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K Krnjević

Publications and source records attributed to K Krnjević.

At least 19 recordsLinked to original sources
PubMed1992

Cellular and synaptic actions of general anaesthetics.

1. This paper briefly reviews mechanisms by which such widely-used volatile anaesthetics as halothane and isoflurane suppress neural function in the brain. 2. In general, anaesthetics tend to depress neuronal firing and excitatory synaptic transmission, and potentiate synaptic inhibition. 3. According to recent evidence, a particular important action of anaesthetics is to inactivate a variety of both voltage-dependent and agonist-triggered Ca-currents. 4. Activation of K outward currents and Na inward currents probably occurs only with higher doses of anaesthetics. 5. How anaesthetics interfere with Ca-channels remains largely a matter of speculation--though some evidence favours a Ca-mediated action, following Ca2+ release from internal stores, that may account also for potentiation of IPSPs by prolonging the opening of GABA-activated Cl- channels. 6. Whatever its precise underlying mechanism, a suppression of Ca-influx into pre-synaptic terminals could well account for the depression of excitatory synaptic transmission.

Anesthesia, General↗
PubMed1992

Developmental and regional differences in the vulnerability of rat hippocampal slices to lack of glucose.

Field excitatory postsynaptic potentials were recorded in stratum radiatum of CA1 and CA3 in submerged hippocampal slices from adult or newborn (postnatal days 5-25) Wistar rats. In adult slices, excitatory postsynaptic potentials were depressed by glucose removal ("aglycemia") more rapidly and to a greater extent in CA1 than in CA3 [respective mean times to 50% reduction in peak amplitude were 7.5 +/- 0.83 (standard error) min and 12.5 +/- 0.27 (standard error) min]. Subsequent recovery of excitatory postsynaptic potentials in normoglycemic medium was correspondingly quicker in CA3 than in CA1. Transmission failure at the synapses was indicated by the preservation of the afferent volley, and sharp depression of synaptic input-output plots. In the early postnatal period, CA1 excitatory postsynaptic potentials were much more resistant to aglycemia, substantially persisting for as long as 75 min, with full subsequent recovery in normoglycemic medium. The higher resistance of slices from newborn rats progressively disappeared over the first two postnatal weeks.

Aging↗
PubMed1992

Glibenclamide depresses the slowly inactivating outward current (ID) in hippocampal neurons.

Sulphonylurea drugs, such as glibenclamide and tolbutamide, are widely used as selective blockers of adenosine triphosphate-sensitive K channels. In experiments on hippocampal slices (from Wistar rats) glibenclamide (and possibly gliquidone and tolbutamide) significantly reduced the highly voltage-dependent, 4-aminopyridine-sensitive D-type outward current of CA3 neurons. Judging by these observations, the sulphonylureas may not be as selective as generally believed.

Animals↗
PubMed1991

Anoxic block of GABAergic IPSPs.

In rat hippocampal slices GABAergic IPSPs are very rapidly suppressed by anoxia (in less than 2 min). Both early (GABAA) and late (GABAB) components are affected. After reoxygenation, the IPSPs recover, but only slowly and not always completely. Iontophoretic applications of GABA or baclofen indicated no major depression of responses during anoxia. It is therefore unlikely that the anoxic suppression of IPSPs is caused by desensitizations of GABA receptors. A more probable explanation is a failure of GABAergic neurons to release GABA from inhibitory nerve terminals.

Action Potentials↗
PubMed1991

Persistent pulsatile release of glutamate induced by N-methyl-D-aspartate in neonatal rat hippocampal neurones.

