bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of baclofen on synaptically‐induced cell firing in the rat hippocampal slice
Authors: Ault Brian , Nadler J. Victor
Published: July 2012

The effects of baclofen on the synaptically‐induced firing of pyramidal and granule cell populations were tested in the rat hippocampal slice. Population spikes were evoked by stimulating excitatory pathways in the presence and absence of bath‐applied drug.

(±)‐Baclofen (20 μM) completely blocked the firing of CA1 or CA3 hippocampal pyramidal cells subsequent to stimulation of projections that originate in area CA3. In contrast, the firing of dentate granule cells evoked by stimulation of the perforant path fibres was depressed by only 46% and baclofen did not affect the monosynaptic firing of CA3 pyramidal cells evoked by mossy fibre stimulation. These results are consistent with the effects of baclofen on the corresponding extracellularly‐recorded excitatory postsynaptic potentials (e.p.s.ps).

The Schaffer coUateral‐commissural population spike in area CA1 was depressed by (−)‐baclofen (EC50 = 2.8 μM), GABA (EC50 = 2.2 mM) and 3‐aminopropanesulphonic acid (3‐APS) (EC50 = 0.34 mM). (−)‐Baclofen was 180 times as potent as (+)‐baclofen.

Bicuculline methiodide (100 μM) did not reverse the depressant action of (−)‐baclofen. GABA‐induced depressions were antagonized to only a small degree, whilst the effect of 3‐APS was readily reversed. Raising the concentration of bicuculline from 100 μM to 500 μM did not further reverse the action of GAB A.

The effects of (−)‐baclofen and 3‐APS on the relationship between extracellular e.p.s.p. and population spike were tested by stimulation of the Schaffer collateral‐commissural fibres in area CA1. (−)‐Baclofen shifted the ‘input/output’ curve to the right at a concentration of 1 μM, but less or not at all at 3 μM. In contrast, increasing the concentration of 3‐APS shifted this curve farther to the right.

These results are consistent with the hypothesis that baclofen and GAB A can depress neuronal firing by interacting with a bicuculline‐insensitive receptor. In the CA1 area, activation of these receptors mainly depresses transmitter release from terminals of projections from area CA3, but also reduces pyramidal cell excitability.
The effects of benzodiazepine agonists, inverse agonists and Ro 15–1788 on the responses of the superior cervical ganglion to GABA in vitro
Authors: Little H.J.
Published: July 2012

The effects of benzodiazepines and their antagonists on the responses to γ‐aminobutyric acid (GABA) of the superior cervical ganglion of the rat were examined using extracellular recording.

Chlordiazepoxide (1 μm to 28.9 μm) and flurazepam (145–725 nm) increased the responses of the ganglion to GABA and the increases were antagonized by Ro 15–1788, at 3.34 μm. The concentration of GABA used was 9.7 μm which gave half‐maximal responses.

Chlordiazepoxide similarly increased the responses of the ganglion to GABA 38.8 μm in the presence of bicuculline 27.2 μm. This concentration of GABA gave, with bicuculline, responses of a similar magnitude as those to 9.7 μm in the absence of bicuculline. Bicuculline did not affect the actions of chlordiazepoxide or the antagonism by Ro 15–1788.

Ro 15–1788 did not affect the increases in GABA response caused by pentobarbitone or by phenobarbitone in the presence of bicuculline.

Ethyl β‐carboline‐3‐carboxylate (βCCE) (207 nm to 1 μm) significantly decreased the responses to GABA in the presence and in the absence of bicuculline. The decreases were antagonized by Ro 15–1788 (3.34 μm). βCCE at 2.1 μm and above did not significantly change the responses to GABA.

Methyl β‐carboline‐3‐carboxylate (βCCM) at 88 to 440 nm significantly decreased the responses to GABA. The decreases were antagonized by Ro 15–1788 (3.34 μm) and were also seen in the presence of bicuculline.

High concentrations of Ro 15–1788 decreased the responses to GABA, 9.7 μm, but increased the responses to GABA 38.8 μm in the presence of 27.2 μm bicuculline.

The pattern of effects of the benzodiazepines, β‐carbo lines and low doses of Ro 15–1788 on the responses to GABA was similar to the effects of these compounds on seizure threshold and anxiety‐related behaviour in vivo.
Development of markers for cholinergic neurones in re‐aggregate cultures of foetal rat whole brain in serum‐containing and serum‐free media: effects of triiodothyronine (T3)
Authors: Atterwill C.K. , Kingsbury A. , Nicholls J. , Prince A.
Published: July 2012

Development has been studied in re‐aggregate cultures derived from the 16 day foetal rat brain and the effects of triiodothyronine (T3) investigated. Cultures were maintained in either a medium containing 10% serum (S+), or in serum‐free culture medium (S−) or in serum‐free medium containing 30nm T3.

The muscarinic cholinoceptor, measured by specific binding of [3H]‐quinuclidinyl benzitate ([3H]‐QNB) at 9 and 14 days in vitro, was at a lower level in the serum‐free cultured cells compared with those in serum‐containing culture medium (S+). In cultures in the latter medium, receptor concentration at day 14 was of a similar magnitude to that in rat brain at an equivalent postnatal age. Binding increased with development from 9 to 14 days in vitro in the S+ medium but not in the S− medium. T3 treatment caused an 85% increase in [3H]‐QNB binding compared with the cultures in S− medium at day 14 to a level equivalent to that found in the cells grown in S+ medium. This increase was reflected in the Bmax but not in the KD (approx. 0.1 nm).

