Masahiko Yonetani

Effects of hypoxia and reoxygenation on nitric oxide production and cerebral blood flow in developing rat striatum

We investigated the role of nitric oxide (NO) in the regulation of regional cerebral blood flow (rCBF) during hypoxia and reoxygenation in developing rat striatum. The subjects were urethane-anesthetized 7- and 14-d-old rats. After 120 min of baseline measurements, the rats received an i.p. injection of either saline (as a control) or an NO synthase inhibitor,N- nitro-l-arginine methyl ester (l-NAME, 30 mg/kg) 30 min before hypoxia. Then they were subjected to a 60-min hypoxia in 8% O2, followed by a 60-min recovery in 21% O2. rCBF and NO concentration in the striatum were measured by laser Doppler flowmetry and an NO electrode throughout the experimental period. In the controls, rCBF decreased to 93± 3% of baseline during hypoxia and increased to 124 ± 3% of baseline during reoxygenation in 7-d-old rats (n = 13), whereas rCBF increased during both hypoxia and reoxygenation in 14-d-old rats to 125± 6% and 168 ± 6% of baseline, respectively (n = 17). l-NAME attenuated the hyperemic response to hypoxia/reoxygenation in both ages(n = 11, in each age). Striatal NO production increased during hypoxia and reoxygenation in both ages, but the increase was significantly less in 7-d-old than in 14-d-old rats. The NO increase was associated with the increase in rCBF, and both were attenuated by l-NAME. We speculate that NO release during hypoxia/reoxygenation modulates rCBF. The immature young rat brain may have less capacity to activate NO production than the more developed brain.

Effect of hemorrhagic hypotension on extracellular level of dopamine, cortical oxygen pressure and blood flow in brain of newborn piglets

The present study describes the relationships between extracellular striatal dopamine, cortical oxygen pressure and blood flow in brain of newborn piglets during hemorrhagic hypotension. Cerebral oxygen pressure was measured optically by the oxygen dependent quenching of phosphorescence; extracellular dopamine by in vivo microdialysis; striatal blood flow was monitored by a laser Doppler. Following a 2 h stabilization period after implanting the microdialysis and laser Doppler probes in the striatum, the mean arterial blood pressure (MABP) was decreased in stepwise manner from 87 +/- 4 Torr (control) to 35 +/- 5 Torr, during 63 min. The whole blood was then reinfused and measurements were continued for 45 min. Statistically significant decrease in blood flow, 10%, was observed when arterial blood pressure decreased to about 53 Torr. With further decrease blood pressure to 35 Torr, blood flow decreased to about 35% of control (P < 0.01). Cortical oxygen pressure decreased almost proportional to decrease in blood pressure. The progressive decrease in MABP from 87 +/- 4 Torr to 65 +/- 6, 52 +/- 7, and 35 +/- 5 Torr resulted in cortical oxygen pressure decreasing from 45 +/- 4 Torr to 33 +/- 3 Torr (P < 0.05), 24 +/- 4 Torr (P < 0.01) and 13 +/- 3 Torr (P < 0.01). The levels of extracellular dopamine in the striatum increased with decreasing cortical oxygen pressure. As cortical oxygen decreased, the extracellular dopamine increased to 230%, 420% and 3200% of control, respectively. Our results show that in mild hypotension total blood flow is well maintained but oxygen pressure in the microvasculature decreases, possibly due to heterogeneity in the regulatory mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Hyperoxia after Transient Hypoxia-Ischemia on Hydroxyl Radical Production in Newborn Rat Striatum

Effect of Hyperoxia after Transient Hypoxia-Ischemia on Hydroxyl Radical Production in Newborn Rat Striatum

Effect of a Nitric Oxide Synthase Inhibitor on Striatal Blood Flow during Hypoxia and Reoxygenation in Immature Rats. † 913

Effect of a Nitric Oxide Synthase Inhibitor on Striatal Blood Flow during Hypoxia and Reoxygenation in Immature Rats. † 913

Effect of Insulin-Induced Hypoglycemia on Cerebral Blood Flow and Nitric Oxide Level in Immature Rat Striatum. † 914

Effect of Insulin-Induced Hypoglycemia on Cerebral Blood Flow and Nitric Oxide Level in Immature Rat Striatum. † 914

