bluuebunny/crossref_metadata_2025 huggingface dataset:
Release of dynorphin, somatostatin and substance P from the vascularly perfused small intestine of the guinea‐pig during peristalsis
Authors: Donnerer Josef , Holzer Peter , Lembeck Fred
Published: July 2012

The release of dynorphin‐(1–17), somatostatin and substance P into the venous effluate of the isolated and vascularly perfused guinea‐pig small intestine was measured during rest and peristaltic activity. The peptides were determined by specific radioimmunoassays.

Increasing the intraluminal pressure by 5 mbar increased the release of dynorphin‐(1–17), somatostatin and substance P. A substantial increase in the release of substance P was only seen in the presence of naloxone (1.5 μM) indicating an inhibitory influence of opioid peptide‐containing neurones on the release of substance P. The pressure‐induced release of substance P and dynorphin‐(1–17) was completely prevented by tetrodotoxin (1.3 μM), which suggests a neural origin of these two peptides. The pressure‐induced release of somatostatin was only partially inhibited by tetrodotoxin (1.3 μM) suggesting that somatostatin may also be released from non‐neuronal sources, i.e. endocrine mucosal cells.

Dimethylphenylpiperazinium (32 μM) increased the release of somatostatin and substance P and this effect was inhibited by tetrodotoxin (1.3 μM). Cholecystokinin‐octapeptide (38 μM) induced a large increase in the release of somatostatin but only a minute increase in the release of substance P; these effects of cholecystokinin‐octapeptide were not blocked by tetrodotoxin (1.3 μM).

Noradrenaline (59 μM) inhibited the pressure‐induced release of substance P but not that induced by dimethylphenylpiperazinium (32 μM). Neither the pressure‐induced nor the dimethylphenylpiperazinium‐evoked release of somatostatin was significantly diminished by noradrenaline.

These results indicate that dynorphin‐(1–17), somatostatin and substance P may be transmitters involved in the coordination of the peristaltic reflex. Part of the inhibitory effects of opioid peptides and noradrenaline on intestinal motility may be brought about by inhibition of the release of substance P.
Acute and chronic effects of the benzodiazepine receptor ligand FG 7142: proconvulsant properties and kindling
Authors: Little Hilary J. , Nutt David J. , Taylor Stuart C.
Published: July 2012

The effects of the acute and chronic administration of the β‐carboline benzodiazepine receptor ligand, FG 7142 were studied in mice.

On acute administration FG7142 (at doses between 10 and 40 mgkg−1) lowered seizure thresholds to infused pentylenetetrazol (PTZ) but showed an unusual dose‐response curve in that higher doses had less effect. The duration of action was considerably longer than that of other β‐carbolines, such as ethyl‐β‐carboline‐3‐carboxylate (βCCE).

During repeated administration, doses of FG7142 which were initially proconvulsant subsequently produced generalized seizures on average in 60% of animals after 12 once daily treatments. This seemed to be a form of chemical kindling.

The effects of different drug administration regimes were studied. Once daily dosage was shown to be the optimum for kindling production, and was therefore used for subsequent experiments.

Kindling lasted for at least one month after 12 single once daily doses of 40 mgkg−1 (FG 7142).

The administration of the benzodiazepine antagonist Ro 15–1788 concurrent with FG7142 prevented kindling. When Ro 15–1788 was given to kindled animals along with a challenge dose of FG7142, it prevented the expression of kindled seizures. These data show that kindling is mediated via the benzodiazepine receptor.
Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation
Authors: Finney M.J.B. , Karlsson J.‐A. , Persson C.G.A.
Published: July 2012

Human lung bronchiolar segments (about 2 mm long and with a diameter of 0.6‐1.5 mm) were dissected and circular muscle tension recorded. Airways were identified by histology and in some preparations by relaxant responses to noradrenaline (0.1–10 μM).

Adenosine (1–100 μM) produced only very weak contractions, whereas carbachol (EC50 = 0.40 μM), histamine (EC50 = 0.63 μM), prostaglandin D2 (EC50 = 0.50 μM), substance P (EC50 = 4.6 μM) and ATP (1–100 μM) produced much greater ones.

The contractions generally developed rapidly and were stable. The mean maximum increase in tension achieved with the most efficient constrictor, carbachol, was 0.5 g. ATP was the least efficient producing only about 40% of carbachol's maximum.

Terbutaline, theophylline and enprofylline relaxed carbachol (2.0 μM = EC70)‐contracted preparations. Terbutaline (3–3000 nM) relaxed 4 out of 11 bronchioles. Theophylline (10–4000 μM) and enprofylline (1–400 μM) consistently relaxed the bronchiolar preparations including those exhibiting little responsiveness to the β2‐adrenoceptor agonist.

Since enprofylline (which does not block adenosine receptors) was a five times more potent relaxant than theophylline and since adenosine produced only weak contractions, antagonism of adenosine receptors is probably not involved in relaxation of the small airways.

It is suggested that the present data, which apparently differ from those obtained with lung parenchymal strips, are of relevance for human small airways responsiveness.
Effect of verapamil and diltiazem on calcium‐dependent electrical activity in cardiac Purkinje fibres
Authors: Amerini Sandra , Giotti Alberto , Mugelli Alessandro
Published: July 2012

The effects of verapamil and diltiazem on normal action potentials, abnormal automaticity at depolarized membrane potential and oscillatory afterpotentials were compared in sheep cardiac Purkinje fibres.

Concentrations of verapamil and diltiazem exerting the same action on abnormal automaticity due to slow action potentials, caused different effects on action potential characteristics and on oscillatory afterpotentials.