Choline acetytransferase (ChAT) activity developed more slowly in the S− medium than in the S+ medium where the specific activity approximated values obtained in vivo. T3 treatment of cultures grow in S− medium significantly enhanced the developmental rate of increase of ChAT activity.

The characteristics of [3H]‐choline uptake and metabolism in the cultures was examined. Uptake was strictly Na+‐independent but was energy‐dependent, and inhibited by 2, 4′‐dinitrophenol (2, 4′‐DNP) and cooling (0–4°C). Neither iodoacetate nor ouabain had any effect on the amount of uptake. Hemicholinium (HC3) was a potent inhibitor of uptake (70% inhibition at 10 μm HC3). Metabolism studies showed virtually no conversion to [3H]‐acetylcholine ([3H]‐ACH) in re‐aggregates grown in either the S+, S− or T3 containing media. However, a small amount of [3H]‐choline was incorporated into phosphorylcholine. T3 treatment had no effect on this metabolic profile.

The kinetics of [3H]‐choline uptake by the re‐aggregates was also studied in the re‐aggregate cultures (after 12 and 22 days in vitro) using [3H]‐choline at 0.05–100 μm. Both Eadie‐Hofstee transformation and least‐squares analysis of the data showed that the uptake comprised only a single low‐affinity component with an apparent Kt = approx. 50 μm. Unlike ChAT and [3H]‐QNB binding, there appeared to be no difference between the uptake in the different culture conditions.

It is concluded that the differentiation of cholinergic neurones and muscarinic receptors in serum‐free cultured re‐aggregates from foetal rat brain is enhanced by thyroid hormone treatment. The development of [3H]‐choline uptake does not seem to be associated with cholinergic cells under these culture conditions, and is unaffected by thyroid hormone treatment.
Lack of a causal relationship between the vasodilator effect of papaverine and cyclic AMP production in the dog basilar artery
Authors: Fujioka Masahiko
Published: July 2012

The effects of papaverine and isoprenaline on smooth muscle cells of the dog basilar artery were investigated using radioimmunoassay, electrophysiological and isometric tension recording methods. For comparative purposes, the actions of these drugs on the guinea‐pig basilar artery were also examined.

Papaverine and isoprenaline (1 μm and 10 μm) increased the amount of cyclic AMP in both dog and guinea‐pig basilar arteries.

Papaverine (up to 100 μm) and isoprenaline (up to μm) had no effect on the membrane potential and membrane resistance measured by recording the amplitudes of the electrotonic potentials in smooth muscle cells of the dog and guinea‐pig basilar arteries.

The action potential evoked by outward current pulses after pretreatment with tetraethylammonium chloride (5–10 mm) was inhibited by papaverine (>1 μm) but not by isoprenaline (up to 10 μm) in smooth muscle cells of the dog and guinea‐pig basilar arteries.

In the dog basilar artery, papaverine (>1 μm) consistently inhibited the contractions evoked by excess concentrations of [K]o (>20.2 mm) or 5‐hydroxytryptamine (10 nm‐10 μm), dose‐dependently. Isoprenaline (1 μm) had only slight effects on the contraction evoked by low concentrations of 5‐hydroxytryptamine (10 nm).

In the Ca2+‐free solution containing EGTA (2 mm), the contraction evoked by 5‐hydroxytryptamine (10 μm) or caffeine (10 mm) was dose‐dependently inhibited by papaverine (>1 μm). However, isoprenaline (1 μm) had no effect on these contractions.

These results indicate that the vasodilator actions of papaverine on the dog basilar artery are mainly due to inhibition of the voltage‐dependent influx of Ca2+ and also to inhibition of the receptor‐activated release of Ca2+ stored in the cell. Since isoprenaline increased the cyclic AMP to the same extent as papaverine but had no effect on the electrical and mechanical responses, the inhibitory actions of papaverine on this tissue may not be causaly related to the increased levels of cyclic AMP induced by inhibition of phosphodiesterase.
Influence of protein‐calorie malnutrition on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats
Authors: Varma D.R. , Yue T.L.
Published: July 2012

The influence of protein‐calorie malnutrition (PCM) on the pharmacokinetics, transplacental passage and tissue localization of dexamethasone was determined in Sprague‐Dawley rats.

PCM increased the plasma half‐life and volume of distribution of dexamethasone in pregnant but not in nonpregnant rats.

Ratios of foetal to maternal serum dexamethasone concentrations were 0.2–0.4 at different dose levels (0.8–20 μmol kg−1), time intervals (0.25–12 h) and gestational ages (day 14–21).

PCM increased the foetal serum and tissue concentrations of dexamethasone but exerted no significant effect on its binding to maternal and foetal serum proteins or on its metabolism by the placenta.

It is suggested that significantly lower foetal than maternal serum levels of dexamethasone are due to efficient elimination of this agent by the foeto‐placental unit and an impairment of this mechanism may account for the observed increase in dexamethasone levels in the foetuses of PCM rats.
Influence of streptozotocin‐diabetes on the pharmacokinetics, placental transfer and tissue localization of dexamethasone in rats
Authors: Mulay S. , Varma D.R.
Published: July 2012

The influence of streptozotocin‐diabetes on the pharmacokinetics, placental transfer and tissue localization of dexamethasone was determined in Sprague‐Dawley rats.

Diabetes significantly increased the volume of distribution of dexamethasone in pregnant but not in nonpregnant rats; plasma half‐life was not significantly increased.

Concentrations of maternally administered dexamethasone in all tissues studied (maternal and foetal serum and livers, foetal lungs and placentas) except the amniotic fluid were lower in diabetic than in control animals.

Diabetes did not alter the binding of dexamethasone to maternal or foetal serum proteins.