1. Intracellular recordings were made from CA3 hippocampal neurones in vitro, during the first ten days of postnatal life and in adulthood. 2. Repeated (three to six) applications of N-methyl-D-aspartate (NMDA), in the presence of tetrodotoxin (TTX, 1-3 microM) and K+ channel blockers (tetraethylammonium chloride or bromide (TEA), 10 mM, and Cs+, 2 mM; or 4-aminopyridine (4-AP), 30-50 microM, and Cs+, 2 mM) induced in neonatal but not in adult neurones, periodic inward currents (PICs) which persisted for several hours after the last application of NMDA. 3. PICs which were due to non-specific cation currents had a frequency of 0.10 +/- 0.04 Hz, and an amplitude of 1.1 +/- 0.28 nA at holding potentials between -40 and -50 mV. The amplitude was a linear function of the membrane potential over the range -70 to +20 mV. They reversed polarity at 4.1 +/- 9.8 mV. 4. K+ channel blockers alone failed to induce PICs. Repeated (three to six) brief applications of high (12 mM) K+ medium also induced PICs. The frequency and amplitude of K(+)-induced PICs were however considerably reduced by concomitant applications of the NMDA receptor antagonist D,L-3-[( +/- )-2-carboxypiperazin-4-yl-]propyl-1-phosphonic acid (CPP, 20 microM). PICs could be induced also by caffeine (1 mM) in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX, 200 microM), TTX, TEA and Cs+. 5. Intracellular injection of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) did not prevent the induction of PICs by NMDA. However PICs were blocked by removal of the external calcium and by the calcium antagonists cobalt (2 mM) and cadmium (50 microM). 6. In spite of blockade of propagated synaptic activity by TTX, PICs were synchronous in a pair of intracellularly recorded cells. They were also synchronous with extracellular spikes recorded by electrodes located into stratum pyramidal or stratum radiatum. 7. Once established, PICs were unaffected by NMDA receptor antagonists D(-)2-amino-5-phosphonovaleric acid (AP-5, 50 microM), CPP (20 microM) and the NMDA channel blocker ketamine (10 microM). They were reversibly blocked by the broad spectrum excitatory amino acid antagonist kynurenic acid (1 mM) and by the selective non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM). 8. It is concluded that PICs are generated in neonatal neurones by a synchronous, pulsatile release of glutamate from presynaptic nerve terminals, secondary to oscillations in intracellular calcium.

Action Potentials↗
PubMed1991

Temperature dependence of extracellular ionic changes evoked by anoxia in hippocampal slices.

1. Extracellular [K] and [Ca] were measured with ion-selective microelectrodes in CA1 pyramidal cell layer of rat hippocampal slices in an interface chamber. 2. Near room temperature (21-22 degrees C), brief periods of anoxia (3- to 4-min substitution of 95% N2-5% CO2 for 95% O2-5% CO2) produced very small changes in [K]o [-0.022 +/- 0.10 (SE) mM] or [Ca]o (-0.030 +/- 0.0029 mM) and were associated with only minor depression of population spikes (-22.5 +/- 11%). 3. Stratum radiatum (SR) stimulation (0.2-5 Hz) could evoke substantial increases in [K]o (by 0.2-2 mM); although variable, they were consistent in any one slice. The same stimulation regularly caused only small depressions of [Ca]o (by less than 0.1 mM, typically). 4. Also at 21-22 degrees neither stimulation nor anoxia generated more than minimal reductions in extracellular space [by 2.3 +/- 0.94%, as measured by the tetramethylammonium (TMA) method], and spreading depression (SD) occurred in only 1 out of 20 slices. 5. At 33-34 degrees C, anoxia (also for 3-4 min) consistently produced more substantial increases in [K]o (0.83 +/- 0.18 mM); but the apparent changes in [Ca]o at 33 degrees C (0.058 +/- 0.12 mM) could not with certainty be distinguished from thermoelectric artifacts. There was a severe depression of population spikes (-76 +/- 10%). 6. Although electrical stimulation evoked greater reductions in [Ca]o, increases in [K]o were 50% smaller. 7. During anoxia at 33-34 degrees C, the extracellular space was significantly reduced, by 6.1 +/- 0.9%. Moreover, in 37% of the slices, either stimulation or anoxia triggered massive increases in [K]o (greater than 10 mM) and large reductions in [Ca]o (less than 1 mM), associated with SD-like swings in focal potential. 8. It is concluded that the extracellular ionic changes evoked by brief anoxia do not contribute in a major way to the depression of synaptic transmission.

Action Potentials↗
PubMed1990

Muscarinic actions in hippocampus are probably not mediated by cyclic GMP.

It has been proposed that, in a variety of tissues, guanosine 3':5'-monophosphate (cyclic GMP) is the intracellular mediator of muscarinic effects. This hypothesis was tested in the CA1 region of the hippocampus, in urethane-anaesthetized rats, by studying extracellularly muscarinic disinhibition of disfacilitation and the effect of dibutyryl cyclic GMP, muscarinic agents and an inhibitor of cyclic nucleotide-dependent kinase (H-8), all applied by microiontophoresis. The main findings were: (a) cyclic GMP analogues do not mimic disfacilitation or disinhibition produced by muscarinic agents; (b) N-(2-(methylamino)ethyl)-5-isoquinoline sulfonamide (H-8) does not prevent the excitatory actions of muscarinic agents; and (c) H-8 alone does not change the field responses. In conclusion, cyclic nucleotide-dependent kinases do not seem to play a major role in the on-going modulation of excitability in the hippocampus and cyclic GMP is unlikely to be a major intracellular messenger mediating directly or indirectly the excitatory actions of acetylcholine.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Activators of ATP-sensitive K+ channels reduce anoxic depolarization in CA3 hippocampal neurons.