Diltiazem significantly shortened action potential duration whereas verapamil slightly lengthened it (NS).

Diltiazem appeared to be more effective than verapamil in preventing the development of oscillatory afterpotentials induced by barium or by strophanthidin.

In 50% of barium‐treated preparations, verapamil caused the appearance of spontaneous activity due to enhanced normal diastolic depolarization, while diltiazem had no such effect.

The observed differences were explained in terms of the different effects of the two drugs on currents other than the slow inward current, since diltiazem was more potent than verapamil in depressing max.
A search for selective antagonists at M2 muscarinic receptors
Authors: Barlow R. B. , Shepherd M.K.
Published: July 2012

Isolated preparations of guinea‐pig ileum and atria have been used to estimate the dose‐ratios produced by antagonists at muscarinic receptors. Experiments with 4‐diphenyl‐acetoxy‐N‐methylpiperidine (4DAMP) metho‐salts and with its isomer, 3DAMP methiodide, indicate that these are only slightly affected by the choice of physiological salt solution, the choice of agonist and the presence or absence of hexamethonium.

Methyl or chloro groups in the p‐position of the two benzene rings in 4DAMP metho‐salts markedly reduce affinity and selectivity.

When the two benzene rings are linked together, as in the fluorene‐9‐carboxylic ester, the affinity for the receptors in the atria is comparable with that of 4DAMP methobromide but that for the ileum is about half, so the selectivity is reduced. When the rings are linked as in the xanthene‐9‐carboxylic ester, the affinity for receptors in both tissues is greater than that of 4DAMP methobromide but there is less selectivity.

When two molecules of 4DAMP are linked together by a polymethylene chain of from 4 to 12 carbon atoms the effects on affinity for muscarinic receptors in the guinea‐pig ileum are different from those on affinity for muscarinic receptors in guinea‐pig atria. The pentamethylene compound is the most selective: compared with 4DAMP methobromide it has slightly less affinity for receptors in the ileum but much less affinity for receptors in the atria.

The effects of the compounds in antagonizing the actions of carbachol on atrial rate are not markedly different from their effects in antagonizing its actions on the force of the atrial contractions.
Effects of conditioned running on plasma, liver and brain tryptophan and on brain 5‐hydroxytryptamine metabolism of the rat
Authors: Chaouloff F. , Elghozi J.L. , Guezennec Y. , Laude D.
Published: July 2012

An investigation was made into the effects of conditioned running (1 h and 2 h at 20 m min−1), which accelerates lipolysis, on the concentrations of tryptophan (Trp) in plasma, liver and brain and on 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) levels in brain.

Running caused time‐dependent increases in plasma free Trp and brain Trp of the rat, leading to increased brain 5‐HT turnover as revealed by higher amounts of its metabolite, 5‐HIAA. The ratio of brain Trp to plasma free Trp was decreased after 2 h of running.

Liver Trp content rose only after 3 h of running, while liver unesterified fatty acid (UFA) concentrations remained unmodified.

A comparison between food deprivation and running (both of which promote lipolysis) was performed. Running for 2 h affected to the same extent plasma Trp disposition when compared with 24 h food deprivation. Nevertheless, the ratio of brain Trp to plasma free Trp was decreased in the food‐deprived rats, when compared to the runners.

Valine, an inhibitor of entry of Trp into the brain decreased its level there to the same extent in both controls and 1 h runners.

Nicotinic acid, which inhibits fat catabolism, completely abolished the plasma UFA increase induced by 1 h of running. The drug did not affect plasma free Trp, brain Trp, 5‐HT or 5‐HIAA but enhanced plasma total Trp level.

Naloxone, an opiate antagonist, which decreased running‐induced lipolysis, did not alter plasma Trp disposition.

Desipramine, an antidepressant compound, affected only peripheral Trp concentrations of the runners. Plasma free and total Trp concentrations were increased in desipramine‐treated runners, compared with saline‐treated runners. In addition, desipramine increased the ratio of brain Trp to plasma free Trp of the runners. Brain 5‐HT and 5‐HIAA were increased in both desipramine‐treated controls and runners.

The results suggest that running, which like food deprivation accelerates lipolysis, increases brain Trp content and then 5‐HT turnover. Comparison of these two physiological situations suggests that effectiveness of brain Trp entry is much more altered by fasting.
AH23848, a thromboxane antagonist, suppresses ischaemia and reperfusion‐induced arrhythmias in anaesthetized greyhounds
Authors: Coker Susan J. , Parratt James R.
Published: July 2012

The effects of the thromboxane antagonist AH23848 (1 mg kg−1 i.v.) were examined in anaesthetized greyhounds prepared for occlusion of the left anterior descending coronary artery with subsequent reperfusion after 40 min of myocardial ischaemia.

Pretreatment with AH23848 30 min before coronary artery occlusion reduced the number of ischaemia‐induced extrasystoles to 339 ± 111 compared with 736 ± 153 in the control group. The incidence of ventricular fibrillation following reperfusion was also markedly reduced; 25% compared with 88% in the controls.

Late intervention with AH23848, 25 min after the onset of myocardial ischaemia did not significantly alter the incidence of reperfusion‐induced ventricular fibrillation; 70% of the control group died and 60% of those that received AH23848.

The ischaemia‐induced release of thromboxane A2 and prostacyclin was not altered by pretreatment with AH23848.