DIRECT MEASUREMENT OF NITRIC OXIDE PRODUCTION DURING HYPOXIA AND REOXYGENATION IN DEVELOPING RAT STRIATUM. ▴ 1287

The aim of the present study was to obtain direct evidence of nitric oxide(NO) production in developing rat striatum during hypoxia and reoxygenation by using a NO-selective amperometric microsensor (NO-501, Inter Medical Co., Nagoya, Japan). The study was carried out in urethane-anesthetized 7-day-old and 14-day-old rats (n=6, in each group). The microsensor was calibrated to NO with S-nitroso-N-acetyl-DL-penicillamine before experiment. A current of 100 pA approximately corresponded to NO concentration of 20 nM. We inserted the working electrode into the right striatum and monitored NO response continuously throughout the experiment. Following stabilization, rats were subjected to 60-min hypoxia with 8% O2 and the subsequent 60-min reoxygenation with 21% O2. In 7-day-old rats, we observed a gradual increase in NO release by 101±44 pA in the course of hypoxia and a secondary increase by 178±62 pA during reoxygenation. In 14-day-old rats, the amount of an increase of NO released in response to hypoxia and that of another increase induced by reoxygenation were 426±136 and 430±139 pA, respectively. They were significantly greater than those in 7-day-old rats(p<0.05). Pretreatment with a NO synthase inhibitor,N-nitro-L-arginine methyl ester (5 mg/kg, i.p.) remarkably attenuated NO release during hypoxia and reoxygenation at both ages. The present study demonstrates that the NO microelectrode can detect nanomolar levels of NO released in developing brain. Smaller NO release induced by hypoxia and reoxygenation in younger rats may indicate that immature brain has less ability to activate NO synthase than more developed brain. (Funded by a Grant-in Aid from the Ministry of Education and Science of Japan)

END-TIDAL CARBON MONOXIDE (ETCO) AND NONHEMOLYTIC HYPERBILIRUBINEMIA IN FULL-TERM INFANTS. † 1394

END-TIDAL CARBON MONOXIDE (ETCO) AND NONHEMOLYTIC HYPERBILIRUBINEMIA IN FULL-TERM INFANTS. † 1394

Comparison of postasphyxial resuscitation with 100% and 21% oxygen on cortical oxygen pressure and striatal dopamine metabolism in newborn piglets

The present study tests the hypothesis that ventilation with 100% O2 during recovery from asphyxia leads to greater disturbance in brain function, as measured by dopamine metabolism, than does ventilation with 21% oxygen. This hypothesis was tested using mechanically ventilated, anesthetized newborn piglets as an animal model. Cortical oxygen pressure was measured by the oxygen-dependent quenching of phosphorescence, striatal blood flow by laser Doppler, and the extra-cellular levels of dopamine and its metabolites by in vivo microdialysis. After establishment of a baseline, both the fraction of inspired oxygen (FiO2) and the ventilator rate were reduced in a stepwise fashion every 20 min over a 1-h period. For the subsequent 2-h recovery, the animals were randomized to breathing 21 or 100% oxygen. It was observed that during asphyxia cortical oxygen pressure decreased from 36 to 7 torr, extracellular dopamine increased 8,300%, and dihydroxyphenylacetic acid and homovanillic acid decreased by 65 and 60%, respectively, compared with controls. During reoxygenation after asphyxia, cortical oxygen pressure was significantly higher in the piglets ventilated with 100% oxygen than in those ventilated with 21% oxygen (19 vs. 11 torr). During the first hour of reoxygenation, extracellular dopamine levels decreased to approximately 200% of control in the 21% oxygen group, whereas these levels were still much higher in the 100% oxygen group (approximately 500% of control). After approximately 2 h of reoxygenation, there was a secondary increase in extracellular dopamine to approximately 750 and approximately 3,000% of baseline for the animals ventilated with 21 and 100%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

79 EFFECT OF REPEATED ASPHYXIA/REVENTRATION ON STRIATAL DOPAMINE RELEASE AND CEREBRAL CORTICAL OXYGEN PRESSURE IN NEWBOFN PIGLETS

The striatum, richly innervated by the nigrostriatal dopaminergic pathway, is a brain region highly vulnerable to ischemic/hypoxic neuronal damage and especially affected by repetitive insults. The present study tests the hypothesis that recurrent asphyxia/reventilation alters extracellular dopamine (DA) by decreasing cerebral cortical oxygenation in the striatum of newborn piglets. Anesthetized, ventilated piglets (n=7) underwent seven repeated episoces of 3 min asphyxia, each followed by 15 min reventilation/recovery. Cortical O2 pressure, phosphorescence quenching, and extracellular striatal DA. by in vivo microdialysis, were measured continuously. Serum lactate levels increased from 4±3 mM/L (baseline) to 16±1 mM/L after the 7th episode of asphyxia/ reventilation. Cortical O2 pressure decreased from 39±9 Torr (baseline) to 11±6 Torr during each asphyxia then rapidly returned to baselne values, except after the 7th asphyxia when it returned to baseline in 10 min then decreased again to 19±4 Torr. Extracellular DA concentration was dependent on the number of asphyxia episodes and was higher after each successive asphyxia. From the 2nd to 7th asphyxia, extracellular DA increased from baseline of 6.5 to 9, 12.6. 26, 57, and 84 pmoles/ml, respectively. During 15 min reventilation. DA returned to baseline levels for the first 5 asphyxias, but after the 6th and 7th episodes, DA remained higher than baseline by 50-70%. This progressive DA accumulation could result from hypoxia-induced DA release or from impaired DA reuptake and/or degradation. Thus, repeated episodes of asphyxia were associated with progressive disturbance of striatal DA metabolism, leading to high levels af extracellular DA which represent a potential mechanism of post-asphyxial striatal neuronal injury. Funded by NIH #HD-20337.