bluuebunny/crossref_metadata_2025 huggingface dataset:
Electrophysiological effects of α‐adrenoceptor antagonists in rabbit sino‐atrial node, cardiac Purkinje cells and papillary muscles
Authors: Dukes I.D. , Williams E.M. Vaughan
Published: July 2012

The effects of prazosin, labetalol, and medroxalol were studied in the rabbit sino‐atrial node, Purkinje cells and papillary muscles.

At concentrations producing similar bradycardia, labetalol and medroxalol reduced the maximum rate of depolarization (Vmax) and overshoot potential in the sinus node. Prazosin had no such effects.

These large and highly significant reductions in Vmax and overshoot in sinus node cells were observed at concentrations of medroxalol and labetalol which had no negative inotropic effect. If depolarization in the sinus node was due to the second inward current, this would imply that such currents in the sinus node and contracting cardiac muscle are pharmacologically distinct.

All three drugs prolonged action potential duration in the sinus node, Purkinje cells and papillary muscles in a dose‐related manner. Recovery after 1 h in drug‐free solution from the effects of medroxalol and labetalol was only partial in the sinus node, but almost complete in Purkinje cells and papillary muscle. Recovery from prazosin was complete in all tissues.

All three drugs depressed Vmax in Purkinje cells and papillary muscles in a dose‐related manner, and recovery was complete.

It is concluded that all three drugs had class 1 and class 3 antiarrhythmic actions, which could contribute to their protective effects in ischaemia and reperfusion independently of blockade of myocardial α‐adrenoceptors.
The periaqueductal gray is the site of the antinociceptive action of carbamazepine as related to bradykinin‐induced trigeminal pain
Authors: Foong Foo‐Wah , Satoh Masamichi
Published: July 2012

Using freely moving and conscious rats, the antinociceptive effects of microinjections of carbamazepine, into the periaqueductal gray (PAG), nucleus reticularis paragigantocellularis (NRPG) and nucleus raphé magnus (NRM) on the biting‐like responses induced by bradykinin applied to the tooth pulp, were investigated to determine the primary site of action of this drug.

Microinjections of carbamazepine into the PAG ipsi‐ and contralateral to the stimulated tooth pulp produced dose‐dependent suppressive effects on the biting‐like responses within 1 min. The ED50 was 1.57 μg per rat, that is about 1,500 times less than that for carbamazepine administered systemically.

The antinociceptive effect of carbamazepine administered into the PAG was inhibited by pretreatment with bicuculline but not by phentolamine, propranolol and haloperidol.

Microinjections of carbamazepine into the NRPG and NRM were rarely effective in the production of antinociception at doses used (up to 3 μg per rat).

These results suggest that the PAG is one of the primary target sites for the antinociceptive activity of carbamazepine, and that GABAergic systems are involved this action of carbamazepine.
Chronic central nicotinic blockade after a single administration of the bisquaternary ganglion‐blocking drug chlorisondamine
Authors: Clarke Paul B.S.
Published: July 2012

Drug‐naive rats were tested for horizontal and vertical activity in photocell cages, for up to 80 min starting immediately after a subcutaneous injection of (−)−nicotine bitartrate or 0.9% w/v NaCl solution (saline). Nicotine (0.1 to 0.4 mg kg−1 base) depressed vertical activity and induced ataxia in the first 20 min, but increased both horizontal and vertical activity later in the session; these actions were dose‐dependent. A single intraventricular (i.v.t.) injection of chlorisondamine Cl (2 μg base), a quaternary ganglion‐blocking drug, given one to two weeks before testing, blocked the ataxic and stimulant actions of nicotine.

The antagonistic actions of chlorisondamine (0.2, 1.0, 5.0 μg i.v.t., single administration) were shown to be dose‐dependent. The stimulant actions of nicotine were blocked in a dose‐dependent way for the duration of the experiment (5 weeks); nicotine's depressant actions were completely blocked at two weeks but not at five weeks.

A ganglion‐blocking dose of chlorisondamine (0.1 mg kg−1), given subcutaneously (s.c.), failed to reduce the behavioural actions of nicotine, whereas a much higher systemic dose (10 mg kg−1 s.c.) was effective for at least five weeks.

Chlorisondamine failed to alter the behavioural effects of (+)‐amphetamine or apomorphine, while blocking those of nicotine.

It is concluded that chlorisondamine antagonizes some of nicotine's central actions in a potent, long‐lasting and pharmacologically selective way.
Kinin effects on chloride secretion do not require eicosanoid synthesis
Authors: Cuthbert A.W. , Halushka P.V. , Kessel D. , Margolius H.S. , Wise W.C.
Published: July 2012

The actions of bradykinin on colonic epithelia from essential fatty acid‐deficient (EFAD) rats has been examined. Electrogenic chloride secretion as short circuit current (SCC) and release of immunoreactive prostaglandin E2 (iPGE2) and i 6‐keto PGF1α have been measured.

Resting release of prostanoids was significantly less in EFAD than in control tissues. Bradykinin, in a maximally effective concentration, produced no increase in prostanoid release in EFAD tissues in contrast to controls, while the SCC response was 55% of that in controls.

In EFAD tissues the SCC response to bradykinin was the same whether or not the cyclooxygenase inhibitor piroxicam was present.

EFAD tissues were not more sensitive to prostaglandins than control tissues.

We conclude that while prostaglandin release contributes to the totality of the response to bradykinin, the latter's effect on electrogenic chloride secretion does not require the obligatory production of arachidonic acid metabolites.
Potentiation of the action of adenosine on cerebral cortical neurones by the tricyclic antidepressants
Authors: Phillis John W.
Published: July 2012

The effects of four tricyclic antidepressants, nortriptyline, iprindole, chlorimipramine and desipramine on adenosine‐evoked depressions of the firings of rat cerebral cortical neurones has been studied.

When applied iontophoretically, all four substances enhanced the depressant actions of iontophoretically applied adenosine but did not affect the depressant actions of the uptake‐resistant analogue, adenosine 5′‐N‐ethylcarboxamide (NECA).

