bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological analysis of the pentagastrin‐tiotidine interaction in the mouse isolated stomach
Authors: Black J.W. , Leff P. , Shankley N.P.
Published: July 2012

The pentagastrin‐tiotidine interaction has been analysed, using improved techniques, in the mouse isolated, lumen‐perfused, stomach assay. For comparison and quantification of the H2‐receptor blocking activity of tiotidine, histamine‐tiotidine interactions have also been analysed in the mouse stomach and guinea‐pig isolated right atrial preparation.

Tiotidine behaved as a competitive antagonist of histamine both in the guinea‐pig right atrium (pKB 7.57) and mouse stomach (pKB 6.96). The difference in pKB was attributed to the loss of tiotidine into the gastric secretion.

On the stomach assay, pentagastrin concentration‐effect curves were significantly flatter with lower maximal responses than those obtained to histamine. In addition the profile of inhibition observed with tiotidine was different in that the pentagastrin curve maxima were depressed with only a small concomitant dextrad shift.

A mathematical model has been developed which accounts for the differences in agonist concentration‐effect curves and describes in a quantitative manner the expectations for the competitive antagonism of endogenous histamine assumed to be released by pentagastrin. Fitting of the pentagastrin‐tiotidine data to this model provided a reasonable goodness‐of‐fit.

The results are discussed in terms of the role of endogenous histamine in gastrin‐stimulated acid secretion. We conclude that the results are consistent with the hypothesis that pentagastrin stimulates acid secretion via the release of endogenous histamine under the present experimental conditions.
Evidence that the accumulation of 5‐hydroxytryptamine in the liver but not in the brain may cause the hypoglycaemia induced by 5‐hydroxytryptophan
Authors: Endo Yasuo
Published: July 2012

Experiments were undertaken to determine whether the site of the hypoglycaemic action of 5‐hydroxytryptophan (5‐HTP), a direct precursor of 5‐hydroxytryptamine (5‐HT), was in the central nervous system or in the liver.

The fall in blood glucose followed the rapid increase in the amount of 5‐HT both in the brain and liver after 5‐HTP injection into pargyline‐treated and non‐treated mice.

Carbidopa, an inhibitor of peripheral aromatic amino acid decarboxylase, prevented the elevation of 5‐HT levels in the liver of both pargyline‐treated and non‐treated mice. In contrast, carbidopa did not prevent but rather enhanced the elevation of 5‐HT levels in the brain of both groups of mice.

Corresponding to the prevention of 5‐HT elevation in the liver, the fall in blood glucose was prevented by carbidopa.

These results support the idea that the accumulation of 5‐HT in the liver but not in the brain causes the hypoglycaemia induced by 5‐HTP.
Carbachol and dibutyryl cyclic GMP on the vulnerability to ventricular fibrillation in rat isolated hearts
Authors: Daugherty Alan , Woodward Brian
Published: July 2012

cyclic monophosphate (cyclic GMP) concentrations may increase electrical stability of the myocardium was examined by determination of ventricular fibrillation thresholds (VFT) on isolated perfused hearts of the rat. Hearts were paced to circumvent any complicating effects of bradycardia. Using this system, carbachol produced a concentration‐related reduction in VFT.

The reduction in VFT produced by carbachol was not significantly modified by a high concentration of atenolol (10−5 M), indicating that the increased vulnerability to ventricular fibrillation was not an indirect consequence of catecholamine release from intramyocardial stores.

Atropine (10−6 M) blocked the carbachol‐induced reduction in VFT.

At the concentrations of carbachol used to reduce VFT, myocardial cyclic GMP concentrations were also elevated. The dibutyryl analogue of cyclic GMP (10−4 M) mimicked the effect of carbachol in reducing VFT.

Carbachol potentiated the adrenaline (3 × 10−7 M)‐induced reduction in VFT.
The ability of thapsigargin and thapsigargicin to activate cells involved in the inflammatory response
Authors: Ali H. , Christensen S. Brøgger , Foreman J.C. , Pearce F.L. , Piotrowski W. , Thastrup O.
Published: July 2012

The ability of thapsigargin and thapsigargicin to activate mast cells and leukocytes has been investigated.

The thapsigargin‐induced histamine release from rat peritoneal mast cells was found to be dependent on the concentration of thapsigargin, the purity of the mast cell preparations, and the number of mast cells in suspension.

Thapsigargin induced histamine release from human basophil leukocytes.

Thapsigargin induced β‐glucuronidase and lysozyme release from human neutrophil leukocytes.

Thapsigargin caused a release of histamine from mesentery, lung, and heart mast cells of the rat, but only to a minor extent from the corresponding guinea‐pig cells.

Thapsigargicin induced histamine release from mesentery, lung, and heart mast cells of the rat at concentrations from 0.1 μM but provoked only a release from the corresponding guinea‐pig cells in the concentration‐range 0.16 to 1.6 μM.

Thapsigargin increased the cytoplasmic free calcium level in intact human blood platelets at concentrations from 3.0 nM
Opioid inhibition of synaptic transmission in the guinea‐pig myenteric plexus
Authors: Cherubini E. , Morita K. , North R.A.
Published: July 2012

Intracellular recordings were made from neurones in the myenteric plexus of the guinea‐pig ileum. Presynaptic nerves were excited by a focal stimulating electrode on an interganglionic strand.

Fast excitatory postsynaptic potentials (e.p.s.ps) were depressed in amplitude by morphine and [Met5]enkephalin in the concentration range of l nM‐l μM. Nicotinic depolarizations evoked by exogenously applied acetylcholine (ACh) were not affected by these opioids.

