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S Stolc

Publications and source records attributed to S Stolc.

At least 37 records · Page 2Linked to original sources
PubMed1995

Local anesthetic effect of carbisocaine and its enantiomers.

The optically active isomers of carbisocaine [1-methyl-2-diethylaminoethyl ester of 2-(n)-heptyloxycarbonilic acid] were prepared. The blocking activity of equimolar concentrations of the carbisocaine and its corresponding enantiomers was tested on isolated rat sciatic nerves. There were no significant differences between the anesthetic action of racemic form and enantiomers, however, lower activity for the (--)-enantiomer was observed. The results may indicate negligible stereoselectivity of action of highly lipophilic local anesthetic carbisocaine in the excitable membrane.

Anesthetics, Local↗
PubMed1995

[Hypoxia-reoxygenation damage to the nervous system and its control with drugs].

Stroke represents an important health problem with serious implications even in the social sphere. Prevention and therapy of this disease has not been satisfactory as yet. The role of ischemia (hypoxia as well as of reperfusion) reoxygenation in the pathogenesis of stroke and neurotrauma is briefly discussed. It is emphasized that an oxidative stress due to activation of spontaneous regulatory mechanisms and/or vigorous reperfusion therapy in such patients may, paradoxically, increase the risk of an additional impairment of nervous tissue leading to worsening of the patient's prognosis. A complex chain of processes triggered by nervous tissue hypoxia including the role of excitatory amino acids, calcium overload and reactive oxygen species is described. Principles of contemporary routine pharmacotherapy of stroke and neurotrauma as well as aims of experimental therapy are briefly outlined. Relevant preclinical data concerning the protective action of the novel antioxidant and free-radical scavenger pyridoindole stobadine on nervous tissue in oxidative stress are summarized. The presented data may contribute to the improvement of prevention and/or therapy of stroke and neurotrauma.

Antioxidants↗
PubMed1995

[The effect of quaternization on local anesthetic effects of trimecaine].

Effects of the local anaesthetic trimecaine and its quaternary derivative on the isolated rat sciatic nerves were examined. Trimecaine inhibited action potential propagation in the isolated nerve in vitro at four-times lower concentrations than its quaternary derivative. Despite extracellular application, the quaternary derivative inhibited action potential propagation in the sciatic nerve but with a longer half-life in comparison with trimecaine. With increasing external pH, the blocking effect of trimecaine was profound. The blocking potency of the quaternary compound was not consistently changed with the changes in external medium pH.

Action Potentials↗
PubMed1994

Pyridoindole stobadine is a nonselective inhibitor of voltage-operated ion channels in rat sensory neurons.

Pyridoindole stobadine, a compound with known neuroprotective, antioxidant, oxygen-free radical scavenging and antiarrhythmic properties, was analysed as to its effect on inward sodium and calcium currents (INa and ICa), respectively, and on fast inactivating and slow non-inactivating components of potassium outward current (IKf and IKs), respectively, in the neuronal membrane. A voltage-clamp technique was used in internally dialyzed single neurons isolated from young rat sensory ganglia. Stobadine inhibited all currents studied in a concentration dependent manner (0.1-3 mmol/l). Apparent affinity constants pD'2,--(i.e. negative logarithm of IC50) were 3.147 +/- 0.030, 3.112 +/- 0.084, 3.089 +/- 0.062 and 2.918 +/- 0.059 for INa, IKs, IKf, and ICa, respectively. Full current inhibition occurred only in INa at concentrations of > 1 and < or = 3 mmol/l. Saturation of the inhibition of both components of IK at approximately 40% of the control level occurred at concentrations > 1 mmol/l. Stobadine was found to be a nonspecific inhibitor of the currents studied. This property as well as the range of pD'2, values are comparable to those observed in the local anesthetics procaine and trimecaine. The inhibition of voltage-operated ion channels in membranes of excitable cells by stobadine might be responsible for its capability to inhibit synaptic transmission and axonal conduction. It might participate also in the antidysrrhythmic effect of stobadine.