Nortriptyline and iprindole administered intravenously (1 mg kg−1) enhanced the depressant actions of iontophoretically applied adenosine.

When applied by larger iontophoretic currents, all four antidepressants inhibited the firing of cerebral cortical neurones. Chlorimipramine‐ and desimipramine‐elicited depressions were antagonized by intravenously administered caffeine, an adenosine antagonist.

Earlier studies showed the tricyclic antidepressants inhibit the uptake of adenosine by rat brain cerebral cortical synaptosomes. The present results demonstrate that four antidepressants are able to potentiate the action of adenosine and that this occurs when these compounds are given in behaviourally meaningful doses. The specificity of the potentiation is demonstrated by the failure of these compounds to potentiate the depressant actions of an uptake‐resistant analogue of adenosine, NECA.

Antagonism of the inhibitory effects of the antidepressants on neuronal firings by caffeine, indicates that these compounds can enhance the extracellular levels of endogenously released adenosine sufficiently to depress cell firing.
Theophylline‐sensitive modulation of non‐cholinergic excitatory neurotransmission in the guinea‐pig ileum
Authors: Barthó L. , Pethö G. , Rónai Z.
Published: July 2012

Atropine‐resistant longitudinal contractions of the guinea‐pig ileum due to field stimulation were greatly augmented by theophylline (150 μM). Adenosine exerted an opposite effect. Theophylline did not potentiate contractions evoked by exogenous substance P. It is suggested that a theophylline‐sensitive inhibitory mechanism (possibly mediated by adenosine or a related substance) controls transmitter release from enteric non‐cholinergic excitatory neurones.
Phorbol myristate acetate enhances human polymorphonuclear neutrophil release of granular enzymes but inhibits chemokinesis
Authors: Hoult J.R.S. , Nourshargh Sussan
Published: July 2012

The effects of the co‐carcinogenic phorbol ester, phorbol myristate acetate (PMA), on N‐formyl‐Met‐Leu‐Phe (FMLP)‐induced human polymorphonuclear leukocyte chemokinesis and release of granular lysozyme and β‐glucuronidase were compared with those of the inactive phorbol didecanoate (PDD).

Release of the enzymes was enhanced by PMA but was unaffected by PDD which also had no effect on chemokinesis.

In contrast, FMLP‐induced chemokinesis was completely suppressed by PMA in a dose‐dependent fashion (ID50 = 3.5 nM).

PMA also inhibited the FMLP‐induced increase in cytoplasmic calcium level, measured by the fluorescent indicator quin‐2.

These and other results suggest that although the diacylglycerol/protein kinase C system is involved in the positive regulation of certain neutrophil functions (degranulation and superoxide generation), if it is very powerfully stimulated, as with PMA, it has inhibitory actions on other neutrophil properties such as motility.
Pharmacological analysis of the muscarinic receptors involved when McN‐A 343 stimulates acid secretion in the mouse isolated stomach
Authors: Black J.W. , Shankley N.P.
Published: July 2012

In view of the recent M1 and M2 subclassification of muscarinic receptors and the suggestion of separate populations of muscarinic receptors on oxyntic and histamine cells in the gastric mucosa, we have analysed the effects of McN‐A 343, classified as an M1‐selective agonist, on gastric acid secretion by the mouse, isolated, lumen‐perfused stomach assay.

Acid secretion stimulated by McN‐A 343 was not inhibited by tetrodotoxin pretreatment, although it was competitively antagonized by atropine (pKB 7.90), suggesting a muscarinic site of action between postganglionic neurones and the final secretory event.

Acid secretion stimulated by McN‐A 343 was more sensitive than 5‐methylfurmethide‐stimulated secretion to H2‐receptor blockade: the profile of inhibition was consistent with expectations for a model of indirect agonism, suggesting that McN‐A 343 preferentially stimulated the release of endogenous histamine from mucosal histamine cells.

In view of this selective action the McN‐A 343‐pirenzepine interaction was studied, the latter being classified as an M1‐selective antagonist. Results were consistent with expectations for a competitive interaction but the pKB (6.69) was not significantly different from the value obtained at the oxyntic cell, using 5‐methylfurmethide as agonist in the presence of H2‐receptor blockade, in a previous study.

We suggest that there is no need to postulate differences in oxyntic and histamine cell muscarinic receptors to account for the selective stimulant activity of McN‐A 343 observed in this study and the relatively selective inhibition of gastric acid secretion by pirenzepine in vivo. McN‐A 343 selectivity may be accounted for by a higher muscarinic receptor density on the histamine cell and pirenzepine selectivity by a smaller degree of loss into the gastric secretion compared to atropine.
Monoaminergic involvement in the pharmacological actions of buspirone
Authors: Skolnick Phil , Weissman Ben Avi , Youdim Moussa B.H.
Published: July 2012

Buspirone, MJ‐13805 and MJ‐13653 did not produce a ‘5‐hydroxytryptamine (5‐HT) syndrome’ in rats at doses up to 20 mg kg−1.

These drugs were very weak 5‐HT uptake blockers (IC50 ≫ 10 μM) compared to drugs such as chlorimipramine.

These drugs did not inhibit either monoamine oxidase (MAO)‐A or MAO‐B.

The Ki values for these agents as inhibitors of [3H]‐5‐HT and [3H]‐ketanserin binding to rat frontal cortex or hippocampal membranes were in the μM range, well above the brain concentrations achieved after an oral dose of 25 mg kg−1.

Parenterally administered buspirone blocked apomorphine‐induced sterotypy, inhibited the 5‐HT syndrome elicited by 5‐methoxy‐N,N‐dimethyltryptamine, and delayed the onset of p‐chloroamphetamine induced behaviours.
Effects of glutamic acid analogues on identifiable giant neurones, sensitive to β‐hydroxy‐L‐glutamic acid, of an African giant snail (Achatina fulica Férussac)
Authors: Nakajima Tadashi , Nomoto Kyosuke , Ohfune Yasufumi , Shiratori Yoshimune , Takemoto Tsunematsu , Takeuchi Hiroshi , Watanabe Kazuko
Published: July 2012

The effects of the seven glutamic acid analogues, α‐kainic acid, α‐allo‐kainic acid, domoic acid, erythro‐L‐tricholomic acid, DL‐ibotenic acid, L‐quisqualic acid and allo‐γ‐hydroxy‐L‐glutamic acid were examined on six identifiable giant neurones of an African giant snail (Achatina fulica Férussac).

