PubMed · 9841133
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D Tousoulis, G Davies. 1998-10-13. Acetylcholine and endothelial function.. https://pubmed.ncbi.nlm.nih.gov/9841133/
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1. We have studied capacitative calcium entry (CCE) under different experimental conditions in fura-2-loaded mouse pancreatic acinar cells by digital microscopic fluorimetry. CCE was investigated during [Ca2+]i decay after cell stimulation with a supramaximal concentration of ACh (10 microM) or during Ca2+ readmission in Ca2+-depleted cells (pretreated with thapsigargin or ACh). 2. La3+ and Zn2+ (100 microM) inhibited CCE during Ca2+ readmission but had negligible effects during ACh decay. In contrast flufenamic acid (100 microM), an inhibitor of non-selective cation channels, genistein (10 microM), a broad-range tyrosine kinase inhibitor, and piceatannol (10 microM), an inhibitor specific for non-receptor Syk tyrosine kinase, inhibited CCE during ACh decay but not during Ca2+ reintroduction. 3. Simultaneous detection of Mn2+ entry and [Ca2+]i measurement showed that, in the presence of extracellular calcium, application of 100 microM Mn2+ during ACh decay resulted in manganese influx without alteration of calcium influx, whilst when applied during Ca2+ readmission, Mn2+ entry was significantly smaller and induced a clear inhibition of CCE. 4. Application of the specific protein kinase C inhibitor GF109293X (3 microM) reduced CCE in Ca2+-depleted cells, whereas the activator phorbol 12-myristate, 13-acetate (3 microM) increased Ca2+ entry. 5. Based on these results we propose that cholinergic stimulation of mouse pancreatic acinar cells induces Ca2+ influx with an initial phase operated by a non-specific cation channel, sensitive to flufenamic acid and tyrosine kinase inhibitors but insensitive to lanthanum and divalent cations, followed by a moderately Ca2+-selective conductance inhibited by lanthanum and divalent cations.
Antisense oligodeoxynucleotides against muscarinic m2 and m4 receptors were used to investigate the role of these receptor subtypes as negative autoreceptors in the regulation of acetylcholine (ACh) release in the rat hippocampus. Following the continuous infusion of antisenses into the third ventricle (1 microgram microliter-1 h-1, 3 days), 3H-AF-DX 384/muscarinic M2-like binding was significantly decreased in the medial septum by the antisense against the m2 receptor whereas M2-like binding in the dorsal striatum was decreased by the antisense against the m4 receptor. In contrast, 3H-pirenzepine/muscarinic M1-like binding was unaffected by either antisense treatment in any of the brain areas investigated. When perfused into the hippocampus via a dialysis probe, the purported muscarinic M2 receptor antagonist AF-DX 384 (100 nM) increased hippocampal ACh release in freely moving rats. This effect of AF-DX 384 was significantly attenuated by the m2, but not the m4, receptor antisense treatment. Hippocampal choline acetyltransferase activity was not affected by either antisense treatments. Taken together, these results suggest that the molecularly defined muscarinic m2 receptor regulates hippocampal ACh release by acting as a negative autoreceptor. In contrast, the molecularly defined m4 receptor is unlikely to be directly involved in the negative regulation of ACh release in the rat hippocampus. Therefore, inhibiting muscarinic m2 receptor function may be an alternative approach to regulate the release of ACh in neurodegenerative diseases associated with impaired cholinergic functions.
Cholinergic receptor agonists nicotine (nicotinic), carbachol (nicotinic/muscarinic) and pilocarpine (muscarinic) were administered into the hippocampus and mRNA levels of neurotrophins and their receptors determined using in situ hybridisation. Drug doses were carefully chosen to avoid the potentially confounding effects of seizure and cell death. Nicotine caused a long-lasting increase in nerve growth factor (NGF) mRNA in all subfields of the hippocampus. The increase was evident from 24 h up to 72 h after drug administration. This increase was dependent on excitatory amino acid neurotransmission as it was blocked by administration of an AMPA or NMDA receptor antagonist. In contrast, carbachol and pilocarpine produced a transient increase in NGF mRNA levels present 4-8 h after drug administration. Pilocarpine caused a transient increase in hippocampal brain-derived neurotrophic factor (BDNF) levels, with carbachol and nicotine showing the same trend. Nicotine and carbachol caused transient decreases in NT-3 mRNA levels in dentate gyrus and CA2 with pilocarpine showing a similar trend. Increases in mRNA encoding full-length trkB were seen 8 h after nicotine, with nicotine also causing elevations in a mRNA encoding a truncated isoform (trkB.T2). TrkC mRNA was not altered by any of the conditions used. The study suggests that muscarinic and nicotinic receptor activation in the hippocampus causes transient changes in all of the neurotrophins, but that NGF levels are selectively up-regulated by nicotinic receptor stimulation. The reciprocal interaction between NGF and ascending cholinergic systems may be a component of the cognitive enhancing effects of nicotine.