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PubMed1990

Functionally distinct muscarinic receptors on gastric somatostatin cells.

The present study was designed to examine the mode of action of muscarinic agonists on somatostatin secretion in intact gastric tissues, i.e., mucosal segments from the fundus and antrum of rat and the isolated luminally perfused mouse stomach. Methacholine caused similar decreases in somatostatin secretion in segments from the fundus (35 +/- 3%; P less than 0.001) and antrum (35 +/- 2%; P less than 0.001) of rat stomach, and in whole mouse stomach (43 +/- 3%; P less than 0.001). The decrease was the net effect of a dominant inhibition and a lesser stimulation of somatostatin secretion. Pretreatment with the permeant derivative of the acetomethoxy ester form of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA/AM, 15 microM) caused a further decrease in methacholine-induced somatostatin secretion, implying that a stimulatory component existed that was mediated by intracellular calcium. Pretreatment with pertussis toxin (125 ng/ml) for 60 min converted the decrease in somatostatin secretion to an increase above basal levels. The increase induced by pretreatment with pertussis toxin was abolished by additional pretreatment with BAPTA/AM. Procaine (5 mM), which blocks release of calcium from intracellular stores, produced an effect on somatostatin secretion similar to that of BAPTA/AM. The results indicate that 1) methacholine exerts dual inhibitory and stimulatory effects on somatostatin cells of rat and mouse stomach, 2) the dominant effect is inhibitory and sensitive to pertussis toxin, and 3) a concurrent stimulatory effect, mediated by calcium, is unmasked after blockade of the inhibitory effect with pertussis toxin.

Animals↗

PubMed1996

Effects of secretion inhibitors on the production of CAMP factor from Streptococcus agalactiae.

Investigations of exopeptide secretion with inhibitors were performed to study the synthesis and release of CAMP factor in drug-treated growing cells of Streptococcus agalactiae. Besides a reduction in cell growth, membrane-active substances including cerulenin and neuroactive drugs, such as procaine, dibucaine and atropine, increased the CAMP factor activity in culture supernatant. Quinacrine and phenylmethylsulphonyl fluoride, inhibitors of exopeptide-releasing proteases, reduced the bacterial growth, but did not affect the differential rate of the CAMP factor release. Polyanethole sulphonic acid, an anticoagulant preventing cell wall autolysis, promoted cell growth, but caused approximately 40% reduction in the production of CAMP factor from growing cells of S. agalactiae.

Anesthetics, Local↗

PubMed1985

Effect of cations and cation channel blockers on human natural killer cells.

We studied the influence of various extracellular Ca++ and Mg++ concentrations on human natural killer (NK) cells and found that NK cell-mediated target cell lysis requires the presence of both divalent cations. The calcium channel blocker verapamil and the local anaesthetics procaine and lidocaine inhibited NK cell-mediated killing of K 562 target cells, whereas the selective K+ channel blocker tetraethylammonium and the selective Na+ channel blocker tetrodotoxin had no effect on NK activity. Our results demonstrate an important role of extracellular Ca++ and Mg++ for NK cell-mediated killing and suggest that a free transmembrane Ca++ passage is required for target cell lysis.

Anesthetics, Local↗

PubMed1983

Role of the ventromedial nucleus of the thalamus in motor behaviour--I. Effects of focal injections of drugs.

An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits gamma-aminobutyrate metabolism, raised gamma-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting gamma-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane carboxylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the gamma-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis- 1,3-aminocyclohexane carboxylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial muscimol. Treating one ventromedial thalamus with muscimol greatly intensified any pre-existing posture directed towards that side, and vice versa. These data suggest that the ventromedial nucleus is not involved with the expression of stereotyped behaviours, but can profoundly influence posture and locomotion, especially in the presence of some other motor stimulus. The recovery of circus movements in rats with impaired ventromedial nucleus function implies this nucleus is not essential for the execution of circling in these models.

Amino Acids↗

PubMed1996

Effect of phosphodiesterase III-inhibitor (E-1020) adjunct to Bretschneider's HTK cardioplegic solution on myocardial preservation in rabbit heart.