Insulin treatment partially reversed the effects of diabetes on the maternal‐foetal exchange of dexamethasone.

Diabetes‐induced decrease in the foetal localization of dexamethasone appears to be caused by a decrease in the maternal serum levels as well as by an increase in the foetal excretion of the steroid into the amniotic fluid.

In so far as the rat model reflects the human situation, the present data suggest that a standard dose of dexamethasone might not be adequate in promoting foetal lung maturation in diabetic pregnancies.
The effect of gallamine, gallopamil and nifedipine on responses to acetylcholine and carbachol in the taenia of the guinea‐pig caecum
Authors: Mitchelson F. , Ziegler A.
Published: July 2012

The effects of gallamine, gallopamil and nifedipine on isotonic contractions of the isolated taenia of the guinea‐pig caecum produced by acetylcholine (ACh) or carbachol (CCh) were investigated.

Gallamine (0.1 to 0.3 mm) inhibited contractions produced by CCh more than those produced by ACh. The difference was still present after pretreatment of the tissue with paraoxon (10 μm for 20 min) to inhibit cholinesterases or in experiments carried out in the presence of tetrodotoxin (0.3 μm) to exclude possible ganglionic stimulation by the agonists.

Gallopamil or nifedipine selectively inhibited the tonic response to ACh in the absence or presence of paraoxon. The phasic response to ACh or the tonic response to CCh (0.1 or 1 μm) was much less affected.

Reduction of the Ca2+ content of the bath medium reduced phasic and tonic responses to ACh more than the tonic response to CCh.

These results suggest that there are differences in the interaction of ACh and CCh with muscarinic receptors in this muscle.
Pharmacological analysis of the responsiveness of guinea‐pig lung parenchymal strip to dopamine
Authors: Cortijo Julio , Esplugues Juan , Morcillo Esteban J. , Perpiñá Miguel
Published: July 2012

Responses to dopamine were examined in the guinea‐pig isolated lung parenchymal strip.

Complete cumulative concentration‐response curves to dopamine exhibited a biphasic pattern with a small initial contraction at concentrations below 10−5 m followed by a dose‐dependent relaxation at higher concentrations.

Phentolamine (10−5 m) completely abolished the contractile component and enhanced sensitivity and maximal relaxation to dopamine. In the presence of phentolamine, propranolol antagonized the dopamine‐induced relaxation (pA2 = 8.54 ± 0.07). In the presence of propranolol (10−6 m), dopamine produced a dose‐related contraction displaced to the right by phentolamine. Incubation with haloperidol (10−5 m) did not modify the characteristics of the concentration‐response curve to dopamine.

Pretreatment with reserpine abolished the contraction to dopamine without affecting its relaxant response. Cocaine significantly increased the pD2 value of dopamine in the presence of propranolol.

It is concluded that dopamine produced both relaxation of lung parenchymal strip due to direct activation of β‐adrenoceptors and contraction mediated through direct and indirect (catecholamine release) actions at α‐adrenoceptors. There is no evidence in favour of the existence of specific dopamine‐receptors in this preparation.
Changing surface charge with salicylate differentiates between subgroups of calcium‐antagonists
Authors: Spedding Michael
Published: July 2012

Sodium salicylate (5–10 mm) has been used to distinguish the effects of the three calcium‐antagonist subgroups which had been previously differentiated in functional studies.

Sodium salicylate (10 mm) reduced the antagonistic effects of verapamil and diltiazem on Ca2+‐induced contractions of K+ (40 mm)‐depolarized taenia preparations from the guinea‐pig caecum. In contrast, salicylate had no effect on the potency of nifedipine and increased the inhibitory effects of cinnarizine and flunarizine. Sodium salicylate (10 mm) had little effect on Ca2‐induced contractions per se.

In preparations pretreated with calcium‐antagonists and recontracted with high concentrations of Ca2+, salicylate (5 mm) caused an additional contraction when the preparations had been pretreated with verapamil or diltiazem but had no effect in control or nifedipine‐treated preparations. In contrast, salicylate relaxed Ca2+‐induced contractions in tissues which had been pretreated with cinnarizine, flunarizine, pimozide, bepridil, fendiline, perhexiline and with the calmodulin antagonist W‐7.

The mechanism of action of salicylate was investigated. Inhibition of prostaglandin biosynthesis or of oxidative phosphorylation by salicylate was not responsible for these effects because indomethacin (28 μm) and 2,4‐dinitrophenol (20 μm) did not differentiate between calcium antagonists. The effects of salicylate are ascribed to an increase in negative surface charge on the membrane because other agents changing surface charge (3,5‐dichlorosalicylate, 0.3 mm; benzoate, 20 mm) have similar effects and their potency is dependent on their affinity for lipid membranes. Furthermore, salicylate increased the effectiveness of the cationic local anaesthetic, (+)‐propranolol (100 μm), but did not change the effects of the neutral local anesthetic, benzocaine (1 mm).

It is argued that salicylate increases the effectiveness of cinnarizine by increasing accumulation of this drug in the cell membrane or at intracellular sites whereas the reduced effectiveness of verapamil and diltiazem is secondary to a change in the state of the Ca2+ channel.
Increased sensitivity of arachidonic acid‐induced platelet aggregation in the presence of carbon dioxide
Authors: Kerry P. J. , Paton Catherine J.
Published: July 2012

The effects of carbon dioxide on citrated human platelet‐rich plasma (PRP) have been studied as a means of imitating the changes in pH and Pco2 observed in inflammation and tissue fluid stasis.

Adenosine diphosphate (ADP)‐induced platelet aggregation was inhibited in CO2‐treated PRP.

