[Contact-allergic eczematous test reaction as test model of the anti-eczematous effect of locally used corticosteroids].
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Administration, Topical↗
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Potentiation of the ganglionic blocking action of norepinephrine by cocaine.
Concentration-response curves for the blocking action of norepinephrine were determined in the isolated stellate ganglion of the hamster. The blocking effect of norepinephrine on the postganglionic compound action potential from preganglionic nerve stimulation at 0.2 Hz was reduced by phentolamine (10(-5) M), but was not altered by propranolol (10(-6) M). Cocaine (10(-6) and 10(-5) M) increased the sensitivity of the ganglion to norepinephrine. These concentrations of cocaine produced less than 25% blockade when applied alone. The local anesthetic, procaine, did not change the sensitivity of the ganglion to norepinephrine. The blockade by norepinephrine in the presence of cocaine was antagonized by phentolamine and unaffected by propranolol. The time course of the blockade by norepinephrine was more rapid in onset and slower in recovery in the presence of cocaine. If it is assumed that cocaine is blocking norepinephrine uptake into cells within the ganglion, these results indicate that the catecholamine uptake mechanism is involved in terminating the blocking action of exogenously applied norepinephrine.
Animals↗
Acetylcholine-like molecular arrangement in psychomimetic anticholinergic drugs.
A study of the relation between the psychotropic activity and the antagonism to acetylcholine observed for some heterocyclic amino esters and compounds of the phencyclidine series suggests some common molecular structural requirements for their properties. Criteria obtained from quantum mechanical calculations of acetylcholine-like molecules indicate that their molecular reactivity with the cholinergic receptor site follows a certain dynamic interaction pattern. This pattern suggests a certain molecular arrangement essential for the interaction, which is based on the electronic properties of the molecules and therefore remains valid for the evaluation of compounds which lack any apparent similarity to acetylcholine. This type of molecular arrangement is shown to be shared by both activators and inhibitors of the acetylcholine receptor discussed here, thus supporting the hypothesis of their binding to a common receptor. The differences in biological activity are attributed to the effect of molecular structural factors which are not commonly included in the molecular arrangement based on the active groups of acetylcholine. The role of such factors is revealed by a study of the observed differences in the cholinergic and psychomimetic activities of related pairs of isomers and enantiomers of the molecules investigated. Structural factors which interfere with the conformational changes occurring in the receptor protein induced by an activator are characterized through differences obtained by the comparative investigation of the activities of the agonist acetate and the antagonist benzilate amino esters of quinuclidine, tropine, and pseudotropine. The same factors are shown in studies of the phencyclidine series to contribute to the antagonism to acetylcholine activity that is closely related to the psychomimetic activity of these drugs in the central nervous system. Similarly, phencyclidine derivatives in which the characteristic acetylcholine-like molecular arrangement is modified by various substitutions are shown to loose both anticholinergic and psychotropic behavior. This close correlation is supported by the identification of molecular regions which will generate the proper molecular arrangement in local anesthetics and morphine, compounds which are known to be involved in cholinergic mechanisms.
Acetylcholine↗
Pharmacology of local anaesthetic agents.
The most important clinical properties of local anaesthetic agents are potency, onset, duration of action and relative blockade of sensory and motor fibres. These qualities are related primarily to the physicochemical properties of the various compounds. In general, lipid solubility determines the relative intrinsic potency of the various agents, while protein binding influences the duration of anaesthesia and pKa is correlated with the onset of action. In general, the local anaesthetics for infiltration, peripheral nerve blockade, and extradural anaesthesia can be classified into three groups: agents of low potency and short duration, for example procaine and chloroprocaine; agents of moderate potency and duration, for example lignocaine, mepivacaine and prilocaine; and agents of high potency and long duration, for example amethocaine, bupivacaine and etidocaine. These local anaesthetics also vary in terms of onset: chloroprocaine, lignocaine, mepivacaine, prilocaine and etidocaine have a rapid onset, while procaine, amethocaine and bupivacaine are characterized by a longer latency period.
Anesthesia, Local↗
In vivo release by histamine agonists and antagonists of endogenous catecholamines in the cat hypothalamus.
