bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of indomethacin, piroxicam and selected prostanoids on gastric acid secretion by the rat isolated gastric mucosa
Authors: Reeves J.J. , Stables R.
Published: July 2012

The effects of the cyclo‐oxygenase inhibitors indomethacin and piroxicam have been investigated on histamine‐ and dibutyryl cyclic AMP‐induced acid secretion in the rat isolated gastric mucosa. The relative potencies of a number of prostanoids as inhibitors of histamine‐induced acid secretion were determined in an attempt to classify the prostaglandin receptor mediating this response.

Indomethacin (8 × 10−9 − 2.7 × 10−6 M) and piroxicam (3 × 10−6 M) potentiated the secretory responses elicited by histamine. This effect might be due to inhibition of the biosynthesis of antisecretory prostanoids. Indomethacin (2.7 × 10−6 M) and piroxicam (3 × 10−6 M) also potentiated the secretory response to dibutyryl cyclic AMP, but since prostaglandin E2 (PGE2, 10−5M) did not inhibit this secretory response, the mechanism of the potentiation may differ from that of histamine.

The potency of the thromboxane mimetic U‐46619 as an inhibitor of histamine‐induced acid secretion was markedly reduced in the presence of indomethacin, suggesting that U‐46619 may release endogenous antisecretory prostanoids.

In the presence of indomethacin (2.7 × 10−6 M) all the prostanoids tested produced concentration‐related inhibitions of histamine‐induced gastric acid secretion. PGE‐analogues were the most potent compounds, the rank order of potency being 16, 16 dimethyl PGE2 > PGE2 > PGF2α > U‐46619 > PGD2 > PGI2. This order of potency is very similar to that obtained in smooth muscle preparations containing ‘EP’ receptors, suggesting that this receptor type also mediates inhibition of histamine‐induced acid secretion in the rat.
The effect of a calcium antagonist, nitrendipine, on the responses of isolated strips of human, chorionic plate artery to prostaglandins E2 and E1
Authors: Pipkin F. Broughton , Chinnery E.
Published: July 2012

Six point concentration‐response curves were established for the contractile effect of prostaglandin E2 (PGE2) on helically‐cut strips of human chorionic plate arteries.

Tissues were then allocated to one of four treatment groups: a control group and 3 groups exposed to the calcium channel blocker nitrendipine at 10−9, 10−7 or 10−5 M. The concentration‐response curves were then repeated.

The addition of nitrendipine was associated with a significant depression of the induced contraction. The contractile response to the lower doses of PGE2 was replaced by a small relaxation in 63% of the treated tissues.

It is suggested that in these tissues PGE2 exerts its constrictor effect via the receptor‐operated channels and that nitrendipine is blocking this effect.

Similar experiments performed with PGE1 showed great variability in the initial response. Nitrendipine 10−5 M failed to exert any detectable effect on this response.

Pregnancy‐induced hypertension is associated with vasoconstriction in both the maternal and placental circulations. There also appears to be a relative excess of vasoconstrictor eicosanoid production. Nitrendipine may be of use in the treatment of this condition.
Cl−/Ca2+‐dependent L‐glutamate binding sites do not correspond to 2‐amino‐4‐phosphonobutanoate‐sensitive excitatory amino acid receptors
Authors: Fagg Graham E. , Lanthorn Thomas H.
Published: July 2012

A series of phosphono and phosphino analogues of glutamate were used to compare the pharmacological properties of (a) Cl−/Ca2+‐dependent, 2‐amino‐4‐phosphonobutanoate (AP4)‐sensitive L‐[3H]‐glutamate binding sites in rat brain synaptic plasma membranes (SPMs) and (b) AP4‐sensitive excitatory synaptic responses by use of electrophysiological techniques.

In the presence of Cl− and Ca2+, L‐[3H]‐glutamate bound to SPMs with Kd804 nM and Bmax 53 pmol mg−1 protein. The AP4‐sensitive (Ki 7.3 μM) population of binding sites represented 61 % of L‐glutamate specifically bound. co‐Substituted analogues of AP4 were potent inhibitors of L‐[3H]‐glutamate binding (Ki values 2.4–38 μM), whereas N‐substituted compounds or propionic acid derivatives were inactive. Experiments with AP4 alone and in combination with other analogues demonstrated that the primary target of all substances was the AP4‐sensitive population of L‐glutamate binding sites.

In the hippocampal slice in vitro, AP4 antagonized lateral perforant path‐evoked field potentials with an IC50 of 2.7 μM. In contrast to their actions at AP4‐sensitive L‐glutamate binding sites, all other compounds (except for the ω‐carboxymethylphosphino analogue, IC50 19 μM) were weak or inactive as antagonists of this synaptic response (IC50 values > 100 μM). Inactive compounds which exhibited activity in the binding assay did not reverse the synaptic depressant effects of AP4, indicating that they were neither agonists nor antagonists at AP4‐sensitive synapses.

The lack of correspondence between (a) the Cl−/Ca2+‐dependent, AP4‐sensitive population of L‐[3H]‐glutamate binding sites and (b) AP4‐sensitive synaptic responses indicates that these binding sites are not the receptors through which AP4 exerts its neuropharmacological effects. The possibility that Cl−/Ca2+‐dependent ‘binding sites’ represent transport into resealed SPM vesicles is discussed.