The neurones studied were: PON (periodically oscillating neurone), d‐RPLN (dorsal‐right parietal large neurone), VIN (visceral intermittently firing neurone), RAPN (right anterior pallial neurone), FAN (frequently autoactive neurone) and v‐RCDN (ventral‐right cerebral distinct neurone). Of these, d‐RPLN and RAPN were excited by the two isomers (erythro‐ and threo‐) of β‐hydroxy‐L‐glutamic acid (L‐BHGA), whereas PON, VIN, FAN and v‐RCDN were inhibited. L‐Glutamic acid (L‐Glu) had virtually no effect on these neurones.

α‐Kainic acid and domoic acid showed marked excitatory effects, similar to those of L‐BHGA, on d‐RPLN and RAPN. Their effective potency quotients (EPQs), relative to the more effective isomer of L‐BHGA were: 0.3 for both substances on d‐RPLN, and 1 for α‐kainic acid and 3‐1 for domoic acid on RAPN. α‐Kainic acid also had excitatory effects on FAN and v‐RCDN (EPQ for both: 0.3), which were inhibited by L‐BHGA but excited by γ‐aminobutyric acid (GABA).

Erythro‐L‐tricholomic acid showed marked effects, similar to those of L‐BHGA, on VIN (EPQ: 0.3) and RAPN (EPQ: 3‐1), but produced weaker effects on PON and d‐RPLN (EPQ: 0.1).

DL‐Ibotenic acid produced marked effects, similar to those of L‐BHGA, on PON, VIN (EPQ for both: 1) and RAPN (EPQ: 1‐0.3), but had weak effects on d‐RPLN (EPQ: <0.1) and FAN (EPQ: 0.1). It had excitatory effects on v‐RCDN (EPQ: 0.1). This neurone was inhibited by L‐BHGA but excited by GABA.

L‐Quisqualic acid showed the same effects as L‐BHGA on all of the neurones examined (EPQ range 30–0.1). It was the most potent of the compounds tested on RAPN (EPQ: 30‐10), FAN (EPQ:30) and v‐RCDN (EPQ:3).

α‐Allo‐kainic acid and allo‐γ‐hydroxy‐L‐glutamic acid had no obvious effect on any of the neurones examined.

As described above, the responses of the neurones examined to these substances varied widely. However, L‐quisqualic acid generally had effects on the neurones similar to those of L‐BHGA; the L‐BHGA‐excited neurones were also excited by α‐kainic acid and domoic acid.
The effects of triazolobenzodiazepines in two animal tests of anxiety and in the holeboard
Authors: File Sandra E. , Pellow Sharon
Published: July 2012

In addition to possessing anti‐anxiety activity in man, triazolobenzodiazepines have been reported to have antidepressant and antipanic properties. In this they differ from classical 1,4‐benzodiazepines that have only anti‐anxiety activity. The purpose of the present study was to examine the effects of the triazolobenzodiazepines in two animal tests of anxiety and in the holeboard, to see whether clear differences could be observed between them and the 1,4‐benzodiazepines.

After acute administration, U‐43,465 (16 mg kg−1) had a significant anxiolytic effect in the social interaction test. Neither adinazolam (1–3.5 mg kg−1) nor alprazolam (0.125‐2 mg kg−1) had a significant effect. It is suggested that this is because, with adinazolam and alprazolam, doses at which anxiolytic effects can be observed are close to those at which sedative effects can be observed.

U‐43,465 (8–16 mg kg−1) and alprazolam (1–2 mg kg−1) had significant anxiolytic effects in the elevated plus‐maze test of anxiety.

U‐43,465 (8–32 mg kg−1), adinazolam (0.5‐5 mg kg−1) and alprazolam (0.2‐2.0 mg kg−1) caused dose‐related reductions in exploratory head‐dipping, locomotor activity and rearing in the holeboard.

In general the results seen in the three tests with the triazolobenzodiazepines alprazolam and adinazolam were similar to those seen with classical 1,4‐benzodiazepines. With U‐43,465, however, an anxiolytic effect was observed in the social interaction test after acute treatment; chronic treatment is required to see an effect with classical 1,4‐benzodiazepines. In this U‐43,465 resembles the effects of several novel non‐benzodiazepine putative anxiolytic compounds that are believed to have less sedative potential than the benzodiazepines.
The effect of chronic haloperidol treatment on some cardiovascular parameters in cats
Authors: Bentley G.A. , Copeland I.W.
Published: July 2012

Blood pressure, heart rate and evoked cardiovascular reflexes were examined in cats following chronic treatment with haloperidol, at a dose of 1 mg kg−1 per day, orally for 23 days. Five days after the final dose the animals were anaesthetized and tested for their reaction to various cardiovascular stimuli and to a number of agonist and antagonist drugs, given both intravenously and into the vertebral artery.

It was found that treatment with haloperidol caused hypertension in the cats, as well as a potentiation of the pressor response to bilateral carotid occlusion. The response to 30° head‐up tilting was also altered so that in treated cats, the blood pressure returned to normal more rapidly during the tilt.

There was no difference in the heart rate of the two groups of cats, nor in the pressor response to intravenous noradrenaline or angiotensin II or to afferent brachial nerve stimulation, nor was the depressor action of bradykinin altered. Hexamethonium reduced the blood pressure in both control and treated cats to approximately the same level. Blood O2, CO2, pH and bicarbonate levels were also unaltered by the treatment, as was plasma renin activity.