The posterior hypothalamus of anaesthetized cats was superfused through a push-pull cannula with histamine agonists and antagonists and the release of endogenous catecholamines was determined in the superfusate. Hypothalamic superfusion with histamine, 2-methylhistamine (H1-agonist), dimaprit (H2-agonist) or metiamide (H2-antagonist) enhanced the release of the catecholamines dopamine, noradrenaline and adrenaline. The releasing effects of these substances depended on the presence of calcium ions. Superfusion with 2-pyridylethylamine (H1-agonist) was virtually ineffective, while superfusion with 2-thiazolethylamine (H1-agonist) enhanced the rates of release of noradrenaline and adrenaline without influencing the release of dopamine. Superfusion with mepyramine (H1-antagonist) inhibited the release of noradrenaline and adrenaline without affecting the release of dopamine. Hypothalamic superfusion with a concentration of procaine which was equi-anaesthetic to that of mepyramine was ineffective. Ranitidine (H2-antagonist) did not alter the rates of release of the catecholamines. The releasing effect of histamine was inhibited on hypothalamic superfusion with mepyramine and ranitidine. Ranitidine also inhibited the releasing effects of dimaprit and 2-methylhistamine thus indicating that the releasing action of the latter compound was mainly due to stimulation of H2-receptors. These data suggest that blockade of H1-receptors of the posterior hypothalamus reduces the release of noradrenaline and adrenaline, while stimulation of H1-receptors seems to increase the rates of release of these two catecholamines. Stimulation of H2-receptors enhances the release of all three catecholamines. Thus, dopaminergic neurones of the hypothalamus seem to possess H2-receptors, while noradrenergic and adrenergic neurones possess H1- and H2-receptors.
Animals↗
[THE "POLARIZING" SOLUTION IN THE DAILY PRACTICE].
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Blood Chemical Analysis↗
Thimerosal potentiates Ca2+ release mediated by both the inositol 1,4,5-trisphosphate and the ryanodine receptors in sea urchin eggs. Implications for mechanistic studies on Ca2+ signaling.
Two intracellular Ca2+ release pathways are modulated by Ca2+ itself, namely Ca(2+)-induced Ca2+ release (classical CICR), and Ca(2+)-sensitized inositol 1,4,5-trisphosphate (InsP3)-induced Ca2+ release (CSIICR). Both of these pathways are thought to be important in generating cytosolic Ca2+ oscillations. Caffeine and the sulfhydryl reagent thimerosal (TMS) are frequently used as selective modulators of CICR and CSIICR, respectively. We have studied the modes of action of caffeine and TMS in sea urchin egg homogenates using the Ca2+ indicator fluo-3. Cyclic ADP-ribose (cADPR), the only known endogenous compound to cause Ca2+ release via the ryanodine receptor, was used as an agonist for the classical CICR pathway. cADPR and InsP3 each alone caused release of sequestered Ca2+. Coaddition of caffeine dose-dependently and dramatically enhanced Ca2+ release induced by cADPR. InsP3-induced Ca2+ release was not affected by caffeine, but it was amplified by TMS, indicating the existence of the CSIICR pathway in this preparation. Surprisingly, cADPR-induced Ca2+ release was also markedly potentiated by TMS. TMS alone caused a slow increase in Ca2+ release which was not inhibited by heparin and/or procaine, indicating that TMS-induced Ca2+ release was not due to the actions of endogenous agonists (InsP3 or cADPR) on their receptors. All observed actions of TMS were abolished by dithiothreitol. We conclude: 1) both the InsP3- and cADPR-controlled Ca2+ release pathways are potentiated by TMS, while caffeine is specific for the cADPR pathway, indicating that TMS cannot be used as a selective reagent for probing the CSIICR mechanism; and 2) the action of TMS on intracellular Ca2+ release is independent of endogenous Ca2+ channel agonists, suggesting a novel action of TMS possibly on intravesicular Ca2+ handling.
Adenosine Diphosphate Ribose↗
Mechanism of vascular actions of prostacyclin in the rat isolated perfused mesenteric arteries.