The results suggest that blockade of thromboxane receptors before myocardial ischaemia is an effective antiarrhythmic strategy in this model.
Effects of aminoglycoside antibiotics on bound calcium and contraction in guinea‐pig atria
Authors: Lüllmann Heinz , Schwarz Bernd
Published: July 2012

We studied the effect of three aminoglycoside antiobiotics which have been shown to replace Ca from lipid monolayers on the superficially bound Ca of isolated beating left atria from guinea‐pigs.

The cellular Ca content was determined by means of 45Ca after having attained complete exchange.

The antibiotics dibekacin, sisomicin, and gentamicin, all reduced the cellular Ca content by 10–20% in a dose‐dependent manner. The loss of superficially bound Ca was accompanied by a decline of the contractile force by 40–90%.

It is concluded that in isolated atrial muscle it is the amount of Ca bound to the outer surface of the cardiac plasmalemma, rather than the extracellular Ca2+ concentration, that determines contraction height.
Histamine and leukotriene‐independent guinea‐pig anaphylactic shock unaccounted for by Paf‐acether
Authors: Detsouli A. , Lefort J. , Vargaftig B. B.
Published: July 2012

Ovalbumin induced dose‐dependent contractions of lung parenchyma strips from sensitized guinea‐pigs, whereas Paf‐acether (1‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphoryl choline), a potential mediator of immediate hypersensitivity, induced a single contraction, followed by specific desensitization to a second exposure.

Lung strips desensitized to Paf‐acether contracted to ovalbumin as did non‐desensitized controls, even in the presence of inhibitors of other mediators of anaphylaxis.

Contractions by Paf‐acether and by ovalbumin were reduced by nordihydroguaiaretic acid (NDGA) and by the phospholipase A2 inhibitor p‐bromophenacyl bromide (0.1–0.3 mm). Three other anti‐lipoxygenase agents (diethylcarbamazine, 5mm; eicosatetraynoic acid and BW755c, 0.1 mm), reduced the contractions by ovalbumin but also those due to acetylcholine, indicating non‐specific effects. Neither the anti‐allergic compound sodium cromoglycate (3 mm) nor the anti‐leukotriene agent, FPL 55712 (0.01 mm), inhibited the contractions by ovalbumin or by Paf‐acether.

A sensitized strip stimulated with ovalbumin released substances which contracted a non‐sensitized strip mounted in the same organ bath. The contractions of the non‐sensitized strip were abolished by FPL 55712 (0.01 mm), by NDGA and BW755c, (0.1 mm), whereas those of the sensitized one were unaffected. Leukotrienes are formed by the lung strips during shock but alone, they do not explain the contractile activity.

The intravenous administration of ovalbumin (1 mg kg−1) led to bronchoconstriction and thrombocytopenia, which were not modified by the anti‐leukotriene substance FPL 55712 nor by aspirin. Bronchoconstriction was suppressed if FPL 55712 was used in combination with aspirin (20 mg kg−1), mepyramine and methysergide (200 μg kg−1 of either). Pretreatment of the guinea‐pigs with propranolol reduced this inhibition to approximately 60%. In no instance was thrombocytopenia prevented.

In vitro contractions of the actively sensitized lung strip are not fully accounted for by histamine, FPL 55712‐inhibitable leukotrienes or Paf‐acether, whereas in systemic anaphylaxis histamine and leukotrienes (inhibited respectively by mepyramine and by FPL 55712) have a significant role.
Prostaglandin formation by isolated gastric parietal and nonparietal cells of the rat
Authors: Postius S. , Ruoff H. ‐J. , Szelenyi I.
Published: July 2012

Rat gastric cells isolated by pronase and subdivided by Percoll into 3 fractions (F1, F2, F3) were used to study prostaglandin E2 (PGE2) formation and, as an indirect measure of parietal cell H+ production, [14C]‐aminopyrine uptake.

Cells that had not been fractionated, with 20 to 25% parietal cells, contained at 0°C 1.7 ± 0.35 (s.e.mean) ng PGE2 108 cells−1. During incubation at 37°C these cells steadily synthesized up to 4.36 ± 0.73 ng PGE2 108 cells−1 from endogenous substrate.

Indomethacin in concentrations higher than 10−6moll−1 inhibited this basal formation completely, but 10−4moll−1 did not reduce the cellular PGE2 level below 1.4 ± 0.2 ng 108 cells−1.

Arachidonic acid in concentrations higher than 10−5moll−1 evoked an abundant formation of PGE2, and 10−4moll−1 built up a plateau of over 7.5 ± 1.65 ng PGE2 108 cells−1 within 15 min.

PGE2 formation in cell fractions increased significantly with the number of parietal cells per assay tube.

Indomethacin (10−8 to 10−4moll−1) did not influence the histamine‐stimulated uptake of [14C]‐aminopyrine, while arachidonic acid (10−5 to 10−4 moll−1) inhibited this process.

PGE2 formation in response to arachidonic acid was prevented by indomethacin, but the inhibition of aminopyrine uptake by arachidonic acid could not be prevented by indomethacin.

The data suggest that isolated gastric cells of the rat sustain constant PGE2 synthesis in vitro, which is more pronounced in parietal than in mucosal and chief cells. PGE2 may exert different effects within distinct gastric cell types.
Modulatory activity of GABAB receptors on cholinergic tone in guinea‐pig distal colon
Authors: Giotti A. , Luzzi S. , Maggi C.A. , Spagnesi S. , Zilletti Lucilla
Published: July 2012

The effect of γ‐aminobutyric acid (GABA) administration was studied in both in vitro and in vivo preparations of the guinea‐pig distal colon.

In in vitro preparations GABA (10−7 − 10−3m) elicited a dose‐dependent relaxation; a decrease in the spontaneous contractions was sometimes observed.

