Automatic activity in depolarized guinea pig ventricular myocardium. Characteristics and mechanisms.
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Membrane potential was changed uniformly in segments, 0.7-1.0 mm long, of guinea pig papillary muscles excised from the right ventricle by using extracellular polarizing current pulses applied across two electrically insulated cf preparations superfused with Tyrode's solution at maximum diastolic membrane potentials ranging from-35.2+/-7.5 (threshold) to +4.0+/-9.2 mV. The average maximum dV/dt of RAD ranged from 17.1 to 18.0 V/sec within a membrane potential range of -40 to +20 mV. Raising extracellular Ca2+ concentration [Ca2+]0 from 1.8 to 6.8 mM, or application of isoproterenol (10(-6)g/ml) enhanced the rate of RAD, but lowering [Ca2+]0 to 0.4 mM or exposure to MnCl2 (6 mM) abolished RAD. RAD were enhanced by lowering extracellular K+ concentration [K+]0 from 5.4 to 1.5 mM. RAD were suppressed in 40% of fibers by raising [K+]0 to 15.4 mM, and in all fibers by raising [K+]0 to 40.4 mM. This suppression was due to increased [K+]0 and not to K-induced depolarization because it persisted when membrane potential was held by means of a conditioning hyperpolarizing puled gradually after maximum repolarization. These observations suggest that the development of RAD in depolarized myocardium is associated with a time-dependent decrease in outward current (probably K current) and with increase in the background inward current, presumably flowing through the slow cha-nel carrying Ca or Na ions, or both. (+info)
Effect of electrotonic potentials on pacemaker activity of canine Purkinje fibers in relation to parasystole.
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Isolated false tendons excised form dog hearts were mounted in a three-chamber tissue bath. Isotonic sucrose solution was perfused in the central chamber to provide a region of depressed conductivity between the fiber segments in chambers 1 and 3, which were perfused with Tyrode's solution. The electrotonic influence of spontaneous or driven responses evoked in chamber 3 during the first half of the spontaneous cycle of a chamber 1 peacemaker delayed the next spontaneous discharge. This effect changed to acceleration when the chamber 3 segment fired during the second half of the spontaneous cycle. We found that subthreshold depolarizing current pulses 50-300 msec applied across the sucrose gap caused similar degrees of delay or acceleration. Furthermore, hyperpolarizing currents caused the reverse pattern. The results indicate that the discharge pattern of a parasystolic focus may be altered by the electrotonic influence of activity in the surrounding tissue. The significance of these findings is considered in relation to the mechanism of production of parasystolic rhythms. (+info)
Effect of paracetamol (acetaminophen) on gastric ionic fluxes and potential difference in man.
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Paracetamol has replaced aspirin as the analgesic of choice in many situations. The major reason is the damaging effect of aspirin on gastric mucosa. Alterations in gastric ionic fluxes and potential difference provide measures of aspirin-induced structural damage. We studied the effect of large doses of paracetamol (acetaminophen 2-0 g) on gastric ionic fluxes in man. In addition, the effect of 2-0 g paracetamol on gastric potential difference was compared with that of 600 mg aspirin. In contrast with salicylates, paracetamol caused no significant alteration in movement of H+ and Na+ ions over control periods. Aspirin causes a significant fall in transmucosal potential difference (PD) across gastric mucosa of 15 mv, while paracetamol cuased no significant change. Paracetamol in a dose four times that recommended does not alter gastric ionic fluxes or potential difference. These studies support choice of paracetamol as analgesic over aspirin where damage to gastric mucosa may be critical. (+info)
Dopamine stimulates salivary duct cells in the cockroach Periplaneta americana.
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This study examines whether the salivary duct cells of the cockroach Periplaneta americana can be stimulated by the neurotransmitters dopamine and serotonin. We have carried out digital Ca2+-imaging experiments using the Ca2+-sensitive dye fura-2 and conventional intracellular recordings from isolated salivary glands. Dopamine evokes a slow, almost tonic, and reversible dose-dependent elevation in [Ca2+]i in the duct cells. Upon stimulation with 10(-)6 mol l-1 dopamine, [Ca2+]i rises from 48+/-4 nmol l-1 to 311+/-43 nmol l-1 (mean +/- s.e.m., N=18) within 200-300 s. The dopamine-induced elevation in [Ca2+]i is absent in Ca2+-free saline and is blocked by 10(-)4 mol l-1 La3+, indicating that dopamine induces an influx of Ca2+ across the basolateral membrane of the duct cells. Stimulation with 10(-)6 mol l-1 dopamine causes the basolateral membrane to depolarize from -67+/-1 to -41+/-2 mV (N=10). This depolarization is also blocked by La3+ and is abolished when Na+ in the bath solution is reduced to 10 mmol l-1. Serotonin affects neither [Ca2+]i nor the basolateral membrane potential of the duct cells. These data indicate that the neurotransmitter dopamine, which has previously been shown to stimulate fluid secretion from the glands, also stimulates the salivary duct cells, suggesting that dopamine controls their most probable function, the modification of primary saliva. (+info)
Trans-synaptically induced bursts in regular spiking non-pyramidal cells in deep layers of the cat motor cortex.