In contrast, CO2‐treated platelets were rendered up to eight times more sensitive to sodium arachidonate and this effect could be imitated by the addition of exogenous calcium 1 min before the addition of arachidonate.

The effects of CO2 on ADP‐induced and arachidonate‐induced aggregation were abolished if the CO2 was allowed to disperse from treated PRP subsequently exposed to air, suggesting no permanent alteration in platelet metabolism.

The increased sensitivity of arachidonate‐induced aggregation with lowered pH may be a significant factor in influencing platelet behaviour in haemostasis.
The relative contribution of affinity and efficacy to agonist activity: organ selectivity of noradrenaline and oxymetazoline with reference to the classification of drug receptors
Authors: Kenakin Terry P.
Published: July 2012

Oxymetazoline demonstrated a pronounced organ selectivity, when compared to noradrenaline, by being a potent full agonist in rat anococcygeus muscle and a partial agonist in rat vas deferens.

Responses of rat anococcygeus muscles to oxymetazoline were relatively more sensitive to antagonism by phenoxybenzamine (Pbz) an alkylating α‐adrenoceptor antagonist. Therefore, although oxymetazoline was more potent than noradrenaline in this tissue, after Pbz (0.3 μm for 10 min), the responses to oxymetazoline were completely inhibited while those to noradrenaline were only partially inhibited.

Schild analysis with phentolamine, corynanthine, prazosin and yohimbine indicated no α‐adrenoceptor heterogeneity within the rat anococcygeus muscle or between this tissue and rat vas deferens. Measurement of agonist Kd values and Schild analysis of oxymetazoline antagonism of responses to noradrenaline (after alkylation) confirmed the homogeneity of α‐adrenoceptors with respect to these two agonists.

The above profiles of activity would be predicted if oxymetazoline had a higher affinity but lower efficacy than noradrenaline. Experimentally this was confirmed when it was found that oxymetazoline had 5 times the affinity but 0.2 to 0.3 times the efficacy of noradrenaline.

These results serve as a caveat to the use of selective receptor desensitization and/or selective receptor alkylation (or protection from alkylation) as means of differentiating drug receptors.

Theoretical modelling and these experimental results indicate that high affinity/low efficacy agonists are much more sensitive to receptor coupling. The implications for therapeutic selectivity could be important in that high affinity/low efficacy agonists theoretically have a much greater potential for organ selectivity.
Prazosin inhibits small intestinal transit in the rat
Authors: Rush B.D. , Ruwart M.J.
Published: July 2012

Gastric emptying, small intestinal transit, and colonic transit were measured in fasted rats preimplanted with either duodenal or colonic cannulae. At the doses stated, prazosin (given subcutaneously) had no effect on gastric emptying or colonic transit, whereas small intestinal transit was significantly delayed.
Pharmacological characterization of amine receptors on embryonic chick sensory neurones
Authors: Canfield D.R. , Dunlap K.
Published: July 2012

The effects of noradrenaline, dopamine and 5‐hydroxytryptamine were investigated on the duration of the action potential of embryonic chick sensory neurones in vitro.

All three amines, like γ‐aminobutyric acid, decreased the duration of the action potential evoked by current injection.

The onset of the noradrenaline‐induced decrease in action potential duration was fast (< 1 s) and the recovery phase was dependent upon the dose of noradrenaline applied. Rapid washout of the noradrenaline revealed a minimum 30 s recovery time which was independent of the initial noradrenaline concentration.

Dopamine and 5‐hydroxytryptamine could mimic the effects of noradrenaline on action potential duration. The ED50 for all three amines was approximately 1 μm. At a saturating concentration of 10 μm, noradrenaline was more potent than dopamine and 5‐hydroxytryptamine.

Saturating doses of noradrenaline and dopamine or 5‐hydroxytryptamine were not additive.

Responses to all three amines were affected similarly by antagonists: they were antagonized by yohimbine, phentolamine, haloperidol and mianserin but not by propranolol, prazosin, domperidone, spiperone or methysergide. Clonidine and xylazine (α2‐adrenoceptor agonists) were also without effect.

In contrast to the amines, saturating concentrations of γ‐aminobutyric acid were additive with those of noradrenaline. Responses to GABA were not antagonized by the amine receptor antagonists.

The evidence described here suggests that the amines and γ‐aminobutyric acid decrease sensory neurone action potential duration via pharmacologically‐distinct membrane receptors. In addition, it is likely that the amines are acting via a single class of receptor whose pharmacology is different from classical adrenoceptors, dopamine receptors and 5‐hydroxytryptamine receptors.
Cyclo‐oxygenase inhibitors antagonize indirectly evoked contractions of the guinea‐pig isolated ileum by inhibiting acetylcholine release
Authors: Okpako David T. , Taiwo Yetunde O.O.
Published: July 2012

The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea‐pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo‐oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied.

The cyclo‐oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh‐induced contractions.

In whole ileum preparations (WIP) indomethacin and ketoprofen (40 μg ml−1) reduced TMS responses by 17 ± 1.8% and 12 ± 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 μg ml−1) reduced TMS responses by 28 ± 2.3% and 34 ± 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo‐oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP.

The cyclo‐oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 μg ml−1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6).

Prostaglandin E2 (PGE2) (0.1–2.5 ng ml−1) restored the contractile responses and ACh release depressed by the cyclo‐oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2α had no effect on mechanical responses or ACh release depressed by the cyclo‐oxygenase inhibitors.

It is concluded that the cyclo‐oxygenase inhibitors studied reduced responses to transmural stimulation and nicotine by inhibiting ACh release. The site of action is the postganglionic parasympathetic nerve.