Of the drugs given into the vertebral artery, only noradrenaline, prazosin, ketanserin and haloperidol caused a significantly greater fall in blood pressure in treated than in control cats, while clonidine and St91 were equally effective in both groups. These results suggest that haloperidol treatment has caused a greater modulation of central α1‐ than of α2‐adrenoceptors.
Effect of the endogenous analgesic dipeptide, kyotorphin, on transmitter release in sympathetic ganglia
Authors: Hirai K. , Katayama Y.
Published: July 2012

The effects of kyotorphin and the synthetic analogue, D‐kyotorphin, on cholinergic fast excitatory postsynaptic potentials (fast‐e.p.s.ps) were studied using intracellular recordings from bullfrog sympathetic ganglion cells.

Kyotorphin and D‐kyotorphin (1–100 μM) increased the amplitude and the mean quantal content of the fast‐e.p.s.p. without changing the mean quantal size in a low Ca2+/high Mg2+ medium.

Kyotorphin and D‐kyotorphin (1–100 μM) did not change the resting membrane potential, input membrane resistance, the amplitude and duration of action potentials and the sensitivity to the transmitter, acetylcholine (ACh), of the ganglion cells.

The facilitatory effect of D‐kyotorphin on the fast‐e.p.s.p. was reversibly inhibited by naloxone (10 μM).

These results indicate that kyotorphin may increase transmitter release from preganglionic nerve terminals. The possible mechanisms underlying this action of kyotorphin are discussed.
Application of the operational model of agonism to establish conditions when functional antagonism may be used to estimate agonist dissociation constants
Authors: Leff P. , Martin G.R. , Morse J.M.
Published: July 2012

The operational model of agonism (Black & Leff, 1983) has been used to analyse comparatively functional antagonism and irreversible antagonism as methods for estimating agonist dissociation constants (KAs).

A general condition is established in terms of the model parameters which defines the type of experimental interventions at the receptor and the post‐receptor level that allow valid KA estimation.

It is shown that functional antagonism and other post‐receptor interventions may produce changes in agonist‐concentration effect curves which are qualitatively indistinguishable but quantitatively distinct, from those produced by irreversible antagonism.

Experimental data obtained with the guinea‐pig tracheal strip preparation are in keeping with the theoretical predictions and show how studies using functional antagonism may overestimate agonist affinity.

In general, functional antagonism, unlike irreversible antagonism, is in principle an unreliable method for quantifying agonism.
Inhibition of monoamine oxidase in 5‐ hydroxytryptaminergic neurones by substituted p‐aminophenylalkylamines
Authors: Ask Anna‐Lena , Fagervall Ingrid , Florvall L. , Ross S.B. , Ytterborn Susanne
Published: July 2012

A series of substituted p‐aminophenethylamines and some related compounds were examined with regards to the inhibition of monoamine oxidase (MAO) in vivo inside and outside 5‐hydroxytryptaminergic neurones in the rat hypothalamus. This was recorded as the protection against the irreversible inhibition of MAO produced by phenelzine by determining the remaining deaminating activity in the absence and presence of citalopram using a low (0.1 μM) concentration of [14C]‐5‐hydroxytryptamine (5‐HT) as substrate.

Some of the phenethylamines were much more potent inside than outside the 5‐hydroxytryptaminergic neurones. This neuronal selectivity was antagonized by pretreatment of the rats with norzimeldine, a 5‐HT uptake inhibitor, which indicates that these compounds are accumulated in the 5‐HT nerve terminals by the 5‐HT pump.

Selectivity was obtained for compounds with dimethyl, monomethyl or unsubstituted p‐amino groups. An isopropyl group appears to substitute for the dimethylamino group but with considerably lower potency. Compounds with 2‐substitution showed selectivity for aminergic neurones and this effect decreased with increased size of the substituent. The 2,6‐dichloro derivative FLA 365 had, however, no neuronal selective action but was a potent MAO inhibitor. Substitutions in the 3‐ and 5‐ positions decreased both potency and selectivity.

Prolongation of the side chain with one methylene group abolished the preference for the MAO in 5‐hydroxytryptaminergic neurones although the MAO inhibitory potency remained. The selectivity disappeared by increasing the α‐substituent to an ethyl group but remained for the α,α‐dimethyl substituted derivatives.

It is concluded that compounds which are (1) transported by the 5‐HT pump and (2) potent reversible MAO‐A inhibitors produce pronounced inhibition of MAO in 5‐hydroxytryptaminergic neurones.
Central δ‐opioid receptor interactions and the inhibition of reflex urinary bladder contractions in the rat
Authors: Dray A. , Nunan L. , Wire W.
Published: July 2012

The in vivo effects of a number of opioid agonists and antagonists were studied on the spontaneous reflex contractions of the urinary bladder recorded isometrically in the rat anesthetized with urethane. All substances were administered into the central nervous system by the intracereboventricular (i.c.v.) or spinal intrathecal (i.t.) route.

The conformationally restricted enkephalin analogues [2‐D‐penicillamine, 5‐L‐cysteine] enkephalin (DPLCE), [2‐D‐penicillamine, 5‐L‐penicillamine] enkephalin (DPLPE) and [2‐D‐penicillamine, 5‐D‐penicillamine] enkephalin (DPDPE) produced dose‐related inhibition of reflex bladder contractions when administered by the i.c.v. or i.t. route.

Both the novel δ‐opioid receptor antagonist ICI 154,129 (200–600 μg) [N,N‐bisallyl‐Tyr‐Gly‐Gly‐ψ‐(CH2S)‐Phe‐Leu‐OH) and ICI 174,864 (1–3 μg) [N,N‐diallyl‐Tyr‐Aib‐Aib‐Phe‐Leu‐OH: Aib = α‐aminoisobutyric acid] attenuated or abolished the effects of DPLCE, DPLPE and DPDPE when administered by the i.c.v. or i.t. route. The antagonism observed was selective since the equipotent inhibition produced by the μ‐opioid receptor agonist [D‐Ala2, Me‐Phe4, Gly(ol)5] enkephalin (DAGO) was unaffected. Overall, ICI 154,129 was considerably weaker than ICI 174,864 and both antagonists inhibited bladder activity at doses higher than those required to demonstrate δ‐receptor antagonism.

Further studies of the agonistic effect of ICI 174,864 showed that it was insensitive to low doses of naloxone (2 μg, i.c.v. or i.t.) but could be abolished by higher (10–15 μg) doses of naloxone. These observations suggested that the agonistic effect of ICI 174,864 was not mediated by μ‐opioid receptor.