Electrophysiological data demonstrate that AP4‐sensitive synaptic receptors display a high degree of ligand selectivity. High antagonist potency is shown only by glutamate analogues with unmodified α‐amino and α‐carboxyl groups, and with a bifunctional (dianionic) ω‐terminal.
Increased total activity in the rat after L‐tryptophan plus the monoamine oxidase‐A inhibitor amiflamine but not after L‐tryptophan plus clorgyline
Authors: Archer T. , Fowler C.J. , Fredriksson A. , Lewander T. , Magnusson O. , Mohringe Bodil , Söderberg U.
Published: July 2012

The effect of pretreatment with either saline or the monoamine oxidase‐A inhibitors clorgyline and amiflamine upon the total activity, locomotion and rearing behaviour of the rat induced by various doses of the monoamine precursor L‐tryptophan was studied by use of automated activity boxes.

Amiflamine (2.5 and 5.0 mg kg−1, i.p.) increased in a dose‐dependent manner total activity and to a lesser extent, locomotion when given 60 min before L‐tryptophan (100 mg kg−1, i.p.). The increased activity was seen after amiflamine plus either 25 or 75 mg kg−1 L‐tryptophan. Rearing behaviour was not affected.

Analysis of 5‐hydroxytryptamine (5‐HT) and its deaminated metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) by high performance liquid chromatography with electrochemical detection indicated that in both frontal cortex and hypothalamus, amiflamine (at both doses) increased 5‐HT and reduced 5‐HIAA concentrations. Combination of amiflamine with L‐tryptophan (100 mg kg−1, i.p.) resulted in a higher 5‐HT concentration being found than after amiflamine alone. L‐Tryptophan treatment alone did not change 5‐HT concentrations but increased 5‐HIAA concentrations.

Clorgyline, at a dose of either 1 or 5 mg kg−1 i.p. plus L‐tryptophan (25 or 100 mg kg−1, i.p.) did not increase total activity, locomotion or behaviour.

A number of possible explanations for the differences in the behavioural effects of clorgyline and amiflamine when given with L‐tryptophan are discussed. It is concluded that in addition to monoamine oxidase‐A inhibition, other pharmacological effects of the drugs, such as 5‐HT release (amiflamine) and inhibition of tryptophan hydroxylation (clorgyline) may be of importance in determining the magnitude of the increase in activity when the compounds are given together with L‐tryptophan.
Reactivity to bradykinin and potassium of the isolated duodenum from rats with genetic and renal hypertension
Authors: Miasiro Nobuco , Paiva Therezinha B. , Pereira Claudia C. , Shimuta Suma I.
Published: July 2012

The biphasic (relaxation‐contraction) response of the isolated duodenum was used to study the reactivity of non‐vascular smooth muscles in genetic (SHR) and renal hypertensive rats compared to their respective controls (WKY and Wistar).

For the contractile component of the response to bradykinin, the duodenum from WKY rats was more sensitive, whereas the duodenum from SHR was both more sensitive and hyperreactive, compared to that from Wistar rats.

The relaxant component of the response to bradykinin was present in the duodenum of both WKY rats and SHR, but was concentration‐dependent only in the WKY group.

The relaxant response to K+ was very small in SHR, and was not concentration‐dependent.

The concentration‐response curves for relaxant responses to adrenaline and for contractile responses to acetylcholine did not differ in the SHR and WKY groups.

Ca2+/Mg2+‐ATPase activity was found to be markedly reduced in the SHR group.

No qualitative or quantitative differences were observed between the responses of the duodenum of renal hypertensive rats and those of their normotensive controls.

It is proposed that the altered reactivity of the SHR duodenum is due to changes in ion handling by the smooth muscle cell membrane.
Acetylcholine acts on m2‐muscarinic receptors to excite rat locus coeruleus neurones
Authors: Egan T.M. , North R.A.
Published: July 2012

Intracellular recordings were made from neurones of the rat locus coeruleus in vitro. Acetylcholine increased the firing rate by depolarizing the membrane; both muscarinic and nicotinic antagonists partially reduced this effect. In hexamethonium, pirenzepine shifted the acetylcholine dose‐response curve to the right with an equilibrium dissociation constant of 200 nM, indicating an interaction with a m2‐type of muscarinic receptor.
Characterization of [3H]‐nitrendipine binding to uterine smooth muscle plasma membrane and its relevance to inhibition of calcium entry
Authors: Batra S.
Published: July 2012

Specific, high affinity (KD = 164 pM) binding of the Ca channel inhibitor [3H]‐nitrendipine was identified in plasma membrane‐enriched fractions from the rat myometrium.

Although dihydropyridines effectively competed for [3H]‐nitrendipine binding sites, both verapamil and D600 were poor competitors. Diltiazem (10 μM) increased [3H]‐nitrendipine binding by about 40%, but had no effect on binding affinity. Among several other drugs tested, diethylstilboestrol (DES) caused a considerable inhibition of binding, with an IC50 value of 4 μM.

Both La3+ and EDTA (or EGTA) inhibited binding. The inhibition by the latter could be overcome by the addition of Ca2+ or Mg2+.

A clear relationship was found between [3H]‐nitrendipine binding and 5′‐nucleotidase activity in the various subcellular fractions.

Data on K+‐stimulated Ca2+ influx in the intact uterine strips showed a good agreement between the inhibition by both nitrendipine and DES of stimulated Ca influx and their inhibitory effect on [3H]‐nitrendipine binding to plasma membrane. This type of correlation was lacking in the case of D600.

These results suggest that Ca channels in the myometrial membrane possess multiple sites at which different drugs can act to block these channels.
Immediate hypersensitivity reactions in epithelia from rats infected with Nippostrongylus brasiliensis
Authors: Baird A.W. , Cuthbert A.W. , Pearce F.L.
Published: July 2012

Colonic epithelia from rats infected with the nematode Nippostrongylus brasiliensis have been studied under short circuit conditions and in response to challenge with worm antigen.

Challenge from the serosal but not the mucosal side with antigen caused a transient increase in inwardly directed short circuit current. No effects were observed in comparable tissues from non‐infected animals.