Hyperpolarization of the presynaptic fibres probably contributed to the depression of the fast e.p.s.p. because fast e.p.s.ps evoked by low stimulus voltages were more depressed than those evoked by high stimulus voltages and fast e.p.s.ps resulting from activation of a single presynaptic fibre were blocked in a non‐graded manner.

Opioids depressed the slow e.p.s.p. in those neurones in which they did not change the resting membrane potential.

The slow e.p.s.p. was increased in amplitude in those neurones hyperpolarized by opioids. Depolarizations resulting from application of barium, substance P or ACh were also enhanced by opioids. Equivalent circuit models in which opioids increase, and substance P or ACh decrease, the same potassium conductance could account for this enhancement.

The actions of opioids were prevented or reversed by naloxone (l nM‐l μM).

It is concluded that morphine and enkephalin inhibit the release of ACh and a non‐cholinergic transmitter from fibres of the myenteric plexus, and that this may involve a hyperpolarization of presynaptic fibres. Additionally, opioids can interact postsynaptically with other substances which affect membrane potassium conductances.
Pharmacological basis for the induction of gastric carcinoid tumours in the rat by loxtidine, an unsurmountable histamine H2‐receptor blocking drug
Authors: Brittain R.T. , Jack D. , Reeves J.J. , Stables R.
Published: July 2012

The very late occurrence of gastric carcinoids in a life‐span carcinogenicity study with loxtidine in the rat might have resulted from continuous achlorhydria induced by this long‐acting unsurmountable histamine H2‐antagonist.

The nature of the anti‐secretory activity of loxtidine was compared with that of ranitidine on histamine‐induced acid secretion in the perfused stomach preparation of the rat and in the rat isolated gastric mucosa preparation.

Ranitidine and loxtidine had qualitatively different inhibitory effects on acid secretion, ranitidine being a competitive antagonist of histamine even at high concentrations, whereas the effect of loxtidine on both preparations was unsurmountable at relatively low concentrations.

These results support the hypothesis that the late formation of gastric carcinoids in rats receiving loxtidine is a consequence of persistent achlorhydria caused by unsurmountable blockade of parietal cell H2‐receptors.
Bay K 8644, a dihydropyridine calcium agonist, augments vasoconstrictor responses to endogenous and exogenous noradrenaline in the peripheral vasculature of the dog
Authors: Goto Toshikazu , Satoh Keisuke , Taira Norio
Published: July 2012

The effect of Bay K 8644 (a substance known to increase calcium influx through the voltage‐dependent calcium channel) on vasoconstrictor responses of resistance vessels to endogenous and exogenous noradrenaline (NA) was investigated in pentobarbitone‐anaesthetized dogs which had also undergone spinal anaesthesia and bilateral vagotomy and received atropine.

In these dogs the saphenous arterial bed was perfused at fixed flow rates with autologous blood to give perfusion pressure close to the systemic blood pressure.

Electrical stimulation (3–30 Hz) of the saphenous nerve and single intra‐arterial (i.a.) injections of noradrenaline (NA, 0.03‐3 μg) produced an increase in perfusion pressure (vasoconstriction) in a frequency‐ and a dose‐dependent manner, respectively.

Intra‐arterial infusions of Bay K 8644 (3 and 10 μg min−1) per se produced no significant change in perfusion pressure. However, these infusions augmented vasoconstrictor responses to both saphenous nerve stimulation (endogenous NA) and i.a. NA (exogenous NA).

These results suggest that augmentation by Bay K 8644 of vasoconstrictor responses of resistance vessels to endogenous and exogenous NA is probably due to promotion of the calcium influx through calcium channels closely associated with α‐adrenoceptors in smooth muscle cells there.
Identification of presynaptic β2‐adrenoceptors on the sympathetic nerve fibres of the human pulmonary artery
Authors: Göthert Manfred , Hentrich Frank
Published: July 2012

Strips of human pulmonary arteries from patients undergoing surgery for lung tumour were incubated with [3H]‐noradrenaline. Subsequently, they were supervised with physiological salt solution containing cocaine and corticosterone. Tritium overflow from the strips was stimulated by transmural electrical impulses (2 Hz). The electrically evoked overflow of tritium consisted of 91% unmetabolized [3H]‐noradrenaline, and this percentage was not altered by isoprenaline.

Adrenaline (in the presence of rauwolscine), isoprenaline and the preferential β2‐adrenoceptor agonist, procaterol, concentration‐dependently increased the electrically evoked tritium overflow. Prenalterol, a β‐adrenoceptor agonist with moderate preference for β,‐adrenoceptors, was considerably less active than the previously mentioned agonists; noradrenaline (in the presence of rauwolscine) was ineffective.

The concentration‐response curve of procaterol was shifted to the right by the preferential β2‐adrenoceptor antagonist ICI 118–551 but was not affected by the β1‐selective antagonist, atenolol. Propranolol, but not atenolol, produced a shift to the right of the concentration‐response curve of isoprenaline.

It is concluded that the sympathetic nerve fibres of the human pulmonary artery are endowed with facilitatory presynaptic β2‐adrenoceptors.
Inhibition of cisplatin‐induced vomiting by selective 5‐hydroxytryptamine M‐receptor antagonism
Authors: Miner Wesley D. , Sanger Gareth J.
Published: July 2012

MDL 72222, the selective 5‐hydroxytryptamine (5‐HT) M‐receptor antagonist, prevented or reduced cisplatin‐induced emesis in ferrets. It is suggested that cisplatin‐induced, and possibly other cytotoxic drug‐induced vomiting may involve a 5‐HT M‐receptor mechanism.
The effects of local anaesthetics on the electrical and mechanical activity of the guinea‐pig ureter
Authors: Burdyga Th.V. , Magura I.S.
Published: July 2012

The effects of local anaesthetic tertiary amines (procaine, lignocaine and tetracaine) as well as neutral (benzocaine) and permanently charged (QX‐314) local anaesthetics were studied on the evoked electrical and mechanical activity of the ureter smooth muscle.