β‐Endorphin (0.2‐1.0 μg, i.c.v.) inhibited bladder contractions but following recovery from this effect, appeared to prevent the expression of δ‐receptor antagonism by ICI 174,864. In addition a previously subthreshold dose of ICI 174,864 now exhibited marked agonistic activity. The inhibitory effect of a submaximal dose of DPDPE was also potentiated by β‐endorphin under these circumstances.

These observations suggest that supra‐spinal and spinal δ‐opioid receptors are involved in the opioid‐mediated inhibition of reflex bladder contractions in the rat. Moreover β‐endorphin may be important in regulating central δ‐opioid receptors.
Affinity and efficacy correlate with chemical structure more than potency does in a series of pentatomic cyclic muscarinic agonists
Authors: Angeli P. , Brasili L. , Giannella M. , Gualtieri F. , Pigini M.
Published: July 2012

The efficacy and affinity of nine pentatomic cyclic muscarinic agonists were determined on the guinea‐pig ileum, according to the method of Furchgott & Bursztyn (1967).

The efficacy and affinity of these agonists are affected differently by structural modifications.

Our results suggest that a strong dipole oriented in the same direction as that of the hydroxy group of muscarine, or the presence of a polarizable atom in the same position, are important for efficacy.
Contractor responses of the isolated colon of the mouse to morphine and some opioid peptides
Authors: Fontaine Jeanine , Reuse Jean
Published: July 2012

Morphine (1 times 10−8‐1 times 10−4M), fentanyl (1 times 10−9− 1 times 10−5M) and alfentanyl (1 times 10−10 − 1 times 10−5M) as well as methionine enkephalin [Met5]enkephalin (1 times 10−11 − 1 times 10−8M), [D‐Ala2, Met5]enkephalin (1 times 10−12 − 1 times 10−8M) and dynorphin A(1 − 13) (1 times 10−9 − 1 times 10−6M) caused a contractor response of the longitudinal musculature of the terminal colon of the mouse.

These effects were competitively antagonized by naloxone. The pA2 values obtained for naloxone antagonism of morphine and opioid peptides and the high sensitivity of the preparation to enkephalins suggest the presence of δ‐opiate receptors in this preparation but μ‐and κ‐receptors may also be present.

Opiate‐induced contractions in the mouse colon were abolished by tetrodotoxin and after incubation with indomethacin.

It is concluded that the excitatory actions of the opiates in the mouse colon are mediated via opiate receptors located on nerves which do not release acetylcholine, noradrenaline or 5‐hydroxytryptamine. The opiates may produce their action by removing an inhibitory neural influence (the nature of which remains to be elucidated) allowing a prostaglandin‐mediated effect to predominate, thereby increasing muscle tone.
The influence of neonatal treatment with capsaicin on the control of blood pressure in adult rats in water‐replete and water‐deprived states
Authors: Bennett T. , Gardiner S.M.
Published: July 2012

Arterial blood pressures and heart rates were measured in water‐replete and in water‐deprived (48 h) conscious, adult rats that had received capsaicin (50 mg kg−1) or its vehicle neonatally.

Resting arterial blood pressures and heart rates in capsaicin‐treated rats were not different from the controls in either the water‐replete or the water‐deprived state.

Inhibition of the vascular actions of vasopressin (with 1‐β‐mercapto,‐β,β‐cyclopentamethylen‐epropionic acid, 8‐D‐arginine vasopressin, (d(CH2)5DAVP)) had no significant effect on blood pressures in the water‐replete animals but caused a significant hypotension in water‐deprived rats; the magnitude of the hypotension was the same irrespective of whether the animals had received capsaicin or its vehicle.

During angiotensin converting enzyme inhibition (with captopril) and ganglion blockade (with pentolinium), the vasopressin‐mediated blood pressure recovery was more gradual in the capsaicintreated animals than in the controls, but after 60 min blood pressures were similar in all groups. Collectively the results indicate that although the full development of vasopressin‐dependent mechanisms following acute hypotension takes longer when a large proportion of unmyelinated afferent fibres have been destroyed by neonatal treatment with capsaicin, 48 h of water deprivation results in a normal involvement of vasopressin‐dependent mechanisms in the maintenance of blood pressure.
Modification of dyskinesias following the intrastriatal injection of prostaglandins in the rodent
Authors: Costall Brenda , Holmes S.W. , Kelly M. Elizabeth , Naylor R.J.
Published: July 2012

The abilities of prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2α to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea‐pig.

Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic biting induced by 2‐di‐n‐propylamino‐5, 6‐dihydroxytetralin (0.025 mg kg‐1 s.c.), ability to antagonize stereotyped behaviour induced by apomorphine (0.5 or 2 mg kg−1 s.c.) and ability to induce catalepsy. Asymmetry/circling behaviour revealed on challenge with apomorphine (0.25 mg kg−1 s.c.) was measured following unilateral injection into the striatum.

In the rat, dyskinetic biting induced by 2‐di‐n‐propylamino‐5, 6‐dihydroxytetralin was antagonized by PGE1 (0.001 − 1 μg) and PGE2 (0.00001 − 1 μg) but not by PGD2 or PGF2α (1 μg). Stereotyped behaviour induced by apomorphine was not antagonized by any of the prostaglandins. A weak catalepsy was induced by PGE1 (1 μg only), PGE2 (0.001 − 1 μg) and PGD2 (0.001 − 1 μg) but not by PGF2α. Asymmetry and circling behaviour was only observed following the unilateral injection into the striatum of PGE1 and PGD2 (0.01 − 1 μg) and challenge with apomorphine.

In the guinea‐pig the actions of PGE1 and E2 were compared with those of PGF2α. Dyskinetic biting induced by 2‐di‐n‐propylamino‐5, 6‐dihydroxytetralin was antagonized by bilateral injections into the striatum of PGE2 (0.001 − 1 μg), but not PGE, (0.5 μg) and PGF2α (1 μg) but not PGE, (0.5 μg) and PGF2α (1 μg). Similar injections of PGE1, E2 and F2α all failed to antagonize apomorphine‐induced stereotyped behaviour, or to induce catalepsy. PGE1 (0.01‐0.5 μg) and PGE2 (0.002 − 1 μg), but not PGF2α, caused asymmetry following unilateral injection into the striatum and peripheral challenge with apomorphine.