Animals↗
PubMed1993

Effect of incomplete ischemia and reperfusion of the rat brain on the density and affinity of alpha-adrenergic binding sites in the cerebral cortex. Prevention of changes by stobadine and vitamin E.

The effect of incomplete 4 hr ischemia and subsequent 1 hr reperfusion of the rat brain on the density and affinity of alpha-adrenergic binding sites was investigated. To assess the involvement of oxygen-derived free radicals in the development of ischemic injury, we tested the effect of stobadine and vitamin E on putative changes of the binding parameters of alpha-adrenergic binding sites in ischemic and reperfused rat brains. Compared to the group of sham operated animals decreased density and increased affinity of [3H]dihydroergocryptine binding sites was found in cerebrocortical membranes of rats subjected to 4 hr incomplete ischemia and 1 hr reperfusion. The reduction of Bmax and Kd induced by ischemia and reperfusion of the brain was prevented by stobadine and vitamin E administration. Neither incomplete ischemia nor incomplete ischemia and subsequent reperfusion of the rat brain exerted significant effect on [3H]rauwolscine binding to alpha 2-adrenergic binding sites. Our results suggest that brain ischemia and reperfusion may affect the density and affinity of alpha 1- rather than of alpha 2-adrenergic binding sites. The beneficial effect of stobadine and vitamin E indicates that increased generation of oxygen free radicals might play a role in the development of these changes.

Animals↗
PubMed1993

Inhibition of ion currents in membrane of sensory neuron by the antiarrhythmic drug BK 129 and selected Ca2+ entry blockers.

The inhibitory effects of the prospective antiarrhythmic drug BK 129 on Ca2+ and Na+ inward currents (ICa and INa, respectively) and on fast inactivating and slow noninactivating K+ outward currents (IKf, IKs, respectively) were tested in young rat sensory neurons by modified whole cell voltage clamp technique in vitro. The effects were compared to those of nifedipine, verapamil and local anesthetic carbisocaine. Both BK 129 and carbisocaine are basic carbanilates. At a frequency of test pulses of 0.2 Hz apparent dissociation constants (pD2) of BK 129 to channels conducting ICa, INa, IKf, and IKs were 5.313, 4.429, 3.985, and 4.154, of carbisocaine 5.428, 5.896, 3.992, and 4.091, and of verapamil 4.249, 4.093, 3.839, and 4.453, respectively. In nifedipine only the pD2 for ICa inhibition could be measured (5.624). This drug failed to exert any appreciable effect on the other currents up to the highest concentration used (15 mumol/l). Higher concentrations could not be tested because of the interfering effect of nifedipine solubilizer (ethanol). The inhibiting effect of verapamil on ICa revealed slight potential dependence which however, could not account for the observed low specificity of this drug. Frequency of calcium channel activations might be more important determinant of the verapamil induced ICa inhibition rather than the holding potential. The weak inhibiting effect of omega-conotoxin GVIA (5 mumol/l) and Ni2+ (100 mumol/l) as well as the strong effect of Cd2+, Co2+ (both 5 mmol/l) and nifedipine on ICa indicated that it was mainly the L type Ca2+ channel that conducted this current. The differential effect of Cd2+ and Co2+ (5 mmol/l) compared to tetrodotoxin (3 mumol/l) on ICa and INa disproved the possibility that these currents would pass via identical channels. While nifedipine was shown to be a highly specific inhibitor of ICa in the young rat sensory neurons the other drugs tested inhibited the currents with a much smaller selectivity, with verapamil being the least specific at low stimulus rates (0.2 Hz). BK 129 is a powerful although nonspecific blocker of the inward ICa in the neuronal membrane. It is suggested that these properties of BK 129 might participate in its antiarrhythmic effect.

Animals↗
PubMed1993

[The effect of articaine on isolated peripheral nerves].

