Rapid relief of block by mecamylamine of neuronal nicotinic acetylcholine receptors of rat chromaffin cells in vitro: an electrophysiological and modeling study.
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The mechanism responsible for the blocking action of mecamylamine on neuronal nicotinic acetylcholine receptors (nAChRs) was studied on rat isolated chromaffin cells recorded under whole-cell patch clamp. Mecamylamine strongly depressed (IC(50) = 0.34 microM) inward currents elicited by short pulses of nicotine, an effect slowly reversible on wash. The mecamylamine block was voltage-dependent and promptly relieved by a protocol combining membrane depolarization with a nicotine pulse. Either depolarization or nicotine pulses were insufficient per se to elicit block relief. Block relief was transient; response depression returned in a use-dependent manner. Exposure to mecamylamine failed to block nAChRs if they were not activated by nicotine or if they were activated at positive membrane potentials. These data suggest that mecamylamine could not interact with receptors either at rest or at depolarized level. Other nicotinic antagonists like dihydro-beta-erythroidine or tubocurarine did not share this action of mecamylamine although proadifen partly mimicked it. Mecamylamine is suggested to penetrate and block open nAChRs that would subsequently close and trap this antagonist. Computer modeling indicated that the mechanism of mecamylamine blocking action could be described by assuming that 1) mecamylamine-blocked receptors possessed a much slower, voltage-dependent isomerization rate, 2) the rate constant for mecamylamine unbinding was large and poorly voltage dependent. Hence, channel reopening plus depolarization allowed mecamylamine escape and block relief. In the presence of mecamylamine, therefore, nAChRs acquire the new property of operating as coincidence detectors for concomitant changes in membrane potential and receptor occupancy. (+info)
Calcium signaling and c-Fos gene expression via M3 muscarinic acetylcholine receptors in human T- and B-cells.
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We previously showed that blood acetylcholine (ACh) originates mainly from T-lymphocytes, and that stimulation of muscarinic ACh receptors (mAChRs) induces Ca2+ oscillations and up-regulates c-fos gene expression in both T- and B-lymphocytes. In the present study, we investigated which mAChR subtypes are involved in Ca2+ signaling and c-fos gene expression in human T- (CEM) and B- (Daudi) cells. Stimulation of mAChRs with 100 microM oxotremorine-M, an M1/M3 agonist, increased levels of intracellular free Ca2+ ([Ca2+]i) and c-fos mRNA expression in both cell lines. 4-DAMP, an M3 antagonist, more effectively blocked the oxotremorine-M-induced increase in [Ca2+]i than pirenzepine and telenzepine, M1-receptor antagonists; AF-DX 116, an M2 antagonist; hexahydrosiladifenidol, a weak M3 antagonist; or hexamethonium and d-tubocurarine, nicotinic receptor antagonists. McN-A-343 (100 microM), a partial M1-receptor agonist, had no apparent effect on [Ca2+]i in either cell line. The oxotremorine-M-induced up-regulation of c-fos transcription was inhibited by 4-DAMP, but not by pirenzepine or AF-DX 116. Our findings thus suggest that ACh released from T-lymphocytes acts as an autocrine/paracrine factor, transmitting a Ca2+-dependent signal to the nuclei of T- and B-lymphocytes via M3 receptors. (+info)
Small diameter dorsal root ganglion (DRG) neurons, which include cells that transmit nociceptive information into the spinal cord, are known to express functional kainate receptors. It is well established that exposure to kainate will depolarize C-fiber afferents arising from these cells. Although the role of kainate receptors on sensory afferents is unknown, it has been hypothesized that presynaptic kainate receptors may regulate glutamate release in the spinal cord. Here we show that kainate, applied at low micromolar concentrations in the presence of the AMPA-selective antagonist (RS)-4-(4-aminophenyl)-1, 2-dihydro-1-methyl-2-propyl-carbamoyl-6,7-methylenedioxyphthalazine++ +, suppressed spontaneous NMDA receptor-mediated EPSCs in cultures of spinal dorsal horn neurons. In addition, kainate suppressed EPSCs in dorsal horn neurons evoked by stimulation of synaptically coupled DRG cells in DRG-dorsal horn neuron cocultures. Interestingly, although the glutamate receptor subunit 5-selective kainate receptor agonist (RS)-2-alpha-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) (2 micrometer) was able to suppress DRG-dorsal horn synaptic transmission to a similar extent as kainate (10 micrometer), it had no effect on excitatory transmission between dorsal horn neurons. Agonist applications revealed a striking difference between kainate receptors expressed by DRG and dorsal horn neurons. Whereas DRG cell kainate receptors were sensitive to both kainate and ATPA, most dorsal horn neurons responded only to kainate. Finally, in recordings from dorsal horn neurons in spinal slices, kainate and ATPA were able to suppress NMDA and AMPA receptor-mediated EPSCs evoked by dorsal root fiber stimulation. Together, these data suggest that kainate receptor agonists, acting at a presynaptic locus, can reduce glutamate release from primary afferent sensory synapses. (+info)
Ileus after administration of cold remedy in an elderly diabetic patient treated with acarbose.
