bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction in guinea‐pigs of airway hyperreactivity and decreased lung β‐adrenoceptor number by 15‐hydroperoxy‐arachidonic acid
Authors: Folkerts Gert , Nijkamp Frans P. , van Oosterhout Antoon J.M.
Published: July 2012

Administration to guinea‐pigs of 15‐hydroperoxy‐arachidonic acid (0.2 mg kg−1 i.p.) caused a 20% reduction of lung β‐adrenoceptor number. Furthermore, in vivo, a hyperreactivity of the airways to nebulized histamine was observed. In contrast, administration of 15‐hydroxy‐arachidonic acid (0.2 mg kg−1 i.p.) did not cause a significant change in either of these parameters.
Inhibition by xanthine derivatives of adenosine receptor‐stimulated cyclic adenosine 3′, 5′‐monophosphate accumulation in rat and guinea‐pig thymocytes
Authors: Fredholm Bertil B. , Sandberg Göran
Published: July 2012

The effect of stable adenosine analogues, including adenosine 5′‐N‐ethylcarboxamide (NECA) and N6‐l‐phenylisopropyl‐adenosine (l‐PIA), were studied on cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) accumulation in rat and guinea‐pig thymocytes.

NECA was approximately 10 times more potent than l‐PIA, in thymocytes from both species. d‐PIA was more potent in guinea‐pig than in rat thymocytes. The effect of a number of adenosine analogues followed the order: NECA > 2‐chloro‐adenosine > l‐PIA > N6‐cyclohexyl‐adenosine (CHA), an order of potency characteristic for adenosine receptors of the A2‐subtype. Thymocytes may be used as a model system to study the pharmacology of such receptors.

Several xanthines were studied as antagonists of the NECA (1 μm)‐induced cyclic AMP accumulation. The order of potency was: 1,3‐diethyl‐8‐phenylxanthine > 8‐phenyl‐theophylline > IBMX = 8‐p‐sulphophenyltheophylline = verrophylline > theophylline > caffeine > enprofylline > theobromine > pentoxiphylline. The pA2 value for 8‐phenyltheophylline was 0.35 μm, and the antagonism was shown to be competitive. The order of potency of the xanthine is virtually identical to that found earlier in several other systems in which the receptors are of the A1‐subtype. None of the xanthine derivatives tested thus seem to discriminate between A1 and A2‐receptor‐mediated adenosine actions.
Effects of adrenoceptor agonists and antagonists on smooth muscle cells and neuromuscular transmission in the guinea‐pig renal artery and vein
Authors: Makita Yuji
Published: July 2012

In the guinea‐pig renal artery and vein, the membrane potential was — 66.8 mV and — 46.8 mV, the length constant 0.54 mm and 0.43 mm, and the time constant 240 ms and 98 ms, respectively. The maximum slope of the depolarization produced by a 10 fold increase [K]o was 46 mV in the renal artery and 39 mV in the renal vein.

Noradrenaline (NA over 5 × 10−7m in the artery and over 10−7m in the vein) depolarized the membrane and slightly reduced the membrane resistance, assessed from relative changes in the amplitude of electrotonic potential. The action of NA was suppressed by prazosin in the artery but by yohimbine in the vein, i.e. the α1‐adrenoceptor is present in the extra junctional muscle membrane in the renal artery while the α2‐adrenoceptor is present in the renal vein. Dopamine and isoprenaline did not modify the membrane properties.

In the renal artery, repetitive perivascular nerve stimulation (0.1 ms, 50 Hz, 5 shocks) evoked excitatory junction potential (e.j.p.). Applications of guanethidine (10−6m) or tetrodotoxin (3 × 10−7m) abolished the generation of the e.j.p. Low concentrations of phentolamine (5 × 10−7 m), prazosin (10−7 m) and yohimbine (5 × 10−7 m) enhanced the e.j.p. amplitude, while high concentrations of phentolamine (10−5 m) and prazosin (> 10−5 m) reduced the amplitude of e.j.p.s. NA, dopamine and Clonidine consistently suppressed the amplitude of e.j.ps, at any given concentration over 10−7m.

Spontaneously generated miniature e.j.ps (m.e.j.ps) were recorded on rare occasions. Phentolamine and yohimbine both at 5 × 10−7m and prazosin 10−7m increased the appearance of m.e.j.ps.