The effect of GABA was mimicked by (—)‐baclofen, which gave a dose‐response curve overlapping that of GABA, while (+)‐baclofen was about one hundred times less potent.

The relaxation responses induced by the above drugs were antagonized by 5‐aminovaleric acid (5 × 10−4m), which did not affect adenosine‐induced relaxation, but they were insensitive to bicuculline (10−5m) and picrotoxin (10−5m). Moreover, they were prevented by tetrodotoxin (6 × 10−7m). In hyoscine (10−7m)‐pretreated preparations, GABA still evoked a small relaxation response (approx. 10% of the maximum) that was bicuculline‐sensitive.

Desensitization to GABA (10−5m) was observed. A specific cross‐desensitization occurred between GABA (10−5m) and (—)‐baclofen (10−5m).

In in vivo preparations, GABA (10 μmol kg−1) and (—)‐baclofen (5 μmol kg−1) produced a dose‐related inhibition of basal tone, while (+)‐baclofen (5 μmol kg−1) had much less effect (about 25%). A decrease in the spontaneous contractions was sometimes observed.

The relaxant effect of GABA and (—)‐baclofen persisted in guinea‐pigs pretreated (1–2 min) with picrotoxin (1.6 μmol kg−1), whereas it was significantly reduced in animals injected 1 min beforehand with 5‐aminovaleric acid (0.2 mmol).

The maximal relaxant effect induced by GABA and (—)‐baclofen did not differ from that of atropine (0.9 μmol kg−1) and after atropine administration GABA had no further inhibitory effect.

Relaxation responses induced by GABA and (—)‐baclofen still occurred after blockade of nicotinic receptors by hexamethonium (0.17 mmol kg−1), which itself caused an increase in the basal tone.

When the tone was increased by topical application of physostigmine (40 μg), GABA and (—)‐baclofen induced a greater relaxation than that obtained in basal conditions.

It is concluded that GABA, both in vitro and in vivo administration, inhibits cholinergic tone in guinea‐pig distal colon and that this effect is mediated mainly by activation of GABAB receptors. Further experiments are required to ascertain the possible physiological role of a GABA‐releasing neuronal system in the colon in vivo.
Influence of the epithelium on responsiveness of guinea‐pig isolated trachea to contractile and relaxant agonists
Authors: Goldie Roy G. , Papadimitriou John M. , Paterson James W. , Rigby Paul J. , Self Hazel M. , Spina Domenico
Published: July 2012

The potency (pD2) and maximal contractile effect (Emax) of histamine, acetylcholine, carbachol and K+ were assessed from cumulative concentration‐effect curves in guinea‐pig isolated tracheal ring preparations with and without an intact epithelium.

Estimates of Emax were not significantly different in epithelium‐denuded preparations compared with those measured in intact preparations; pD2 values for acetylcholine, carbachol and K+ were not significantly altered. In contrast, the potency of histamine was significantly increased by about 4 fold in preparations devoid of epithelial cells.

Estimates of potency and Emax were also determined for the smooth muscle relaxants isoprenaline, forskolin and theophylline (which increase intracellular cyclic AMP) and for nitroglycerin (which increases cyclic GMP) in both intact and epithelium‐stripped tracheal rings. The pD2 values for these relaxants were not significantly altered by the removal of the epithelium. However, with the exception of nitroglycerin, Emax values for these relaxants were significantly lower in stripped than in intact tracheal rings that had been maximally precontracted with carbachol.

The autoradiographic localisation of binding sites for the non‐selective β‐adrenoceptor ligand [125I]‐iodocyanopindolol (I‐CYP) showed that the epithelium of the guinea‐pig trachea had a 75 ± 16% greater density of β‐adrenoceptors than the smooth muscle. Removing the epithelium did not significantly alter either the density of smooth muscle binding sites or the affinity of I‐CYP binding. It was concluded that the reduced functional response of guinea‐pig trachea to isoprenaline was probably not due to smooth muscle β‐adrenoceptor dysfunction.

Results indicate that the epithelium plays an important role in the modulation of responsiveness of guinea‐pig trachea to histamine and relaxants that mediate their effects by selectively increasing intracellular cyclic AMP levels.
Blockade of Ca‐activated K conductance by apamin in rat sympathetic neurones
Authors: Kawai Tomoyuki , Watanabe Minoru
Published: July 2012

Effects of apamin on rat sympathetic neurones were investigated by means of intracellular and extracellular recording.

Apamin (50 nM) significantly shortened the after‐hyperpolarization (AH) following the spike evoked by current injection and slightly decreased its peak amplitude without affecting the time course of the spike.

The AH following the synaptically‐evoked spike was also blocked by apamin. This effect was dose‐and time‐dependent (ID50 estimated by extracellular recording approximately 15 nM, 20 min after application) and poorly reversible. Transmission of a single volley was not affected by 50 nM apamin.

Though a long depolarizing current caused one or two spikes in the cell, greater repetitive firing was observed in the presence of apamin. Spontaneous repetitive firing, however, was not observed except for anodal‐break spikes. Resting potential and input membrane resistance were essentially unchanged by apamin.

The maximum rate of rise of the Ca spike was not decreased by 50 nM apamin but the duration of the spike was lengthened by 60%. The AH following the Ca spike was also blocked by apamin.