‘Low’ concentrations of procaine and lignocaine (0.1‐1 mM) at pH 7.4 increased the duration of the slow plateau component of the evoked action potentials. The amplitude of the phasic contraction was consequently increased within the first 5 min of exposure. Tetracaine 0.1 mM caused a transient increase in the duration of the plateau and amplitude of the phasic contraction within the first 1–2 min only. The stimulant action of the local anaesthetics was greatly reduced in the presence of tetraethylammonium (TEA).

All the tertiary local anaesthetics caused depolarization of the membrane accompanied by an increase in the size of the electrotonic potentials. Lignocaine normally initiated the discharge of spontaneous action potentials.

High concentrations of lignocaine (5 mM) and tetracaine (0.5 mM) caused complete inhibition of the evoked action potentials and phasic contractions. Procaine 5 mM predominantly inhibited the contractile responses.

The permanently charged local anaesthetic QX‐314 (1 mM) caused an increase in the duration and amplitude of the plateau, increasing the number of spikes and the amplitude and duration of the phasic contraction. It also depolarized the ureter smooth muscle cells increasing the size of electronic potentials.

The neutral local anaesthetic benzocaine at 1 mM caused a reversible selective blockade of the plateau component of the evoked action potential and a gradual reduction in the amplitude of the phasic contraction. No change in either the membrane potential or the membrane conductance was observed.

High pHo (pH 9) significantly increased while low pHo (pH 6) decreased the inhibitory action of procaine and lignocaine but did not alter the effects of benzocaine and QX‐314.

Benzocaine caused a relaxation of the high‐K‐induced contraction, preferentially blocking the tonic component, whereas QX‐314 had no effect on the KCl‐contracture of the ureter muscle.

Two sites of action in the ureter smooth muscle cell membrane for local anaesthetics are suggested. One site interacts with local anaesthetics in a charged form, while the other one interacts with those in a lipid‐soluble neutral form. The charged form of local anaesthetics has a TEA‐like action, while the neutral form predominantly causes blockade of ‘slow’ Na/Ca channels.
Convulsant doses of penicillin shorten the lifetime of GABA‐induced channels in cultured central neurones
Authors: Chow Phoebe , Mathers David
Published: July 2012

The influence of sodium benzylpenicillin (PCN) on membrane channels activated by γ‐aminobutyric acid (GABA) was studied in cultured spinal neurones of the mouse by the extracellular patch clamp technique.

In whole‐cell, current clamp recordings, concentrations of PCN above 0.2 mM significantly reduced the amplitude of the GABA response.

Single channel currents activated by GABA were studied in outside‐out patches of neuronal membrane. In both the absence and presence of PCN, cumulative open time distributions for GABA‐activated channels were well fitted by the sum of two exponential terms, characterized by fast (τf) and slow time constants (τs).

PCN (2 mM) reduced the mean value of τs from 4.29 ± 0.56 ms (mean ± s.e.mean) to 1.12 ± 0.09 ms but had no significant effect on τf.

The mean open time of GABA‐activated channels, calculated from the double exponential fits, decreased from 1.39 ± 0.35 ms to 0.53 ± 0.02 ms in the presence of 2 mM PCN.

The reduced mean open time of GABA‐sensitive channels seen in the presence of PCN may contribute to the convulsant action of the drug in vivo.
Pharmacological characterization of the receptor involved in chemoexcitation induced by adenosine
Authors: McQueen D.S. , Ribeiro J.A.
Published: July 2012

Experiments were performed on cats anaesthetized with pentobarbitone in which carotid body chemoreceptor activity was recorded from the peripheral end of a sectioned carotid nerve.

Intracarotid (i.c.) injections of adenosine and its analogues, NECA (5′‐N‐ethylcarboxamidoadenosine), L‐PIA (L‐N6‐phenylisopropyladenosine), and D‐PIA (D‐N6‐phenylisopropyladenosine), caused dose‐related increases in chemosensory discharge. The rank order of potency as chemoreceptor stimulants was: NECA > adenosine > L‐PIA > D‐PIA.

Infusion of theophylline antagonized the chemoexcitatory effects of NECA, and infusion of 8‐phenyltheophylline (8‐PT), which is a more potent adenosine antagonist with less activity as a phosphodiesterase inhibitor, reduced the chemoexcitation induced by adenosine.

Infusion of 8‐PT (10 μg min−1 i.c.), a dose which substantially reduced the effect of injected adenosine, also reduced the sensitivity of carotid chemoreceptors to hypoxia (10% O2 for 4 min).

It is concluded that the adenosine receptors in the cat carotid body which mediate chemosensory excitation are xanthine‐sensitive and appear to be of the A2 sub‐type. Adenosine, released within the carotid body by physiological stimuli, may be involved in chemoexcitation.
The hypothermic action of carbachol in the rat brain periaqueductal grey area may involve neurotensin
Authors: Griffiths E.C. , Slater P. , Widdowson P.S.
Published: July 2012

Neurotensin (NT) and carbachol both caused hypothermia when injected into the periaqueductal grey area (PAG) of rat brain.

Atropine prevented carbachol‐ but not NT‐induced hypothermia.

NT‐induced hypothermia was unaffected by various neurotransmitter agonists and antagonists in the PAG.

Both NT antibodies and thyrotrophin releasing hormone prevented carbachol hypothermia.