In the renal vein, repetitive nerve stimulation failed to generate the e.j.p. Sympathetic innervation to this tissue seems to be sparse.

Specificity of innervation and adrenoceptors present on smooth muscle cells in both the renal artery and vein are discussed, and the presynaptic regulation of NA release is compared with findings in other vascular tissues.
Studies on an isolated innervated preparation of guinea‐pig trachea
Authors: Blackman J.G. , McCaig Dorothy J.
Published: July 2012

An isolated preparation of the guinea‐pig trachea with intact parasympathetic and sympathetic innervation has been devised. Responses to nerve stimulation were recorded as increases or decreases in intraluminal pressure from the fluid‐filled trachea.

The preparation maintained a positive resting intraluminal pressure of 3–4 cmH2O. This was unaffected by atropine, hexamethonium or propranolol.

Brief pressor responses, which could be completely blocked by atropine or hexamethonium, were obtained by applying short trains of stimuli to the cervical segment of the right vagus. The amplitude of responses was frequency‐dependent up to a maximum at 40 Hz.

Depressor responses, more delayed and prolonged than the pressor responses and blocked by propranolol but not by hexamethonium, were obtained by stimulation of the right cervical sympathetic trunk or stellate ganglion in 70% of preparations. Dual pressor‐depressor responses were observed in the remaining 30% of preparations. The pressor component was blocked by atropine, the depressor component by propranolol.

In the presence of atropine and propranolol, sustained sympathetic stimulation sometimes evoked a small, delayed pressor response which was blocked by phentolamine.

Under the same conditions, transmural stimulation produced a depressor response evidently due to non‐adrenergic, non‐cholinergic nerves.

Spontaneous activity was observed in some preparations under normal conditions, but could always be evoked by hypoxia. Responses to sympathetic stimulation were reduced both by hypoxia and during periods of spontaneous activity.

The principal advantage of this preparation is that it permits both excitatory and inhibitory responses to be elicited by stimulation of vagal and sympathetic nerves separately in the isolated trachea in the absence of agonist and antagonist drugs.
Adenosine inhibits and potentiates IgE‐dependent histamine release from human basophils by an A2‐receptor mediated mechanism
Authors: Church Martin K. , Holgate Stephen T. , Hughes Philip J.
Published: July 2012

Adenosine added to human basophils before anti‐IgE challenge inhibited histamine release, whereas addition after challenge potentiated release. Peak responses for the two effects occurred 15 min before and after challenge respectively.

The effects of adenosine on histamine secretion were dose‐related over concentration ranges of 1–100 μm for inhibition and 0.01–1 μm for potentiation.

The capacity of adenosine to inhibit and potentiate histamine secretion was inversely related to the strength of immunological challenge.

The ability of theophylline (50 μm) to inhibit and dipyridamole (1 μm) to enhance slightly adenosine‐induced responses, and the differing pharmacological effect of 2′,5′‐dideoxyadenosine suggested that adenosine's effects on basophil histamine secretion were mediated by stimulation of cell surface adenosine receptors.

The order of potency of adenosine and its analogues l‐ and d‐ N6‐phenylisopropyladenosine (PIA) and 5′‐N‐ethylcarboxamideadenosine (NECA) in inhibiting and potentiating IgE‐dependent histamine release from basophils indicated that both responses were mediated by stimulation of the adenosine A2‐receptor subtype.

The capacity of adenosine to cause a transient increase of cyclic AMP levels in 40–70% basophil‐enriched leucocytes confirmed the association between stimulation of A2‐receptors and activation of adenylate cyclase.
Barbiturates increase the rate of voltage‐dependent inactivation of the calcium current in snail neurones
Authors: Nishi K. , Oyama Y.
Published: July 2012

Effects of barbiturates (thiopentone, pentobarbitone, phenobarbitone and barbitone) on the calcium current (ICa) in identified Helix neurones were studied, using a conventional suction pipette technique.

Barbiturates depressed the maximal peak amplitudes (MPA) of ICa in a dose‐dependent manner without shifting the current‐voltage relationships along the voltage axis.