In CA3 hippocampal neurons of the rat, brief anoxic episodes produce a depolarization which is probably due to a synaptic release of glutamate. Diazoxide, an activator of ATP-sensitive K+ channels (K+ ATP), blocks the anoxic depolarization and has no effect in control oxygenated artificial cerebrospinal fluid. The hormone somatostatin which activates K+ ATP channels in the pancreas also reduces the anoxic depolarization in CA3 neurons. We suggest that drugs that open K+ ATP channels may constitute a novel approach to selectivity reducing the deleterious effects of excessive release of glutamate during anoxia without producing a generalized blockade of glutamatergic synaptic transmission.

Adenosine Triphosphate↗
PubMed1990

Acidosis and blockade of orthodromic responses caused by anoxia in rat hippocampal slices at different temperatures.

1. Interstitial pH (pHo) and field responses (to stratum radiatum stimulation) were recorded simultaneously with double-barrelled microelectrodes in the CA1 region of hippocampal slices from Sprague-Dawley rats. 2. Both the relative acidity and amplitude of field responses increased with depth, reaching a maximum near the centre of the slice. When the temperature was raised from 22 to 37 degrees C, this pHo gradient was greater than 2 times steeper, but the field responses were much diminished. 3. Standard anoxic tests (substituting 95% N2 + 5% CO2 for 95% O2 + 5% CO2, for 2 min) tended to reduce pHo and population spikes, but these effects were highly temperature sensitive: at approximately 22 degrees C the blocking rate was only 12.3 +/- 4.6% and delta pHo -0.018 +/- 0.0157 units, both per minute; corresponding changes at 34-35 degrees C were 67.6 +/- 11.9% and -0.065 +/- 0.0046 units per minute. Highly significant linear correlations between rates of block and delta pHo gave a mean slope of 90.4 +/- 17.6% per 0.1 unit of acid change. 4. Anoxia caused similar temperature-dependent increases in acidity in stratum pyramidale and radiatum, but in the latter field responses (EPSPs) were much less depressed after 2 min of anoxia. 5. When slices were superfused with acid medium (low [HCO3-]), much greater reductions in pHo were needed to depress responses, giving a mean slope of 17.7% per 0.1 pH unit. 6. In glucose-free medium, there was a slow alkaline shift in pHo (0.13 +/- 0.036 units); population spikes and the acid transients evoked by anoxia disappeared. 7. It was concluded that acidosis cannot be the immediate cause of the similar depressions of postsynaptic excitability seen during anoxia and hypoglycaemia. 8. In further tests, DL-p-hydroxyphenyl-lactic acid, a blocker of lactate transport, failed to diminish acid transients evoked by anoxia, indicating that these are not mediated principally by lactate transport.

Action Potentials↗
PubMed1990

Systemic CI-966, a new gamma-aminobutyric acid uptake blocker, enhances gamma-aminobutyric acid action in CA1 pyramidal layer in situ.

A new potent, blood-brain barrier permeable gamma-aminobutyric acid (GABA) uptake blocker, 1-[2-[bis[4-(trifluoromethyl)-phenyl]methoxy]ethyl]-1,2,5,6- tetrahydro-3-pyridinecarboxylic acid (CI-966) was administered systemically by i.p. injection (5 mg/kg) in Sprague-Dawley rats under urethane anaesthesia. Twenty to thirty minutes after injection there was a highly variable, but overall significant, enhancement of the inhibition of hippocampal population spikes by GABA applied by microiontophoresis in the CA1 region. Like the effect of nipecotic acid (applied locally by iontophoresis), the potentiation by CI-966 was clearest when GABA was applied in or near the stratum pyramidale where its action normally is weakest and shows the most pronounced fading. This change in GABA potency is most simply explained by a reduction in GABA uptake.

Animals↗
PubMed1990

Mechanisms underlying anoxic hyperpolarization of hippocampal neurons.

The outward current evoked in CA1 neurons by brief anoxia is strongly voltage dependent and is abolished by an atropine-sensitive action of carbachol (and also when recording with a GTP gamma S-containing microelectrode). In this respect, it closely resembles the M-type K current, but the involvement of other, voltage-independent, carbachol-sensitive K channels has not been excluded. When the anoxic outward current is eliminated, an anoxic inward current is revealed, which may be Cl- mediated. It is suggested that an early release of Ca2+ from a dantrolene (and perhaps GTP)-sensitive internal store activates Ca-sensitive Cl channels, as well as carbachol-sensitive (mainly M-type?) K channels. The opposing Cl- and K currents would account for the variable depolarizing and hyperpolarizing effects of anoxia.