It is suggested that the reason why previous investigators needed to use high doses of cyclo‐oxygenase inhibitor in the ileum is because the action of the inhibitor is limited by diffusion barriers. There was no evidence to support the view that there is more than one pool of cyclo‐oxygenase in guinea‐pig gut.
The effects of external potassium, multivalent cations and temperature on caffeine contractures in rat skeletal muscle
Authors: Anwyl R. , Bruton J.D. , McLoughlin J.V.
Published: July 2012

The effects of multivalent cations, membrane potential and temperature on caffeine contractures of rat soleus and extensor digitorus longus (e.d.l.) muscles were investigated.

The amplitude of the caffeine contracture was depressed by the removal of calcium and by the addition of a high concentration (1 mm) of lanthanum. Low concentrations of lanthanum (0.1–0.5 mm) augmented the caffeine contracture.

Low levels of depolarization by potassium (10–40 mm) augmented the amplitude of the caffeine contracture, while higher concentrations of potassium depressed the contracture. Maximum augmentation of the caffeine contracture occurred with a higher concentration of potassium (20 mm vs 10 mm) in the e.d.l. than in the soleus muscle.

The amplitude of contractures was directly related to temperature between 22 and 37°C and inversely related to temperature below 22°C.

The effects of caffeine in rat skeletal muscle are suggested to be exerted on the sarcolemma and the mechanisms of action are by modification of the processes of activation and inactivation.
Potassium contractures and mechanical activation in rat skeletal muscle: effects of multivalent cations, temperature and tetracaine
Authors: Anwyl R. , Bruton J.D. , McLoughlin J.V.
Published: July 2012

The effects of cations, temperature and tetracaine on potassium‐induced contractures of rat soleus and extensor digitorus longus (e.d.l.) muscles were investigated.

In the soleus, the threshold for the potassium contracture was lower (10–20 vs 20–40 mm), the peak amplitude was up to fourteen times larger, and the time course was about one half that in the e.d.l. muscle. The extent of inactivation of a test potassium contracture was directly related to the concentration of potassium in the conditioning solution and the period of exposure.

Removal of calcium reduced the amplitude and time course of potassium contractures in both preparations. Addition of cobalt (10 mm) reduced the amplitude but prolonged the time course of contractures.

Exposure of muscles to tetracaine (10−5‐10−6m for 30 min) increased, but higher concentrations reduced, the amplitude of potassium contractures. When present for one minute, tetracaine (1 mm) moved the potassium activation curve to higher, and the potassium inactivation curve to lower, potassium concentrations.
Effects of injectable anaesthetics on responses to L‐glutamate and on spontaneous synaptic activity in lamprey reticulo‐spinal neurones
Authors: Cullen K.D. , Martin R.J.
Published: July 2012

Intracellular recordings were made from reticulo‐spinal cells in the medulla of lamprey ammocoetes; potential changes in response to iontophoretically applied l‐glutamate were measured before, during and after the preparation was superfused with anaesthetic solutions.

Of the anaesthetics pentobarbitone, ketamine, alphaxalone/alphadolone (Saffan) and metomidate, only pentobarbitone (> 10 μm) had a consistent dose‐related depressant effect on glutamate responses.

Spontaneous excitatory postsynaptic potentials (e.p.s.ps) and inhibitory postsynaptic potentials (i.p.s.ps) were diminished in frequency by high concentrations (1 mm) of all anaesthetics. Anaesthetic concentrations of all drugs also reduced i.p.s.ps; for e.p.s.ps this was true of pentobarbitone (100 μm) immediately, and of ketamine (370 μm) and alphaxalone (10–30 μm) after a transitory increase in activity.

Consideration of the results in the light of previous observations on inhibitory responses suggests a basis for some of the excitatory side effects of these compounds, assuming that the equivalent mammalian cells are similarly affected.
Effects of neomycin on galactose absorption across rat jejunum
Authors: Debnam E.S. , Thompson C.S.
Published: July 2012

The effects of neomycin sulphate on galactose absorption have been studied using in vivo and in vitro preparations of rat small intestine.

Neomycin (10−3m) produced an increase in the maximum transport capacity (Jmax) for the active component of absorption in vivo. The apparent Kt for absorption was unaffected.

The antibiotic caused a dose‐dependent increase in the potential difference across the mucosal membrane (Vm) measured in vitro, a maximal effect being seen at a concentration of 10 −4m. Furthermore, the magnitude of the depolarization induced by the addition of galactose (4 mm) to the mucosal fluid was enhanced by neomycin (10−4m). Phlorhizin (10 −4m) abolished the galactose‐induced depolarization in both the absence and presence of the antibiotic.

It is concluded that neomycin increases the electrical driving force for Na+ during Na+‐coupled galactose entry into the enterocyte.
Anti‐arrhythmic effects of prazosin and propranolol during coronary artery occlusion and re‐perfusion in dogs and pigs
Authors: Benfey B.G. , Elfellah M.S. , Ogilvie R.I. , Varma D.R.
Published: July 2012

Open‐chest dogs and pigs anaesthetized with pentobarbitone were used to evaluate the antiarrhythmic effect of prazosin and propranolol during a 30 min period of occlusion of the left anterior descending coronary artery followed by 15 min of reperfusion.

In dogs, both prazosin and propranolol reduced the incidence of ventricular premature depolarizations and ventricular tachycardia during the occlusion period. During the 45 min period of occlusion and re‐perfusion, the incidence of ventricular fibrillation was significantly reduced in the prazosin‐treated and propranolol‐treated dogs.