It is concluded that the major effect in the striatum of the prostaglandins of the E series is to antagonize dyskinetic biting; this action is not shared by other prostaglandins tested, and does not reflect a generalised ability to antagonize striatal dopamine function. It is suggested that the actions of the prostaglandins to modify differentially dopamine‐dependent behaviours from the striatum may reflect activity at a site subsequent to the dopamine receptor.
Calcium‐dependent contractile response of arterial smooth muscle to a jellyfish toxin (pCrTX: Carybdea rastonii)
Authors: Azuma Hiroshi , Ishikawa Masayuki , Nakajima Terumi , Satoh Akihiko , Sekizaki Satomi
Published: July 2012

The purpose of the present experiments was to investigate the pharmacological mechanisms of the vasoconstriction caused by the toxin (pCrTX) which had been partially purified from the tentacles of the jellyfish Carybdea rastonii (‘Andonkurage’).

pCrTX (0.1 to 10 μg ml−1) produced a tonic contraction of rabbit aortic strips, which was nearly abolished in Ca2+‐free medium and was significantly reduced by verapamil or diltiazem.

pCrTX stimulated 45Ca2+‐influx and this effect was markedly attenuated by verapamil.

pCrTX‐induced vasoconstriction was significantly attenuated by phentolamine, 6‐hydroxydopamine (6‐OHDA) and in low Na+‐medium, but not by bretylium, guanethidine, reserpinization or tetrodotoxin (TTX).

pCrTX continuously and significantly increased the 3H‐efflux from [3H]‐noradrenaline preloaded aortic strips and this effect was completely inhibited by pretreatment with 6‐OHDA and in Ca2+‐free medium, but not by phentolamine, bretylium, guanethidine or TTX.

A single exposure to pCrTX for 30 min greatly reduced the contractile responses to tyramine, nicotine and transmural electrical stimulation, but not those to noradrenaline or KCl. In addition, incorporation of [3H]‐noradrenaline was reduced.

Pretreatments with chlorphenylamine or indomethacin failed to modify the contractile response to pCrTX.

These results suggest that the pCrTX‐induced vasoconstriction is caused by a presynaptic action, releasing noradrenaline from the intramural adrenergic nerve terminals, and by a postsynaptic action, which consists at least in part of stimulation of the transmembrane calcium influx. Both pre‐ and postsynaptic actions depend on the external calcium concentration. The data further suggest that pCrTX damages the noradrenaline uptake and/or storage mechanisms without damaging postsynaptic contractile systems.
Calcium channel inhibitors suppress the morphine‐withdrawal syndrome in rats
Authors: Bongianni F. , Carla' V. , Moroni F. , Pellegrini‐Giampietro D.E.
Published: July 2012

The effects of the Ca2+‐channel blockers verapamil and nimodipine, on the behavioural signs of naloxone (1 mg kg−1)‐induced abstinence syndrome in morphine‐dependent rats, were evaluated. The content of noradrenaline (NA) and of its metabolite 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) was measured, using high performance liquid chromatography and electrochemical detection or gas chromatography‐mass spectrometry, in various brain regions of these animals. Possible interactions of nimodipine and verapamil with opioid receptors were evaluated by examining their ability to displace [3H]‐naloxone binding to brain membranes.

Verapamil (5, 10 and 50 mg kg−1) and nimodipine (1,5 and 10 mg kg−1) dose‐dependently reduced most of the signs of morphine abstinence.

Naloxone‐precipitated abstinence decreased the NA content in the cortex, hippocampus, brainstem and cerebellum. In the same brain regions the content of MHPG increased, suggesting an increased release of the amine during morphine abstinence.

Nimodipine (10 mg kg−1 i.v.) did not change the content of NA or MHPG in the cortex, hippocampus and brainstem. However, nimodipine pre‐treatment markedly reduced the changes in NA and MHPG content induced by the abstinence syndrome.

Neither verapamil nor nimodipine displaced [3H]‐naloxone from its binding sites.

These results suggest that Ca2+‐channel blockers suppress the behavioural and neurochemical expressions of morphine abstinence by a mechanism that differs from those of opioids or α2‐adrenoceptor agonists.
Peripheral 5‐HT2‐like receptors. Can they be classified with the available antagonists?
Authors: Leff P. , Martin G.R.
Published: July 2012

Interactions between 5‐hydroxytryptamine (5‐HT) and the so‐called 5‐HT2 receptor antagonists ketanserin, spiperone, trazodone and methysergide were studied in isolated preparations of the rabbit aorta, rat jugular vein, and rat caudal artery.

Trazodone and spiperone were apparently simple competitive antagonists since they produced antagonism that was surmountable over the concentration range studied and, in each tissue, their apparent affinity appeared to be independent of the antagonist concentration. Furthermore, concentration‐ratios obtained with the two antagonists in combination suggested that antagonism was additive, implying mutual competition with a single population of 5‐HT receptors.

Ketanserin was a non‐surmountable antagonist of 5‐HT in the rat caudal artery and methysergide demonstrated surmountable, competitive antagonism only in the rabbit aorta.

Antagonist dissociation constants estimated for apparently competitive interactions showed that ketanserin, spiperone and trazodone expressed affinities which differed according to the tissue used. In the case of trazodone, affinity estimates differed by as much as 12 fold. These discrepancies were independent of the 5‐HT receptor agonist used and could not be attributed to an inadequate equilibration of the antagonist.

These results can be interpreted in two ways: either the receptors in the different tissues are heterogeneous or the antagonists used here must be considered as unreliable probes for the classification of 5‐HT2‐like receptors.
Autoradiographic localization of β‐adrenoceptors in pig lung using [125I]‐iodocyanopindolol
Authors: Goldie R.G. , Papadimitriou J.M. , Paterson J.W. , Rigby P.J. , Spina D.
Published: July 2012

The binding of the β‐adrenoceptor radioligand [125I]‐iodocyanopindolol (I‐CYP) has been studied in pig lung parenchyma and the distribution of binding sites visualised by light microscopic autoradiography.