Barbiturates accelerated the decay phase of ICa at high concentrations (1 × 10−4 to 3 × 10−3 m), at which concentrations double‐pulse experiments showed the increased rate of a voltage‐dependent inactivation of ICa.

It is concluded that the acceleration of the decay phase of ICa by barbiturates may be due to the increased rate of the voltage‐dependent inactivation of ICa.
Homotaurine: a GABAB antagonist in guinea‐pig ileum
Authors: Giotti A. , Luzzi S. , Spagnesi S. , Zilletti Lucilla
Published: July 2012

Homotaurine (3‐aminopropane sulphonic acid) did not inhibit the twitch response in guinea‐pig ileum longitudinal muscle whilst γ‐aminobutyric acid (GABA) and (−)‐baclofen evoked dose‐dependent inhibitions.

The inhibitory effects of GABA and (−)‐baclofen were prevented in the presence of homotaurine 2 × 10−4 and 10−3 M.

The log dose‐effect curves of GABA and (−)‐baclofen were shifted in a parallel manner compatible with competitive antagonism. The pA2 of homotaurine with GABA (4.22 ± 0.05) and (−)‐baclofen (4.26 ± 0.1) were the same.

Homotaurine did not antagonize the inhibitory effects of morphine (ED50 4 × 10−7 M), noradrenaline (ED50 10−6 M) or ATP (ED50 1.5 × 10−5 M).

The inferior homologue of homotaurine, taurine 10−3 M, did not modify the inhibitory effects of GABA and (−)‐baclofen.

Picrotoxin 5 × 10−5 M antagonized GABAA receptor‐mediated contraction but did not affect GABAB receptor‐mediated inhibition. At the same concentration the drug did not influence the antagonistic action of homotaurine, thus showing no GABAA receptor‐mediated interference.

It may be concluded that homotaurine is a competitive antagonist of GABAB mediated effects in the guinea‐pig ileum.
The effects of chloroquine and other weak bases on the accumulation and efflux of digoxin and ouabain in HeLa cells
Authors: Griffiths N. , Lamb J.F. , Ogden P.
Published: July 2012

We have studied the effects of the weak bases chloroquine, NH4Cl and amantadine on the handling of certain cardiac glycosides by HeLa cells.

When these weak bases are applied acutely to HeLa cells they have only minor effects on the binding of cardiac glycosides to the sodium pumps and on the recovery of pump function following block.

When cells are grown in these weak bases there is a variable (10–30%) reduction in pump numbers. This effect is additive to that of chronic treatment with cardiac glycosides.

If all sodium pumps are blocked with ouabain, digoxin or digitoxin then recovery of function recovers with a T1/2 of about 7 h (10% h−1); digoxin and digitoxin molecules are excreted at a similar rate but ouabain excretion occurs at a much slower rate (3% h−1).

These weak bases greatly slow (× 3) the rate of excretion of digoxin and digitoxin but do not alter that of ouabain. The process affected by chloroquine was estimated to have a T1/2 of 8 h.

Cells grown in the presence of cardiac glycosides accumulate large numbers of glycoside molecules; chloroquine, NH4Cl and amantadine increase the accumulation of digoxin and digitoxin and may decrease that of ouabain.

Quantitatively these results fit a model whereby cardiac glycosides are accumulated by HeLa cells bound to the sodium pumps, are processed by the lysosomes and then excreted.

The results are consistent with a process of internalisation and renewal of sodium pumps by HeLa cells.
β‐Adrenoceptor heterogeneity in guinea‐pig airways: comparison of functional and receptor labelling studies
Authors: Carswell Heather , Nahorski Stefan R.
Published: July 2012

The distribution of β‐adrenoceptor subtypes in guinea‐pig airways has been studied by radioligand binding assays and analysis of mechanical responses.

Binding studies with the ligands [3H]‐dihydroalprenolol and [125I]‐cyanopindolol, revealed that β‐adrenoceptors were unevenly distributed throughout the airways with the highest density located in the parenchyma and the lowest density in the trachea.

The relative proportion of β1:β2‐adrenoceptor binding sites was assessed by computer‐assisted analysis of the inhibition curves generated by selective agents. It was virtually identical in each region and in the order of 15:85%.

β‐Adrenoceptor agonists caused concentration‐dependent relaxations of both tracheal spirals and parenchymal lung strips. This response appeared to be mediated by both β1‐ and β2‐adrenoceptors in tracheal spirals as the pA2 value for the β1‐selective antagonist, atenolol, varied depending upon which agonist was used, and, in the presence of the β2‐adrenoceptor antagonist ICI 118,551, noradrenaline and isoprenaline produced biphasic concentration‐effect curves. In parenchymal lung strips only the one subtype was involved as antagonist pA2 values were not dependent on the agonist used and the properties were consistent with those expected for a β2‐adrenoceptor.
Structure‐activity studies on the potentiation of benzodiazepine receptor binding by ethylenediamine analogues and derivatives
Authors: Morgan P.F. , Stone T.W.
Published: July 2012

The effect of ethylenediamine analogues on in vitro binding of [3H]‐diazepam to crude cerebral cortical synaptosomal membranes in the rat was studied.

Ethylenediamine significantly increased [3H]‐diazepam binding to a maximum potentiation of 154% control (EC50 = 18 × 10−4 M) and was the most active compound studied in terms of both potency and the maximum potentiation observed.

Potentiation of [3H]‐diazepam binding by ethylenediamine analogues is dependent on carbon‐chain length, appears to require two terminal amino groups, and is not observed in the rigid analogues studied.

Potentiation of [3H]‐diazepam binding by ethylenediamine analogues is mediated largely by a change in receptor number and not receptor affinity.

Results are discussed in terms of the possible nature of the ethylenediamine binding site.
Effects of histamine and the histamine antagonists mepyramine and cimetidine on human coronary arteries in vitro
Authors: Godfraind T. , Miller R.C.
Published: July 2012

The effects of histamine have been studied on human isolated coronary artery preparations taken from hearts ranging in age from 9 to 73 years.

Histamine in large concentrations (100 μM) contracted arteries which were without tone or spontaneous activity and sometimes induced rhythmic contractile activity. If spontaneous rhythmic activity was present it was enhanced by histamine. The contractile effects of histamine were inhibited by mepyramine but not by cimetidine.

Arteries which were contracted by depolarization responded with relaxation to histamine concentrations lower than those required to evoke a contraction; arteries from younger hearts were more sensitive than those from older hearts.

Mepyramine potentiated the maximal relaxant effect of histamine in arteries from hearts of all ages but cimetidine had very little effect.

In the presence of mepyramine, cimetidine antagonized the relaxant effect of histamine, shifting the concentration‐effect curve to the right.

It is concluded that human coronary arteries contain both H1‐ and H2‐type receptors, the H1‐receptors mediating contraction. The relaxant effects of histamine can only be inhibited by a combination of both H1‐ and H2‐receptor antagonists.
Yohimbine and prolongation of stimulation pulse duration alter similarly 3H‐transmitter efflux in heart: an alternative to the negative feedback hypothesis
Authors: Kalsner Stanley
Published: July 2012

The hypothesis of negative feedback regulation of noradrenaline release was studied in guinea‐pig left atrial halves mounted in vitro.

Tissues were transmurally stimulated with 30, 100 or 300 pulses at 2 Hz with pulse durations ranging from 50 μS to 2,000 μS, and the efflux of 3H‐transmitter determined.

The efflux of tritium increased with increasing pulse duration as was anticipated, but the effects of supposed presynaptic antagonism by yohimbine were opposite to expectations for a negative feedback system. The magnification of efflux by yohimbine, compared to untreated controls was less rather than more as stimulation‐induced transmitter efflux climbed with increases in pulse duration, and with all other parameters of stimulation held constant.

It is concluded that the neuronal effect of yohimbine is not linked to negative feedback or to any other system sensing the perineuronal concentration of previously released transmitter.

Analysis of the effects on tritium efflux of yohimbine and of prolongation of the stimulation pulse duration, reveals a similarity in the way that they promote transmitter release. Yohimbine increased efflux to approximately the same value at all pulse durations between 50 and 1,000 μS and the value reached was equivalent to that obtained in untreated atria during stimulation with very long pulses (2,000 μS duration). It is suggested that yohimbine prolongs the outward current attributable to the efflux of potassium from axon terminals, and by this means prolongs depolarization and the period of transmitter release.

Tetraethylammonium (TEA), a quaternary ion known to plug potassium efflux channels, had an effect on transmitter efflux that was, in some ways, similar to that of yohimbine but of greater magnitude. The present findings provide, for the first time, an alternative to the hypothesis of negative feedback, that might explain the presynaptic effects of adrenoceptor antagonists and possibly other compounds.
Hypothalamic regulation of the cardiovascular and respiratory systems: role of specific opiate receptors
Authors: Faden Alan I. , Feuerstein Giora
Published: July 2012

Experiments were designed to evaluate the role of μ and δ opiate receptors in central cardiovascular control in the hypothalamic nucleus preopticus medialis of rats anaesthetized with pentobarbitone.

The highly selective μ opiate receptor agonist D‐Ala2‐MePhe4‐Gly5‐ol‐enkephalin was extremely potent in eliciting hypotension and bradypnoea; tachycardia was elicited by a low dose (0.064 nmol), but not by higher doses (0.64–6.4 nmol).

Other selective μ receptor agonists (morphine sulphate, morphiceptin) caused tachycardia at lower doses (0.64, 6.4 nmol), hypotension and bradypnoea after the highest dose (64 nmol).

The relatively selective δ receptor agonist D‐Ala2‐D‐Leu5‐enkephalin caused profound bradypnoea and hypotension at the high dose (64 nmol), tachycardia after the lowest dose (0.64 nmol), but bradycardia was found during the hypotension induced by the high dose (64 nmol).

All of the opiate/opioid effects were reversed by naloxone (0.5 mg kg−1, i.v.).

It is concluded that μ receptors may mediate the cardiovascular and respiratory effects of opiates and opioid peptides in the nucleus preopticus medialis of the rat.
The relationship between stimulus‐induced antidromic firing and twitch potentiation produced by paraoxon in rat phrenic nerve‐diaphragm preparations
Authors: Clark A.L. , Hobbiger F. , Terrar D.A.
Published: July 2012

The relationship between stimulus‐induced repetitive antidromic firing (ADF) in the motor nerve and twitch potentiation produced by the organophosphate anticholinesterase paraoxon, has been investigated in rat diaphragm preparations.

Little or no ADF was produced by paraoxon in preparations bathed in a Tyrode solution containing 1 mM calcium and 1 mM magnesium ions although the preparations showed marked twitch potentiation.

Increases in the calcium: magnesium ion ratio produced a ratio‐dependent increase in the ADF but had no consistent effect on peak twitch potentiation.

Dithiothreitol, a disulphide bond reducing agent which decreases the affinity of acetylcholine for nicotinic cholinoceptors, abolished ADF but only modified the time course of twitch potentiation.

It is concluded that the initiation of ADF is a consequence of the prolonged action of acetylcholine within the synaptic cleft following inhibition of acetylcholinesterase, and that ADF is not the only mechanism by which twitch potentiation can be produced.
Inhibition of gastric acid secretion in the conscious dog by the mast‐cell stabilizing agent, FPL 52694
Authors: Canfield S.P. , Curwain B.P.
Published: July 2012

The effects of the mast‐cell stabilizing agent, FPL 52694, on gastric acid secretion in conscious dogs with gastric fistulae have been studied.

FPL 52694 (5 or 10 mg kg−1 h−1) given intravenously during a plateau response to pentagastrin stimulation (2 μg'kg−1 h−1) caused a maximum inhibition of acid output of about 50% but had no significant effect on volume output so that the [H+] in the juice was markedly reduced. The ratio of mucosal blood flow/acid output (Ra) was increased in the presence of FPL 52694. There was no maintained reduction of [H+] when inhibition was due to cimetidine (4 μmol kg−1, i.V.).

Instillation of FPL 52694 (4.35 mg ml−1) directly into the stomach via the fistula for 30 min also resulted in an inhibition of acid output and reduction of [H+] during both pentagastrin‐(2 μg kg−1 h−1) and histamine‐stimulated (30 μg kg−1 h−1) secretion. Inhibition of pentagastrin‐stimulated acid output by intragastric administration of FPL 52694 was much greater than the maximum effect seen following intravenous infusion.

The results are discussed in relation to the possible mode of action of FPL 52694. It is concluded that FPL 52694 is active orally and has a novel action on acid secretion which may include stimulation of gastric bicarbonate secretion.
A comparison of the electrophysiological actions of phentolamine with those of some other antiarrhythmic drugs on tissues isolated from the rat heart
Authors: Northover B.J.
Published: July 2012

Glass microelectrodes were used to record transmembrane electrical activity from cells located just beneath the endocardial surface of segments from the atrial and right ventricular free walls of rat hearts during superfusion and electrical stimulation in vitro at 37°C.

Availability of the fast sodium channels for current flow was inferred from the maximum rate of rise of membrane potential during phase 0 of the action potential.

Phentolamine mesylate (2 to 20 μM) caused a concentration‐dependent block of the fast sodium channel. This was reflected in prolongation of the refractory period and slowing of recovery of excitability following the action potential, without significant change in action potential duration or resting membrane potential.

Increase in the concentration of KCl in the superfusate from 5 to 10 mM depolarized the muscle and potentiated the blocking action of phentolamine. Both the depolarizing and the phentolamine‐potentiating actions of KCl were counteracted by simultaneous elevation of the concentration of CaCh in the superfusate from 2 to 10 mM.

The blocking action of phentolamine was enhanced by increasing the frequency of electrical stimulation in the range 0.01 to 10 Hz.

In respect of the properties listed above, lignocaine hydrochloride was similar to phentolamine but was different from quinidine sulphate in that the effects of the latter drug were not potentiated by KCl.

Two other α‐adrenoceptor antagonists, prazosin and yohimbine, both displayed actions similar to those shown by phentolamine. Tolazoline was only weakly active and dihydroergotamine (60 μM) was inactive. Dibenamine and phenoxybenzamine, unlike the previously named drugs, caused an irreversible block of the fast sodium channel. These blocking actions of α‐adrenoceptor antagonists were not prevented by simultaneous exposure to the α‐adrenoceptor agonist phenylephrine (1 HIM).

Muscle from both reserpine pretreated and non‐pretreated rats responded indistinguishably to phentolamine.
Tyramine‐induced noradrenaline release from rat brain slices: prevention by (‐)‐deprenyl
Authors: Glover Vivette , Pycock C.J. , Sandler M.
Published: July 2012

Clorgyline (1 and 10 μM) and (+)‐deprenyl (10 μM) both significantly potentiated the tyramine (100 μM)‐induced release of [3H]‐noradrenaline from rat cerebral cortex slices. (‐)‐Deprenyl (50 μM) significantly reduced it, while lower concentrations had no effect on noradrenaline release. However, in combination, 1 μM (‐)‐deprenyl blocked the release‐facilitating action of 1 μM clorgyline, and 10 μM (‐)‐deprenyl that of 10 μM (+)‐deprenyl.

Low concentrations of (+)‐ and (‐)‐deprenyl (1 and 10 μM), both selectively inhibited phenylethylamine oxidation by monoamine oxidase B. Higher concentrations of (‐)‐deprenyl (20 and 50 μM) also inhibited 5‐hydroxytryptamine oxidation by monoamine oxidase A. Clorgyline (1 and 10 μM) inhibited both enzymes. Thus, the effects of these drugs on noradrenaline‐release cannot be explained solely in terms of irreversible inhibition of monoamine oxidase A and B, and other possible mechanisms are discussed.

If the brain‐slice model faithfully mirrors the sequence of events manifesting peripherally as the tyramine hypertensive response (‘cheese effect”), then it is possible that low doses of (‐)‐deprenyl, administered with antidepressant monoamine oxidase inhibitors, can prevent this adverse reaction.
Evidence for pharmacological similarity between α2,‐adrenoceptors in the vas deferens and central nervous system of the rat
Authors: Doxey J.C. , Gadie B. , Lane A.C. , Tulloch I.F.
Published: July 2012

Seven α2‐adrenoceptor antagonists with diverse chemical structures have been examined for their effects at α2‐adrenoceptors in the vas deferens and central nervous system of the rat.

Antagonist potency assessed against the presynaptic α2‐adrenoceptor agonist action of clonidine in the isolated vas deferens (RX 781094 > AWy 26703 > yohimbine > rauwolscine > piperoxan > mianserin > RS 21361) was highly correlated with the ability of these drugs to displace saturable [3H]‐RX 781094 binding from cerebral cortex membranes.

Similarly, antagonist potency in the vas deferens was highly correlated with antagonist activity in reversing the centrally‐mediated mydriasis induced by the selective α2‐adrenoceptor agonist, guanoxabenz, in pentobarbitone‐anaesthetized rats.

The results indicate that the presynaptic α2‐adrenoceptors in the vas deferens are pharmacologically similar to characterized these α2‐adrenoceptors in the central nervous system of the rat.
Mechanism of vanadate‐induced contraction of airways smooth muscle of the guinea‐pig
Authors: Nayler Ross A. , Sparrow Malcolm P.
Published: July 2012

The characteristics of vanadate‐induced contraction of airways smooth muscle are described in isolated preparations of guinea‐pig central and peripheral airways. Vanadate (1–1000 μM) induced sustained contractions of trachea and lung parenchymal strips within 1 min of challenge. It was more potent (P < 0.001) on the lung strip (EC50 = 63 μM) than on the trachea (EC50 =123 μM). The lung strip also developed greater maximum isometric tension (P < 0.001) than the trachea. The efficacy on the lung strip was 2 and the trachea 0.6, relative to the response to acetylcholine (efficacy = 1).

Vanadate‐induced contractions of the trachea were not inhibited by atropine, mepyramine, phentolamine or indomethacin, nor after mast cell depletion by compound 48/80, showing that contractions were not mediated via specific receptors or by release of endogenous mediators of tone.

Inorganic phosphate specifically inhibited vanadate responses in a dose‐dependent and reversible manner, suggesting a common site of action.

Contractions could be elicited in depolarized muscle and after treatment with ouabain plus propranolol, showing that membrane depolarization and inhibition of the Na, K‐ATPase system were not involved in the contractile action of vanadate.

Pretreatment of tracheal smooth muscle with verapamil had no influence on contractions elicited by vanadate. After removal of extracellular calcium, vanadate‐induced contractions declined slowly with time, indicating that influx of extracellular calcium was not giving rise to contractions elicited by vanadate.

Vanadate markedly increased the rate of calcium efflux from trachealis muscle loaded with 45Ca into both Ca2+‐free and normal Krebs solutions; this is compatible with vanadate mobilizing an intracellular store of Ca2+. Such a store involving sites with Ca‐ATPase activity would be consistent with the action of vanadate in isolated membrane preparations.

Membrane‐skinned tracheal fibres contracted by micromolar Ca2+ were relaxed by vanadate in a reversible dose‐related manner, indicating that the contractile action of vanadate was not related to its interaction with proteins at the cross‐bridge level.
Stimulation of endothelial prostacyclin production plays no role in endothelium‐dependent relaxation of the pig aorta
Authors: Gordon John L. , Martin William
Published: July 2012

Stimulation of prostacyclin production by pig aortic endothelial cells adhering to microcarrier beads supervised in columns, or 3H release from cells prelabelled with [3H]‐arachidonate, was studied in response to a range of agents that induce endothelium‐dependent vascular relaxation.

Bradykinin, adenosine triphosphate (ATP) and ionophore A23187 each stimulated release of prostacyclin from unlabelled cells and of 3H from prelabelled cells but acetylcholine did not.

Bradykinin induced a parallel, dose‐dependent increase in 3H release and 86Rb efflux, measured simultaneously from columns of aortic endothelial cells preloaded with 86Rb and [3H]‐arachidonate.

The rank‐order of effectiveness at inducing both 3H and 86Rb release, measured simultaneously from columns of aortic endothelial cells prelabelled with 86Rb and [3H]‐arachidonate and challenged with maximal doses of each agonist, was: A23187 > bradykinin > ATP.

The similarity between agonist‐induced 3H release (from cells prelabelled with [3H]‐arachidonate) and 86Rb efflux indicates that a common mechanism may be responsible, and the effectiveness of ionophore A23187 suggests that a rise in the intracellular level of calcium may be involved.

The lack of effect of acetylcholine on release of prostacyclin from unlabelled cells or of 3H from cells prelabelled with [3H]‐arachidonate provides further evidence that acetylcholine acts on endothelial cells by a mechanism that does not involve calcium mobilisation.