These results suggest that apamin suppressed the slow AH without any inhibition of the Ca flux into the cell and is useful as a blocker of GK(Ca) in the rat sympathetic neurone.
Evidence for sympathetic, purinergic transmission in the mesenteric artery of the dog
Authors: Muramatsu Ikonobu
Published: July 2012

Electrical transmural stimulation of isolated mesenteric artery of the dog produced a transient contraction which consisted of adrenergic and non‐adrenergic components. In contrast to the adrenergic component, the nonadrenergic component was resistant to prazosin and other adrenoceptor‐blocking agents. However, the nonadrenergic component was completely blocked by guanethidine and by desensitization with α,β‐methylene‐ATP (α,β‐MeATP). Desensitization induced by α,β‐MeATP also inhibited the contractile response to ATP but not the adrenergic responses induced by electrical transmural stimulation and exogeneous noradrenaline. These results suggest that the nonadrenergic contraction induced by electrical transmural stimulation is a sympathetic, purinergic response.
Pharmacological studies with SK&F 93944 (temelastine), a novel histamine H1‐receptor antagonist with negligible ability to penetrate the central nervous system
Authors: Brown E. Ann , Griffiths R. , Harvey Carol A. , Owen D.A.A.
Published: July 2012

SK&F 93944 (temelastine), a novel histamine H1‐receptor antagonist, has been studied in a variety of in vitro and in vivo test systems.

SK&F 93944 was a competitive antagonist of histamine‐induced contractions of guinea‐pig ileum with a pA2 of 9.55 and a weak, non‐competitive, inhibitor of the effects of histamine on guinea‐pig atrium.

In anaesthetized guinea‐pigs SK&F 93944 displaced histamine bronchoconstriction dose‐response curves at doses which had negligible effects on histamine tachycardia.

In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine H1‐receptor agonists, 2‐(2‐aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2‐receptor agonist, dimaprit.

Oral pretreatment with SK&F 93944 in conscious rats and guinea‐pigs afforded protection versus the response to intradermal histamine injection.

Comparative studies in each of the test systems showed that SK&F 93944 was of comparable or significantly greater potency than the standard compound, mepyramine.

SK&F 93944 was found to be a weak, non‐competitive antagonist of carbachol on the guinea‐pig ileum but was devoid of measurable anticholinergic activity in vivo.

Studies on the penetration of [14C]‐SK&F 93944, labelled either in the isocytosine ring or in the butyl chain, showed that brain concentrations were very low when compared with the steady‐state blood concentrations. In contrast, brain concentrations of [3H]‐mepyramine exceeded blood concentrations by a factor of approximately 3.

SK&F 93944 may have an advantage over classical histamine H1‐receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.
The effects of alfentanil and selected narcotic analgesics on the rate of action potential discharge of medullary respiratory neurones in anaesthetized rats
Authors: Fone K.C.F. , Wilson H.
Published: July 2012

The effects of intravenous injections of alfentanil, fentanyl, phenoperidine or morphine on respiratory and peak inspiratory air flow rate, the diaphragm electromyogram (EMG), the activity recorded extracellularly from respiratory neurones located in the ventral respiratory group and the cardiovascular system were examined in anaesthetized rats.

Alfentanil produced dose‐dependent changes in peripheral and central respiratory parameters, which were prevented by naloxone pretreatment. Minimal effects were produced on the cardiovascular system. The bradypnoea was principally due to a prolongation of the inspiratory phase and was accompanied by a comparable decrease in the peak inspiratory air flow rate.

Alfentanil prolonged the discharge duration of inspiratory neurones such that it still maintained a strict phase correlation with the diaphragm EMG, but changes in firing frequency were inconsistent and negligible. The action on expiratory neuronal discharge was analogous to that on inspiratory neuronal discharge but delayed in onset.

Hypotension produced by morphine limited the dose used but the respiratory responses to morphine and other selected narcotic analgesics were otherwise similar to that of alfentanil, differing mainly in time‐course and magnitude. From the respiratory parameters assessed, the order of duration of effect was morphine > phenoperidine > fentanyl > alfentanil and the relative potencies were 0.1, 0.5, 2.5 and 1 respectively.

The selective prolongation of inspiration and the immediate action on inspiratory neurones suggests that systemically administered narcotic analgesics may alter the mechanisms within the central respiratory rhythm generator which determine the cessation of inspiration.
A new class of potent centrally acting muscle relaxants: pharmacology of oxazolidinones in rat decerebrate rigidity
Authors: Masaki M. , Shinozaki H.
Published: July 2012

The severity of anaemic decerebrate rigidity was quantitatively determined by measuring the frequency of electromyographic potentials in the rat.

Some oxazolidinones markedly reduced the severity of this decerebrate rigidity in a dose‐dependent manner, (4S,5R)‐4‐(2‐methylpropyl)‐3‐[3‐(perhydroazepin‐1‐yl)propyl]‐5‐phenyl‐1,3‐oxazolidin‐2‐one (MLV‐6976) being the most potent. In addition to the oxazolidinones, an aminoalcohol derivative, (1RS,2SR)‐5‐methyl‐1‐phenyl‐2‐(3‐piperidinopropylamino)hexan‐1‐ol (MLV‐5860) also reduced the rat decerebrate rigidity.

In the oxazolidinone series, the optical isomers with absolute configuration (S) at the 4‐position were more potent than the corresponding (4R)‐isomers, while there was no significant difference in their LD50 values.

Normal rats and mice receiving MLV‐6976 at doses which reduced decerebrate rigidity showed no behavioural changes, impairment of motor coordination only appearing at extremely high doses. MLV‐6976 and its derivatives did not affect spinal reflex potentials in cats.

MLV‐6976 reduced the severity of harmaline‐induced tremor in mice in a dose‐dependent manner, but slightly augmented tremorine‐induced tremor.