Simultaneous measurements of short circuit current and of the fluxes of sodium or chloride ions showed there was an increase in electrogenic chloride secretion and an inhibition of electroneutral sodium chloride absorption, associated with antigen challenge. This result, together with the inhibitory effects of piretanide on the response to antigen challenge, indicate that chloride ions are a major carrier of the short circuit current response. However, the equivalence of the biophysical response to ion fluxes was not established, there being an excess of chloride secretion.

The mast cell stabilizing agent, FPL 52694, significantly inhibited the current responses to antigen, while cromoglycate and doxantrazole were ineffective. Mepyramine, an H1‐receptor antagonist, and indomethacin, an inhibitor of fatty acid cyclo‐oxygenase, were without effect on the responses to antigen challenge.

Anti‐rat IgE produced qualitatively similar responses to antigen in both normal and sensitized colonic epithelia. However, the responses were significantly greater in tissues derived from infected animals. Maximally effective antigen concentrations prevented subsequent responses to anti‐rat IgE in sensitized tissues, while anti‐rat IgE only attenuated the responses to antigen.

The ways in which antigen challenge modifies epithelial function is discussed, particularly in relation to its possible role in promoting rejection of the nematodes during secondary infection.

A reprint similar to this one, in which the nematode Trichinella spiralis was used, has appeared recently (Russell & Castro, 1985).
Inhibition of ionophore‐stimulated leukotriene B4 production in human leucocytes by monohydroxy fatty acids
Authors: Camp R.D.R. , Fincham N.J.
Published: July 2012

Leukotriene B4 (LTB4) release by calcium ionophore‐stimulated human leucocytes was measured by use of selective solvent partition of reaction mixtures and an agarose microdroplet chemokinesis assay, and the inhibitory effects of four monohydroxy fatty acids were determined.

15‐Hydroxy‐eicosatetraenoic acid (15‐HETE) was the most effective inhibitor of LTB4 production with an approximate IC50 value of 6 μM and 99% inhibition at 50 μM, whereas 13‐hydroxyoctadecadienoic acid (13‐HODD) and 12‐HETE were weaker inhibitors with approximate IC50 values of 32 μM and 23 μM, and 59% and 68% inhibition at 50 μM, respectively.

We suggest that 13‐HODD and 12‐HETE, which are present in large amounts in the lesions of the skin disease psoriasis, may act as endogenous modulators of 5‐lipoxygenase activity in skin.
The effects of drugs acting at the GABAA‐receptor/ionophore after chemical kindling with the benzodiazepine receptor ligand FG 7142
Authors: Little H.J. , Nutt D.J. , Taylor S.C.
Published: July 2012

Repeated administration of the β‐carboline benzodiazepine receptor ligand FG 7142 produces sensitization to its effects so that full seizures develop (chemical kindling); initially it is only proconvulsant. The present study investigated alterations in the function of drugs which act at the different sites at the γ‐aminobutyric acid (GABA) benzodiazepine receptor complex, after repeated administration of FG 7142.

In FG 7142 kindled mice decreased anticonvulsant and hypothermic effects of the GABA agonist muscimol were observed. The hypothermic effects of the GABA agonist progabide were reduced. In contrast a small increase in the hypothermic effect of pentobarbitone was seen.

The convulsant effects of bicuculline and picrotoxin were unaltered when they were given intravenously but marginally increased when they were given by the intraperitoneal route. No changes were seen in the hypothermic effects of these drugs.

No significant changes were seen in the convulsant or hypothermic effects of pentylenetetrazol.

These results suggest that kindling with FG 7142 may alter GABA receptor function.
Impromidine is a partial histamine H2‐receptor agonist on human ventricular myocardium
Authors: English T.A.H. , Gristwood R.W. , Owen D.A.A. , Wallwork J.
Published: July 2012

The inotropic effects of impromidine have been studied and compared with those of histamine on human isolated left ventricular preparations stimulated at 1 Hz. Both drugs caused concentration‐related increases in force of contraction and were of similar potency, although the maximum response to impromidine was markedly and significantly less than that to histamine.

The positive inotropic responses of impromidine were inhibited by cimetidine 1 × 10−5 M, consistent with histamine H2‐receptor involvement.

Impromidine 1 × 10−4 M inhibited maximal responses to histamine to a level equal to the maximal impromidine response; however, impromidine did not inhibit responses to isoprenaline.

Positive inotropic activity and inhibition of maximal responses to histamine occurred over a similar impromidine concentration‐range.

Impromidine displaced histamine concentration‐response curves to the right, whereas mepyramine had no effect on responses to histamine.

It is concluded that impromidine has positive inotropic activity on the human ventricle, that the response is mediated via histamine H2‐receptors, and that impromidine is a partial agonist compared with histamine.
Receptor‐responses in fresh human ciliary muscle
Authors: Lograno Marcello D. , Reibaldi Alfredo
Published: July 2012

The physiological and pharmacological properties of ciliary muscle isolated from fresh human eyes were investigated.

The muscle exhibited no spontaneous activity. Concentration‐dependent contractions in response to carbachol were competitively antagonized by atropine (pA2 = 8.95).

The muscle, precontracted by carbachol (2.7 × 10−4 M), responded to the application of isoprenaline by concentration‐dependent relaxation blocked by propranolol (3.5 × 10−9 M to 3.5 × 10−8 M; pA2 = 9.15).

Angiotensin‐evoked contractions were antagonized by 8‐Ala‐angiotensin II (4.5 × 10−8 M) in a competitive manner, but were not inhibited by phentolamine or propranolol.

