Intracellular signals coupled to muscarinic acetylcholine receptor activation in cerebral frontal cortex from hypoxic mice

The aim of the present work was to determine hypoxia-induced modifications in the cascade of intracellular events coupled to muscarinic acetylcholine receptor (mAChR) activation in brain. For this purpose, enzymatic activitie s were measured on normoxically incubated frontal cortical slices from mice exposed to hypobaric hypoxia for 72 hr. We found that hypoxia induced alterations in several cerebral enzymatic bas al activities: it increased nitric oxide synthase (NOS), but it decreased b oth membrane protein kinase C (PKC) and phospholipase C activities. The mAChR agonist carbachol was found to increase phosphoinositide hydrolys is to greater values in hypoxic tissues than those found in normoxic condit ions. Furthermore, a greater translocation of PKC in response to carbachol was observed in hypoxic tissues than in normoxic ones. Besides, carbachol induced a drastic reduction of NOS activity in hypoxic b rains, at concentrations that stimulated this enzyme activity in normoxic p reparations. In the latter, inhibition is obtained only with high concentra tions of the cholinergic muscarinic agonist. These results pointed to a carbachol-mediated mAChR hyperactivity induced b y hypoxic insult. The possibility that these effects would account for a compensatory mechani sm to diminish NOS hyperactivity, probably protecting for NO neurotoxic act ion in hypoxic brain, is also discussed.