The frequency of the spike discharges induced by iontophoretically applied glutamate was reduced by MLV‐6976 in a dose‐dependent manner in rat cortical neurones.

The amplitude of miniature endplate potentials of the rat diaphragm was decreased by MLV‐6976 only at concentrations greater than 0.1 mM.

It is concluded that MLV‐6976 acts on the brainstem or/and higher levels of the brain rather than on the spinal cord or the peripheral nervous system to reduce the excessive activities of the nervous system.
Anti‐anginal arylalkylamines and sodium channels: [3H]‐batrachotoxinin‐A 20‐α‐benzoate and [3H]‐tetracaine binding
Authors: Grima M. , Schwartz J. , Spach M.O. , Velly J.
Published: July 2012

[3H]‐batrachotoxinin‐A 20‐α‐benzoate ([3H]‐BTX‐B) and [3H]‐tetracaine are useful ligands for the study of sodium channels.

Inhibition of their binding by various anti‐anginal drugs was tested on a rat synaptosomal preparation and on a heart membrane preparation.

Diphenylalkylamines and structurally related drugs inhibited [3H]‐BTX‐B binding in both the synaptosomal preparation and heart membrane preparation. They were almost inactive on [3H]‐tetracaine binding.

These results suggest that activity of arylalkylamines could be mediated by an interaction on the sodium channel.
Cortical acetylcholine release is increased and γ‐aminobutyric acid outflow is reduced during morphine withdrawal
Authors: Antonelli T. , Beani L. , Bianchi C. , Rando S. , Simonato M. , Tanganelli S.
Published: July 2012

The effects of naloxone on acetylcholine (ACh) and γ‐aminobutyric acid (GABA) outflow from the cerebral cortex of freely moving, morphine‐dependent guinea‐pigs was studied.

The cortical efflux of ACh in chronically‐treated guinea‐pigs was about half of that of normal animals. GABA efflux was unaffected.

During opioid withdrawal precipitated by naloxone (0.1–10 mg kg−1, i.p.) the guinea‐pigs showed jumping, hyperactivity and wet dog shakes, the intensity of which was directly related to the dose of naloxone. The withdrawal syndrome was accompanied by a dose‐dependent increase in ACh release and reduction in GABA outflow; ACh release was increased by naloxone at doses lower (0.1–3 mg kg−1) than those acting on GABA efflux (1–10 mg kg−1). Atropine (10 mg kg−1) and diazepam (5 mg kg−1) did not prevent GABA and ACh changes.
The role of prostaglandins in the nociceptive response induced by intraperitoneal injection of zymosan in mice
Authors: Doherty Niall S. , Beaver Thomas H. , Chan Kenneth Y. , Coutant John E. , Westrich Gerald L.
Published: July 2012

Intraperitoneal injection of zymosan (1 mg in 0.5 ml saline) in mice induces a transient writhing response accompanied by the synthesis of small amounts of prostaglandin E2 (PGE2, < 2 ng) and larger amounts of PGI2 (200 ng per mouse), measured as its non‐enzymatic breakdown product, 6‐keto‐PGF1α.

Although both centrally‐acting analgesics (morphine, clonidine) and prostaglandin biosynthesis inhibitors (aspirin, indomethacin, ibuprofen) blocked the writhing response to intraperitoneal injection of zymosan, only the latter reduced prostaglandin levels in the peritoneal cavity.

The writhing response correlated equally well with PGE2 levels and 6‐keto‐PGF1α levels when data from mice treated with centrally‐acting analgesics were excluded. However, intraperitoneal injection of PGI2, but not PGE2, reversed the analgesia induced by indomethacin in zymosan‐injected mice.

Centrally‐acting agents, but not ibuprofen, blocked the ability of PGI2 to reverse the analgesic activity of indomethacin.

PGI2 (2 μg per mouse), injected intraperitoneally in otherwise untreated mice, induced writhing.

These data indicate that PGI2 is the prostaglandin involved in mediation of the writhing response to zymosan and that prostaglandin biosynthesis inhibitors, but not centrally‐acting analgesics, exert their analgesic activity by reducing the peritoneal level of PGI2. It is possible that PGI2 may have the ability to stimulate pain receptors directly in the mouse peritoneal cavity, in addition to its previously recognized ability to sensitize pain receptors to other pain‐producing stimuli.
Effects of α‐adrenoceptor agonists on cardiac output and its regional distribution in the pithed rat
Authors: Hiley C. Robin , Thomas G. Roger
Published: July 2012

Cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in pithed rats during pressor responses elicited by either α1‐adrenoceptor agonists (cirazoline, phenylephrine) or α2‐adrenoceptor agonists (xylaxine, B‐HT 933). Two doses were used for each of cirazoline and B‐HT 933 and phenylephrine was investigated in the presence of propranolol (3 mg kg−1). The rats were pithed under halothane anaesthesia.

Cardiac output was increased by xylazine, the higher dose of B‐HT 933 and phenylephrine. Heart rate was increased by phenylephrine and the higher doses of both cirazoline and B‐HT 933. Stroke volume was greater in those groups given xylazine, phenylephrine and the higher dose of B‐HT 933 but was decreased in those animals given the higher dose of cirazoline.

Both α2‐adrenoceptor agonists increased the number of microspheres trapped in the lungs and the proportion of the cardiac output passing through the hepatic artery but decreased that flowing through the spleen and gastrointestinal tract. The higher dose of B‐HT 933 also decreased the fraction of cardiac output flowing to the kidneys but kidney blood flow was maintained as a result of the increased cardiac output. Also, this treatment reduced blood flow in the epididimal fat pads.