In pigs prazosin reduced the incidence of ventricular premature depolarizations during occlusion and propranolol reduced the incidence of both ventricular premature depolarizations and ventricular tachycardia during occlusion, but the incidence of ventricular fibrillation was not significantly reduced in the prazosin‐ and propranolol‐treated pigs.

Prazosin reduced arterial pressure and propranolol lowered heart rate in both dogs and pigs, but a comparison of mean arterial pressure and heart rate in animals surviving and those not surviving the 30 min of coronary artery occlusion and 15 min of re‐perfusion showed no significant difference.
A comparison of histamine secretion from peritoneal mast cells of the rat and hamster
Authors: Leung K.B. P. , Pearce F.L.
Published: July 2012

Functional mast cells have been obtained by peritoneal lavage of the rat and hamster.

Both cell types released histamine on stimulation with appropriate dilutions of anti‐rat IgE and anti‐hamster serum. The maximum response evoked by each reagent was significantly greater for the hamster cells. The release was non‐cytotoxic and was in each case blocked by the corresponding soluble antigen.

The rat and hamster cells responded to concanavalin A and the lectin from lentil. Phosphatidylserine (PS) potentiated the release only from the rat cells. In the absence of the lipid, the hamster cells were more reactive. The lectin from wheat germ, in the presence of PS, evoked histamine secretion only from the rat cells. Both populations were refractory to the lectin from soybean and to protein A.

Rat peritoneal cells were more responsive to the basic secretagogues compound 48/80 and peptide 401 (the MCD‐peptide from bee venom). These differences were less marked in the case of polylysine and polyarginine.

The two cell populations responded to the calcium ionophores A23187, ionomycin and Chlortetracycline. The hamster cells were significantly more sensitive to the former two liberators but markedly less reactive to Chlortetracycline.

Adenosine 5′‐triphosphate (ATP) and dextran were potent histamine liberators from the rat cells but were totally ineffective against the hamster.

Acetylcholine and carbamylcholine had no effect on either cell type.

These results are discussed in terms of the functional heterogeneity of mast cells from different sources.
6,9‐deepoxy‐6,9‐(phenylimino)‐Δ6,8‐Prostaglandin I1, (U‐60, 257) stimulates prostaglandin D2 and inhibits thromboxane B2 release from ionophore challenged human dispersed lung cells
Authors: Holgate S.T. , Robinson C.
Published: July 2012

6,9‐deepoxy‐ 6,9‐ (phenylimino)‐Δ6,8‐Prostaglandin I1 (U‐60,257), a prostaglandin analogue known to inhibit leukotriene formation in a number of cell systems, potentiates mast cell release of prostaglandin D2 from human dispersed lung cells activated with ionophore A23187. Over the same concentration range of 30−300 μm there was a related inhibition of ionophore‐induced generation of thromboxane B2 (r = 0.93, P < 0.01). As both prostaglandin D2 and thromboxane A2 are potent bronchoconstrictors, these observations may be relevant to the potential of this drug in the treatment of asthma.
Induction and inhibition of pinocytosis by aminoglycoside antibiotics
Authors: Johansson P. , Josefsson J.O. , Nässberger L.
Published: July 2012

We investigated whether differences in induction or stimulation of pinocytosis by six aminoglycosides reflected reported differences in their nephrotoxicity. Pinocytosis induced by antibiotics, Na+, K+ or Ca2+ was quantified by the number of pinocytotic channels in Amoeba proteus, a cell suitable for the study of the pinocytotic process.

The aminoglycosides were potent inducers of pinocytosis. They were effective in the order of their cationic charge: neomycin > gentamicin > netilmicin = tobramycin > kanamycin > streptomycin. Factors which reduced the charge of the molecules, i.e. alkaline pH and combination with carbenicillin or heparin, diminished pinocytosis.

Like La3+ the antibiotics inhibited Na+‐induced pinocytosis. The order of efficacy was netilmicin > gentamicin > neomycin. A similar rank order, which is the reverse of the order of nephrotoxicity, was observed for inhibition of Ca2+‐stimulated, Na+‐induced pinocytosis. Netilmicin was also the most potent inhibitor of the Ca2+‐induced pinocytosis in cells treated with concanavalin A. Inhibition of Ca2+‐stimulated pinocytosis by netilmicin was reversed by Ca2+, the calcium ionophore A 23187, or 4‐aminopyridine.

We have shown that several nephrotoxic cations are strong inducers of pinocytosis in the amoeba, that aminoglycosides in Ringer solution induce pinocytosis in the approximate order of their nephrotoxicity and that factors which are known to diminish toxicity reduce pinocytosis. It, therefore, appears that the mechanism of aminoglycoside nephrotoxicity is related to their ability to induce pinocytosis in the amoeba. Low inducing potency and strong Ca2+‐antagonism, as for netilmicin, are qualities which may reduce the tendency of polycationic compounds to damage proximal tubular cells.
Bronchodilator‐mediated relaxation of normal and ovalbumin‐sensitized guinea‐pig airways: lack of correlation with lung adenylate cyclase activation
Authors: Burka John F. , Saad Maan H.
Published: July 2012

Isoprenaline, vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and forskolin caused a dose‐dependent relaxation of normal and ovalbumin‐sensitized guinea‐pig tracheal spirals and lung parenchymal strips in vitro. There was no difference in magnitude of relaxation or sensitivity to these relaxants between normal and sensitized tissues. The rank order of potency (concentration of each drug at which 50% of the maximum is obtained) for these relaxants on both trachea and parenchyma was VIP > isoprenaline > PGE2 > forskolin, although the parenchyma was more sensitive than the trachea.