Contractions generated by electrical stimulation of the muscle (30 ms, 20 Hz, 60 pulses) were antagonized by atropine (10−7 M) and tetrodotoxin (6.3 × 10−7 M). Phentolamine and propranolol did not influence these responses.

An increase of the external potassium concentration ([K+]o) from 5.4 to 158.8 mM produced a mechanical response, antagonized by atropine, but not influenced by tetrodotoxin, phentolamine or propranolol.

The human ciliary muscle appears to carry muscarinic and angiotensin receptors and β2‐adrenoceptors. The estimate of Katropine for muscarinic receptors mediating carbachol‐induced contractions agrees with estimates of Katropine reported for human and rabbit iris.
Investigation into the cardioregulatory properties of the α1‐adrenoceptor blocker indoramin
Authors: Pierce Vanessa , Shepperson N.B. , Todd M.H. , Waterfall J.F.
Published: July 2012

The cardioregulatory properties of the α1‐adrenoceptor blocker indoramin have been compared with those of prazosin in the anaesthetized rat. The effects of autonomic blockade on heart rate responses evoked by these two agents and their effects on blood pressure and heart rate after peripheral or central administration have been compared.

Cumulative administration of indoramin (0.8–25.6 mg kg−1 i.v.) evoked significant decreases in arterial blood pressure and a concomitant bradycardia. Pithing or autonomic blockade, by pretreatment with a combination of practolol and bilateral vagotomy, prevented the bradycardia evoked by indoramin (0.8–3.2 mg kg−1 i.v.). Atropine sulphate pretreatment abolished the bradycardia until a cumulative dose of 25.6 mg kg−1 (i.v.) of indoramin had been reached. Bilateral vagotomy, intravenous administration of atropine methylnitrate or practolol pretreatment attenuated the bradycardia.

Prazosin (0.02–0.64 mg kg−1 i.v.) evoked a fall in arterial blood pressure of similar magnitude to that observed following indoramin. A bradycardia was evoked only at a relatively high dose (0.64 mg kg−1 i.v.).

Intracisternal injection of indoramin or prazosin evoked bradycardia and hypotension at a dose which had no effect after intravenous injection (25 μg). Intracerebroventricular injection of indoramin (25 μg) had no significant effect on heart rate or blood pressure compared to control values, whereas prazosin (25 μg) evoked a significant tachycardia and hypotension.

It is concluded that the bradycardia evoked by indoramin in the rat is not due to a direct action on the heart except possibly at high doses. Central α1‐adrenoceptor blockade, possibly in the brainstem region, results in a bradycardia and this may explain the lack of reflex tachycardia following the administration of indoramin.
Analysis of competitive antagonism when this property occurs as part of a pharmacological resultant
Authors: Black J.W. , Gerskowitch V.P. , Left P. , Shankley N. P.
Published: July 2012

In this paper, pharmacological resultant is defined as the net effect of a single compound resulting from the simultaneous expression of two or more specific actions.

The principles of concentration‐ratio analysis are extended to develop a method for detecting and quantifying competitive antagonism when this property is a component of a pharmacological resultant. The method is general to the extent that it allows analysis of competitive antagonism in combination with all types of post‐receptor intervention. Essentially it depends on the altered expression of competition by a reference antagonist. It incorporates tests for validating its application and it is independent of agonist concentration‐effect curve shape: in these respects the method is analogous to Schild plot‐analysis of simple competition.

The methodology for the practical application of the analysis is exemplified by studying the net effect of a combination of a phosphodiesterase inhibitor (isobutylmethylxanthine) and histamine H2‐ receptor antagonist (metiamide) on histamine‐stimulated tachycardia in guinea‐pig, isolated, right atrium. Cimetidine was used as the reference antagonist.

The equation used in this analysis is similar in form to one recently described by Hughes & Mackay (1985) to elucidate the situation when competitive antagonism occurs in combination with functional interactions. The relation between their method and the present analysis is discussed.
Nicotinic antagonists produce differing amounts of tetanic fade in the isolated diaphragm of the rat
Authors: Gibb A. J. , Marshall I.G.
Published: July 2012

The effects of nicotine antagonists on single twitches, trains of four twitches and tetanic contractions of the isolated diaphragm of the rat were examined.

Different drugs were found to produce different amounts of tetanic fade relative to depression of twitch tension.

The order of activity from most able, to least able to produce fade was: hexamethonium> trimetaphan = atracurium = tubocurarine>pancuronium>erabutoxin b.

The effect of erabutoxin b was distinctive for its almost complete lack of tetanic fade.

3,4‐Diaminopyridine increased tetanic fade produced by tubocurarine, atracurium and hexamethonium, but not that produced by erabutoxin b.

It is concluded that nicotinic antagonists act at more than one site at the neuromuscular junction. Assuming block of the postjunctional acetylcholine receptor produces tension depression, a second or third site must be involved in producing tetanic fade.

The possibility that tetanic fade results from block of the ion channel associated with the postjunctional acetycholine receptor or from the block of a prejunctional nicotinic receptor is discussed.
The effect of GR38032F, novel 5‐HT3‐receptor antagonist on gastric emptying in the guinea‐pig
Authors: Costall Brenda , Gunning S.J. , Naylor R.J. , Tyers M.B.
Published: July 2012

The effects of GR38032F a novel, selective and potent 5‐hydroxytryptamine (5‐HT3)‐receptor antagonist on gastric emptying in the guinea‐pig were investigated and compared to those of metoclopramide and haloperidol. Both GR38032F and metoclopramide increased gastric emptying in a dose‐dependent manner. In contrast, haloperidol was ineffective. GR38032F was about 200 times more potent than metoclopramide in enhancing gastric emptying over the 2 h period studied.
Stimulation of α1‐adrenoceptors in rat kidney mediates increased inositol phospholipid hydrolysis
Authors: Neylon Craig B. , Summers Roger J.
Published: July 2012

The molecular events which follow activation of α1‐adrenoceptors in rat kidney were investigated by measuring inositol phospholipid hydrolysis. Slices were labelled with [3H]‐inositol (0.25 μm) and the accumulation of [3H]‐inositol phosphates ([3H]‐IP's) was measured after stimulation with α‐adrenoceptor agonists.