We examined the hypothesis that an increase in the myocardial cyclic adenosine monophosphate (cAMP) by a phosphodiesterase III inhibitor, E-1020, may ameliorate the hemodynamic and biochemical changes in rabbit hearts after cardioplegic arrest, and that this enzyme-mediated process is temperature-sensitive. Sixty-one male Japanese white rabbits weighing 2.8 to 3.5 kg were used. Isolated hearts were prepared for modified Langendorff circulation using modified Krebs-Henseleit bicarbonate solution bubbled with a 95% O2-5% CO2 gas mixture. Thirty or sixty minutes of cardioplegia at 37 degrees C, or thirty minutes of cardioplegia at 15 degrees C was followed by normothermic reperfusion for 60 minutes. E-1020, 0.1 mmol/L was added to the cardioplegic solution (Bretschneider's HTK solution). The left-ventricular function was measured with a latex balloon placed in the left-ventricular cavity. The myocardial cAMP was higher, the total myocardial calcium was lower in hearts with E-1020 than in hearts with HTK alone (p < 0.05). E-1020 at 0.1 mmol/L did increase the myocardial concentration of cAMP and the functional recovery, and prevented the increase in the myocardial total calcium. Temperature affected the myocardium to preserve myocardial concentrations of adenine nucleotide compounds and cAMP. Our results suggest that a 0.1 mmol/L E-1020 adjunct to HTK solution at 37 degrees C completely prevents left-ventricular functional depression during 30 min of cardioplegia induced with non-oxygenated HTK, but decreases its potential efficacy at 15 degrees C. The protective effects disappear if the ischemic period lasts 60 min at 37 degrees C.

Animals↗

PubMed1996

Determination of the chemical mechanism of neurotransmitter receptor-mediated reactions by rapid chemical kinetic methods.

When neurotransmitters bind to their specific receptors in the membrane of nerve and muscle cells they induce conformational transitions leading to the formation of open receptor-channels and desensitized receptor forms. A knowledge of the rate and equilibrium constants associated with these transitions is required to (i) relate the mechanism of the receptor-mediated reaction to the resulting changes in transmembrane voltage that trigger signal transmission between neurons, (ii) calculate changes in transmembrane voltage that result from the interaction of diverse excitatory and inhibitory receptors in the same cell, and (iii) understand the mechanism by which receptor function is affected by activators, inhibitors, including clinically important compounds, and diseases of the nervous system. The conformational transitions of interest occur in the millisecond and the sub-millisecond time region. Chemical kinetic techniques for studying reactions mediated by membrane-bound neurotransmitter receptors in cells or vesicles in this time domain were not available. Here we describe the development and use of a laser pulse photolysis technique suitable for chemical kinetic investigations of neurotransmitter receptors in the mu s and ms time region. The type of information that can be obtained is also discussed.

Animals↗

PubMed2000

Identification of lidocaine and its metabolites in post-administration equine urine by ELISA and MS/MS.

Lidocaine is a local anesthetic drug that is widely used in equine medicine. It has the advantage of giving good local anesthesia and a longer duration of action than procaine. Although approved for use in horses in training by the American Association of Equine Practitioners (AAEP), lidocaine is also an Association of Racing Commissioners International (ARCI) Class 2 drug and its detection in forensic samples can result in significant penalties. Lidocaine was observed as a monoprotonated ion at m/z 235 by ESI+ MS/MS (electrospray ionization-positive ion mode) analysis. The base peak ion at m/z 86, representing the postulated methylenediethylamino fragment [CH2N(CH2CH3)2]+, was characteristic of lidocaine and 3-hydroxylidocaine in both ESI+ and EI (electron impact-positive ion mode) mass spectrometry. In addition, we identified an ion at m/z 427 as the principal parent ion of the ion at m/z 86, consistent with the presence of a protonated analog of 3-hydroxylidocaine-glucuronide. We also sought to establish post-administration ELISA-based 'detection times' for lidocaine and lidocaine-related compounds in urine following single subcutaneous injections of various doses (10, 40, 400 mg). Our findings suggest relatively long ELISA based 'detection times' for lidocaine following higher doses of this drug.