Prostacyclin (PGI2) did not alter the basal perfusion pressure in the isolated rat mesenteric arteries perfused with Krebs' solution, but produced a biphasic effect in arteries preconstricted with norepinephrine or arginine vasopressin: constriction, then prolonged dilation. Both these components of PGI2 effect were diminished in arteries denuded of their endothelia by a 10 min perfusion with distilled water or p-bromophenacyl bromide (10 microM). The present study elucidates the mechanism of these PGI2 actions. Indomethacin (0.28 microM) SQ 29548 (1 microM, thromboxane A2 receptor antagonist), saralasin (1 microM, angiotensin II receptor antagonist) or the free radical scavengers, superoxide dismutase (60 U/ml) and catalase (40 U/ml) did not inhibit the initial vasoconstriction, suggesting it was not mediated through endothelially generated thromboxane A2, angiotensin II or oxygen-derived free radicals. However, ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (50 microM; Ca++ chelating agent), 8-(diethyl-amino)octyl 3,4,5-trimethoxy benzoate (10 microM; intracellular Ca++ antagonist), or neomycin (5 mM; phospholipase-C inhibitor) abolished the vasoconstriction. Ouabain (0.5 mM) did not affect the vasodilation, but perfusion with excess (50 mM) or 0 K+ Krebs' solution abolished it, suggesting this PGI2 action involves changes in membrane K+ conductance via a mechanism independent of Na+/K+ adenosine triphosphatase. Vasodilation evoked by BRL 34915 (K+ channel activator) was similarly attenuated under these conditions, but not by ouabain. Furthermore, procaine (1 mM; nonspecific K+ channel inhibitor), but not apamin (0.5 microM) or tetraethylammonium (10 mM) blocked PGI2- and BRL 34915-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenylyl Cyclases↗
Behavioral and electrophysiological recovery following cryogenic nerve injury.
Postthoracotomy pain can be reduced by cryoanalgesia of intercostal nerves. The technique involves focal freezing of peripheral nerves to interrupt pain pathways, producing immediate functional changes that recover as the nerves regenerate. To assess the time-course of functional changes that follow nerve injury, unilateral freeze lesions of sciatic nerve were induced in rats with a cryosurgical unit. The contralateral nerves were used as sham-operated controls. Following nerve injury, behavioral and electrophysiologic tests were repeated to 90 days. The acute effect of nerve injury was a decrease in behavioral measures of hind limb function (P less than 0.05), an increase in electrical threshold to elicit hind limb contraction (P less than 0.005), and an absence of stimulus-evoked compound action potential (P less than 0.005). Morphologic changes included substantial endoneurial edema associated with Wallerian degeneration. Remyelination occurred subsequently during the following 35 days. Although all physiologic measures returned toward normal, nerve conduction velocities were still much slower in the experimental group. In a second study, the long-term effects of cryogenic injury were compared with neurolytic injury with 10% procaine HCl, both of which produced a conduction velocity deficit that persisted at least 90 days after the initial injury. These behavioral and electrophysiologic results complement previous reports of morphologic deficits in the nerves including incomplete recovery of nerve fiber diameter and increased thickness of the perineurial sheath.
Action Potentials↗
THE DRUG TREATMENT OF COMPLETE A-V HEART BLOCK.
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Adams-Stokes Syndrome↗
Effect of the anticonvulsant U-54494A on cortical neuron excitability: comparison to the kappa agonist U-50488H.