Phospholipid labelling was both time‐and Ca2+‐dependent. In kidney, Ca2+ (1 mm) increased the incorporation of [3H]‐inositol by 49% and in cerebral cortex reduced it by 46%.

Following addition of noradrenaline (NA, 1 mm), accumulation of [3H]‐IP's increased linearly for at least 60 min. In Ca2+‐free buffers a 2.1 fold increase in [3H]‐IP accumulation was observed and further increases in stimulated and control levels were produced in the presence of Ca2+ (2.5 mm). These responses were attenuated by the inclusion of indomethacin (10 μm) and abolished in the presence of EGTA (0.5 mm). Responses to (−)‐NA were more than 4 fold higher in the renal cortex than in the medulla.

Separation of the IP's which accumulate after α‐adrenoceptor agonists showed that after 60 min stimulation the major products were glycerophosphoinositol and inositol‐phosphate with smaller amounts of inositol‐bisphosphate and inositol‐trisphosphate.

The most effective agonists tested for stimulation of accumulation of [3H]‐IP's were (–)‐ NA > phenylephrine > methoxamine, (+)‐NA. Clonidine and (–)‐isoprenaline were ineffective at concentrations up to 100 μm. The order of effectiveness of α‐adrenoceptor antagonists was prazosin > BE2254 > phentolamine > idazoxan > rauwolscine.

The results indicate that α1‐adrenoceptors in rat kidney are linked to phosphoinositide hydrolysis and that this response is localized mainly to the renal cortex.
Interaction of phorbol esters with Ca2+ channels in smooth muscle
Authors: Spedding Michael
Published: July 2012

The phorbol ester 12‐O‐tetradecanoyl phorbol‐13‐acetate (TPA), a selective activator of protein kinase C, had no effect on the sensitivity to Ca2+ or verapamil of K+‐depolarized taenia preparations from the guinea‐pig caecum, despite the use of high concentrations (1 μm for 3 h); this preparation is sensitive to Ca2+ channel activators and antagonists.

TPA (0.03‐3 μm) caused a slow contraction of rat aorta preparations; the contractions were resistant to the calcium‐antagonists nifedipine (0.01 μm), verapamil (10 μm), diltiazem (10 μm) and cinnarizine (10 μm), but were antagonized by N‐(6‐aminohexyl)‐5‐chloro −1‐naphthalensulphonamide (W‐7, 50–200 μm). Prolonged exposure to TPA (> 2h) resulted in spontaneous contractions which were sensitive to verapamil (1 μm).

Isoprenaline and sodium nitroprusside relaxed phenylephrine‐induced contractions in rat aorta preparations. TPA (0.3 μm) blocked the maximal response to isoprenaline but not to sodium nitroprusside indicating that TPA did selectively activate protein kinase C under these experimental conditions.

These findings indicate that protein kinase C activation does not result in direct effects on Ca2+ channel function, but may exert effects indirectly (e.g. by modifying intracellular sensitivity to Ca2+, Ca2+ extrusion, or cellular depolarization).
Effects of nipradilol on myocardial ischaemia produced by coronary stenosis in dogs
Authors: Noguchi Katsuhiko , Sakanashi Matao
Published: July 2012

Effects of nipradilol which is a new β‐adrenoceptor blocking agent endowed with nitroglycerin‐like vasodilator actions, its denitrated derivative (denitro nipradilol) and propranolol on abnormalities of regional myocardial shortening produced by partial occlusion of the left circumflex coronary artery (LCX) were studied in anaesthetized open‐chest dogs.

In the presence of LCX stenosis, nipradilol (0.1 mg kg−1, i.v.) produced marked decreases in heart rate and LV dP/dt without a significant increase in left ventricular end‐diastolic pressure (LVEDP). It improved impaired myocardial segment shortening and restored normal cardiac lactate metabolism.

Denitro nipradilol (0.2 mg kg−1 i.v.) and propranolol (0.2 mg kg−1 i.v.) both caused similar haemodynamic changes to nipradilol but also produced a significant increase in LVEDP. However, improvement by these two agents of regional dysfunction in the ischaemic myocardium was comparable to those seen with nipradilol.

All three agents markedly inhibited isoprenaline‐induced tachycardia, but vehicle did not.

Atrial pacing abolished the beneficial effect of nipradilol on myocardial shortening in the ischaemic region without affecting other haemodynamic parameters.

These results indicate that nipradilol alleviates acute myocardial ischaemia produced by coronary stenosis with similar efficacy to denitro nipradilol and propranolol suggesting, that a major part of the beneficial effect of nipradilol may be attributable to its β‐adrenoceptor blocking action.
Electrophysiological effects of diclofurime on rabbit and frog atrial heart muscle
Authors: Gautier Patrick , Guiraudou Pierre , Sauviat Martin‐Pierre
Published: July 2012

The effects of diclofurime on the electrical activity of the rabbit sinus node, rabbit atria and frog atrial fibres were studied using microelectrode and the double sucrose gap voltage‐clamp techniques respectively.

In rabbit sinus node, diclofurime (10−7 m to 10−6 m) decreased the action potential (AP) amplitude and maximum rate of depolarization , increased the AP duration and slowed the sinus rate.