Anesthetics, Local↗

PubMed1976

[Pharmacological studies on basic ethers (R111 and R97) with antispasmodic activity].

Pharmacological properties and acute toxicity of 2-tolyl 1-phenyl-3-(2-methylpiperidino) propyl ether methyl bromide (R111) and 2-chlorophenyl 1-phenyl-3-(2-methylpiperidino) propyl ether methyl iodide (R97) were examined. The results obtained were as follows: (1) In the analgesic effects, RIII and R97 inhibited markedly the acetic acid-induced writhing in mice, but in reducing pain induced by heat, R111 and R97 showed negative results. The local anesthetic effect of R111 was approximately equal to that of procaine. R111 and R97 showed no effects on spontaneous locomotion, the convulsion induced by strychnine or pentetrazol, and normal body temperature. (2) R111 and R97 antagonized acetylcholine, barium chloride, nicotine and serotonine-induced spasm, but not that of histamine and bradykinin. In particular they possessed marked anti-barium chloride activity, where their effects were 20 to 30 times more active than that of papaverine. (3) R111 and R97 indicated weak mydriatic activity. (4) R111 and R97 showed inhibitory effects on the pilocarpine-induced sialic secretion and the propulsive movements of the small intestine, but their inhibitory effects on the gastric secretion were relatively weak. (5) R111 and R97 displayed protective effects in Shay's ulcer, but had no curative effects on acetic acid ulcer. (6) R111 and R97 induced temporary reduction of arterial blood pressure and blood flow immediately after the administration of the test compounds in anesthetized rabbits. However, these agents induced no change in ECG, heart rate and respiration. (7) Intraperitoneally administered R111 and R97 were effective in inhibiting the carrageenin-induced edema in the hind paw of rats. From the above results, it may be considered that R111 and R97 have together strong cholinergic blocking and muscotropic antispasmodic effects, moreover, no significant effects on the central nervous system.

Analgesics↗

PubMed2001

Optimisation and validation of a capillary electrophoresis method for the simultaneous determination of diazepam and otilonium bromide.

A simultaneous assay of diazepam and otilonium bromide in coated tablets by capillary zone electrophoresis (CZE) was developed. The influence of various parameters (voltage, temperature, buffer concentration and pH, ethanol percentage) on analysis time and on the theoretical plates of the two peaks was investigated by means of experimental design. A response surface study was carried out by means of a 27-run D-optimal matrix. The best background electrolyte was found to be 0.13 M, pH 2.9 Britton-Robinson buffer, containing 10% v/v ethanol. Other optimised parameters were voltage (30 kV) and temperature (30 degrees C). The UV detector for quantitation of otilonium bromide and diazepam was set at 280 nm and 230 nm, respectively. Procaine hydrochloride was used as internal standard and run time was less than five minutes. Validation was performed, for drug substance and drug product, according to ICH3 guidelines. For drug product the recovery for otilonium bromide and diazepam ranged from 98.3% to 101.2% and from 97.1% to 99.0%, respectively; the RSD values found for otilonium bromide and diazepam ranged from 2.4% to 3.0% and from 1.1% to 4.5%, respectively.

Calcium Channel Blockers↗

PubMed1983

Batrachotoxin-induced depolarization and [3H]batrachotoxinin-a 20 alpha-benzoate binding in a vesicular preparation from guinea pig cerebral cortex.