U-54494A, a 1,2-diamine anticonvulsant, and U-50488H, a structurally related agonist for opiate kappa receptors, were tested for effects on spontaneous and glutamate-evoked firing rates in cerebral cortex of urethane-anesthetized male Sprague-Dawley rats. Iontophoretic application of 1,2-diamines, glutamate diethyl ether (GDEE), or procaine depressed spontaneous and amino acid-induced firing of cortical neurones. With continued ejection of 1,2-diamines or procaine, firing was silenced completely, but GDEE could maintain a partial suppression. A rapid rebound of excitation followed cessation of procaine ejections, but not of other agents. Procaine, but not U-54494A, blocked axonal conduction of rabbit sciatic nerve. Intravenous U-54494A and U-50488H significantly depressed spontaneous firing rates of cortical neurones, but only the U-50488H effects were antagonized by naloxone. It is concluded that U-54494A inhibits neuronal excitability by a mechanism independent of the analgesic kappa receptor. Biochemical and physiological studies have demonstrated that U-54494A and the kappa opioid agonist U-50488H (a structurally related diamine) (1) have anticonvulsant activity (2, 3). U-54494A lacks kappa analgesic and sedative properties, and it has been suggested that the mechanism of action of this compound may be mediated by a subtype of kappa opioid receptor (3). The effects of kappa analgesics on neuronal firing in nociceptive pathways have been described (4, 5). However, no previous electrophysiological studies on U-54494A have been done. Since U-54494A antagonizes amino acid-induced seizures (3), the interactions of this compound with glutamate are of interest. In the present study, the antagonist efficacies of U-54494A and U-50488H for inhibiting spontaneous and 1-glutamate stimulated neurons of the rat prefrontal cerebral cortex were assessed after i.v. and microiontophoretic administration of the compounds. Effects observed with these routes of administration allow the observation of neuronal changes occurring immediately after administration and take advantage of the high temporal resolution provided by the electrophysiological recording techniques of single cells. A preliminary account of portions of this work have been previously disclosed (6).
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
The action of local anesthetics on myelin structure and nerve conduction in toad sciatic nerve.
X-ray scattering and electrophysiological experiments were performed on toad sciatic nerves in the presence of local anesthetics. In vitro experiments were performed on dissected nerves superfused with Ringer's solutions containing procaine, lidocaine, tetracaine, or dibucaine. In vivo experiments were performed on nerves dissected from animals anesthesized by targeted injections of tetracaine-containing solutions. In all cases the anesthetics were found to have the same effects on the x-ray scattering spectra: the intensity ratio of the even-order to the odd-order reflections increases and the lattice parameter increases. These changes are reversible upon removal of the anesthetic. The magnitude of the structural changes varies with the duration of the superfusion and with the nature and concentration of the anesthetic molecule. A striking quantitative correlation was observed between the structural effects and the potency of the anesthetic. Electron density profiles, which hardly showed any structural alteration of the unit membrane, clearly indicated that the anesthetics have the effect of moving the pairs of membranes apart by increasing the thickness of the cytoplasmic space. Electrophysiological measurements performed on the very samples used in the x-ray scattering experiments showed that the amplitude of the compound action potential is affected earlier than the structure of myelin (as revealed by the x-ray scattering experiments), whereas conduction velocity closely follows the structural alterations.
Action Potentials↗
[Effect of prajmalium bitartrate and procaine amide on ventricular extrasystoles (author's transl)].
Prajmalium bitartrate (Neo-Gilurytmal) was given to 19 patients, who had either runs of ventricular extrasystoles or frequent extrasystoles. The E. C. G. was continuously monitored on magnetic tape. At a dosage of 80 mg/d (20 mg every six hours) a significant reduction in ventricular extrasystoles was demonstrated on 20 separate occasions. After two hours extrasystoles decreased to 63% of the initial level. After six hours practically the full effect of the drug had been reached; the reduction in extrasystoles stabilized after 12 hours at an average of 30% of initial level. Ten hours after the last tablet had been taken the frequency of extrasystoles had risen to 57% of initial level. Comparison with procaine amide (3 g/d) in 14 patients revealed no significant difference between the two drugs. Prajmalium bitartrate was well tolerated, while three patients receiving procaine amide complained of nausea and gastrointestinal symptoms, so that treatment had to be discontinued in two. In one patient, receiving procaine amide by continuous drip, there were reversible joint pains, resembling lupus erythematodes.
Adult↗
Compounds that increase oxygen diffusion in plasma.
The rate of diffusion of oxygen in blood plasma is increased by adding certain compounds to plasma at very low concentration levels. Decreased oxygen diffusion rates in plasma causes local hypoxic conditions and this may play an important part in the pathogenesis of atherosclerosis.
Arteriosclerosis↗
Depolarizing effect of various local anaesthetics on the Helix aspersa neurons: dose-response relationship.
