Effects of Oxygen Depletion on Norepinephrine‐ and Carbachol‐Stimulated Phosphoinositide Turnover in Rat Brain Slices

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Abstract
We examined the effects of in vitro anoxia and in vivo hypoxia (8% 02/92% N2) on norepinephrine (NE)‐ and carbachol‐stimulated phosphoinositide (PI) turnover in rat brain slices. The formation of 3H‐labeled polyPI in cortical slices was impaired by in vitro anoxia and fully restored by reoxygenation. Accumulation of 3H‐labeled myo‐inositol phosphates (3H‐IPs) stimulated by 10−5M NE was significantly reduced by anoxia (control at 60 min, 1,217 ± 86 cpm/mg of protein; anoxia for 60 min, 651 ±82 cpm/mg; mean ± SEM; n =5;p > 0.01), and reoxygenation following anoxia resulted in overshooting of the accumulation (control at 120 min, 1,302 ± 70 cpm/mg; anoxia for 50 min plus oxygenation for 70 min, 1,790 ± 126 cpm/mg; n = 5; p > 0.01). The underlying mechanisms for the two phenomena—the decrease caused by anoxia and the overshooting caused by reoxygenation following anoxia—seemed to be completely different because of the following observations, (a) Although the suppression of NE‐stimulated accumulation at low 02 tensions was also observed in Ca2+‐free medium, the overshooting in response to reoxygenation was not. (b) Carbachol‐stimulated accumulation was significantly reduced by anoxia and was restored by reoxygenation only to control levels. Thus, the postanoxic overshooting in accumulation of 3H‐IPs seems to be a specific response to NE. (c) The decrease observed at low 02 tensions was due to a decrease in Emax value, whereas the postanoxic overshooting was due to a decrease in EC50 value. There was also a significant increase in NE‐stimulated accumulation of 3H‐IPs in cortical slices from rats exposed to in vivo hypoxia (8% 02/92% N2) for <6 h, compared with those from rats exposed to room air. These results indicate that depletion of oxygen causes significant changes in receptor‐mediated PI metabolism in brain slices and may provide a clue for understanding biochemical mechanisms for the electrophysiologically demonstrable effects of hypoxia/anoxia on synaptic transmission.

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