The sodium channel-specific agent batrachotoxin (BTX) has been shown to induce a time- and concentration-dependent depolarization of a vesicular preparation from guinea pig cerebral cortex. The K0.5 for depolarization by BTX was 0.011 microM at 30 min. Membrane potential was determined by the equilibrium distribution of [3H]triphenylmethylphosphonium ion. A series of seven local anesthetics was shown to inhibit BTX-induced depolarization competitively with Ki values ranging from 0.9 microM for dibucaine to 780 microM for lidocaine ethiodide. The specific binding of labeled batrachotoxinin-A 20 alpha-benzoate ([3H]BTX-B) to voltage-sensitive channels in vesicular preparations from mouse cerebral cortex in the presence of scorpion venom was measured and found to yield a range of Kd values from 25 to 30 nM and Bmax values of 0.5 and 1.0 pmole/mg of protein; the same preparation from guinea pig cerebral cortex was found to yield Kd values from 13 to 56 nM and Bmax values of 0.8-2.2 pmoles/mg of protein. A series of 14 local anesthetics was shown to inhibit the specific binding of [3H]BTX-B with Ki values ranging from 0.6 microM for dibucaine to 400 microM for benzocaine. The rank order of potency of the local anesthetics as antagonists of [3H]BTX-B binding was as follows: dibucaine greater than tetracaine greater than bupivacaine greater than diphenhydramine greater than piperocaine greater than cocaine greater than procaine greater than lidocaine greater than benzocaine. The quaternary local anesthetic dimethyl-di(phenylcarbamoylmethyl)ammonium chloride was comparable in potency to tetracaine. The rank order and relative potency of the local anesthetics tested in both paradigms were similar with the exception of lidocaine ethiodide, which was 18 times more potent as an inhibitor of binding of [3H]BTX-B than it was as an inhibitor of BTX-elicited depolarization.

Anesthetics, Local↗

PubMed1981

Cocaine cue in pigeons: time course studies and generalization to structurally related compounds (norcocaine, WIN 35,428 and 35,065-2) and (+)-amphetamine.

1 Pigeons trained to discriminate between the presence or absence of effects induced by cocaine hydrochloride (5.6 mg/kg) were tested for generalization with norcocaine and two phenyltropane analogues (WIN 35,428 and WIN 35,065-2). Separate dose-effect curves were obtained at different intervals after the injections so that possible changes both in potency and duration of action could be evaluated.2 Results showed that all of these drugs fully generalized to cocaine. The order of potency was WIN 35,428 > norcocaine > WIN 35,065-2 > cocaine when tested either at 15 or 60 min after injection. The cocaine-like effects were strongest for all drugs when tested 15 min after injection as compared to the tests at the 60 min interval. The decay of the cocaine-like stimulus effects occurred at about the same rate.3 Apomorphine (0.3, 0.56 and 1 mg/kg), morphine (3 and 5.6 mg/kg), Delta(9)-tetrahydrocannabinôl (0.3 and 0.56 mg/kg), and lysergic acid diethylamide (LSD-25, 0.056 and 0.1 mg/kg) did not induce more than 30% cocaine appropriate responses. (+)-Amphetamine produced 73% and 85% cocaine appropriate responses depending on the injection-test interval used, 15 and 30 min respectively.4 The amphetamine homologue, para-hydroxyamphetamine (3.8 mg/kg) did not generalize to cocaine. Tests with 30 mg/kg of procaine produced 40% cocaine appropriate responses. Cocaine is effective also when administered by gavage into the opening of the proventriculus.5 The use of the drug discrimination technique for studying structure activity relationships of drugs is discussed.

Animals↗

PubMed1987

Enhancement of local anaesthesia action by organic acid salts. (I): Possible change of excitability in nerve fibre membrane.

Measurements of action potentials recorded from giant nerve fibres of the crayfish abdomen showed that by addition of an organic acid salt to a local anaesthetic solution, the onset of anaesthetic action became more rapid and the duration of action was prolonged. Similar results were also obtained in rat vagal nerves. The chemical structure of compounds having these enhancing effects was found to have, in common, a carboxyl group connected with either a benzene ring or an aliphatic hydrocarbon. Topical application of anaesthetic solutions to the skin of flexor side of the forearm in humans revealed that the duration of anaesthesia evaluated by the apparent decrease of the number of pain points was significantly prolonged by the addition of salicylate. The use of local anaesthetics combined with organic acid salts would be promising in clinical practice to enhance their action greatly.

Action Potentials↗

PubMed1994

Lack of cardioplegia uniformity in clinical myocardial preservation.