Action Potentials↗
PubMed1990

Adenosine triphosphate-sensitive potassium channels in anoxia.

Potassium channels that are activated by decreasing adenosine trisphosphate levels are blocked by sulfonylurea drugs such as glibenclamide but are opened by diazoxide and some endogenous peptides. Judging from the effects of such drugs, it seems that in the hippocampus, these channels are present not on cell bodies but rather on glutamate-releasing nerve terminals (especially those of mossy fibers in the CA3 region). Because activation of these presynaptic potassium channels reduces anoxic glutamate release, they may be a useful target for specific drug therapy that might prevent the excitoxic effects of excessive glutamate release during anoxia/ischemia.

Adenosine Triphosphate↗
PubMed1989

Anoxic changes in dentate granule cells.

In most of the granule cells recorded, by current clamp and single-electrode voltage-clamp (SEVC), only small depolarizations (or inward currents) and minor conductance increases were observed during brief periods of anoxia (2-3 min). Thus, unlike pyramidal cells, granule cell bodies show little sign of K channel activation by anoxia. Post-anoxic hyperpolarizations were also minimal. Moreover, diazoxide (an activator of ATP-sensitive K conductance (GK(ATP]) had no consistent hyperpolarizing action. The depressant effect of diazoxide on anoxic glutamate release from mossy fibres is therefore likely to be mediated by GK(ATP) channels situated on granule cell axons or terminals rather than on the cell bodies.

Animals↗
PubMed1989

Mediation of acetylcholine's excitatory actions in central neurons.

In experiments on the hippocampus in situ (in rats under urethane), neither cyclic GMP nor H-8 (an antagonist of cyclic nucleotide-dependent kinases) had much effect on CA1/CA3 population spikes or on the excitatory action of ACh. This is further evidence against the idea that cyclic nucleotides play a major role as cholinergic second messengers. On the other hand, the results of tests with a PKC antagonist sphinganine are in keeping with some involvement of PKC in cholinergic actions. (Another PKC antagonist, H-7, proved to be a very powerful excitant, probably via disinhibition). Preliminary experiments on CA1 neurons in hippocampal slices (by single electrode voltage clamp), confirmed previous reports that carbachol depresses A- and C-type K currents, as well as inward Ca2+ currents; though the latter effect was sometimes mainly due to frequency-dependent inactivation of Ca currents. It is suggested that a single, primary muscarinic action, the acceleration of phosphinositide turnover, may account for a variety of secondary effects: on the one hand, via activation of PKC, a number of possible PKC-mediated actions, such as block of the slow AHP; on the other, via IP3 formation, a block of IM and a rise in cycloplasmic free Ca2+ that may cause inactivation of both Ca2(+)-inward currents, and Ca2(+)-dependent GKs.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Serotonin blocks the facilitatory action of muscarinic and nicotinic agents in the hippocampus in vivo.

The inhibitory effect of serotonin, released iontophoretically, on acetylcholine-induced facilitation of population spikes evoked by fimbria-commissural stimulation was studied in the CA1 region of rat hippocampus in vivo. After serotonin was applied for 2.6 +/- 0.8 min, acetylcholine's action was inhibited in 39 cases out of 57 (68.4%), by 68.9 +/- 23.1%, irrespective of whether serotonin alone increased or reduced the population spike. Spiperone, used as a 5-hydroxytryptamine1A (5-HT1A) antagonist, suppressed the inhibitory action of serotonin in 14 of 21 tests. Serotonin had similar effects on population spike facilitations induced by acetyl-beta-methylcholine and dimethylphenylpiperazinium. Thus serotonin, probably acting on 5-HT1A receptors, blocks effectively but indiscriminately all cholinergic facilitations, whether mediated by nicotinic or muscarinic receptors.

Acetylcholine↗
PubMed1989

Dantrolene suppresses the hyperpolarization or outward current observed during anoxia in hippocampal neurons.

Hyperpolarizations, or outward currents, recorded in CA1 pyramidal cells during brief anoxia (2-3 min) (but not postanoxic hyperpolarizations) are markedly reduced (92 +/- 4.8%) by dantrolene sodium, applied by superfusion (10-20 microM). This effect, which is at least partly reversible by prolonged washing, is in keeping with the idea that anoxia activates a Ca2(+)-sensitive K conductance by releasing Ca2+ from internal stores.

Animals↗