177,172 research outputs found
Voltage- and activity-dependent chloride conductance controls the resting status of the intact rat sympathetic neuron
No full textRemarkable activity dependence was uncovered in the chloride conductance that operates in the subthreshold region of membrane potential, by using the two-microelectrode voltage-clamp technique in the mature and intact rat sympathetic neuron. Both direct and synaptic neuron tetanization (15 Hz, 10-s duration to saturate the response) resulted in a long-lasting (not less than 15 min) increase of cell input conductance (+70-150% 10 min after tetanus), accompanied by the onset of an inward current with the same time course. Both processes developed with similar properties in the postganglionic neuron when presynaptic stimulation was performed under current- or voltage-clamp conditions and were unaffected by external calcium on direct stimulation. The posttetanic effects were sustained by gCl increase because both conductance and current modifications were blocked by 0.5 mM Anthracene-9-carboxylic acid (a chloride channel blocker) but were unaffected by TEACl or cesium chloride treatments. The chloride channel properties were modified by stimulation: their voltage sensitivity and rate of closure in response to hyperpolarization strongly increased. The voltage dependence of the three major conductances governing the cell subthreshold status (gCl, gK, and gL) was evaluated over the -40/-110 mV membrane potential range in unstimulated neurons and compared with previous results in stimulated neurons. A drastic difference between the voltage-conductance profiles was observed, exclusively sustained by gCl increase. The chloride channel thus hosts an intrinsic mechanism, a memory of previous neuron activity, which makes the chloride current a likely candidate for natural controller of the balance between opposite resting currents and thus of membrane potential level
Mitogenic effect of serotonin in human small cell lung carcinoma cells via both 5-HT1A and 5-HT1D receptors
No full textWe have recently shown that the mitogenic effect of serotonin (5-hydroxytryptamine, 5-HT) on human small lung carcinoma (SCLC) cells is at least partly due to stimulation of a 5-HT1D receptor type. We now report that the 5-HT1A receptor agonist R(+)-8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT) is also capable of stimulating [3H]thymidine incorporation into SCLC GLC-8 cells, although with lower efficacy than 5-HT. The simultaneous administration of maximal doses of 8-OH-DPAT and the 5-HT1D receptor agonist sumatriptan reproduced the maximal [3H]thymidine incorporation observed with 5-HT alone. The 5-HT1A receptor antagonists spiperone and SDZ 216-525 completely abolished the effect of 8-OH-DPAT (IC50 30 nM for both drugs) behaving as pure antagonists. Accordingly, the two drugs partially inhibited the mitogenic effect of 5-HT. These data indicate that the mitogenic effect of 5-HT in SCLC cells involves both 5-HT1A and 5-HT1D receptor types
Pre- and Postsynaptic Effects of Glutamate in the Frog Labyrinth
No full textThe role of glutamate in quantal release at the cytoneural junction was examined by measuring mEPSPs and afferent spikes at the posterior canal in the intact frog labyrinth. Release was enhanced by exogenous glutamate, or DL-TBOA, a blocker of glutamate reuptake. Conversely, drugs acting on ionotropic glutamate receptors did not affect release; the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) blocker CNQX decreased mEPSP size in a dose-dependent manner; the NMDA-R blocker p-AP5 at concentrations <200 mu M did not affect mEPSP size, either in the presence or absence of Mg and glycine. In isolated hair cells, glutamate did not modify Ca currents. Instead, it systematically reduced the compound delayed potassium current, IKD, whereas the metabotropic glutamate receptor (mGluR)-II inverse agonist, (2S)-2-amino-2-[(1S,2S)2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (LY341495), increased it. Given mGluR-II decrease cAMP production, these finding are consistent with the reported sensitivity of IKD to protein kinase A (PKA)mediated phosphorylation. LY341495 also enhanced transmitter release, presumably through phosphorylation-mediated facilitation of the release machinery. The observed enhancement of release by glutamate confirms previous literature data, and can be attributed to activation of mGluR-I that promotes Ca release from intracellular stores. Glutamate-induced reduction in the repolarizing IKD may contribute to facilitation of release. Overall, glutamate exerts both a positive feedback action on mGluR-I, through activation of the phospholipase C (PLC)/IP3 path, and the negative feedback, by interfering with substrate phosphorylation through G(i/0)-coupled mGluRs-II/III. The positive feedback prevails, which may explain the increase in overall rates of release observed during mechanical stimulation (symmetrical in the excitatory and inhibitory directions). The negative feedback may protect the junction from over-activation. (C) 2018 The Author(s). Published by Elsevier Ltd on behalf IBRO
Static and dynamic properties of synaptic transmission at the cyto-neural junction of frog labyrinth posterior canal.
