Sulfide catabolism ameliorates hypoxic brain injury.

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

Improvement in Outcomes After Cardiac Arrest and Resuscitation by Inhibition of S-Nitrosoglutathione Reductase.

BACKGROUND: The biological effects of nitric oxide are mediated via protein S-nitrosylation. Levels of S-nitrosylated protein are controlled in part by the denitrosylase, S-nitrosoglutathione reductase (GSNOR). The objective of this study was to examine whether GSNOR inhibition improves outcomes after cardiac arrest and cardiopulmonary resuscitation (CA/CPR). METHODS: Adult wild-type C57BL/6 and GSNOR-deleted (GSNOR-/-) mice were subjected to potassium chloride-induced CA and subsequently resuscitated. Fifteen minutes after a return of spontaneous circulation, wild-type mice were randomized to receive the GSNOR inhibitor, SPL-334.1, or normal saline as placebo. Mortality, neurological outcome, GSNOR activity, and levels of S-nitrosylated proteins were evaluated. Plasma GSNOR activity was measured in plasma samples obtained from post-CA patients, preoperative cardiac surgery patients, and healthy volunteers. RESULTS: GSNOR activity was increased in plasma and multiple organs of mice, including brain in particular. Levels of protein S-nitrosylation were decreased in the brain 6 hours after CA/CPR. Administration of SPL-334.1 attenuated the increase in GSNOR activity in brain, heart, liver, spleen, and plasma, and restored S-nitrosylated protein levels in the brain. Inhibition of GSNOR attenuated ischemic brain injury and improved survival in wild-type mice after CA/CPR (81.8% in SPL-334.1 versus 36.4% in placebo; log rank P=0.031). Similarly, GSNOR deletion prevented the reduction in the number of S-nitrosylated proteins in the brain, mitigated brain injury, and improved neurological recovery and survival after CA/CPR. Both GSNOR inhibition and deletion attenuated CA/CPR-induced disruption of blood brain barrier. Post-CA patients had higher plasma GSNOR activity than did preoperative cardiac surgery patients or healthy volunteers ( P<0.0001). Plasma GSNOR activity was positively correlated with initial lactate levels in postarrest patients (Spearman correlation coefficient=0.48; P=0.045). CONCLUSIONS: CA and CPR activated GSNOR and reduced the number of S-nitrosylated proteins in the brain. Pharmacological inhibition or genetic deletion of GSNOR prevented ischemic brain injury and improved survival rates by restoring S-nitrosylated protein levels in the brain after CA/CPR in mice. Our observations suggest that GSNOR is a novel biomarker of postarrest brain injury as well as a molecular target to improve outcomes after CA.

[Successful Awake Intubation with Airway Scope? for a Difficult Airway Patient with Enormous Angioma Protruding out of the Mouth].

A 48-year-old man (165 cm, 53 kg), was scheduled for an angioma resection. The tumor was so large that together with tongue, grew from the buccal region to the lower jaw and protruded out of the mouth. Mouth opening was only 2.5-finger-width. Expected as a case of difficult airway, we planned awake intubation using Airway Scope® (AWS) and gum-elastic bougie while maintaining spontaneous ventilation according to the difficult airway algorithm of American Society of Anes- thesiologists. Although fiberscope (FB) is a common choice for awake intubation, it requires proficient skills. In addition, as the distal end of endo-tracheal tube cannnot be visualized by FB, the angioma might be damaged during the intubation. Instead, AWS can visualize the tip of the tube without displacing oropha- ryngeal tissue and it is unlikely to damage the tumor because of a tube guide groove on the inner side of the AWS blade. We experienced successful awake intuba- tion with AWS for a patient with difficult airway due to an enormous angioma protruding out of the mouth.

[The effect of transversus abdominis plane block for pediatric patients receiving bone graft to the alveolar cleft].

BACKGROUND: Transversus abdominis plane block (TAP block) is useful for lower abdominal operations. Recently, ultrasound guided nerve block has been performed with ultrasound scanning. METHODS: We investigated the effectiveness of TAP block in 64 pediatric patients (aged 5-12 years, F/M = 21/43) receiving bone graft from the ilium to the alveolar cleft. We compared the dosages for postoperative analgesics between the groups of TAP block and non-TAP block. RESULTS: In the TAP block group, the frequency of using the postoperative analgesics was lower compared with non TAP block group (P < 0.05). CONCLUSIONS: We concluded that TAP block was effective in pediatric patients receiving bone graft to the alveolar cleft.

[Case of inguinal hernia repair with transversus abdominis plane block and rectus sheath block].

Transversus abdominis plane block is effective for lower abdominal and inguinal operations, and rectus sheath block is effective for abdominal operations. Recently, ultrasound guided nerve block has been employed, and these techniques can be performed with ultrasound scanning. An 82-year-old man with severe coronary failure and chronic obstructive pulmonary disease was scheduled for inguinal hernia repair. We did not want to select general anesthesia for him, and performed rectus sheath block and transversus abdominis plane block. We achieved good anesthetic management using two peripheral blocks under ultrasound scanning.

Supraclinical concentrations of dexmedetomidine evoke norepinephrine release from rat cerebrocortical slices possible involvement of the orexin-1 receptor.

Dexmedetomidine is a highly selective alpha(2)-agonist and reduces norepinephrine release from several neuronal tissues. However, supraclinical concentrations of dexmedetomidine have been reported to increase norepinephrine release from cardiac stores. In addition, some report using microdialysis shows that intrathecal clonidine increased norepinephrine release from the dorsal horn in mid-thoracic spinal cord but dexmedetomidine did not. Thus, in the present study we have studied effects of dexmedetomidine on norepinephrine release from rat cerebrocortical slices and compared this with clonidine. We have also used a selective alpha(2)-antagonist yohimbine and an orexin-1 receptor antagonist SB-334867 to examine whether the effects of dexmedetomidine on norepinephrine release are mediated via alpha(2)-adrenergic or orexin (OX) receptors. In addition, concentrations of orexin A in the evoked sample were also measured. Dexmedetomidine significantly increased norepinephrine release (basal=100%) from rat cerebrocortical slices in a concentration-dependent manner with E(max) 377.3+/-8.6% and pEC(50) 6.12+/-0.07, whereas clonidine significantly reduced the release with E(max) 62.1+/-6.8% and pEC(50) 4.55+/-0.25. Yohimbine (10(-5)M) did not affect the concentration-response curve of dexmedetomidine for norepinephrine release. However, SB-334867 concentration-dependently antagonized dexmedetomidine-evoked norepinephrine release with I(max) 91.0+/-9.4% and pIC(50) 5.99+/-0.18. Orexin A concentrations did not differ between the samples. Thus, supraclinical concentrations of dexmedetomidine increase norepinephrine release from rat cerebrocortical slices, and this release may be mediated via OX(1) but not alpha(2)-adrenoceptors.