Biomedical subjects
Publications and source records attributed to D Noble.
Streptomyces cattleya produced a new cyclopentenedione antibiotic, G2201-C [C6H6O4(I)], which is moderatley active in vitro against Gram-positive bacteria, weakly active against Gram-negative bacteria, and inactive against fungi. G2201-C is toxic to mice.
Antibiotic G7063-2, isolated from a Streptomyces species, is a new nitrogen-containing analogue of phyllostine and terreic acid. In vitro G7063-2 is moderately active against both Gram-positive and Gram-negative bacteria and weakly active against fungi. It is toxic to mice.
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The current-voltage relations obtained by integrating the Nernst-Planck equations for a variety of energy profiles are obtained. A simple and approximate method for comparing these relations is described. The method is based on using a linearized transform of current-voltage relations for an Eyring single barrier model. A parameter, gamma, related to the location of the single barrier in the Eyring model, and to the shape of the barrier in other models, is readily obtained from the slopes of the linearized relations. It is then a simple matter to determine whether a given current-voltage relation allows discrimination between any particular energy profiles. The results show that the equivalent Eyring model does not always place the peak energy barrier in the same position as other models and that quite large errors in the assignment of position may be made if such a model is used. The results are also used to test the ability of some experimental current-voltage diagrams to discriminate between various energy profiles.
Differences in action potential duration in different regions of the mammalian ventricle are not systematically present when quiescent tissue is first stimulated, but develop rapidly during repetitive activity. The effects of ouabain and temperature suggest the involvement of the Na+-K+ exchange pump.
1. A method is described for determining the space constant gamma of heart muscle strips using a sucrose gap technique. 2. The average value of gamma for frog atrial trabeculae was found to be nearly 700 mum. This value is nearly twice the length of the test gap (400 mum). Near the resting potential, the voltage non-uniformity should be about 10%. This was confirmed experimentally by comparing the membrane voltages recorded across the current-passing and voltage-recording sucrose gaps. 3. The non-uniformity during large depolarizations was calculated using a computer model. This model includes the inward-going rectification displayed by iK1 and the delayed rectification that occurs following depolarizations beyond -40mV. A single component of delayed rectification was included. 4. It is shown that even very large non-uniformities have relatively small effects on the shape of the activation curve and on the time course of onset or decay of current. 5. It is comcluded that the fast component of current decay described in a previous paper (Brown, Clark & Noble, 1976b) is not attributable to a non-uniformity artifact.
1. The reversal potential for the pace-maker K current, iK2, was measured in sheep cardiac Purkinje fibres at extracellular K concentrations, [K]O, between 2-7 and 8 mM. The reversal potentials were found to be significantly more negative than the values predicted using the Nernst equation for any reasonable value of intracellular K+ concentration or activity. 2. It is suggested that this discrepancy may be explained by postulating that the extracellular K+ concentration [K]e in the cleft spaces between cells is smaller than [K]o as a result of ion pumping and restricted diffusion from the bulk extracellular medium. 3. In conformity with this hypothesis, it was shown that the value of [K]e may be further reduced by hyperpolarizing pulses, presumably as a consequence of K+ depletion during the passage of inward current. 4. The influence of temperature on the kinetics of the gating mechanism, s, controlling iK2 was investigated. The Q10 for the time constant, pis, of current change following voltage clamp steps was found to be about 17. This corresponds to an apparent activation enthalpy of 50 kcal/mole. 5. The Q10 of the maximum amplitude iotaK2, was found to 1-3. 6. The activation curve, s infinity (Em), spread slightly to more negative potentials by cooling from 37 to 30 degrees C and the curve became less steep. 7. There is a large decrease in the inward background current on cooling, as estimated by measuring the net membrane current when iK is presumed to be zero, i.e. at the reversal potential for iK2.
1. The influence of low concentrations (5 X 10(-8) to 5 X 10(-7) M) of ouabain on the K gradient in sheep cardiac Purkinje fibres was observed by measuring changes in the reversal potential for a K specific current iK2, and by measuring total steady-state current-voltage relations. 2. Provided that the bathing solution K concentration, [K]o was not too low, these doses of ouabain were often observed to increase the K gradient, i.e. the reversal potential was shifted in a negative direction. 3. The change in the reversal potential and in the current-voltage relation could be mimicked by reducing the value of [K]o in the absence of ouabain. It is therefore suggested that ouabain may stimulate the Na+-K+ exchange pump and so reduce the K concentration, [K]e, in the clefts of the preparation. 4. At sufficiently low values of [K]o, a dose of ouabain that was stimulatory may become inhibitory. The reversal potential for iK2 then shifts in a positive direction. 5. During either stimulation or inhibition, the speed of change of reversal potential is consistent with a change in [K]e, which may change fairly rapidly. It is not possible to account for the results solely by changes in intracellular concentration, [K]i. 6. Low concentrations of ouabain were found to have no effect on the activation curve, s infinity (Em), controlling iK2. It is concluded that the changes in iK2 are solely attributable to changes in reversal potential. 7. Since net stimulation of the Na+-K+ exchange pump was observed to occur at doses of ouabain that exert a strong positive inotropic action on Purkinje fibres (Blood, 1975), it is not likely that the inotropic action is causally related to net pump inhibition.
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Pacemaker activity in atrial muscle and in Purkinje fibres is generated by a time-dependent decay of potassium current that allows the membrane to be depolarized to the threshold for action potential initiation. The kinetics of the pacemaker potassium currents in these two parts of the heart are sufficiently different to indicate that they correspond to different membrane structures. This conclusion is strengthened by the discovery that the mechanisms of acceleration produced by adrenaline are also quite different. In Purkinje fibres, the activation threshold for the potassium current is shifted in a depolarizing direction with no change in maximum amplitude. This voltage shift is adequate by itself to explain the acceleration. In atrial fibres the pacemaker potassium current is increased in amplitude with no shift in threshold. By itself, this action of adrenaline would slow pacemaker activity and the acceleration in this case is dependent on a large increase in the current attributable to calcium ions. The roles of cyclic 3',5'-AMP and of intracellular calcium ions in mediating the pacemaker actions of adrenaline will also be discussed.
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1. The electrical activity of Cardiac Purkinje fibres was reconstructed using a mathematical model of the membrane current. The individual components of ionic curent were described by equations which wee based as closely as possible on previous experiments using the voltage clamp technique. 2. Membrane action potentials and pace-maker activity were calculated and compared with time course of underlying changes in two functionally distinct outeard currents, iX1 and iK2. 3. The repolarization of the theoretical action potential is triggered by the onset of iX1, which becomes activated over the plateau range of potentials. iK2 also activates during the plateau but does not play a controlling role in the repolarization. Hwever, iK2 does govern the slow pace-maker depolarization through its subsequent deactivation at negative potentials. 4. The individual phases of the calculated action potential and their 'experimental' modifications were compared with published records. The upstroke is generated by a Hodgkin-Huxley type sodium conductance (gNa), and rises with a maximum rate of 478 V/sec, somewhat less than experimentally observed values ( up to 800 V/sec). The discrepancy is discussed in relation to experimental attempts at measuring gNa. 5. The ole of the transient outward chloride current (called igr) was studied in calculations of the rapid phase of repolarization and 'notch' configuration...
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