The effects of a new local anesthetic articaine (Spofa) (licence of the firm Hoechst) on isolated sciatic nerve were tested. Its actions were compared with the effects of rapidly and shortly acting lidocaine and with a newly synthetized long acting local anesthetic carbizocaine--derivative of carbanillic acid. Articaine acted 3 times more slowly than lidocaine, although it was twice as effective. EC50 showed carbizocaine to be 40 times more effective than articaine at pH 7.2 and its action was slower and prolonged. On lowering external pH, the blocking effects of articaine and lidocaine were diminishing, but the effect of carbizocaine was profound. The nerve sheath decreased and slowed down the local anesthetic activity of articaine. The results indicate that in the light of its pharmacodynamic properties articaine can be arranged with local anesthetics similar to lidocaine. (Tab. 2, Fig. 4, Ref. 19.).

Action Potentials↗
PubMed1993

Effect of oxidative stress on (3H)N-methylscopolamine binding and production of thiobarbituric acid reactive substances in rat cerebral cortex membranes.

We investigated the effect of lipid peroxidation, in vitro induced by H2O2 or FeSO4 and ascorbic acid, on binding properties of muscarinic receptors in rat cerebral cortex membranes. Simultaneously the concentrations of thiobarbituric acid reactive substances (TBARS) were measured to assess the extent of lipid peroxidation. In conditions of increased TBARS levels the density of (3H)N-methylscopolamine [(3H)NMS] binding sites in rat cerebral cortex membranes was not affected. Decreased numbers of (3H)NMS binding sites observed in the presence of high concentrations of H2O2 (100 and 1000 mmol.l-1) accompanied by a decrease of TBARS levels might be related to a nonspecific effect of H2O2 on cellular proteins.

Animals↗
PubMed1993

Comparison of local anesthetic activity of pentacaine (trapencaine) and some of its derivatives by three different techniques.

The local anesthetic potency of the carbanilic drug pentacaine (1; trapencaine) was compared to that of a series of its derivatives as well as procaine and cocaine. It is known that 1 exhibits potent local anesthetic, gastroprotective and antiulcer activities. The local anesthetic potency of the drugs under study was tested by three different techniques, i.e. analysis of compound action potential amplitude in rat sciatic nerve in vitro, duration of full anesthesia in rabbit cornea in vivo as well as in guinea-pig skin in vivo. The potency was expressed as drug concentration evoking either 50% reduction in action potential amplitude in the isolated nerve or anesthesia lasting for 20 min in the other two techniques. The most powerful anesthetics were found to be 1, K1905, and K2002 with their potency exceeding that of procaine and cocaine by 1-2 orders. The derivatives P1, P2, and P3 were much less effective, their potency being comparable to the two reference drugs. Although there were remarkable differences in the ranges of effective concentrations of particular drugs in the techniques used, a comparatively good agreement was found in the orders of the drug potencies. Plotting local anesthetic potency and drug lipophilicity revealed a good positive correlation between these two parameters in the group of the drugs tested.

Action Potentials↗
PubMed1992

[The effect of BL 343 Ac, a beta-adrenolytic, on the cervical ganglion].

The activity of the newly synthetized substance BL 343 Ac (propyl-3-acetyl-4[/2-hydroxy-3-isopropyl amino/propoxy] carbanylate of hydrochloride), a beta 1-adrenolytic with sympathomimetic activity was investigated by means of the electrophysiological method of sucrose gap. Its effect on the membrane potential of a population of neurons of the superior cervical ganglion (GCS) of the cat was analyzed with the aim to contribute to the knowledge on the selectivity of action of this substance. In the GCS of the cat, which contains predominantly beta 2-adrenoceptors, BL 343 Ac given in concentrations from 0.01 to 50 mumol.l-1 and after single application into the superfusion stream close to the ganglion in doses from 0.01 to 1,000 nmol did not induce an unequivocal change in the membrane potential or a response comparable to that elicited by isoprenaline. No blocking effect of the substance BL 343 Ac (0.01-50 mumol.l-1) was observed on isoprenaline induced depolarization of the cat GCS. The obtained results indicate that BL 343 Ac fails to exert either beta 2-adrenomimetic or beta 2-adrenolytic effect on the GCS of the cat. (Fig. 2, Ref. 11.)