Advances in myocardial preservation have led to improved patient survival after open heart operations. However, few studies have detailed the nature of national or regional patterns of cardioplegia use. To determine the regional pattern, all open heart surgery programs in Missouri were surveyed. During 1 year, it was found that cardioplegia was administered to 8,382 patients by 61 cardiothoracic surgeons at ten academic affiliated hospitals and 16 nonteaching hospitals. All cardioplegic solutions were hospital produced. Of 13 crystalloid solutions, 11 differed from one another and eight were intracellular formulations. Of 28 multidose blood-based cardioplegic solutions, there were 23 different mixtures. Most crystalloid (69%) and blood-based (89%) solutions differed substantially from commonly reported formulations. The incidences of the various additives to crystalloid solutions were as follows: bicarbonate, 92%; glucose, 69%; lidocaine, 54%; mannitol, 46%; magnesium, 31%; calcium, 23%; methylprednisolone, 15%; heparin, 8%; and acetate, 8%. Of the common blood-based cardioplegic solution additives, the following incidences were observed: glucose, 79%; bicarbonate, 43%; trishydroxyaminomethane, 36%; acetate, 29%; magnesium, 29%; procaine (or lidocaine), 25%; citrate-phosphate-dextrose, 18%; mannitol/albumin, 14%; nitroglycerin, 11%; glutamate/aspartate, 11%; calcium, 7%; insulin, 3%; and methylprednisolone, 3%. No calcium channel blocker or high-energy phosphate additives were reported. We conclude that many different cardioplegic admixtures that have not been tested experimentally are used routinely in clinical practice, presumably with acceptable results. Because the salutary effects of induced cardiac arrest and hypothermia may mask suboptimal solutions, further study of customized cardioplegia should be considered, particularly with regard to high-risk patients.

Blood↗

PubMed1993

On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: drug structure-activity studies on isolated peripheral nerve.

Impulse inhibition by local anesthetics (LAs) is potentiated by extracellular solutions containing HCO3-. CO2 (BC), relative to the inhibition in BC-free solutions at the same pH. We studied the mechanistic basis of this potentiation by assaying compound action potential amplitudes in desheathed frog sciatic nerves with the sucrose-gap method. We compared the potencies of 12 different impulse-blocking agents in Ringer's buffered with BC (BC-R) and in Ringer's containing only atmospheric CO2 and buffered by a zwitterionic compound (3-(N-morpholino)propanesulfonic acid-Ringer's). The relative inhibition produced by an agent in BC divided by the inhibition produced in 3-(N-morpholino)propanesulfonic acid, was defined as the potentiation factor (PF). The organic guanidinium blockers of sodium channels, tetrodotoxin and saxitoxin, which act at a different site from that for LAs, were, by our definition, nominally potentiated (PF = 1.33 +/- 0.04, mean +/- SEM, n = 4, and 1.24 +/- 0.07, n = 10, respectively), implying that BC induces a decrease in the safety margin for impulse conduction, a decrease that cannot itself alone account for the much larger potentiation (PF = 5-8) by BC observed with certain LAs. Only nominal potentiations occurred with charged LAs (PF = 1.15), showing that little direct potentiation of the cationic LA species per se occurs. Inhibition by the permanently neutral LA benzocaine had a significantly larger than nominal potentiation (PF = 1.8) showing that BC can potentiate neutral LAs. Among the tertiary amine LAs, potentiation of ester-linked drugs (procaine, RAG505; PF = 3.9, 5.4, respectively), exceeded that of their amide-linked homologues (procainamide, lidocaine; PF = 1.3, 2.8, respectively) which have higher pKa values. This result is consistent with an ion trapping mechanism whereby CO2 acidifies the axoplasm and thereby increases the concentration of protonated LA inside the nerve fibers. However, slight differences in the molecular structure of 3 degrees-amine LAs with similar pKa values resulted in significantly different potentiations (e.g., procaine, PF = 3.9; 2-chloroprocaine, PF = 8.7), suggesting that the HCO3- or CO2 molecules interact specifically with the LA molecule or with LA binding sites in the nerve membrane. Spectrophotometric measurements of the free [Ca2+] in Ringer's showed it to be similar (+/- 0.03 mM) for both buffers, obviating changes in extracellular Ca2+ as a mechanism of BC potentiation. The resting potential of the nerve was slightly more negative (approximately -4 mV) in BC-R, so membrane depolarization cannot explain the potentiation.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1978

Carrier-mediated transport of the organic cation procaine amide ethobromide by isolated rat liver parenchymal cells.