It is concluded that the hypothermic action of carbachol in the PAG is mediated via endogenous NT.
Structure‐activity relationships of alloxan‐like compounds derived from uric acid
Authors: Ashcroft Stephen J.H. , Harrison Donna E. , Poje Mirko , Rocic Boris
Published: July 2012

The diabetogenic activity of a range of alloxan‐like compounds derived from uric acid has been investigated.

The classes of derivatives were: 5‐substituted‐isouric acids; 4,5‐disubstituted‐4, 5‐dihydrouric acids; 5‐substituted‐pseudouric acids; salts of dehydro‐uramil hydrate; salts of dehydro‐isouramil hydrate; alloxan derivatives.

Compounds were tested by intravenous injection into rats and diabetogenic activity assessed by production of persistent hyperglycaemia and glycosuria.

The only essential structural feature common to all active compounds was the presence of a quinonoid pyrimidine system or its hydrated equivalent. The presence of the five‐membered ring of uric acid (or an opened form thereof) did not abolish and in some compounds enhanced diabetogenic activity.
Hypersensitivity of mesenteric veins to 5‐hydroxytryptamine‐ and ketanserin‐induced reduction of portal pressure in portal hypertensive rats
Authors: Cummings Susan A. , Groszmann Roberto J. , Kaumann Alberto J.
Published: July 2012

Isolated superior mesenteric veins from portal hypertensive rats were 3 to 10 times more sensitive to 5‐hydroxytryptamine (5‐HT) and 3 times less sensitive to (‐)‐noradrenaline than veins from sham‐operated rats. The sensitivity to vasopressin did not differ in the 2 groups.

Ketanserin competitively antagonized the effects of 5‐HT in superior mesenteric veins and portal veins with high affinity (KB values 0.1‐0.3 nM), as expected for 5‐HT2‐receptors. The affinity of ketanserin for 5‐HT2‐receptors was similar in veins from normal, sham‐operated or portal‐hypertensive rats.

Intraportal injections of low doses of 5‐HT caused increases in portal pressure which were more pronounced in portal hypertensive rats than in sham‐operated rats and were blocked by 0.3 mg kg−1 ketanserin in both groups. Ketanserin 0.3 mg kg−1 did not block the portal pressor response to (‐)‐noradrenaline in either group of rats.

In portal hypertensive rats but not in sham‐operated rats, 0.3 mg kg−1 ketanserin caused decreases in portal pressure, portal flow and cardiac output, as estimated by radioactive microspheres.

The reduction in portal pressure caused by ketanserin was due mainly to a decrease in portal venous inflow secondary to a decreased cardiac output. The reduction in cardiac output, which was observed only in the portal hypertensive rats but not in sham‐operated rats, is consistent with venous dilatation and pooling of blood in the portal venous system. The venous pooling could be secondary to the blockade of 5‐HT2‐receptors in the portal venous system. It is proposed that ketanserin should be explored for the treatment of patients with portal hypertension.
Role of cyclic GMP in the modulation by endothelium of the adrenolytic action of prazosin in the rat isolated aorta
Authors: Alosachie Iyad , Godfraind Théophile
Published: July 2012

The effect of endothelium on the adrenolytic action of prazosin was studied in the rat isolated aorta.

Prazosin showed a non‐competitive type of antagonism in preparations with intact endothelium while in preparations where endothelium had been removed, prazosin at concentrations between 0.3 nM‐10 nM acted as a competitive antagonist.

Methylene blue, used to decrease tissue levels of guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP), converted prazosin from a non‐competitive antagonist into an apparently competitive antagonist in the presence of endothelium.

Increasing tissue levels of cyclic GMP by incubation with 8‐bromo‐cyclic GMP converted prazosin from an apparently competitive antagonist into a non‐competitive antagonist in the absence of endothelium.

Analysis of concentration‐response curves for noradrenaline in the presence and absence of endothelium showed that the affinity for noradrenaline was the same but the efficacy, measured by estimating the receptor reserve, was not; it was lower in the presence than in the absence of endothelium.

It was concluded that the change in the mode of antagonism of prazosin after endothelium removal could be related to an alteration in the efficacy of the agonist, brought about by a change in the tissue levels of cyclic GMP.
Action of enflurane on cholinergic transmission in identified Aplysia neurones
Authors: Arimura Hiroyuki , Ikemoto Yoshimi
Published: July 2012

Effects of enflurane on the cholinergic transmission in Aplysia neurones were studied by current and voltage clamp methods. Acetylcholine (ACh) evoked three types of postsynaptic responses on different identified neurones: (1) a depolarizing response due to an increase in Na and K conductances (D‐response), (2) a fast hyperpolarizing response due to an increase in Cl conductance (Cl‐response), and (3) a slow hyperpolarizing response due to an increase in K conductance (K‐response).

Enflurane altered neither the action potential nor the membrane resistance of the neurones but depressed the three ACh‐induced responses, non‐competitively, in a dose‐dependent manner. The K‐response was less suppressed than the other two.

Blockade of the closed state of ion channel was suggested by a reduction in the first ACh response evoked 1 min after administration of enflurane.

The anaesthetic facilitated the decay of the neurally evoked e.p.s.c. and i.p.s.c. in suggesting a reduction in the mean open time of the postsynaptic ion channel.

It is concluded that enflurane depresses excitatory and inhibitory cholinergic transmission by reducing the postsynaptic currents.
Plasma protein extravasation induced by mammalian tachykinins in rat skin: influence of anaesthetic agents and an acetylcholine antagonist
Authors: Couture Réjean , Kérouac René
Published: July 2012

The effect of mammalian tachykinins on plasma protein extravasation was assessed in the rat dorsal skin. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) increased vascular permeability in a dose‐related manner with a threshold dose of about 0.07 pmol in sodium pentobarbitone‐anaesthetized animals.

