Biomedical subjects
O Matzner
Publications and source records attributed to O Matzner.
Hyperosmotic regulation of voltage-gated calcium currents in rat anterior pituitary cells.
1. The sensitivity of voltage-gated calcium currents to hyperosmotic media containing mannitol or sucrose (373-723 mOsm) and to the dihydropyridine (DHP) calcium channel agonist Bay K 8644 was examined in enriched populations of rat anterior pituitary somatotrophs by using the whole cell mode of the patch-clamp technique. 2. Hyperosmotic media reduced the amplitude of voltage-gated calcium currents. With a 61.9% increase in extracellular medium osmolarity (523 mOsm), low voltage-activated (LVA) calcium currents were reduced to 67.9 +/- 17.8% of control size and high voltage-activated (HVA) calcium currents were reduced to 57.0 +/- 5.7% (mean +/- SD) of control size. The hyperosmotic suppression of HVA calcium currents was usually accompanied with a negative shift of 6.0 +/- 2.9 mV (mean +/- SD) in the activation curve of HVA currents. 3. The DHP calcium-channel agonist Bay K 8644 (10 microM), which stimulates hormone secretion from somatotrophs, increased the amplitude of HVA calcium currents to 212.6 +/- 67.2% of their control size, prolonged their tail currents, and negatively shifted the activation curve of HVA calcium currents by 6.2 +/- 2.8 mV. 4. Hyperosmotic media reduced the amplitude of DHP-sensitive HVA calcium currents and their associated prolonged tail currents, thus providing direct evidence for hyperosmotic suppression of DHP-sensitive currents. 5. Hence, exposure of pituitary cells to hyperosmotic media reduced voltage-sensitive calcium influx through LVA and DHP-sensitive HVA calcium channels. The inhibition of calcium influx through DHP-sensitive channels, which are implicated in regulation of hormone secretion in these cells, suggests that inhibitory hyperosmotic effects on hormone secretion from pituitary cells may stem from inhibition of calcium influx, before the exocytotic process. These results may also be relevant to effects of hypertonicity on neurosecretion in the nervous system.
Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels.
1. We used the tested fiber method to record from single myelinated afferents axons ending in a chronic nerve injury site (neuroma) in the rat sciatic nerve or L4,5 dorsal root. Axons were chosen for study that fired spontaneously with a stable tonic or interrupted (bursty) autorhythmic firing pattern. 2. Agents that block voltage-sensitive Na+ channels [tetrodotoxin (TTX), lidocaine], voltage-sensitive Ca2+ channels (Cd2+, Co2+, Ni2+, verapamil, D600, nifedipine, and fluarizine), volt-age-sensitive K+ channels [tetraethylammonium (TEA), 4-aminopyridine (4-AP)], and Ca(2+)-activated K+ channels (gK+Ca2+;quinidine, apamine) were applied topically to the neuroma. Effects on baseline rhythmogenesis and on the duty cycle of bursting were documented. Spike pattern analysis was used to determine whether changes in firing frequency were associated with changes in impulse initiation (electrogenesis), or resulted from (partial) block of impulse propagation downstream from the site of electrogenesis. Effects of veratridine were also noted. 3. Na+ channel blockers consistently quenched neuroma firing, and they did so by suppressing the process of impulse initiation. Only rarely was propagation block the dominant process. In bursty fibers the duration of on-periods shortened as the duration of off-periods lengthened, without a significant change in the baseline interspike interval (ISI). Veratridine accelerated firing, also via the impulse generating process. 4. Ca2+ channel blockers had essentially no effect on baseline firing rate (i.e., ISI). 5. Ca2+ channel blockers, as well as blockers of gK+Ca2+, had substantial, but inconsistent effects on burst pattern. It is not clear whether this reflects variability in the experimental conditions, or heterogeneity among the fibers sampled. 6. Blockade of K+ channels failed to evoke rhythmogenesis in acutely cut axons as it does in chronically injured axons, even in the presence of veratridine. This is consistent with other evidence that ectopic neuroma firing depends on postinjury remodeling of membrane electrical properties. 7. The data indicate that, in chronically injured axons, the inward currents that underly electrogenicity, enable ectopic discharge, and, together with outward K+ currents, set the fundamental firing rhythm (ISI), operate primarily with the use of voltage-sensitive Na+ rather than Ca2+ channels. 8. The on-off duty cycle in bursty fibers was affected by Na+ channel ligands and also, although less so, and less consistently by, Ca2+ channel ligands. This indicates that both may play a role in the slow modulations of membrane potential that presumably underly interrupted autorhythmicity.
Method for distinguishing between drug action on impulse propagation versus impulse generation.
Systemic or regional application of local anaesthetics or tetrodotoxin eliminate repetitive impulse discharge, but do they do so by blocking impulse propagation or by suppressing impulse initiation? A method is described for making this distinction based on differences in the pattern of discharge change during the onset of the block. Suppression of conductances involved in downstream impulse propagation produces integer multiplication of the fundamental interspike interval (interspike interval (ISI) doubling, tripling, etc.) In contrast, progressive block of conductances responsible for either the creation of the generator potential, or for its encoding into a spike train, causes a smooth increase in the rhythmic ISI. These two patterns of block, predicted on the basis of fundamental principles and numerical simulations, were verified in in vivo single-axon recordings.
Na+ conductance and the threshold for repetitive neuronal firing.
The Hodgkin-Huxley equation for electrogenesis in the voltage clamped squid giant axon was used to predict the effect of altering maximal Na+ conductance (gNa+max) on the repetitive firing process. The main finding was that increasing gNa+max, without changing any other membrane parameter, reduced the threshold current required to evoke repetitive firing. That is, it rendered the membrane hyperexcitable. Threshold for evoking single action potentials was also affected, but much less so. Other consequences of increasing gNa+max were a decrease in the minimum sustainable rhythmic firing frequency (mRFF), a monotonic increase in firing frequency at any given suprathreshold stimulus intensity, an increase in the current value at which intense depolarizing stimuli block rhythmogenesis, an increase in the maximal sustainable firing frequency using intense currents (MRFF), and the consequent expansion of the dynamic range for stimulus encoding. Thus, the control of gNa+max through the regulation of Na+ channel synthesis and membrane incorporation at sites of rhythmogenesis (e.g. axon hillock-initial segment region, or peripheral sensory endings) is a potential regulatory mechanism for neuronal excitability and stimulus encoding.