In rabbit atria, the drug reduced the amplitude of the depolarizing phase and , lengthened the AP duration and decreased the resting membrane potential.

In frog atrial fibres, the drug (10−5 m) depolarized the resting membrane potential, decreased as well as the plateau amplitude. It inhibited the sodium current (INa) with a dissociation constant of 3.7 × 10−6 M and a one to one relationship between the drug molecule and the Na channel. Diclofurime did not alter the apparent reversal potential for the fast Na current (ENa) but it inhibited the sodium conductance (GNa) in a frequency‐dependent manner.

Diclofurime also blocked the slow inward current (Islow) without alteration of Eslow. The block of Islow occurred with a dissociation constant of 2 × 10−5 m and unity stoichiometry.

The data suggest that diclofurime might be effective in the control of cardiac arrythmias since it exhibited both local anaesthetic‐like and calcium antagonistic properties.
Neuroleptic‐induced hypothermia in mice: lack of evidence for a central mechanism
Authors: Boschi Gabrielle , Launay Nicole , Rips Richard
Published: July 2012

The present study investigated the ability of neuroleptic drugs to induce hypothermia in mice when they were administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.).

Twelve neuroleptics belonging to five chemical classes including phenothiazines, butyrophenones, benzamides, thioxanthenes and diphenylbutylpiperidines were injected i.p. All of them, except benzamides, induced a dose‐dependent decrease in rectal temperature.

Neuroleptics were administered i.c.v. via cannulae previously implanted in mice to determine whether this response might have a central origin. None of the drugs tested induced hypothermia at doses which did not produce toxic effects. These negative results suggest that neuroleptics act to elicit hypothermia via a peripheral, rather than a central mechanism.

Since some neuroleptics possess α‐adrenolytic properties which could induce hypothermia by promoting vasodilatation, we attempted to antagonize the hypothermia produced by peripheral administration of two neuroleptics with phenylephrine, an α‐adrenoceptor agonist that does not cross the blood‐brain barrier. The hypothermia induced by both chlorpromazine and haloperidol was attenuated by phenylephrine, supporting the view that peripheral α‐adrenoceptors may mediate neuroleptic‐induced hypothermia.
The actions of the peptides, neuropeptide Y and peptide YY, on the vascular and capsular smooth muscle of the isolated, blood‐perfused spleen of the dog
Authors: Corder R. , Lowry P.J. , Withrington P.G.
Published: July 2012

The two peptides, neuropeptide Y (NPY) and peptide YY (PYY) were compared for potency on the vascular and extravascular smooth muscle of the isolated, blood‐perfused spleen of the dog.

The only vascular response to both NPY and PYY was vasoconstriction; the maximum effect was to arrest splenic arterial blood flow completely.

On a molar basis both NPY and PYY were significantly more potent (P < 0.01) as splenic arterial vasoconstrictors than the transmitter noradrenaline (NA).

PYY was approximately 7 times more potent as a vasoconstrictor than NPY.

In contrast to their potency on the vascular smooth muscle, NPY and PYY were significantly (P < 0.01) less potent than NA in causing contraction of the splenic capsule. The two peptides were equipotent in eliciting this contraction.
Inhibition of GABA release from slices prepared from several brain regions of rats at various times following a convulsion
Authors: Green A. Richard , Minchin Michael C.W. , Vincent Nigel D.
Published: July 2012

A method is described for the measurement of the K+‐evoked release of endogenous γ‐aminobutyric acid (GABA) from slices of rat cortex, hippocampus and striatum.

In tissue prepared 30 min following an electroconvulsive shock, K+‐evoked GABA release (above basal release) was inhibited by 45% in cortex, 50% in hippocampus and 75% in striatum. A similar inhibition of release was observed with slices prepared from rats in which a convulsion had been induced by flurothyl. There was no change in spontaneous (basal) release following either procedure.

An inhibition of K+‐evoked endogenous GABA release was also seen in tissue prepared 4 min postictally but not 2 h after the seizure.

No difference was observed in the release of [3H]‐GABA from preloaded cortical slices prepared from rats given a single electroconvulsive shock.

It is proposed that a convulsion results in an inhibition of GABA release and that this inhibition may in turn inhibit GABA synthesis as described in the preceding paper.

It is also proposed that changes in the endogenous releasable pool of GABA may not be detected by preloading slices with [3H]‐GABA.
Effects of calcium entry blockers on calcium‐dependent contractions of rat portal vein
Authors: Dacquet C. , Mironneau C. , Mironneau J.
Published: July 2012

The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200‐110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high‐K+ solutions, noradrenaline, acetylcholine and caffeine.

The rank order of potency was PN 200‐110>nicardipine = nifedipine = D888>D600>diltiazem from experiments on spontaneous contractions and high‐K+ induced contractions. With depolarized preparations, the concentration‐response curves for nicardipine, PN 200‐110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage‐dependent inhibitory properties. This effect was not significant with D888 and diltiazem.

All the calcium entry blockers strongly reduced the noradrenaline (NA)‐ and acetylcholine (ACh)‐induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine‐induced contractions.

In Ca2+‐free, EGTA‐containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug‐sensitive calcium store. The filling of the calcium store was maximal after 10–12 min of calcium loading in 2.1 mm Ca2+, while the depletion was complete after 4–6 min of perfusion in Ca2+‐free solution.

At concentrations which abolished spontaneous contractions, PN 200‐110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+‐free solutions by ACh, NA and caffeine. When added in Ca2+‐containing solutions diltiazem and, to a lesser extent, nicardipine strongly reduced the contractions evoked in Ca2+‐free solutions, suggesting that they inhibited the filling of the internal calcium store.