The rank order of efficacy of the drugs used in relaxing both the trachea and lung parenchyma was isoprenaline (10 μm) > forskolin (30 μm) > VIP (0.1 μm) > PGE2 (10 μm). PGE2 at concentrations greater than 1 μm sometimes contracted the lung strip.

Pretreatment with indomethacin (8.5 μm), a cyclo‐oxygenase inhibitor, reduced the resting tone of tracheal spirals, but did not significantly affect the tone of lung strips. Indomethacin‐pretreatment did not affect drug‐induced relaxations of either normal or sensitized tracheal spirals. However, both normal and sensitized indomethacin‐pretreated lung strips relaxed significantly less (P<0.05) to isoprenaline, PGE2 and forskolin. Indomethacin‐pretreatment did not affect sensitivity of normal and sensitized trachea or parenchyma to the relaxant drugs.

All the relaxant drugs used stimulated adenylate cyclase activity in normal or sensitized lung parenchyma membrane preparations. The rank order of efficacy (maximal activation) was forskolin > isoprenaline = VIP > PGE2. There was no difference in response between normal and sensitized lungs. Adenylate cyclase activity of normal lung was stimulated as follows: forskolin (100 μm), 500.0 ± 50.0%; isoprenaline (100 μm), 186.0 ± 29.0%; VIP (10 μm), 213.0 ± 19.0% and PGE2 (100 μm), 155.0 ± 23.0% of basal activity. Similar values were obtained for sensitized lung parenchyma.

Indomethacin pretreatment did not significantly affect normal or sensitized lung adenylate cyclase stimulation by isoprenaline, VIP, forskolin or PGE2.

It was concluded that: (a) Immunological sensitization to ovalbumin does not induce hypoactivity of relaxant drug receptors and/or the adenylate cyclase system of the airway tissues of the guinea‐pig. (b) There is an apparent lack of correlation between tissue relaxation in vitro and adenylate cyclase activity since the rank order of the efficacy of a range of relaxants was different for the two effects and furthermore indomethacin‐treatment of airway tissues yielded differential results.
Evidence for a peripheral component in the sympatholytic effect of clonidine in rats
Authors: Brown Morris.J. , Harland Deborah
Published: July 2012

In an attempt to assess separately the peripheral and central effects of clonidine on cardiovascular parameters and plasma catecholamine levels, the selective α2‐adrenoceptor antagonist idazoxan (RX 781094) was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before administration of intravenous clonidine. Plasma noradrenaline and plasma growth hormone concentrations were used as indices of peripheral sympathetic nervous activity and central α‐adrenoceptor stimulation, respectively.

Peripheral and central administration of idazoxan antagonized the cardiovascular responses to i.v. Clonidine, 5 μg kg−1. However, idazoxan was more effective against the hypotension than the bradycardia induced by clonidine.

Idazoxan 300 μg kg−1 i.v. and 50 μg i.c.v. prevented clonidine‐induced falls in plasma noradrenaline and adrenaline. The results suggest that 50 μg idazoxan i.c.v. caused some blockade of peripheral as well as central α2‐adrenoceptors. Idazoxan, 10 μg i.c.v., caused similar inhibition of the hypotensive response to clonidine as 300 μg kg−1 i.v. and 50 μg i.c.v. but did not significantly inhibit the clonidine‐induced fall in plasma noradrenaline concentration.

Animals pretreated with i.v. or i.c.v. idazoxan had significantly lower levels of plasma growth hormone than vehicle‐treated rats. Idazoxan 10 μg and 50 μg i.c.v. suppressed growth hormone secretion to the same extent.

These results suggest that stimulation of peripheral, prejunctional α2‐adrenoceptors in anaesthetized rats may contribute to the fall in plasma catecholamines produced by i.v. clonidine, and confirm that the hypotensive effect is centrally mediated.
2‐Alkyl analogues of idazoxan (RX 781094) with enhanced antagonist potency and selectivity at central α2‐adrenoceptors in the rat
Authors: Gadie B. , Lane A.C. , McCarthy P.S. , Tulloch I.F. , Walter D.S.
Published: July 2012

Four 2‐alkyl (methyl, ethyl, n‐propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central α2/α1‐adrenoceptor selectivity and a2‐adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat.

In cortical binding assays using [3H]‐idazoxan and [3H]‐prazosin, idazoxan had a 5 times greater α2/α1‐selectivity than yohimbine. The 2‐alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [3H]‐idazoxan binding sites.

In terms of central antagonist potency in vivo, the most favourable substitutions were 2‐ethyl (RX 811033) and 2‐n‐propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz‐induced mydriasis in the pentobarbitone‐anaesthetized rat.

All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine.

The results indicate that introduction of alkyl groups in the 2‐position of idazoxan greatly increases the α2/α1‐adrenoceptor selectivity as measured in binding studies. Improved α2‐adrenoceptor affinity and antagonist potency were particularly associated with the 2‐ethyl and 2‐n‐propyl analogues.
A microiontophoretic study of the actions of μ‐, δ‐ and κ‐opiate receptor agonists in the rat brain
Authors: Bradley P.B. , Brookes Anne
Published: July 2012

The actions of μ‐, δ‐ and κ‐opiate receptor agonists have been compared on the activity of single neurones in the brain stem, caudate nucleus and hippocampus of the rat, using the technique of microiontophoresis.

In the brain stem and caudate nucleus the predominant effect of all the opiate agonists tested was depression of neuronal activity which was antagonized by naloxone. The selectivity of naloxone as an opiate receptor antagonist was indicated by its lack of effect on γ‐aminobutyric acid (GABA)‐induced responses.