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A 69-year-old type 2 diabetic man was admitted due to diabetic gangrane. He had a history of subtotal gastrectomy. During hospitalization, he was treated with regular insulin and 300 mg/day of acarbose. He developed a low grade fever, cough and nasal discharge, and was given a compound "cold" remedy with anticholenergic properties. The next day, he suffered from a paralytic ileus. Oral intake and acarbose were withheld and the ileus spontaneously resolved after 2 days. These finding indicate the possibility that the ileus was triggered by drugs with anticholinergic properties in this elderly diabetic patient treated with alpha-glucosidase inhibitors. (+info)
Sedation in outpatient bronchoscopy.
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Bronchoscopy is a procedure that is likely to provoke anxiety as the patient is surrounded by monitoring and bronchoscopy equipment, and care is administered by strangers who perform intimate, invasive, and sometimes, painful procedures. Sedation is needed, therefore, to allay anxiety and reduce stress, improve patient comfort and co-operation, provide amnesia and facilitate the bronchoscopic procedure. In this review we try to summarize the current knowledge on currently used sedation protocols with special reference to the commonly used pharmacological agents. We believe sedation should be used routinely in fiberoptic bronchoscopy in order to achieve a safe and pleasant procedure for both the patient and the pulmonologist. (+info)
The biological role of non-neuronal acetylcholine in plants and humans.
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Acetylcholine, one of the most exemplary neurotransmitters, has been detected in bacteria, algae, protozoa, tubellariae and primitive plants, suggesting an extremely early appearance in the evolutionary process and a wide expression in non-neuronal cells. In plants (Urtica dioica), acetylcholine is involved in the regulation of water resorption and photosynthesis. In humans, acetylcholine and/or the synthesizing enzyme, choline acetyltransferase, have been demonstrated in epithelial (airways, alimentary tract, urogenital tract, epidermis), mesothelial (pleura, pericardium), endothelial, muscle and immune cells (granulocytes, lymphocytes, macrophages, mast cells). The widespread expression of non-neuronal acetylcholine is accompanied by the ubiquitous expression of cholinesterase and acetylcholine sensitive receptors (nicotinic, muscarinic). Both receptor populations interact with more or less all cellular signalling pathways. Thus, non-neuronal acetylcholine can be involved in the regulation of basic cell functions like gene expression, proliferation, differentiation, cytoskeletal organization, cell-cell contact (tight and gap junctions, desmosomes), locomotion, migration, ciliary activity, electrical activity, secretion and absorption. Non-neuronal acetylcholine also plays a role in the control of unspecific and specific immune functions. Future experiments should be designed to analyze the cellular effects of acetylcholine in greater detail and to illuminate the involvement of the non-neuronal cholinergic system in the pathogenesis of diseases such as acute and chronic inflammation, local and systemic infection, dementia, atherosclerosis, and finally cancer. (+info)
Encoding of different aspects of afferent activities by two types of cells in the corpus glomerulosum of a teleost brain.
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The corpus glomerulosum (CG) is an expansive nucleus in acanthopterigian teleosts that has been suggested to be involved in vision-related information processing and the control of the hypothalamic function. The CG has only two types of constituent cells, the large cell and the small cell, and well-defined afferent/efferent fiber connections. One of the three types of teleostean CG, type III has additional outstanding morphological characters: clearly laminated organization and giant (>50 microm in diameter) tips of postsynaptic dendrites. Although such histological architecture is potentially advantageous for the study of information processing in a brain nucleus based on the physiological properties of identified cells and synapses, previous studies on the CG have been limited to anatomy. In this study, we developed a slice preparation of the type III CG in a teleost, Stephanoplepis cirrhifer, and studied the morphology and physiology of individual cells and synaptic transmission by means of dendritic intracellular and somatic whole cell recordings. The characteristic morphology of the two types of cells was revealed by intracellular staining. While both of them received similar glutamatergic and GABAergic projections from the nucleus corticalis mediated by AMPA, N-methyl-D-aspartate, and GABA(A) receptors, they showed quite distinctive firing properties and postsynaptic responses with current injection and synaptic inputs: the large cell fired a single spike, and the small cell fired a spike train whose frequency was dependent on the stimulus intensity. Furthermore, the large cell showed low-pass temporal filtering properties with paired stimuli. These results suggest that the large cell and the small cell may encode different aspects of the corticalis activities. (+info)
Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing.
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OBJECTIVE: To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people. DESIGN: Randomised controlled trial with three arms (individual visits, group visits, and a control arm). SETTING: Southwest Netherlands. PARTICIPANTS: 190 general practitioners and 37 pharmacists organised in 21 peer review groups were studied using a database covering all prescriptions to people covered by national health insurance in the area (about 240 000). INTERVENTION: All general practitioners and pharmacists in both intervention arms were offered two educational visits. For physicians in groups randomised to the individual visit arm, 43 of 70 general practitioners participated; in the group visit intervention arm, five of seven groups (41 of 52 general practitioners) participated. MAIN OUTCOME MEASURES: Numbers of elderly people (>/=60 years) with new prescriptions of highly anticholinergic antidepressants and less anticholinergic antidepressants. RESULTS: An intention to treat analysis found a 26% reduction in the rate of starting highly anticholinergic antidepressants in elderly people (95% confidence interval -4% to 48%) in the individual intervention arm and 45% (8% to 67%) in the group intervention arm. The use of less anticholinergic antidepressants increased by 40% (6% to 83%) in the individual intervention arm and 29% (-7% to 79%) in the group intervention arm. CONCLUSIONS: Both the individual and the group visits decreased the use of highly anticholinergic antidepressants and increased the use of less anticholinergic antidepressant in elderly people. These approaches are practical means to improve prescribing by continuing medical education. (+info)