These results indicate that the six calcium entry blockers are potent inhibitors of calcium influx through voltage‐dependent calcium channels. Two of them (diltiazem and nicardipine) may exert an additional effect to depress contractions dependent on intracellular calcium release.
Relaxation of guinea‐pig tracheal smooth muscle to arachidonate is converted to contraction following epithelium removal
Authors: Farmer Stephen G. , Hay Douglas W.P. , Raeburn David , Fedan Jeffrey S.
Published: July 2012

The effect of epithelium removal on responses of guinea‐pig isolated trachealis to sodium arachidonate has been examined.

Arachidonate (100 μm) caused relaxation of epithelium‐intact preparations, but following epithelium removal, the response to arachidonate was converted to contraction. In the presence of indomethacin (1 μm), arachidonate caused contraction in intact and denuded trachea.

Arachidonate also produced concentration‐dependent effects, the qualitative nature of which varied with the presence or absence of the epithelium. In the presence of indomethacin, tracheal strips contracted in a concentration‐dependent manner whether or not the epithelium had been removed.

Nordihydroguaiaretic acid (NDGA; 11 μm) markedly inhibited the contractile response of denuded strips to arachidonate. In intact tissues this lipoxygenase inhibitor converted the arachidonate‐induced relaxation to a concentration‐dependent contraction. The contraction to arachidonate, in the presence of NDGA, was epithelium‐dependent. In the presence of both indomethacin and NDGA, responses to arachidonate were abolished.

It is concluded that the relaxation of guinea‐pig trachea to arachidonic acid is epithelium‐dependent and is mediated by an inhibitory product of the cyclo‐oxygenase metabolic pathway. The contraction in denuded trachea, and trachea in the presence of indomethacin, may be mediated by lipoxygenase products of arachidonic acid metabolism, i.e. peptidoleukotrienes. The mediator of the epithelium‐dependent contraction in NDGA‐treated tissues is unknown.
Studies on the induction of pharmacological responses to des‐Arg9‐bradykinin in vitro and in vivo
Authors: Bouthillier Johanne , Deblois Denis , Marceau François
Published: July 2012

The mechanisms by which agents modulate the induction of kinin B1‐receptors were investigated by studying the effects of kinins in vitro, by use of the rabbit isolated aorta, and in vivo by measuring the blood pressure of anaesthetized rabbits.

The contractile response of the rabbit isolated aorta to kinins increased in a time‐dependent manner in vitro. This effect was abolished by continuous exposure to the protein synthesis inhibitor cycloheximide (71 μm).

Several substances were found to increase specifically the rate of sensitization to des‐Arg9‐bradykinin (des‐Arg9‐Bk), when applied continuously in vitro to tissues isolated from normal animals: bacterial lipopolysaccharide (LPS; 1 μg ml−1), muramyl‐dipeptide (MDP; 2 μg ml−1), phorbol myristate acetate (PMA; 320 nm), epidermal growth factor (EGF; 100 ng ml−1) and endothelial cell growth factor (150 μg ml−1).

The protease inhibitors phenylmethylsulphonyl fluoride and aprotinin, a non‐adjuvant isomer of MDP, rabbit purified leukocyte interferon, fibroblast growth factor and the chemotactic peptide N‐formyl‐l‐methionyl‐l‐leucyl‐l‐phenylalanine (FMLP) did not have this effect.

It has been demonstrated that LPS induces B1‐receptors in rabbits enabling des‐Arg9‐Bk to act as a hypotensive agent. In these experiments neutropenia induced by nitrogen mustard, did not prevent the in vivo effect of LPS. MDP (300 μg) and PMA (100 μg) were also found to induce a state of responsiveness to des‐Arg9‐Bk in vivo. FMLP (1 mg i.v.) induced a temporary decrease in blood neutrophil counts but had no effect on the induction of responses to des‐Arg9‐Bk.

The development of responses mediated by the B1‐receptor in the two experimental systems seems to be unrelated to the activation of neutrophil leukocytes, but may be related to the activation of tissue macrophages. Approximately 3% of cultured adherent cells derived from rabbit aorta strips following protease digestion were stained for non‐specific esterase, supporting such a possibility.
Differential effects of epithelium removal on the responsiveness of guinea‐pig tracheal smooth muscle to bronchoconstrictors
Authors: Hay D.W.P. , Farmer S.G. , Raeburn D. , Muccitelli R.M. , Wilson K.A. , Fedan J.S.
Published: July 2012

The influence of the epithelium on contractions produced by the peptidoleukotrienes, 5‐hydroxytryptamine (5‐HT) and the thromboxane mimetic, U‐44069, was examined in trachea from control and ovalbumin‐sensitized guinea‐pigs.

In control tissues removal of the epithelium produced an approximately 2 to 4 fold leftward shift in leukotriene C4 (LTC4) and LTD4 concentration‐response curves, but no effect on LTE4‐induced contractions. Similar results were obtained in preparations from ovalbumin‐sensitized animals.

Responses produced by 5‐HT or U‐44069 were similar in the presence and absence of the epithelium in control guinea‐pigs.

Indomethacin produced contrasting effects on leukotriene‐induced contractions in control guinea‐pigs: an increase in sensitivity to LTC4 in the presence but not absence of the epithelium, no effect on LTD4‐induced contractions and a decrease in sensitivity to LTE4 in both epithelium‐containing and epithelium‐free preparations.