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In deep layers of the cat motor cortex, we have investigated the properties of neurons displaying trans-synaptically induced bursts. In in vivo experiments, extracellularly recorded burst neurons were separated into two subtypes based on their dependence on stimulation sites, the medullary pyramid or the ventrolateral (VL) thalamic nucleus, from which bursts of 10-20 spikes were triggered. The spike amplitude attenuation and frequency adaptation during a burst were more prominent in pyramid-dependent burst neurons than in VL-dependent burst neurons. Intracellular recordings in in vivo experiments revealed that pyramid-dependent bursts emerged from a long-lasting depolarization, while each spike during a VL-dependent burst was narrow in half-width and was followed by a fast AHP, similar to fast spiking neurons. In in vitro slice experiments, intracellular recordings were obtained from neurons that displayed a burst of attenuated spikes emerging from a long-lasting depolarization, and were also obtained from fast spiking neurons. They were morphologically recovered to be multipolar cells with sparsely spiny dendrites and local axonal networks, suggesting that they are inhibitory interneurons. The multipolar neurons displaying bursts of attenuated spikes may mediate the recurrent inhibition of pyramidal tract cells. (+info)
Low resting potential and postnatal upregulation of NMDA receptors may cause Cajal-Retzius cell death.
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Using in situ patch-clamp techniques in rat telencephalic slices, we have followed resting potential (RP) properties and the functional expression of NMDA receptors in neocortical Cajal-Retzius (CR) cells from embryonic day 18 to postnatal day 13, the time around which these cells normally disappear. We find that throughout their lives CR cells have a relatively depolarized RP (approximately -50 mV), which can be made more hyperpolarized (approximately -70 mV) by stimulation of the Na/K pump with intracellular ATP. The NMDA receptors of CR cells are subjected to intense postnatal upregulation, but their similar properties (EC50, Hill number, sensitivity to antagonists, conductance, and kinetics) throughout development suggest that their subunit composition remains relatively homogeneous. The low RP of CR cells is within a range that allows for the relief of NMDA channels from Mg2+ blockade. Our findings are consistent with the hypothesis that CR cells may degenerate and die subsequent to uncontrolled overload of intracellular Ca2+ via NMDA receptor activation by ambient glutamate. In support of this hypothesis we have obtained evidence showing the protection of CR cells via in vivo blockade of NMDA receptors with dizocilpine. (+info)
UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells.
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Uncoupling proteins (UCPs) are a family of mitochondrial transporter proteins that have been implicated in thermoregulatory heat production and maintenance of the basal metabolic rate. We have identified and partially characterized a novel member of the human uncoupling protein family, termed uncoupling protein-4 (UCP4). Protein sequence analyses showed that UCP4 is most related to UCP3 and possesses features characteristic of mitochondrial transporter proteins. Unlike other known UCPs, UCP4 transcripts are exclusively expressed in both fetal and adult brain tissues. UCP4 maps to human chromosome 6p11.2-q12. Consistent with its potential role as an uncoupling protein, UCP4 is localized to the mitochondria and its ectopic expression in mammalian cells reduces mitochondrial membrane potential. These findings suggest that UCP4 may be involved in thermoregulatory heat production and metabolism in the brain. (+info)
Individual subunits contribute independently to slow gating of bovine EAG potassium channels.
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The bovine ether a go-go gene encodes a delayed rectifier potassium channel. In contrast to other delayed rectifiers, its activation kinetics is largely determined by the holding potential and the concentration of extracellular Mg2+, giving rise to slowly activating currents with a characteristic sigmoidal rising phase. Replacement of a single amino acid in the extracellular linker between transmembrane segments S3 and S4 (L322H) strongly reduced the prepulse dependence and accelerated activation by 1 order of magnitude. In addition, compared with the wild type, the half-activation voltage of this mutant was shifted by more than 30 mV to more negative potentials. We used dimeric and tetrameric constructs of the bovine eag1 gene to analyze channels with defined stoichiometry of mutated and wild-type subunits within the tetrameric channel complexes. With increasing numbers of mutated subunits, the channel activation was progressively accelerated, and the sigmoidicity of the current traces was reduced. Based on a quantitative analysis, we show that the slow gating, typical for EAG channels, is mediated by independent conformational transitions of individual subunits, which gain their voltage dependence from the S4 segment. At a given voltage, external Mg2+ increases the probability of a channel subunit to be in the slowly activating conformation, whereas mutation L322H strongly reduces this probability. (+info)