Plasma protein extravasation induced by the tachykinins was 100–500 times less in magnitude in animals anaesthetized with urethane.

Plasma protein extravasation induced by SP (66 pmol) was significantly reduced (63%; P < 0.001) by atropine (a muscarinic inhibitor) while that induced by NKA or NKB was unaffected by the inhibitor suggesting that a cholinergic component might only be involved in the vascular permeability elicited by SP.

The rank order of potency for the tachykinins on plasma protein extravasation was: NKB > SP > NKA (in absence of atropine) and NKB > NKA > SP (in presence of atropine), suggesting that this vascular response is mediated by a SP‐E‐receptor type.

The amplitudes of the plasma protein extravasation induced by NKB and its hydrophilic analogue [Arg°]NKB were similar, indicating that the lipophilic features of the native peptide cannot account for its potent biological activity.

Plasma protein extravasation was enhanced by the SP analogue [d‐Pro4, Lys6, d‐Trp7,9,10, Phe11] SP (4–11), thus showing the limitation of such SP analogues (antagonists) for characterizing the tachykinin receptors involved in vascular permeability.
A Contrasting effect of the diabetic state upon the contractile responses of aortic preparations from the rat and rabbit
Authors: Head Richard J. , Longhurst Penelope A. , Panek Robert L. , Stitzel Robert E.
Published: July 2012

Diabetes was induced in rats by a single intraperitoneal injection of streptozotocin (65 mg kg−1). Rabbits were rendered diabetic by injecting alloxan (100 mg kg−1) into the lateral ear vein. Diabetes was confirmed by a significant elevation of serum glucose in both species 8 weeks after injection.

The maximum contraction to noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and KCl was markedly diminished in thoracic aortic rings (AR) from diabetic rats with no change in the EC50 of the agonists. There were no differences in the contractile properties of AR from diabetic rabbits to NA, 5‐HT or KCl. Diabetes did not alter the responsiveness of AR from the rat to angiotensin II (AII). However, AR from diabetic rabbits displayed a decreased maximal contraction and an increased EC50 to AII.

The magnitude of the acetylcholine‐induced relaxation to precontracted AR was not different between diabetic and control rats and rabbits.

The contractile responses of AR to NA, 5‐HT and KCl were depressed in diabetic rats, regardless of the control tissue to which they were compared. The decrease in maximal contraction to NA, 5‐HT and KCl seen in diabetic animals was prevented by insulin replacement.

The results demonstrated that while both rats and rabbits exhibited a similar degree of hyperglycemia after treatment with a diabetogenic agent, aortic preparations from the rabbit are not affected in the same way as the aorta from the diabetic rat when exposed to NA, 5‐HT and KCl. This feature may be related to the marked differences between the extent of sympathetic innervation of the aorta in the rabbit and rat. Furthermore, the decrease in maximal contraction in rat aorta was nonspecific with respect to agonists since it could also be demonstrated with KCl. Therefore, it follows that the diabetic state may affect processes responsible for contraction beyond the level of receptor activation.
Vasocortin: a novel glucocorticoid‐induced anti‐inflammatory protein
Authors: Carnuccio Rosa , Di Rosa Massimo , Guerrasio Bruno , Iuvone Teresa , Sautebin Lidia
Published: July 2012

The preliminary characterization of ‘vasocortin’ a novel glucocorticoid‐induced anti‐inflammatory protein, is described. Vasocortin is released into the rat peritoneal cavity following systemic dexamethasone administration, has an apparent mol. wt. of 100 kD and inhibits rat dextran oedema. Vasocortin is distinct from lipocortin and is likely to be associated with the anti‐inflammatory effect of glucocorticoids.
Pharmacological characterization of binding sites identified in rat brain following in vivo administration of [3H]‐spiperone.
Authors: Chivers Jane , Jenner Peter , Marsden C. David
Published: July 2012

[3H]‐spiperone is commonly used to label dopamine receptors in vitro in brain tissue. However, spiperone also interacts with brain 5‐hydroxytryptamine and noradrenaline receptors. In vivo, [3H]‐spiperone has been used for identifying dopamine receptors in both animals and man but the nature of the sites identified is unknown.

The in vivo administration of [3H]‐spiperone to rats leads to a selective accumulation of radioactivity in the olfactory lobes, tuberculum olfactorium, nucleus accumbens, striatum, substantia nigra, hippocampus, frontal cortex and hypothalamus, when compared to the cerebellum.

In vivo drug displacement studies suggest that the binding of [3H]‐spiperone in these areas may be to dopamine, 5‐HT or noradrenaline receptors.

[3H]‐spiperone in vivo mainly labels dopamine receptors in striatum, tuberculum olfactorium, hypothalamus, substantia nigra and olfactory lobes. However, in the frontal cortex and nucleus accumbens specific binding involves not only dopamine receptors but also 5‐HT and/or noradrenaline receptors.

Interpretation of in vivo studies in man using radioactive spiperone and its derivatives must take into account the fact that this ligand only labels dopamine receptors in some brain areas.
Modulation of GABAA receptor activity by alphaxalone
Authors: Cottrell Glen A. , Lambert Jeremy J. , Peters John A.
Published: July 2012

The modulation of the γ‐aminobutyric acidA (GABAA) receptor by alphaxalone has been investigated by use of voltage‐clamp recordings from enzymatically isolated bovine chromaffin cells maintained in cell culture.

Alphaxalone (> 30 nm) reversibly and dose‐dependently potentiated the amplitude of membrane currents elicited by locally applied GABA (100 μm). The potentiation was not associated with a change in the reversal potential of GABA‐evoked currents and was not influenced by the benzodiazepine receptor antagonist, Ro15‐1788 (300 nm).