These results indicate that there is selectivity in the effects of epithelium removal on agonist‐induced contractions of the guinea‐pig trachea. This provides further evidence for the modulatory influence of the epithelium on the reactivity of mammalian airway smooth muscle and supports the postulated existence of an epithelium‐derived inhibitory factor. The observation that in intact trachea indomethacin mimics the effects of epithelium removal on LTC4‐induced responses, suggests the involvement of a prostanoid(s) in this phenomenon.
Pharmacological characterization of 5‐hydroxytryptamine‐induced hyperpolarization of the rat superior cervical ganglion
Authors: Ireland S.J. , Jordan C.C.
Published: July 2012

A study has been made of the pharmacology of 5‐hydroxytryptamine (5‐HT)‐induced hyperpolarization responses recorded extracellularly from the rat isolated superior cervical ganglion (SCG).

Hyperpolarization responses induced by 5‐HT (1 × 10−8‐1 × 10−4 m) in the presence of MDL 72222 (1 × 10−5 m) were not antagonized by phentolamine (1 × 10−6 m), prazosin (1 × 10−7‐3 × 10−7 m), haloperidol (1 × 10−6 m) or ketanserin (1 × 10−7‐1 × 10−6 m). However, the latter two compounds both potentiated and increased the persistence of the hyperpolarization induced by moderate to high concentrations of 5‐HT. Spiperone (1 × 10−7 m) caused similar effects. All further experiments were performed in the presence of ketanserin (1 × 10−6 m) as well as MDL 72222.

8‐Hydroxy‐2(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT; 1 × 10−7‐1 × 10−4 m) and ipsapirone (3 × 10−5‐3 × 10−4 m) behaved as weak hyperpolarizing agonists on the SCG. However, at concentrations below those required to produce hyperpolarization, both compounds acted as unsurmountable antagonists of 5‐HT‐induced hyperpolarization.

5‐Carboxamidotryptamine (5‐CT; 1 × 10−9‐1 × 10−5 m) mimicked the hyperpolarizing activity of 5‐HT on the SCG. The EC50 for 5‐CT was approximately 9 fold lower than that for 5‐HT.

Spiperone (1 × 10−7‐1 × 10−5 m) behaved as a reversible competitive antagonist of hyperpolarization responses induced by 5‐HT with a pKB value of 7.40 ± 0.09. Spiperone (1 × 10−7‐1 × 10−6 m) also caused concentration‐dependent rightward displacement of the 5‐CT concentration‐hyperpolarization response curve. In this case, the pKB was 7.80 ± 0.05.

(±)‐Cyanopindolol (3 × 10−7‐3 × 10−6 m) caused non‐parallel rightward displacements of the 5‐HT concentration‐response curve. Against 5‐CT, (±)‐cyanopindolol (3 × 10−7‐3 × 10−6 m) caused a concentration‐independent rightward displacement of the concentration‐response curve, accompanied by a large increase in the maximum response. 5‐CT‐induced hyperpolarization recorded in the presence of (±)‐cyanopindolol (3 × 10−7 m) was not significantly antagonized by methiothepin (1 × 10−6 m) or methysergide (1 × 10−6 m).

It is concluded that 5‐HT‐induced hyperpolarization of the rat SCG is mediated via a 5‐HT1‐like receptor which resembles the 5‐HT1A binding site. However, a lack of selective drugs precludes more definitive characterization of this receptor.
Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand
Authors: Spedding Michael , Mir Anis K.
Published: July 2012

Palmitoyl carnitine, a lipid metabolite which accumulates in cytoplasmic membranes during ischaemia, has been shown to resemble the Ca2+ channel activator, Bay K 8644, in K+‐depolarized smooth muscle. Palmitoyl carnitine caused concentration‐dependent (1–1000 μmol l−1) augmentations in the sensitivity to Ca2+ of K+‐depolarized taenia preparations from the guinea‐pig caecum. The (±)‐isomer was equieffective with the (–)‐isomer, whereas carnitine was ineffective and palmitic acid relaxed the tissues. The shift to the left of Ca2+ concentration‐response curves induced by palmitoyl carnitine (100 μmol l−1) was additive with that of Bay K 8644 (1 μmol l−1).

The interactions of palmitoyl carnitine with the different classes of calcium‐antagonist were similar to those seen with Bay K 8644. Schild plots of the calcium‐antagonist effects of nifedipine were shifted to the right following preincubation of the taenia with palmitoyl carnitine (30–300 μmol l−1). The inhibitory effects of verapamil were especially sensitive to palmitoyl carnitine (100 μmol l−1). Whereas the potency of diltiazem as a calcium‐antagonist was reduced by palmitoyl carnitine (100 μmol l−1), the inhibitory effects of the lipophilic class III calcium‐antagonists, cinnarizine and flunarizine, were entirely resistant to palmitoyl carnitine (100 μmol l−1).

Although palmitoyl carnitine has detergent properties in high concentrations and lyses red blood cells, these effects were not Ca2+‐dependent, nor were they modified by calcium‐antagonists. Other detergents did not have selective interactions with Ca2+ channels.

Palmitoyl carnitine inhibited [3H]‐nitrendipine, [3H]‐verapamil and [3H]‐diltiazem binding to rat cortical membranes with IC50 values (μmol l−1) of 120 ± 1, 95 ± 17 and 120 ± 15 μmol l−1 respectively. The inhibition showed little temperature‐dependence, in contrast to that of Bay K 8644, except for a small reduction in the IC50 value for [3H]‐verapamil binding at 37°C (42 ± 5 μmol l−1). Palmitoyl carnitine interacted selectively with the Ca2+ channel, in that effects on ligand binding to α‐adrenoceptors, β‐adrenoceptors and 5‐HT1A receptors occurred only at 5–10 fold higher concentrations.

It is concluded that palmitoyl carnitine, at concentrations which have previously been shown to occur in the cytoplasm during myocardial ischaemia, may interact directly with Ca2+ channels and may therefore be considered as an endogenous modulator of channel function. The site of action differs from that of other agents.