I‐CYP binding was saturable (maximum binding capacity Bmax = 51 ± 3 fmol mg−1 protein), involving sites with high affinity (dissociation constant KD = 73 ± 10 pM).

Specific I‐CYP binding was displaceable both by β‐adrenoceptor agonists ((−)‐isoprenaline > (−)‐adrenaline > (±)‐fenoterol > (−)‐noradrenaline > (+)‐isoprenaline > (±)‐RO363) and antagonists ((±)‐propranolol > ICI‐118551 > atenolol), indicating a predominance of β2‐adrenoceptors. Further analysis showed that displacement data for the β1‐selective antagonist atenolol and the β2‐selective antagonist ICI‐118551 were fitted best to a 2 binding site model and that both β1‐ and β2‐adrenoceptors were present in pig lung in the ratio 28:72 respectively.

Autoradiographic grains were localized over tissue and were most dense over alveolar walls > vascular endothelium > vascular smooth muscle > bronchial smooth muscle = bronchial epithelium. Atenolol (10−5 M) caused a 31 % reduction in specific grain density over alveolar wall tissue, while a 10 fold lower concentration of ICI‐118551 (10−6 M) caused a 50% decrease. These results are consistent with binding data in pig lung parenchyma demonstrating a mixed population of β‐adrenoceptors with a predominance of the β2 subtype.

Approximately 95 % of the parenchymal β‐adrenoceptors were associated with the alveolar wall as a mixed population of the β1 and β2 subtypes in the ratio 30:70 respectively. A greater proportion of the β‐adrenoceptors associated with bronchial and vascular smooth muscle seemed to be of the β2 subtype.

It is possible that the previously described relaxant responses of the pig lung parenchyma strip to β‐agonists, mediated via β2‐adrenoceptors, resulted from the sum of reactivities in airway and vascular smooth muscle together with relaxation of alveolar interstitial cells.
Differences in cardiovascular responses to peripherally administered GABA as influenced by basal conditions and type of anaesthesia
Authors: Giuliani Sandro , Maggi Carlo Alberto , Meli Alberto
Published: July 2012

The cardiovascular (blood pressure, heart rate, cardiac contractility) effects of i.v. γ‐aminobutyric acid (GABA) were investigated in guinea‐pigs anaesthetized with barbitone or urethane.

GABA (0.1–10 mg kg−1) produced a transient ‘depressive’ effect on cardiovascular parameters which in barbitone‐anaesthetized animals was followed by a transient ‘excitatory’ effect. Resting cardiovascular parameters were higher in urethane‐ as compared to barbitone‐ anaesthetized animals.

Picrotoxin pretreatment (2 mg kg−1, i.v.) barely affected the cardiovascular changes produced by GABA in barbitone‐anaesthetized animals. In picrotoxin pretreated animals anaesthetized with urethane, GABA produced an initial depression of cardiovascular parameters followed by an excitatory phase.

Hexamethonium (20 mg kg−1, i.v) suppressed or reduced markedly the GABA‐induced cardiovascular changes both in barbitone‐ or urethane‐ anaesthetized animals.

Reserpine pretreatment lowered resting cardiovascular parameters. In these animals, regardless of type of anaesthesia, the effects of i.v. GABA were of the ‘excitatory’ type only. Reserpine pretreated animals anaesthetized with barbitone were selected for further experiments.

Various GABAA receptor agonists (homotaurine, muscimol, THIP, 5‐aminovaleric acid) mimicked the ‘excitatory’ effect of GABA in reserpine pretreated animals anaesthetized with barbitone and prevented the effects of subsequent GABA administration. On the other hand (±)‐baclofen, a selective GABAB receptor agonist, had a slight depressant effect and did not prevent the ‘excitatory’ cardiovascular effects of GABA.

Neither bicuculline nor picrotoxin pretreatment prevented the ‘excitatory’ cardiovascular effect of i.v. GABA in reserpine pretreated, guinea‐pigs anaesthetized with barbitone.

In adrenalectomized guinea‐pigs or in preparations receiving i.v. phentolamine plus propranolol, GABA produced only a small ‘depressant’ effect on cardiovascular parameters.

These findings demonstrate that GABA exerts a neuromodulatory effect on cardiovascular function via peripheral actions which is influenced by: (a) type of anaesthesia (b) resting values of cardiovascular parameters (c) degree of activity of the sympathetic nervous system and (d) catecholamine release from the adrenal medulla.
False labelling of dopaminergic terminals in the rabbit caudate nucleus: uptake and release of [3H]‐5‐hydroxytryptamine
Authors: Feuerstein T.J. , Hertting G. , Lupp A. , Neufang B.
Published: July 2012

The effect of the catecholamine uptake inhibitor nomifensine and of the 5‐hydroxytryptamine (5‐HT) uptake blocker 6‐nitroquipazine on the accumulation of [3H]‐5‐HT (0.1 μM, 60 min incubation) and [3H]‐dopamine (0.1 μM, 30 min incubation) into slices of hippocampus and caudate nucleus of the rabbit was investigated. In addition, the influence of nomifensine on the electrically evoked [3H]‐5‐HT release from caudate nucleus slices and of nomifensine and 6‐nitroquipazine on [3H]‐5‐HT released from caudate nucleus slices was analysed.

In hippocampal slices, which contain practically no dopaminergic but densely distributed 5‐hydroxytryptaminergic and noradrenergic nerve terminals (ratio of dopamine:5‐HT:noradrenaline about 1:30:25), nomifensine (1, 10μM) did not affect the accumulation of [3H]‐5‐HT; 6‐nitroquipazine (1 μM) reduced [3H]‐5‐HT uptake to about 35% of controls. In the caudate nucleus, however, where dopamine is the predominant monoamine (ratio of dopamine:5‐HT:noradrenaline about 400:25:15) nomifensine (1, 10 μM) reduced the tritium accumulation to 65% whereas 6‐nitroquipazine (1 μM) was ineffective. The combination of both drugs (1 μM each) led to a further decrease to about 15%.