Both α1‐adrenoceptor agonists increased the fraction of cardiac output received by the coronary vasculature but the only other effect on distribution common to these agents was an increase in the percentage of the cardiac output passing to the hepatic artery. Cirazoline decreased the proportion of cardiac output distributed to the gastrointestinal tract and spleen but the total fraction of cardiac output passing to the hepatosplanchnic region was maintained as a result of the increase to the hepatic artery.

Cirazoline markedly reduced the proportion of the cardiac output received by the kidneys and absolute flow in these organs was only 1.4% of control after the higher dose of this agonist but flow at the lower dose was maintained by the higher cardiac output.

It is concluded that there is a significant contribution to the pressor responses elicited by α‐agonists resulting from an α‐adrenoceptor‐mediated increase in cardiac output that may result from greater heart rates or stroke volumes. Also, there is a differential distribution of α‐receptor subtypes throughout the vasculature which is especially noticeable in the kidneys.
The action of pentobarbitone on stimulus‐secretion coupling in adrenal chromaffin cells
Authors: Pocock G. , Richards C.D.
Published: July 2012

The action of pentobarbitone on stimulus‐secretion coupling was studied in bovine isolated adrenal medullary cells.

Pentobarbitone inhibited catecholamine release evoked by 500 μm carbachol with half maximal inhibition (IC50) around 50 μm. It also inhibited catecholamine release induced by depolarization with 77 mm potassium (IC50 100 μm). These effects of pentobarbitone were observed with concentrations that lie within the range encountered during general anaesthesia.

Evoked secretion required the presence of calcium in the extracellular medium and was associated with an influx of Ca2+ through voltage‐sensitive channels. Pentobarbitone inhibited 45Ca influx in response to both carbachol (IC50 50 μm) and K+‐depolarization (IC50 150 μm).

The action of pentobarbitone on the relationship between intracellular free Ca and exocytosis was examined using electropermeabilised cells which were suspended in solutions containing a range of concentrations of ionised calcium between 10−8 and 10−4 M. Catecholamine secretion was measured in the presence of 0, 50, 200 or 500 μm pentobarbitone. The anaesthetic had no effect on the activation of exocytosis by intracellular free calcium.

When catecholamine secretion in response to potassium or carbachol was modulated by varying extracellular calcium or by adding pentobarbitone to the incubation medium, the amount of catecholamine secretion for a given Ca2+ entry was the same.

Pentobarbitone inhibited the secretion and 45Ca uptake induced by carbachol in a non‐competitive manner.

The secretion evoked by nicotinic agonists was associated with an increase in 22Na influx. Pentobarbitone inhibited this influx with an IC50 of 100 μm.

We concluded that: (a) Pentobarbitone inhibits the catecholamine secretion from bovine adrenal chromaffin cells induced by nicotinic agonists by non‐competitive inhibition of the nicotinic receptor. (b) The decrease in Ca influx caused by pentobarbitone accounts fully for the decrease in secretion in response to depolarization with potassium.
PD117302: a selective agonist for the κ‐opioid receptor
Authors: Clark C.R. , Birchmore B. , Sharif N.A. , Hunter J.C. , Hill R.G. , Hughes J.
Published: July 2012

A new nonpeptide κ‐opioid compound, a cyclohexyl benzeneacetamide derivative (PD117302), has been synthesized and its affinity for the different types of opioid receptor determined. The ability of PD117302 to modify the activity of the electrically‐stimulated guinea‐pig ileum and rabbit vas deferens has also been evaluated.

In binding studies using guinea‐pig brain homogenates, unlabelled PD117302 had a high affinity (Ki = 3.7 nm) at [3H]‐etorphine labelled κ sites and a low affinity at [3H]‐[d‐Ala2, MePhe4, glyol5]‐enkephalin ([3H]‐DAGOL) labelled μ sites (Ki = 408 nm) and [3H]‐SKF 10047 labelled s sites (Ki = 1.8 μm). In bioassay studies, PD117302 was a potent agonist, producing a maximum inhibition of the electrically‐evoked contractions of the guinea‐pig ileum (IC50 = 1.1 nm) and rabbit vas deferens (IC50 = 45 nm) which was naloxone‐reversible.

In guinea‐pig brain, [3H]‐PD117302 bound to a high‐affinity opioid binding site with a KD of 2.7 nm and a Bmax of 3.4 pmol g−1 wet weight. The Bmax was found to be less than 50% of the Bmax values for [3H]‐etorphine and [3H]‐bremazocine suggesting that [3H]‐PD117302 may be a specific ligand for a subtype of κ receptor. [3H]‐PD117302 also bound with micromolar affinity to a non‐opioid binding site.

Kinetic studies found that [3H]‐PD117302‐specific binding to the high affinity site was saturable, reaching equilibrium within 20 min at 4°C, and reversible, with a half‐life of dissociation of 3.9 min.

Several unlabelled compounds with high affinities for the [3H]‐etorphine labelled κ binding site, had comparable affinities when competing for the [3H]‐PD117302‐specific high affinity binding site. In contrast, DAGOL, [d‐Ala2, d‐Leu5] enkephalin (DADLE) and [d‐Pen2, d‐Pen5] enkephalin (DPDPE) had no significant effect on [3H]‐PD117302 binding, suggesting minimal interaction with μ and δ binding sites.