At relatively high concentrations (> 1 μm), alphaxalone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor activation since they were reversibly suppressed by bicuculline (3 μm), dose‐dependently enhanced by phenobarbitone (100–500 μm), and had a similar reversal potential (∼ 0 mV) to currents elicited by GABA. Additionally, on outside‐out membrane patches, alphaxalone activated single channel currents with amplitudes and a reversal potential similar to those evoked by GABA.

Alphaxalone (30 nm‐1 μm) had no effect upon the amplitude of membrane currents elicited by locally applied acetylcholine (ACh) (100 μm). However, higher concentrations of alphaxalone (10–100 μm) reversibly suppressed ACh‐evoked currents, the IC50 for blockade being 20 μm.

The β‐hydroxy isomer of alphaxalone, betaxalone (100 nm‐1 μm), did not potentiate GABA‐induced currents, nor did higher concentrations of the steroid (10–100 μm) directly evoke a membrane current. However, over the latter concentration range, betaxalone suppressed the amplitude of currents elicited either by GABA or ACh.

The relevance of the present results to the anaesthetic action of alphaxalone is discussed together with the broader implications of steroidal modulation of the GABAA receptor.
Prostacyclin analogues reduce ADP‐ribosylation of the α‐subunit of the regulatory Gs‐protein and diminish adenosine (A2) responsiveness of platelets
Authors: Edwards Robert J. , MacDermot John , Wilkins Amanda J.
Published: July 2012

Prostacyclin and adenosine activate adenylate cyclase in human platelet membranes and inhibit platelet aggregation. Results are presented which show that prolonged incubation of platelets with iloprost (a stable prostacyclin analogue) results in a reduction in the capacity for adenylate cyclase activation by the adenosine analogue 5′‐(N‐ethyl)‐carboxamidoadenosine (NECA), NaF, guanyl‐5′‐yl imidodiphosphate or GTP. However, iloprost pretreatment resulted in no change in the binding of [3H]‐NECA to platelet membranes.

These results contrast with those obtained after pretreatment with 2‐chloroadenosine which revealed no change in NaF or guanyl‐5′‐yl imidodiphosphate sensitivity of adenylate cyclase. Pretreatment with 2‐chloroadenosine resulted in reduced NECA‐dependent adenylate cyclase activation, and loss of [3H]‐NECA binding sites.

The heterologous desensitization of adenosine A2‐receptors by iloprost is accompanied by a loss (greater than 80%) of a 45 kDa protein from the plasma membrane, as revealed by [32P]‐ADP‐ribosylation in the presence of cholera toxin.

It is proposed that this example of heterologous desensitization is mediated by elimination of Gsα, a subunit of the stimulatory guanyl nucleotide‐binding regulatory protein.
Examination of the mechanisms involved in tetanic fade produced by vecuronium and related analogues in the rat diaphragm
Authors: Gibb A.J. , Marshall I.G.
Published: July 2012

The effects of vecuronium (Org NC45), Org 7678 and Org 7684 were examined on twitches and tetani recorded from rat isolated diaphragms

Org 7678 and Org 7684 exhibited approximately one tenth of the neuromuscular blocking potency of vecuronium.

At concentrations producing equivalent amounts of twitch block, Org 7684 produced significantly less tetanic fade than did vecuronium or Org 7678.

In cut muscles both vecuronium and Org 7684 reduced the endplate current (e.p.c.) amplitude (Ie.p.c.), reduced e.p.c. decay time constant (ẗe.p.c.), and increased the e.p.c. train rundown.

The effects of vecuronium were not voltage‐dependent and vecuronium did not change ẗnoise.

The effect of Org 7684 on Ie.p.c. and ẗe.p.c. became greater with hyperpolarization, but the effect on e.p.c. train rundown was not voltage‐dependent.

It is concluded that both vecuronium and Org 7684 produce e.p.c. train rundown and tetanic fade by a prejunctional mechanism. However, whereas postjunctionally vecuronium blocks only the acetylcholine receptor, Org 7684 blocks both the receptor and its associated ion channel.
Cardiovascular effects of injections of vasopressin into the nucleus tractus solitarius in conscious rats
Authors: King Kathryn A. , Pang Catherine C. Y.
Published: July 2012

The effects of injections of arginine vasopressin (AVP) into the nucleus tractus solitarius (NTS) on mean arterial pressure (MAP), heart rate (HR) and plasma concentrations of noradrenaline and adrenaline were investigated in conscious, unrestrained rats.

Injection of 2 ng AVP into the NTS significantly increased MAP but not plasma catecholamine concentrations, while injection of 10 ng AVP significantly increased MAP and plasma noradrenaline and adrenaline levels.

Neither dose of AVP produced any change in HR. The vehicle did not affect MAP, HR or plasma catecholamine levels.

Injection of a specific pressor antagonist of AVP, d(CH2)5Tyr‐(Me)AVP (10 ng), did not change MAP, HR or plasma noradrenaline or adrenaline levels.

These results suggest that the NTS is a central site of the pressor action of AVP. However, since the injection of the AVP antagonist did not reduce MAP or plasma noradrenaline or adrenaline levels, it suggests that AVP does not act tonically at the NTS to influence sympathoadrenal outflow.
Characterization of tachykinin receptors in isolated basilar arteries of guinea‐pig
Authors: Edvinsson Lars , Jansen Inger
Published: July 2012

In circular lengths cut from the basilar artery of guinea‐pig (0.2‐0.3 mm o.d.) relaxations induced by substance P and neurokinin A were highly susceptible to mechanical damage of the endothelium by rubbing. The precontraction induced by prostaglandin F2α but not that of 124 mm potassium was reduced considerably by the rubbing procedure.