Using hepatocytes isolated by collagenase perfusion, we studied the kinetic characteristics of the uptake process for procaine amide ethobromide (PAEB). Determination of initial uptake velocities (Vo) at substrate concentrations from 30 to 400 micrometer demonstrated a saturable process with a Km of 54 +/- 10 micrometer and a Vmax of 0.13 +/- 0.01 nmol/min/mg of protein. Pretreatment of cells with metabolic inhibitors and reduction of the incubation temperature significantly reduced the Vo of 100 micrometer PAEB. Replacement of sodium ions with lithium had no effect, while replacement with choline decreased Vo by 75%. The intracellular concentration of PAEB was 18 times the medium concentration after 90 min, but 33% of that was in the acetylated form. Uptake of N4-acetyl PAEB occurred at a much lower rate and reached a cell/medium ratio of only 6 after 90 min. Only one of seven quaternary amines tested inhibited PAEB uptake at an inhibitor/substrate ratio (I/S) of 7.5, while four out of five tertiary amines significantly decreased Vo at an I/S of 0.75 and all five decreased it at a ratio of 7.5. Some organic acids and steroidal compounds also significantly decreased PAEB Vo at an I/S of 0.75, while others from each group had no effect at an I/S of 7.5. Because uptake is saturable, requires metabolic energy, and occurs against an electrochemical gradient, it is suggested that the hepatic accumulation of PAEB occurs via an active, carrier-medicated transport process.

Animals↗

PubMed1993

[Autoradiographic and biochemical studies of protein synthesis in nucleated erythrocytes during the formation of their segregation apparatus].

It has been shown that during novocaine (4.6 x 10(-3) M) induced formation of the segregation apparatus (SA) the total protein synthesis decreases, the synthesis of certain proteins being characterized by a high rate turnover. In the intact erythrocytes, 1 x 10(-2) cycloheximide (CHM) inhibits the novocaine induced formation of segregation apparatus (SA) and protein synthesis by 90%. The combined action of novocaine and CHM on erythrocytes is accompanied by a decrease in CHM inhibiting effect on protein synthesis. This effect retains for 1.5 h during the action of both compounds. Some vacuoles of SA disposed cytochemically exposed acid phosphatase (AP), which enabled us to consider these as lysosomes. According to AP distribution in lysosomes, they can be classified into 3 groups. In group 1 AP is distributed along the membrane of vacuoles, in group 2 it is associated with the material inside the lysosome, and in group 3 the enzyme is both distributed along the membrane and associated with the material enclosed within the segregation vacuole. Such a mode of AP distribution reflects presumably the functional heterogeneity of lysosomes.

Acid Phosphatase↗

PubMed1985

Excitation-contraction coupling in crab muscle fibers with swollen T tubules.

Single crab (Callinectes danae) fibers were equilibrated with isotonic, high KCl solutions and were subsequently returned to the control saline. This caused marked swelling of the T tubules. Fibers treated with 100 mM KCl had a 2.5-mV residual depolarization, a 50% decrease in effective membrane resistance (Reff) and a 75% reduction in membrane time constant (tau m). These fibers exhibited large increases in membrane conductance upon depolarization and were inexcitable; membrane depolarization with current pulses elicited no contraction. The effects of the KCl treatment on membrane properties were not reproduced by treatment with high potassium gluconate solutions, which did not cause tubular swelling. Tetrabutylammonium (10 mM) or Ba ions (10-20 mM), but not tetraethylammonium (40-100 mM), Sr ions (15-70 mM), or procaine (1-8 mM) reversed the effects of the KCl treatment on Reff, tau m, membrane excitability, and excitation-contraction coupling. The time course of the Ba effects was consistent with the suggestion that the KCl treatment increases the K conductance of the tubular membranes, which in turn prevents the activation of voltage-dependent Ca channels located in the membranes of the T system. This results in inhibition of the Ca-dependent electrogenesis and consequently, the absence of contraction upon depolarization of the plasma membrane.

Animals↗

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↗