bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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.