Concentration‐dependent relaxations were evoked by tachykinin agonists in the following order of potency: substance P = physalaemin > neurokinin A > eledoisin. Physalaemin was, however, a partial agonist, giving only half the maximum relaxation as compared to the other tachykinins.

The two putative tachykinin receptor antagonists, spantide ([d‐Arg1, d‐Trp7,9, d‐Leu11] substance P) and [d‐Pro2, d‐Trp7,9] substance P, shifted the concentration‐dependent relaxations of substance P to the right in a parallel manner. Calculation of pA2 values and Schild plot analysis revealed pA2 values of 7.4–7.6 for spantide and 6.9‐7.0 for [d‐Pro2, d‐Trp7,9] substance P, irrespective of whether substance P or neurokinin A was used as agonist. The pA2 values and the Schild plot analysis suggest a specific interaction between tachykinin agonists and antagonists that follow a simple bimolecular process.

The results suggest the presence of tachykinin receptors of the ‘SP‐P’ type in guinea‐pig basilar arteries which, for induction of relaxation, involves the release of an endothelium‐derived relaxing factor.
Effects of repeated intravenous administration of haem arginate upon hepatic metabolism of foreign compounds in rats and dogs
Authors: Tokola Olavi
Published: July 2012

Haem arginate is a new haem compound, recently introduced for the treatment of acute hepatic porphyrias. Porphyrias are characterized biochemically by decreased formation of haem due to defects in certain enzyme activities involved in the haem biosynthesis.

Haem is essential for cell respiration and oxidative biotransformation. Hepatic drug metabolism, haem biosynthesis and catabolism were investigated after repeated intravenous administration of haem arginate in connection with toxicity studies.

The daily doses of haem for rats were 4, 12 and 40 mg kg−1 and for dogs 3 and 9 mg kg−1 for 30 days and for 28 days, respectively.

Hepatic microsomes were used in the assay of the following drug metabolizing enzymes: cytochrome P‐450 and b5, aminopyrine N‐demethylase, ethoxyresorufin O‐deethylase and UDP‐glucuronyl transferase. The assay of NADPH‐cytochrome C‐reductase and the enzymes reflecting synthesis and metabolism of haem in the liver (δ‐aminolaevulinic acid synthase, δ‐aminolaevulinic acid dehydratase, uroporphyrinogen I‐synthase, uroporphyrinogen decarboxylase, haem synthase, haem oxygenase and biliverdin reductase) were performed from 20,000 g supernatants.

The lowest dose administered to rats and dogs did not cause any significant changes compared to controls in the parameters measured.

The highest doses significantly increased the activities of haem oxygenase and uroporphyrinogen I‐synthase but decreased concentrations or activities of other enzymes, e.g. cytochrome P‐450 and ethoxyresorufin O‐deethylase.

The results show that it is important to avoid overdosage of haem when restoration of mixed function oxygenase activity is needed.
Endothelium‐derived relaxing factor inhibits in vitro platelet aggregation
Authors: Furlong B. , Henderson A.H. , Lewis M.J. , Smith J.A.
Published: July 2012

We studied the effects of endothelium‐derived relaxing factor (EDRF), bovine retractor penis muscle inhibitory factor and sodium nitroprusside, three stimulants of guanylate cyclase, on the in vitro aggregation of washed human platelets.

Platelet aggregation induced either by collagen or by the thromboxane A2 analogue U46619 was inhibited by all three agents.

The anti‐aggregatory effect of each agent was inhibited by haemoglobin.

The anti‐aggregatory effect of EDRF was potentiated by superoxide dismutase.

These findings are discussed in relation to a potential role for EDRF in haemostasis.
Inhibition of the rate of GABA synthesis in regions of rat brain following a convulsion
Authors: Green A. Richard , Metz Alan , Minchin Michael C.W. , Vincent Nigel D.
Published: July 2012

The rate of synthesis of γ‐aminobutyric acid (GABA) in the cortex, hippocampus and striatum of rat brain was assessed by measuring the linear rate of accumulation of GABA following injection of amino‐oxyacetic acid (AOAA).

Five min after a single electrically induced seizure there was a rise in GABA content in these brain regions and an almost total inhibition of the rate of synthesis.

Five min after seizure induced by the inhalant convulsant flurothyl there was no rise in GABA content in these brain regions but a similar marked degree of inhibition of GABA synthesis.

Two hours after the convulsion the rate of GABA synthesis had returned to control values in all three brain regions.

A single convulsion did not alter the glutamic acid decarboxylase activity in these brain regions either in the absence or presence of added co‐factor (pyridoxal phosphate).

Evidence for an inhibition of GABA release following a convulsion which may be associated with the inhibition of GABA synthesis is presented in the following paper.
The effect of repeated electroconvulsive shock on GABA synthesis and release in regions of rat brain
Authors: Green A. Richard , Vincent Nigel D.
Published: July 2012

The release of endogenous γ‐aminobutyric acid (GABA) from slices of rat cortex, hippocampus and striatum prepared both 30 min and 24 h after the last of a series of electroconvulsive shocks (5 seizures given spread out over 10 days) has been investigated.

No change in spontaneous (basal) release was observed. However, 30 min after the last convulsion, K+‐evoked GABA release above basal release was inhibited in both hippocampus (20%) and striatum (33%) but not in the cortex. Release was still inhibited in striatum (22%) 24 h after the last seizure.

In confirmation of an earlier report, chronic electroconvulsive shock was found to increase basal GABA content in striatum and inhibit synthesis by 34%. The synthesis rate was also inhibited in the hippocampus (44%) but not in the cortex.

Glutamic acid decarboxylase activity was unchanged in all regions after repeated electroconvulsive shock treatment.