In autoradiography studies [3H]‐PD117302 binding sites were found throughout the brain with the greatest density in the striatum, cerebral cortex (layers V‐VI), substantia nigra, and the molecular layer of the cerebellum. Lowest levels were found in the granular layer of the cerebellum, thalamus and cerebral cortex (layers I‐IV).
Autoregulation of acetylcholine release from vagus nerve terminals through activation of muscarinic receptors in the dog trachea
Authors: Ito Yushi , Yoshitomi Takeshi
Published: July 2012

The effects of pirenzepine and gallamine on the membrane and contractile properties of smooth muscle cells and on excitatory neuro‐effector transmission in the dog trachea were investigated by means of microelectrode, double sucrose gap and tension recording methods.

Pirenzepine (10−7 m) and gallamine (10−5 m) had no effect on the resting membrane potential or the input resistance of the smooth muscle cells.

Pirenzepine (10−10‐10−9 m) and gallamine (10−7 m) enhanced the amplitude of twitch contractions evoked by field stimulation in the combined presence of indomethacin (10−5 m) and propranolol (10−6 m). At higher concentrations pirenzepine (10−8 m) inhibited the twitch contractions in a dose‐dependent manner. Both pirenzepine and gallamine in doses over 10−7 and 10−5 m, respectively, reduced muscle tone.

Pirenzepine (10−10‐10−9 m) and gallamine (10−7 m) enhanced the amplitude of excitatory junction potentials (e.j.ps) evoked by field stimulation (single or repetitive stimulation). However, a high concentration of pirenzepine (10−8 m) reduced the amplitude of e.j.ps. In parallel with its action on e.j.ps, pirenzepine (over 10−9 m) reduced the response of smooth muscle cells to acetylcholine (ACh), in a dose‐dependent manner. Gallamine (5 × 10−5 m) markedly enhanced the amplitude of e.j.ps but also reduced the response of muscle cells to ACh.

ACh (10−10‐10−9 m) inhibited twitch contractions evoked by field stimulation, with a slight increase of resting tension.

Gallamine enhanced the summation of e.j.ps during repetitive field stimulation at a high frequency (20 Hz), but was without effect on the depression phenomena of e.j.ps observed during double stimulus experiments at different time intervals (5–60 s).

These results indicate that both pirenzepine and gallamine have dual actions on pre‐ and postjunctional muscarinic receptors in dog tracheal tissue. At low concentrations both agents potentiate excitatory neuro‐effector transmission, presumably due to enhancement of release of ACh from vagal nerve terminals through blockade of a negative auto‐regulatory process activated by endogenous ACh. At higher concentrations, these agents inhibit the response of smooth muscle cells to ACh through post‐junctional muscarinic receptors and relaxation of the muscle tissue occurs.
Nisoldipine and perfusion of post‐stenotic myocardium in conscious pigs with different degrees of concentric stenosis
Authors: Duncker Dirk J. , Heiligers Jan P.C. , Saxena Pramod R. , Verdouw Pieter D.
Published: July 2012

The effects of oral nisoldipine on the perfusion and wall function of a myocardial segment distal to a fixed coronary artery stenosis were studied in 2 groups of conscious pigs with different degrees of stenosis. In group 1 (n = 8) systolic wall thickening (SWT) of the post‐stenotic segment was more than 15% (27 ± 4%); in group 2 (n = 7) SWT was less than 10% (7 ± 1%).

The systemic haemodynamic profiles at baseline and during nisoldipine were similar in both groups. Dose‐titrations of nisoldipine (0.24 + 0.02 mg kg−1 and 0.47 + 0.04 mg kg−1) were performed to obtain increases in heart rate of 25% and 50%, respectively. These increases were accompanied by increases in cardiac output (up to 50%) and left ventricular (LV)dP/dt max (60%), while systemic vascular resistance (35%) and mean arterial blood pressure (10%) were reduced. Left ventricular systolic and end‐diastolic blood pressure and stroke volume were not affected.

In both groups, nisoldipine caused increases in blood flow to the non‐stenotic area which favoured the subepicardium more than the subendocardium. Blood flow to the post‐stenotic area of group 1 was normal at baseline and was only slightly enhanced (preferentially to the subepicardium) by nisoldipine. In the post‐stenotic area of group 2 transmural and subendocardial blood flow were lower at baseline compared to the control area. Nisoldipine did not affect subepicardial blood flow but reduced subendocardial blood flow.

In spite of the reflex‐mediated positive chronotropic actions of nisoldipine, the acute poststenotic systolic wall thickening was not affected by nisoldipine in either group.

We conclude that, under the experimental conditions employed (concentric stenosis, no coronary collaterals and acute drug administration), nisoldipine does not have a useful effect on post‐stenotic myocardial blood flow, particularly in animals with severe stenosis. In view of a possible resetting of the baroreceptors (subsiding of the tachycardia) with chronic treatment and the presence of eccentric stenosis in many patients, additional studies are warranted.
Expression of functional postjunctional α2‐adrenoceptors in rabbit isolated distal saphenous artery—a permissive role for angiotensin II?
Authors: Dunn W.R. , McGrath J.C. , Wilson V.G.
Published: July 2012

In the rabbit isolated distal saphenous artery, the population of postjunctional adrenoceptors is of the α1 variety under normal in vitro experimental conditions, based on the potency order of selective agonists and on the effects of the antagonists prazosin and rauwolscine against responses to UK‐14304. Angiotensin II (AII, 0.05 μm) however, without affecting resting baseline tension, markedly enhanced responses to UK‐14304, particularly at low concentrations. This previously unseen component of the response to UK‐14304 was resistant to prazosin (0.1 μm) but susceptible to rauwolscine (1 μm). AII would therefore appear to have a permissive role for the expression of a quiescent population of postjunctional α2‐adrenoceptors in the rabbit distal saphenous artery.