 ± 2 mins without any change in the rectal temperature in the nasopharyngeal cooling group, whereas a decrease in hippocampal temperature to 31°C took 33 ± 1 mins in the whole body cooling group. Although skull base region was cooled by nasopharyngeal cooling, the epidural temperature of the parietal region was lower than the hippocampal temperature, indicating that brain temperature was hematogeneously lowered. There was no difference between changes in cerebral blood flow or between the ratios of oxygen extraction from arterial blood in the head region in the nasopharyngeal cooling and whole body cooling groups. In the second study, all animals were successfully resuscitated, and the times required for recovery of mean arterial blood pressure (60 mm Hg) after resuscitation in the nasopharyngeal cooling and normothermic groups were the same. The histologic damage was significantly attenuated in the nasopharyngeal cooling group (33 ± 21% cell death in the hippocampus) compared with that in the normothermic group (73 ± 11%). ConclusionsNasopharyngeal cooling enables rapid and selective reductions in cortical and subcortical temperatures without disturbing the recovery of systemic circulation after resuscitation.

Quantitative evaluation of the neuroprotective effects of hypothermia ranging from 34°C to 31°C on brain ischemia in gerbils and determination of the mechanism of neuroprotection

ObjectiveThe present study was designed to determine whether the predominant factor responsible for neuroprotection of hypothermia ranging from 31 to 34°C is prolongation of onset of ischemic depolarization or suppression of neuronal injury during ischemic depolarization and to quantitatively determine the neuroprotective effects of hypothermia of 34°C and 31°C. DesignProspective animal study. SettingA university research laboratory. SubjectsEighty-nine gerbils. InterventionsBilateral common carotid arteries were occluded for 3–20 mins. The brain temperature was set at 37°C, 34°C, or 31°C before and during ischemic depolarization. Measurements and Main ResultsDC potentials were measured in the CA1 region, where histologic evaluation was performed 7 days later. Onset times of ischemic depolarization were 1.3 ± 0.2, 1.6 ± 0.4, and 2.4 ± 0.7 mins at 37°C, 34°C, and 31°C, respectively. The logistic regression curve demonstrated a close relationship between duration of ischemic depolarization and neuronal damage and showed a rightward shift by lowering the brain temperature. In the 37°C, 34°C, and 31°C groups, the durations of ischemic depolarization causing 50% neuronal damage were estimated to be 8.0, 14.2, and 26.0 mins, respectively, and the ischemia times causing 50% neuronal damage were estimated to be 4.9, 8.1, and 14.2 mins, respectively. ConclusionsThe onset of ischemic depolarization was prolonged in the 34°C and 31°C groups by only 0.3 and 1.1 mins, respectively, compared with that in the 37°C group. Most of the neuroprotection by hypothermia was attributed to the suppression of neuronal injury during ischemic depolarization, suggesting that hypothermia has neuroprotective effects if it is initiated during the ischemic depolarization period. The results also indicate that the neuroprotective effect at 31°C is about three times greater than that at 34°C and that neuronal cells can withstand 2.9 times longer duration of ischemia at 31°C than at 37°C.