Intracellular signals coupled to muscarinic acetylcholine receptor activation in cerebral frontal cortex from hypoxic mice.
1. 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 activities were measured on normoxically incubated frontal cortical slices from mice exposed to hypobaric hypoxia for 72 hr. 2. We found that hypoxia induced alterations in several cerebral enzymatic basal activities: it increased nitric oxide synthase (NOS), but it decreased both membrane protein kinase C (PKC) and phospholipase C activities. 3. The mAChR agonist carbachol was found to increase phosphoinositide hydrolysis to greater values in hypoxic tissues than those found in normoxic conditions. Furthermore, a greater translocation of PKC in response to carbachol was observed in hypoxic tissues than in normoxic ones. 4. Besides, carbachol induced a drastic reduction of NOS activity in hypoxic brains, at concentrations that stimulated this enzyme activity in normoxic preparations. In the latter, inhibition is obtained only with high concentrations of the cholinergic muscarinic agonist. 5. These results pointed to a carbachol-mediated mAChR hyperactivity induced by hypoxic insult. 6. The possibility that these effects would account for a compensatory mechanism to diminish NOS hyperactivity, probably protecting for NO neurotoxic action in hypoxic brain, is also discussed.
Borda
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TG
Centro de Estudios Farmacológicos y Botánicos, CEFYBO-CONICET, Buenos Aires, Argentina.
Genaro
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Cremaschi
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D000399:Air Pressure; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005625:Frontal Lobe / Q000166:cytology / Q000502:physiology*; D002534:Hypoxia, Brain / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D048448:Phenylcarbamates; D010716:Phosphatidylinositols / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D002219:Carbamates; D002614:Chelating Agents; D018679:Cholinergic Agonists; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D048448:Phenylcarbamates; D010716:Phosphatidylinositols; D010726:Phosphodiesterase Inhibitors; D011976:Receptors, Muscarinic; C025508:2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate; D019323:omega-N-Methylarginine; D004533:Egtazic Acid; D001285:Atropine; D002217:Carbachol; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D011493:Protein Kinase C; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid