bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bronchodilator‐mediated relaxation of normal and ovalbumin‐sensitized guinea‐pig airways: lack of correlation with lung adenylate cyclase activation
Authors: Burka John F. , Saad Maan H. 
Published: July 2012

Isoprenaline, vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and forskolin caused a dose‐dependent relaxation of normal and ovalbumin‐sensitized guinea‐pig tracheal spirals and lung parenchymal strips in vitro. There was no difference in magnitude of relaxation or sensitivity to these relaxants between normal and sensitized tissues. The rank order of potency (concentration of each drug at which 50% of the maximum is obtained) for these relaxants on both trachea and parenchyma was VIP > isoprenaline > PGE2 > forskolin, although the parenchyma was more sensitive than the trachea.
The rank order of efficacy of the drugs used in relaxing both the trachea and lung parenchyma was isoprenaline (10 μm) > forskolin (30 μm) > VIP (0.1 μm) > PGE2 (10 μm). PGE2 at concentrations greater than 1 μm sometimes contracted the lung strip.
Pretreatment with indomethacin (8.5 μm), a cyclo‐oxygenase inhibitor, reduced the resting tone of tracheal spirals, but did not significantly affect the tone of lung strips. Indomethacin‐pretreatment did not affect drug‐induced relaxations of either normal or sensitized tracheal spirals. However, both normal and sensitized indomethacin‐pretreated lung strips relaxed significantly less (P<0.05) to isoprenaline, PGE2 and forskolin. Indomethacin‐pretreatment did not affect sensitivity of normal and sensitized trachea or parenchyma to the relaxant drugs.
All the relaxant drugs used stimulated adenylate cyclase activity in normal or sensitized lung parenchyma membrane preparations. The rank order of efficacy (maximal activation) was forskolin > isoprenaline = VIP > PGE2. There was no difference in response between normal and sensitized lungs. Adenylate cyclase activity of normal lung was stimulated as follows: forskolin (100 μm), 500.0 ± 50.0%; isoprenaline (100 μm), 186.0 ± 29.0%; VIP (10 μm), 213.0 ± 19.0% and PGE2 (100 μm), 155.0 ± 23.0% of basal activity. Similar values were obtained for sensitized lung parenchyma.
Indomethacin pretreatment did not significantly affect normal or sensitized lung adenylate cyclase stimulation by isoprenaline, VIP, forskolin or PGE2.
It was concluded that: (a) Immunological sensitization to ovalbumin does not induce hypoactivity of relaxant drug receptors and/or the adenylate cyclase system of the airway tissues of the guinea‐pig. (b) There is an apparent lack of correlation between tissue relaxation in vitro and adenylate cyclase activity since the rank order of the efficacy of a range of relaxants was different for the two effects and furthermore indomethacin‐treatment of airway tissues yielded differential results.
Evidence for a peripheral component in the sympatholytic effect of clonidine in rats
Authors: Brown Morris.J. , Harland Deborah 
Published: July 2012

In an attempt to assess separately the peripheral and central effects of clonidine on cardiovascular parameters and plasma catecholamine levels, the selective α2‐adrenoceptor antagonist idazoxan (RX 781094) was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before administration of intravenous clonidine. Plasma noradrenaline and plasma growth hormone concentrations were used as indices of peripheral sympathetic nervous activity and central α‐adrenoceptor stimulation, respectively.
Peripheral and central administration of idazoxan antagonized the cardiovascular responses to i.v. Clonidine, 5 μg kg−1. However, idazoxan was more effective against the hypotension than the bradycardia induced by clonidine.
Idazoxan 300 μg kg−1 i.v. and 50 μg i.c.v. prevented clonidine‐induced falls in plasma noradrenaline and adrenaline. The results suggest that 50 μg idazoxan i.c.v. caused some blockade of peripheral as well as central α2‐adrenoceptors. Idazoxan, 10 μg i.c.v., caused similar inhibition of the hypotensive response to clonidine as 300 μg kg−1 i.v. and 50 μg i.c.v. but did not significantly inhibit the clonidine‐induced fall in plasma noradrenaline concentration.
Animals pretreated with i.v. or i.c.v. idazoxan had significantly lower levels of plasma growth hormone than vehicle‐treated rats. Idazoxan 10 μg and 50 μg i.c.v. suppressed growth hormone secretion to the same extent.
These results suggest that stimulation of peripheral, prejunctional α2‐adrenoceptors in anaesthetized rats may contribute to the fall in plasma catecholamines produced by i.v. clonidine, and confirm that the hypotensive effect is centrally mediated.
2‐Alkyl analogues of idazoxan (RX 781094) with enhanced antagonist potency and selectivity at central α2‐adrenoceptors in the rat
Authors: Gadie B. , Lane A.C. , McCarthy P.S. , Tulloch I.F. , Walter D.S. 
Published: July 2012

Four 2‐alkyl (methyl, ethyl, n‐propyl and isopropenyl) analogues of idazoxan (RX 781094) have been synthesized and assessed in terms of their central α2/α1‐adrenoceptor selectivity and a2‐adrenoceptor antagonist potency using both in vitro and in vivo tests in the rat.
In cortical binding assays using [3H]‐idazoxan and [3H]‐prazosin, idazoxan had a 5 times greater α2/α1‐selectivity than yohimbine. The 2‐alkyl substituted analogues all showed improved selectivity, being between 17 and 29 times more selective than yohimbine for [3H]‐idazoxan binding sites.
In terms of central antagonist potency in vivo, the most favourable substitutions were 2‐ethyl (RX 811033) and 2‐n‐propyl (RX 811054). Compared with yohimbine, these analogues were, respectively, 36 and 18 times more potent intravenously and 5 and 7.5 times more potent orally in their antagonism of guanoxabenz‐induced mydriasis in the pentobarbitone‐anaesthetized rat.
All the analogues had a duration of action similar to that of idazoxan, which was significantly shorter than that of yohimbine.
The results indicate that introduction of alkyl groups in the 2‐position of idazoxan greatly increases the α2/α1‐adrenoceptor selectivity as measured in binding studies. Improved α2‐adrenoceptor affinity and antagonist potency were particularly associated with the 2‐ethyl and 2‐n‐propyl analogues.
A microiontophoretic study of the actions of μ‐, δ‐ and κ‐opiate receptor agonists in the rat brain
Authors: Bradley P.B. , Brookes Anne 
Published: July 2012

The actions of μ‐, δ‐ and κ‐opiate receptor agonists have been compared on the activity of single neurones in the brain stem, caudate nucleus and hippocampus of the rat, using the technique of microiontophoresis.
In the brain stem and caudate nucleus the predominant effect of all the opiate agonists tested was depression of neuronal activity which was antagonized by naloxone. The selectivity of naloxone as an opiate receptor antagonist was indicated by its lack of effect on γ‐aminobutyric acid (GABA)‐induced responses.
In the hippocampus both μ‐ and δ‐agonists mainly caused an increase in neuronal firing rates, though some neurones were depressed. In contrast, all the κ‐agonists, including the proposed endogenous ligand for the κ‐receptor, dynorphin, caused depression of neuronal activity. All of these effects were antagonized by naloxone.
There was a clear distinction in the areas within the hippocampus in which the μ‐ and δ‐agonists produced different effects. Neurones in the pyramidal cell layer were always excited by these drugs, whereas neurones in the granule cell layer of the dentate gyrus were always depressed by the same drug.
Pharmacological investigations of the vasodilator nerves supplying the duck's foot
Authors: Bell C. , Rome Annette C. 
Published: July 2012

Vasodilator responses to electrical nerve stimulation and to various putative autonomic inhibitory neurotransmitters were studied in the Krebs‐perfused foot of the domestic duck.
Electrical stimulation resulted in frequency‐dependent vasoconstrictor responses which were abolished by the infusion of guanethidine. After abolition of the vasoconstriction, electrical stimulation produced a frequency‐dependent vasodilatation.
The putative inhibitory transmitter substances tested were substance P, somatostatin, vasoactive intestinal polypeptide, adenosine triphosphate and dopamine. Of these only dopamine produced dilator responses similar in appearance to those following nerve stimulation.
Infusion of metoclopramide (170 μM) greatly reduced dilator responses to nerve stimulation and to dopamine but not those to glyceryl trinitrate.
These results suggest that the vasculature of the duck foot may be supplied by dopaminergic vasodilator nerves.
Differential effect of cyclo‐oxygenase inhibition on antigen‐ and ionophore‐induced release of slow reacting substance from fragmented guinea‐pig lung
Authors: Krell Robert D. , Kusner Edward J. 
Published: July 2012

The nonsteroidal anti‐inflammatory drugs (NSAID) indomethacin and mefenamic acid, at concentrations ranging from 3 μM to 18 μM, enhanced antigen‐induced slow reacting substance of anaphylaxis (SRS‐A) release from sensitized fragmented guinea‐pig lung. In contrast, these agents had no effect on SRS‐A release from nonsensitized guinea‐pig lung induced by several concentrations of the calcium ionophore, A23187.
Neither increasing preincubation time with the NSAID nor the use of sensitized tissue resulted in an enhancement of A23187‐induced SRS‐A release by indomethacin.
NSAID did not alter histamine release by either stimulus.
These results suggest that antigen and A23187 induce SRS‐A release from different sources or by different mechanisms in guinea‐pig lung.
Antinociception from a stereospecific action of morphine microinjected into the brainstem: a local or distant site of action?
Authors: Prado W. A. , Roberts M.H.T. 
Published: July 2012

Morphine (1 μg) was microinjected into rats in the midline medullary nucleus raphe magnus (NRM); 1 mm lateral into nucleus reticularis paragigantocellularis (NRPG); 2 mm lateral into the VIIth nerve nucleus and 3 mm lateral into the Vth nerve nucleus. The time course of changes in the sensitivity to noxious heat was followed by the tail flick test.
Significant and prolonged antinociception was seen following microinjection into NRPG. At sites 1 mm from NRPG very weak effects were seen and at 2 mm from NRPG no antinociception occurred.
It is concluded that 1 μg of morphine microinjected into the brainstem is unlikely to cause antinociception by entering the circulation and having effects at remote sites. The distance diffused by morphine to cause significant antinociception after microinjection of 1 μg is less than 1 mm.
Levorphanol (1 μg) had very similar effects to morphine but dextrorphan and saline were ineffective.
It is concluded that although the concentrations achieved following microinjections may be high, they are not excessive as the effects show stereospecificity. The concentrations of endogenous substances released into the synaptic cleft may also be high.
The affinity and efficacy of the selective β1‐adrenoceptor stimulant RO363 at β1‐ and β2‐adrenoceptor sites
Authors: McPherson G. A. , Malta E. , Molenaar P. , Raper C. 
Published: July 2012

(−)−Isoprenaline and the selective β1‐adrenoceptor agonist RO363 were tested for their inotropic effects in left atrial (β1) and relaxant effects in K+‐depolarized uterine (β2) preparations from the guinea‐pig. The drugs had similar activities as positive inotropic agents but RO363 was approximately 400 times less active than (−)−isoprenaline as a uterine relaxant. RO363 had intrinsic activities of 0.8 and 0.25 ((−)−isoprenaline = 1) in atrial and uterine preparations, respectively.
Apparent dissociation constants (KD values) determined from the ability of the agonists to displace (−)−[125I]‐iodocyanopindolol ([125I]‐CYP) bound to membranes prepared from both tissues were used as a measure of affinity. The [125I]‐CYP binding sites possessed the characteristics of homogeneous populations of β1‐adrenoceptors in atrial and β2‐adrenoceptors in uterine membrane preparations.
The pKD values for (−)−isoprenaline were similar in the two tissues (left atria 6.4, uterus 6.0) whilst for RO363 the atrial value (7.8) was considerably greater than that for the uterus (6.0). The latter value is very similar to the pKB value determined from shifts in (−)−isoprenaline curves produced by RO363 in uterine preparations.
Graphical plots of the fraction of receptors occupied vs response were constructed. The relative efficacy of (−)−isoprenaline with respect to RO363 was calculated to be 25 in atrial and 2633 in uterine preparations.
The selective β1‐adrenoceptor stimulant actions of RO363 are a reflection of both its greater affinity and efficacy for β1− as opposed to β2‐adrenoceptor sites. The potent actions of (−)−isoprenaline in both tissues are largely dependent on efficacy.
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.
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.