It is proposed that repeated electroconvulsive shocks lead to a substantial inhibition of release in the striatum and hippocampus and a long‐term inhibition of GABA synthesis in these regions. Such changes may be associated with the altered monoamine biochemistry and function observed after repeated electroconvulsive shock and with the mechanism of the antidepressant action of electroconvulsive therapy.
The effects of single and repeated electroconvulsive shock administration on the release of 5‐hydroxytryptamine and noradrenaline from cortical slices of rat brain
Authors: Green A. Richard , Heal David J. , Vincent Nigel D.
Published: July 2012

A method is described of measuring the K+‐evoked release of endogenous 5‐hydroxytryptamine (5‐HT) and noradrenaline (NA) from slices prepared from rat cortex.

There was no difference in either the spontaneous (basal) or K+‐evoked release of 5‐HT or NA from cortical slices prepared from handled animals and those given a single electroconvulsive shock (ECS) either 30 min or 24 h earlier.

In chronic studies, rats were either handled or given an ECS 5 times over 10 days and cortical slices prepared. There was no difference in 5‐HT or NA release between the groups 30 min after the last treatment other than a modest attentuation of spontaneous NA release following ECS treatment. However 24 h after the last treatment K+‐evoked release (above basal release) of 5‐HT and NA was inhibited by 84% and 48%, respectively.

These data demonstrate that following a single ECS, normal 5‐HT and NA release is seen at a time when GABA release is markedly inhibited. After repeated ECS the release of both monoamines was markedly inhibited. These 5‐HT changes may be involved in the enhanced 5‐HT‐receptor function seen after repeated ECS.
Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone
Authors: Pallandi Regan T. , Campbell Terence J.
Published: July 2012

The cellular electrophysiological effects of amiodarone and its metabolite desethylamiodarone (DEA) were studied in guinea‐pig ventricular myocardium by use of standard microelectrode techniques.

Both compounds produced significant increases in action potential duration (Class III antiarrhythmic effect) and decreases in maximum rate of depolarization (Class I effect), at clinically relevant concentrations.

The Class I effects were rate‐dependent, with small (0–16%) falls in maximum depolarization rate in the absence of stimulation (‘resting block’) and progressively larger effects at decreasing interstimulus intervals (range 1200‐300 ms).

The kinetics of onset and offset of the Class I effect in response to a step change in driving rate were quite fast for both drugs (comparable to those reported for Class Ib agents).

It is concluded that this unique combination of Class III action plus Class I effects with fast onset and offset kinetics may help explain the great efficacy of amiodarone in antiarrhythmic therapy.
Effect of cholera toxin on the production of eicosanoids by rat jejunum
Authors: Autore Giuseppina , Capasso Francesco , Di Carlo Giulia , Mascolo Nicola
Published: July 2012

Cholera toxin injected i.v. into rats stimulated the production of prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and LTC4 by segments of jejunum, but it had no effect when added to the tissue in vitro.

Pretreatment of the animals with the compound BW 755C reduced the increased production of PGE2, LTB4 and LTC4 by i.v. cholera toxin. Pretreatment with indomethacin reduced the production of PGE2.

These findings are consistent with the hypothesis that arachidonate metabolites are involved in the diarrhoea induced by cholera toxin.
Comparative pharmacology of endothelium‐derived relaxing factor, nitric oxide and prostacyclin in platelets
Authors: Radomski M.W. , Palmer R.M.J. , Moncada S.
Published: July 2012

The pharmacological effects of endothelium‐derived relaxing factor (EDRF), nitric oxide (NO) and prostacyclin on human and rabbit platelets were examined.

EDRF is released from porcine aortic endothelial cells, cultured on microcarriers and treated with indomethacin, in sufficient quantities to inhibit platelet aggregation induced by 9,11‐dideoxy‐9α,11α‐methano epoxy‐prostaglandin F2α (U46619) and collagen.

The anti‐aggregating activity of EDRF was potentiated by M&B 22948, a selective inhibitor of cyclic GMP phosphodiesterase, and by superoxide dismutase (SOD) and was inhibited by haemoglobin and Fe2+.

Both NO and prostacyclin inhibited platelet aggregation.

The anti‐aggregatory activity of NO, but not that of prostacyclin, was potentiated by M&B 22948 and by SOD and was inhibited by haemoglobin and Fe2+. Thus NO is a potent inhibitor of platelet aggregation whose activity on platelets mimics that of EDRF.

It is likely that the inhibitory effect of NO on platelets represents the action of endogenous EDRF and therefore this substance, together with prostacyclin, is a regulator of platelet‐vessel wall interactions.
Neuropharmacological and neurochemical properties of N‐(2‐cyanoethyl)‐2‐phenylethylamine, a prodrug of 2‐phenylethylamine
Authors: Baker Glen B. , Coutts Ronald T. , Rao Tadimeti S.
Published: July 2012

N‐(2‐cyanoethyl)‐2‐phenylethylamine (CEPEA) was examined as a possible prodrug of 2‐phenylethylamine (PEA).

Pharmacokinetics of PEA and CEPEA were investigated in rat brain, blood and liver by gas chromatography with electron‐capture detection (GC‐ECD). Interactions of PEA and CEPEA with putative neurotransmitter amines were investigated by use of high performance liquid chromatography with electrochemical detection (h.p.l.c.‐e.c.).

Administration of PEA caused transient increases in PEA concentrations which decreased rapidly in brain and blood and at a slower rate in liver. Administration of CEPEA caused sustained elevations of PEA concentrations and elimination of PEA was markedly decreased in these tissues relative to the situation after administration of PEA itself.

Administration of CEPEA caused more prolonged decreases in brain noradrenaline, dopamine and 5‐hydroxytryptamine concentrations than those observed after PEA administration, although values increased to control levels eventually.