In the hippocampus both μ‐ and δ‐agonists mainly caused an increase in neuronal firing rates, though some neurones were depressed. In contrast, all the κ‐agonists, including the proposed endogenous ligand for the κ‐receptor, dynorphin, caused depression of neuronal activity. All of these effects were antagonized by naloxone.

There was a clear distinction in the areas within the hippocampus in which the μ‐ and δ‐agonists produced different effects. Neurones in the pyramidal cell layer were always excited by these drugs, whereas neurones in the granule cell layer of the dentate gyrus were always depressed by the same drug.
Pharmacological investigations of the vasodilator nerves supplying the duck's foot
Authors: Bell C. , Rome Annette C.
Published: July 2012

Vasodilator responses to electrical nerve stimulation and to various putative autonomic inhibitory neurotransmitters were studied in the Krebs‐perfused foot of the domestic duck.

Electrical stimulation resulted in frequency‐dependent vasoconstrictor responses which were abolished by the infusion of guanethidine. After abolition of the vasoconstriction, electrical stimulation produced a frequency‐dependent vasodilatation.

The putative inhibitory transmitter substances tested were substance P, somatostatin, vasoactive intestinal polypeptide, adenosine triphosphate and dopamine. Of these only dopamine produced dilator responses similar in appearance to those following nerve stimulation.

Infusion of metoclopramide (170 μM) greatly reduced dilator responses to nerve stimulation and to dopamine but not those to glyceryl trinitrate.

These results suggest that the vasculature of the duck foot may be supplied by dopaminergic vasodilator nerves.
Differential effect of cyclo‐oxygenase inhibition on antigen‐ and ionophore‐induced release of slow reacting substance from fragmented guinea‐pig lung
Authors: Krell Robert D. , Kusner Edward J.
Published: July 2012

The nonsteroidal anti‐inflammatory drugs (NSAID) indomethacin and mefenamic acid, at concentrations ranging from 3 μM to 18 μM, enhanced antigen‐induced slow reacting substance of anaphylaxis (SRS‐A) release from sensitized fragmented guinea‐pig lung. In contrast, these agents had no effect on SRS‐A release from nonsensitized guinea‐pig lung induced by several concentrations of the calcium ionophore, A23187.

Neither increasing preincubation time with the NSAID nor the use of sensitized tissue resulted in an enhancement of A23187‐induced SRS‐A release by indomethacin.

NSAID did not alter histamine release by either stimulus.

These results suggest that antigen and A23187 induce SRS‐A release from different sources or by different mechanisms in guinea‐pig lung.
Antinociception from a stereospecific action of morphine microinjected into the brainstem: a local or distant site of action?
Authors: Prado W. A. , Roberts M.H.T.
Published: July 2012

Morphine (1 μg) was microinjected into rats in the midline medullary nucleus raphe magnus (NRM); 1 mm lateral into nucleus reticularis paragigantocellularis (NRPG); 2 mm lateral into the VIIth nerve nucleus and 3 mm lateral into the Vth nerve nucleus. The time course of changes in the sensitivity to noxious heat was followed by the tail flick test.

Significant and prolonged antinociception was seen following microinjection into NRPG. At sites 1 mm from NRPG very weak effects were seen and at 2 mm from NRPG no antinociception occurred.

It is concluded that 1 μg of morphine microinjected into the brainstem is unlikely to cause antinociception by entering the circulation and having effects at remote sites. The distance diffused by morphine to cause significant antinociception after microinjection of 1 μg is less than 1 mm.

Levorphanol (1 μg) had very similar effects to morphine but dextrorphan and saline were ineffective.

It is concluded that although the concentrations achieved following microinjections may be high, they are not excessive as the effects show stereospecificity. The concentrations of endogenous substances released into the synaptic cleft may also be high.
The affinity and efficacy of the selective β1‐adrenoceptor stimulant RO363 at β1‐ and β2‐adrenoceptor sites
Authors: McPherson G. A. , Malta E. , Molenaar P. , Raper C.
Published: July 2012

(−)−Isoprenaline and the selective β1‐adrenoceptor agonist RO363 were tested for their inotropic effects in left atrial (β1) and relaxant effects in K+‐depolarized uterine (β2) preparations from the guinea‐pig. The drugs had similar activities as positive inotropic agents but RO363 was approximately 400 times less active than (−)−isoprenaline as a uterine relaxant. RO363 had intrinsic activities of 0.8 and 0.25 ((−)−isoprenaline = 1) in atrial and uterine preparations, respectively.

Apparent dissociation constants (KD values) determined from the ability of the agonists to displace (−)−[125I]‐iodocyanopindolol ([125I]‐CYP) bound to membranes prepared from both tissues were used as a measure of affinity. The [125I]‐CYP binding sites possessed the characteristics of homogeneous populations of β1‐adrenoceptors in atrial and β2‐adrenoceptors in uterine membrane preparations.

The pKD values for (−)−isoprenaline were similar in the two tissues (left atria 6.4, uterus 6.0) whilst for RO363 the atrial value (7.8) was considerably greater than that for the uterus (6.0). The latter value is very similar to the pKB value determined from shifts in (−)−isoprenaline curves produced by RO363 in uterine preparations.

Graphical plots of the fraction of receptors occupied vs response were constructed. The relative efficacy of (−)−isoprenaline with respect to RO363 was calculated to be 25 in atrial and 2633 in uterine preparations.

The selective β1‐adrenoceptor stimulant actions of RO363 are a reflection of both its greater affinity and efficacy for β1− as opposed to β2‐adrenoceptor sites. The potent actions of (−)−isoprenaline in both tissues are largely dependent on efficacy.