The uptake of [3H]‐dopamine into hippocampal slices was blocked by both nomifensine (1 μM) and 6‐nitroquipazine (1 μM) whereas in caudate nucleus slices only nomifensine (1, 10 μM) reduced the accumulation of [3H]‐dopamine. The combination of both drugs was not more effective than nomifensine alone. The different effects of both uptake inhibitors in the hippocampus and caudate nucleus suggest a neurone specific rather than a substrate specific mode of action.

In caudate nucleus slices incubated with [3H]‐5‐HT and superfused continuously the electrically evoked 5‐HT release was diminished by the D2‐dopamine receptor agonist LY 171555 and enhanced by the D2‐receptor antagonist domperidone. If, however, the labelling of caudate nucleus slices was performed in the presence of 1 μM or 10 μM nomifensine, the modulation of 5‐HT release via D2‐receptors was reduced or abolished, respectively. In the hippocampus both LY 171555 and domperidone were completely ineffective in modulating 5‐HT release regardless of the absence or presence of nomifensine.

The present results indicate that an inverse cross labelling of [3H]‐5‐HT into dopaminergic and of [3H]‐dopamine into 5‐hydroxytryptaminergic terminals may occur despite the low concentration (0.1 μM) of tritiated transmitters used. Such cross labelling, as demonstrated with the incubation period of 60 min in the caudate nucleus, may falsely indicate the existence of D2‐dopamine receptors modulating [3H]‐5‐HT release. If both 5‐hydroxytryptaminergic and dopaminergic terminals are present within the brain region under investigation false labelling can be corrected using neuronally specific uptake inhibitors.
Receptors for neurotransmitters in opossum oesophagus muscularis mucosa
Authors: Daniel E.E. , Jury J. , Robotham K.H.
Published: July 2012

Muscularis mucosa of the distal oesophagus of the opossum contains nerves which release acetylcholine and substance P(SP)‐like material on field stimulation. The release of SP‐like material appeared to be inhibited by the presence of exogenous muscarinic agonists and potentiated by muscarinic antagonists. Analysis of the postjunctional receptors involved using carbachol, McNeil A‐343 (McN A‐343), atropine and pirenzipine suggested that the receptors were not typical M2‐muscarinic receptors. The potency of agonists and antagonists were consistent with some receptor properties resembling M1‐muscarinic receptors.

Prejunctional receptors to opiates, adenosine, agonists at α2‐adrenoceptors and prostaglandins were not detected.

Receptors for tachykinins were present on the muscle in this tissue, but did not resemble clearly either SP‐E or SP‐P type receptors. They appear to be undifferentiated since most tachykinins were of similar potency.

These results suggest that not all postjunctional muscarinic receptors in intestinal smooth muscle are M2 in type. There may be a gradation of types between M1 and M2.
Involvement of 5‐HT1A‐ and α2‐receptors in the decreased 5‐hydroxytryptamine release and metabolism in rat suprachiasmatic nucleus after intravenous 8‐hydroxy‐2‐ (n‐dipropylamino) tetralin
Authors: Marsden C.A. , Martin K.F.
Published: July 2012

The 5‐hydroxytryptamine1A‐receptor agonist 8‐hydroxy‐2‐(n‐dipropylamino) tetralin (8‐OH‐DPAT, 0.1 mg kg−1 i.v.) decreased the height of the extracellular 5‐hydroxyindoleacetic acid (5‐HIAA) oxidation peak recorded in the suprachiasmatic nucleus (SCN) of the anaesthetized rat by use of differential pulse voltammetry.

The decrease in extracellular 5‐HIAA produced by 8‐OH‐DPAT could be partially attenuated by prior administration of the non‐selective 5‐HT receptor antagonist methiothepin (1 mg kg−1 i.v.). The 5‐HT2‐receptor antagonist ritanserin (0.2 mg kg−1 i.v.) did not appear to block the effects of 8‐OH‐DPAT.

The selective ligand for 5‐HT1A recognition sites TVX Q 7821 (isapirone, 1 mg kg−1 i.v.) decreased the extracellular level of 5‐HIAA in the SCN but to a lesser extent than 8‐OH‐DPAT. The response to 8‐OH‐DPAT was attenuated by prior administration of TVX Q 7821 to a level suggesting that TVX Q 7821 had blocked the effect of intravenous 8‐OH‐DPAT.

Idazoxan (0.2 mg kg−1 i.v.) an α2‐adrenoceptor antagonist, completely blocked the effect of 8‐OH‐DPAT on the 5‐HIAA oxidation peak recorded in the SCN, whilst having no effect on the 5‐HIAA oxidation peak when given alone.

At a dose of 0.5 mg kg−1 i.v. idazoxan induced a 120% increase in the height of the indole oxidation peak, suggesting that 5‐HT release and metabolism in the rat SCN may be influenced by tonic adrenergic inputs.

The data in this paper suggest that 5‐HT1A‐ and α2‐receptors are involved in the effects of i.v. administered 8‐OH‐DPAT on 5‐HT release and metabolism in the SCN in vivo.
Probenecid potentiates the hyperglycaemic effect but reduces the diuretic effect of frusemide in mice
Authors: Sandström Per‐Erik
Published: July 2012

The effect of probenecid on frusemide‐induced diuresis and hyperglycaemia was studied in mice.

Probenecid, a known inhibitor of tubular secretion of organic anions in the kidney, strongly reduced the diuretic response to frusemide (25 or 200 mg kg−1 body weight). This effect of probenecid appeared to be dose‐dependent up to 240 mg kg−1 body weight, at least at the lower concentration of frusemide.

Pretreatment with probenecid (240 mg kg−1 body weight) potentiated the hyperglycaemic effect of frusemide (25 or 200 mg kg−1 body weight).

The results show that probenecid has opposite effects on frusemide‐induced diuresis and hyperglycaemia in mice. It is suggested that the acute hyperglycaemic effect of frusemide is not directly linked to diuresis.