Adrenergic beta-Antagonists↗
PubMed1991

Reproductive toxicity studies with cis-(-)-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate in rats.

cis-(-)-2,3,4,4a,5,9b-Hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate (stobadin dipalmitate; in the following briefly called STB) a new prospective cardioprotective drug, was evaluated for effects on fertility, general reproductive performance, prenatal and peri-postnatal development in the rat. Doses of 5, 15 and 50 mg/kg/d were administered orally in aqueous suspension to rats in all studies. Daily treatment of male rats for 70 days before mating and female rats for 14 days before mating and during gestation and lactation had no adverse effects on fertility, survival rate and weight gains of parental animals or on prenatal and postnatal development of pups. There was only evidence of slight adult toxicity late in the experiment, significant increase of anomalous foetuses in both the 15 and 50 mg/kg/d doses and decreased body weight of the young at 50 mg/kg/d on day 21 post partum. Daily oral treatment of pregnant rats with STB throughout organogenesis (day 4 to 16) had no overt effects on dams or on embryo-foetal development, except of increased incidence of some skeletal variations in all treated groups. In the peri-postnatal toxicity study treatment of pregnant dams with STB continuously from day 15 of gestation through parturition and lactation had no adverse effects on reproductive parameters of dams or on survival and development of F1 offspring at any dose used. There were only signs of slight maternal toxicity at 50 mg/kg/d, which consisted of sedated behaviour, reduced liver weight and reversible histopathological changes in kidney tissue. The results of these studies did not reveal serious developmental hazard potentials of STB administered to rats in doses up to 50 mg/kg/d.

Animals↗
PubMed1990

3,4-Diaminopyridine induced stimulus-bound repetitive firing in frog sympathetic ganglion: no changes in postsynaptic membrane excitability.

It has been shown previously that 3,4-diaminopyridine (3,4-DAP) facilitates synaptic transmission in the frog sympathetic ganglion inducing so-called stimulus-bound repetition (SBR), i.e. a brief burst of repetitive postganglionic discharges after a single orthodromic stimulus. In the present study we analyzed one of the possible mechanisms of the 3,4-DAP-induced SBR, namely changes in postsynaptic membrane excitability. We found that 3,4-DAP in concentration optimal for inducing SBR (2 X 10(-4) mol.l-1) had no direct effect on the excitability of the postsynaptic membrane of frog sympathetic neurones. The excitability was expressed as the threshold for action potentials elicited orthodromically, antidromically and directly, as well as the spike activity evoked by constant depolarizing current pulses. We also indirectly excluded the involvement of two other possible mechanisms of neuronal membrane excitability modulation in the 3,4-DAP-induced SBR, i.e. the M-current suppression by analyzing the participation of muscarinic receptor activation in the SBR, and inhibition of the Ca(2+)-activated K+ currents by measuring the duration of afterhyperpolarization of antidromic action potential. Our findings indicate that no remarkable changes in the properties of the postsynaptic membrane contribute to the generation of 3,4-DAP-induced SBR in the frog sympathetic ganglion. This strongly supports the hypothesis that the mechanism underlying SBR evoked by this drug is presynaptic.

4-Aminopyridine↗
PubMed1990

Time course of lipid peroxidation during incomplete ischaemia followed by reperfusion in rat brain.