The depolarizing effect of various local anaesthetics (LA) on the membrane potential of Helix central neurons has been examined. There is a relation between depolarizing effect and concentration of LA in the bath that is linear over a range of concentrations. The slope of the curve is significantly higher for amethocaine (tetracaine) than for procaine while for dibucaine the dose-response relation is not linear. The blockade of a response to acetylcholine (ACh) is about two fold higher for dibucaine and amethocaine than for procaine. These results suggest that both amethocaine and procaine act at the ACh-site in addition to their binding with specific sites located within the ionic channel lumen; dibucaine appears to act through another mechanism.
Anesthetics, Local↗
Calcium release and subsequent development induced by modification of sulfhydryl groups in porcine oocytes.
The mechanism of Ca2+ release induced by modification of sulfhydryl groups and the subsequent activation of porcine oocytes were investigated. Thimerosal, a sulfhydryl-oxidizing compound, induced Ca2+ oscillation in matured oocytes. In thimerosal-preincubated oocytes, the amount of Ca2+ released after microinjection of inositol 1,4,5-trisphosphate (InsP3) or ryanodine increased strikingly, indicating that thimerosal potentiated both InsP3- and ryanodine-sensitive Ca2+ release pathways. Thimerosal also enhanced the sensitivity of oocytes to microinjected Ca2+ so that in pretreated oocytes a Ca2+ injection triggered a larger transient. Heparin at concentrations that normally block the InsP3-induced Ca2+ release were without effect; higher doses significantly increased the time leading up to the first spike. The thimerosal-induced Ca2+ release could not be blocked by procaine, and it did not require the formation of InsP3 since preinjection with neomycin did not prevent the oscillation. Immunocytochemistry revealed that thimerosal treatment destroyed the meiotic spindle, preventing further development, an effect that could be reversed by dithiothreitol. The combined thimerosal/dithiothreitol treatment triggered second polar body extrusion in 50% of the oocytes, and as a result of this activation scheme approximately 15% of the in vitro- and approximately 60% of the in vivo-matured oocytes developed to blastocyst during a 7-day culture in vitro.
Animals↗
[Membrane mechanisms of activating depolarized smooth muscle contraction (guinea pig small intestine) during exposure to physiologically active compounds].
The experiments were performed on the depolarized smooth muscle of taenia coli with the use of double sucrose-gap arrangement. Muscle contractions were induced by 1) application of hystamin or bradikynin; 2) rectangular long-lasting (10--20 s) pulses of hyperpolarizing current--the strong contraction appeared in response to the switching off the current (off-response). Both the on- and off-responses to the hyperpolarizing current recorded before, during and after hystamine (or bradikynin)-induced contration were, as a rule, very similar. Treatment of smooth muscle with local anaesthetics (procaine, trimecaine, QX-572) removed hystamine- and bradikynin-induced contrations and only decreased off-responses. The analysis of the data obtained suggested the existence of the independent electrically and chemically excitable systems (channels?) OF Ca2+ ion transport in the membrane of smooth muscle cells.
Animals↗
Isolation of basic drugs from plasma using solid-phase extraction with a cyanopropyl-bonded phase.
The use of a CN sorbent for the isolation of basic compounds from plasma is described. Adsorption from water and plasma was investigated for a test set of 30 basic drugs. It was found that compounds with a carbon chain length greater than or equal to 11 are totally retained and that the competitive effect of the matrix on the adsorption is minimal. Methanol-phosphate buffer (pH 3, mu = 0.05) (50:50) yielded good recoveries for more polar compounds; apolar basic drugs can be efficiently eluted using methanol containing 0.1% propylamine. Water up to 3 ml can be used for the washing step. This approach was applied to the determination of eight drugs in plasma at therapeutic levels. The absolute recoveries (n = 6) obtained were 98.8 +/- 7.3% for papaverine, 82.3 +/- 3.9% for practolol, 83.4 +/- 2.6% for metoclopramide, 87.3 +/- 5.8% for imipramine, 82.8 +/- 3.3% for procaine, 82.7 +/- 4.6% for morphine, 87.5 +/- 7.2% for propranolol and 90.4 +/- 6.2% for yohimbine.
Adsorption↗