No full textThe properties of synaptic transmission have been studied at the cyto-neural junction of the frog labyrinth posterior canal by examining excitatory postsynaptic potential (EPSP) activity recorded intraaxonally from the afferent nerve after abolishing spike firing by tetrodotoxin. The waveform, amplitude, and rate of occurrence of the EPSPs have been evaluated by means of a procedure of fluctuation analysis devised to continuously monitor these parameters, at rest as well as during stimulation of the semicircular canal by sinusoidal rotation at 0.1 Hz, with peak accelerations ranging from 8 to 87 deg.s-2. Responses to excitatory and inhibitory accelerations were quantified in terms of maximum and minimum EPSP rates, respectively, as well as total numbers of EPSPs occurring during the excitatory and inhibitory half cycles. Excitatory responses were systematically larger than inhibitory ones (asymmetry). Excitatory responses were linearly related either to peak acceleration or to its logarithm, and the same occurred for inhibitory responses. In all units examined, the asymmetry of the response yielded nonlinear two-sided input-output intensity functions. Silencing of EPSPs during inhibition (rectification) was never observed. Comparison of activity during the first cycle of rotation with the average response over several cycles indicated that variable degrees of adaptation (up to 48%) characterize the excitatory response, whereas no consistent adaptation was observed in the inhibitory response. All fibers appeared to give responses nearly in phase with angular velocity, at 0.1 Hz, although the peak rates generally anticipated by a few degrees the peak angular velocity. From the data presented it appears that asymmetry, adaptation, and at least part of the phase lead in afferent nerve response are of presynaptic origin, whereas rectification and possible further phase lead arise at the encoder. To confirm these conclusions a simultaneous though limited study of spike firing and EPSP activity has been attempted in a few fibers
Controllo della concentrazione plasmatica dei farmaci
No full textAspetti teorici e pratici sull'impostazione di regimi terapeutici basati sulle proprietà farmacocinetiche dei farmac
Spontaneous [Ca2+]i fluctuations in rat chromaffin cells do not require inositol 1,4,5-trisphosphate elevations but are generated by a caffeine- and ryanodine-sensitive intracellular Ca2+ store.
No full textA considerable fraction (65%) of single rat chromaffin cells loaded with the fluorescent [Ca2+]i indicator fura-2 exhibited spontaneous rhythmic fluctuations with an average period of approximately 100 s. Parallel patch clamp experiments as well as fura-2 experiments carried out in Ca2(+)-free and other modified media in the presence of Ca2+ and Na+ channel blockers indicated an origin from intracellular stores. Appropriate concentrations of agonists (bradykinin and histamine) for receptors (B2 and H1) that trigger generation of inositol 1,4,5-trisphosphate induced increased fluctuation frequency, recruitment of silent cells, and large [Ca2+]i changes at high doses. These effects were blocked by cell pretreatment with neomycin, a drug that inhibits inositol 1,4,5-trisphosphate generation. In contrast, spontaneous fluctuations and the effects of another drug, caffeine, which also induced increased frequency and recruitment, were unaffected by neomycin. Ryanodine caused first a prolongation and then (approximately 10 min) a block of both spontaneous fluctuations and caffeine effects, where the single transients after bradykinin and histamine were maintained. Caffeine and ryanodine are known to affect selectively the process of calcium-induced Ca2+ release; this is the first demonstration of [Ca2+]i fluctuation activity arising from Ca2(+)-induced Ca2+ release in nonmuscle cells with no strict requirement for inositol 1,4,5-trisphosphate involvement
Basi cellulari della farmacocinetica
No full textBasi cellulari e fisiche del passaggio di farmaci tra compartimenti e delle cinetiche relativ
Assorbimento e vie di somministrazione dei farmaci
No full textCinetiche di assorbimento, limiti, vantaggi e aspetti pratici delle delle diverse vie di somministrazione dei farmac
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