The time course of lipid peroxidation was studied in the rat brain cortex after ischaemia and reperfusion. The ischaemia was induced by 4-hour occlusion of both common carotid arteries and was followed by reperfusion of different duration (10, 30 or 60 min). The extent of lipid peroxidation was determined by measurement of conjugated dienes (CD) and TBA reactive products. Maximal values of CD and TBA reactive products were found after 10- and 30-minute reperfusion. This indicated the most suitable time interval for studying the effect of antioxidants and oxygen radical scavengers in this model of brain ischaemia.

Animals↗
PubMed1989

Local anesthetics: lipophilicity, charge, diffusion and site of action in isolated neuron.

Sodium channel blocking activity was measured in a series of newly synthesized tertiary amine compounds and their quaternary derivatives applied externally on internally in the rat sensory neuron. The large difference in effectiveness of the quaternary compounds on external and or internal application became smaller and even disappeared with increasing lipophilicity of the compounds. No such difference was observed in the tertiary analogs. It was concluded that lipophilicity played an important role in determining the channel blocking activity of externally applied quaternary compounds. The results suggest that, in addition to the neutral form, highly lipophilic amine local anesthetics may penetrate into and/or pass across the neuronal membrane probably as electroneutral ion pair complexes consisting of the cationic form and an appropriate anion. The present results support our hypothesis which stresses, in addition to dissociability, the role of lipophilicity of amine local anesthetics in the pH dependence of their effect.

Anesthetics, Local↗
PubMed1988

Comparison of effects of selected local anesthetics on sodium and potassium channels in mammalian neuron.

Effects of procaine, trimecaine, and a new carbanilate local anesthetic, carbizocaine, on early sodium inward current and fast and slow components of potassium outward current in the membrane of the rat dorsal root ganglion neuron were studied using the internal dialysis and potential clamp techniques. All the currents studied were depressed in the presence of the drugs tested. However, for inhibition of the inward current concentrations lower by approximately one to more than two orders were sufficient compared to those required for similar inhibition of the outward currents. Carbizocaine was the most effective, procaine the least effective drug. Almost identical ratios of the negative logarithms of mean effective concentrations for blocking the inward and the outward current respectively, were found for each of the drugs tested. None of the drugs could be characterized as a specific blocker of sodium or potassium channels. It is concluded that the mechanisms of action of these three local anesthetics in all the three types of ion channels studied in the neuronal membrane are very similar regardless of both the type of the chemical bond in the intermediary chain of the molecules (ester, anilide, carbanilate) and the structure of the aromatic moiety, or the absolute potency of the drug.

Anesthetics, Local↗
PubMed1988

Comparison of the effects of carbisocaine and other local anesthetics on 32P incorporation into individual and total phospholipids in synaptosomes.

The aim of the paper was to study the effect of carbisocaine, a new local anesthetic with high liposolubility on incorporation of 32P into individual and total phospholipids and to compare its effect with that of other local anesthetics (procaine, lidocaine, cinchocaine, heptacaine). Carbisocaine decreased 32P incorporation into neutral phospholipids and increased the incorporation into acid phospholipids, presumably by inhibiting phosphatidate phosphohydrolase, similarly as reported for other anesthetics (Brindley and Bowley 1975). The increased incorporation of 32P into phosphatidylserine induced by carbisocaine suggests that this phospholipid is also synthetised from phosphatidic acid. At low concentrations, the local anesthetics studies were found to increase 32P incorporation into total phospholipids, whereas at high concentrations they reduced 32P incorporation. This biphasic effect is in agreement with the incorporation of 14C from glucose into lipids (Lassánová et al. 1984) and with the effect of cinchocaine on glycerol incorporation into phospholipids (Allan and Michell 1975), suggesting that local anesthetics affect de novo synthesis of phosphatidic acid. Carbisocaine increased 32P incorporation into phospholipids, in concentrations lower by several orders of magnitude as compared to the other local anesthetics studied. A rough correlation was observed between the concentrations at which the local anesthetics showed stimulatory effect on 32P incorporation, and the average effective concentrations of the respective anesthetics. No such correlation could be found for carbisocaine.

Anesthetics, Local↗