Although bradykinin, ATP and ionophore A23187 each induced release of prostacyclin from aortic endothelial cells, prostacyclin did not relax the pig aorta. Furthermore, endothelium‐dependent relaxation was unaffected by pretreating aortic strips with aspirin. It therefore appears that neither prostacyclin nor any other cyclo‐oxygenase product mediates endothelium‐dependent relaxation of the pig aorta.
The effect of p‐chloromercuribenzoate on structure‐binding relationships of muscarinic receptors in the rat cerebral cortex
Authors: Birdsall N.J.M. , Burgen A.S.V. , Hulme E.C. , Wong E.H.F.
Published: July 2012

Muscarinic receptors in the rat cerebral cortex, reacted with p‐chloromercuribenzoate (PCMB) under different conditions (Phase I and II), have modified binding sites.

These exhibit remarkable changes in the structural dependence of the binding of drugs.

In Phase I, the structure‐binding profile of agonists for both the high and low affinity agonist sites are altered.

In Phase II, the structure‐binding profile of antagonists is also observed.

In Phase II, the ability of potent agonists to discriminate between sub‐classes of agonist binding sites is eliminated. There is also a loss of heterogeneity in the binding of the selective antagonist pirenzepine.

Of the 16 agonists examined, only pilocarpine has a heterogeneous binding profile in Phase II, the dispersity of binding being increased.

The changes in binding properties of the receptors are discussed in terms of general theories of drug‐receptor interactions.
Quinine blocks a calcium‐activated potassium conductance in mammalian enteric neurones
Authors: Cherubinim E. , North R. A. , Surprenant A.
Published: July 2012

Quinine (100 μm) abolished the slow calcium‐dependent afterhyperpolarization which occurs after an action potential in some neurones of the guinea‐pig myenteric and submucous plexus. This occurred without any effect on the amplitude or time course of the action potential itself, or on the faster calcium‐independent afterhyperpolarization. Tetraethylammonium did not reduce the slow afterhyperpolarization. Quinine also abolished the hyperpolarization which was evoked by intracellular injection of calcium ions.
Dual effect of (−)‐N6‐phenylisopropyl adenosine on guinea‐pig trachea
Authors: Caparrotta L. , Cillo F. , Fassina G. , Gaion R.M.
Published: July 2012

The effect of (−)‐N6‐phenylisopropyl adenosine (PIA), a metabolically stable P1‐receptor agonist, was investigated on guinea‐pig isolated trachea.

PIA showed two opposite effects: contraction, evident at low concentrations (10−7 to 2–5 × 10−6m), and relaxation at higher doses.

Relaxation by PIA was antagonized in an apparently competitive manner by two antagonists of extracellular (P1) adenosine receptors: theophylline (Theo) and 8‐phenyltheophylline (PT).

Contraction by PIA was not inhibited by methylxanthines and was not mediated by stimulation of cholinergic or histaminergic systems.

Inhibitors of arachidonic acid cascade acting at different levels, i.e. indomethacin, nordihyd‐roguaiaretic acid (NDGA) and BW755C, all inhibited the contraction by PIA, while they potentiated the relaxation in a concentration‐dependent manner. Mepacrine, an inhibitor of phospholipase A2, inhibited the contraction by PIA, but did not affect the relaxation.

These results indicate that the contractile effect induced by PIA is supported by an indirect mechanism involving the release of arachidonic acid derivatives (via P2‐purinoceptor?). Thus the balance between the two opposite effects of adenosine on tracheal tone is possibly modulated by the prostaglandin turnover.
The role of accelerated colonic transit in prostaglandin‐induced diarrhoea and its inhibition by prostacyclin
Authors: Rush Bob D. , Ruwart Mary J.
Published: July 2012

Rats treated with subcutaneous 16,16‐dimethyl prostaglandin E2 (16,16‐dimethyl PGE2, 100 μg kg−1) exhibited diarrhoea even when their ileo‐caecal junctions were tied, thereby eliminating contributions from small intestinal transit or fluid accumulation (enteropooling).

The origin of the watery stool appeared to be the caecum, since tying the caecal‐colonic junction eliminated it.

The acceleration of colonic transit is likely to be a primary mechanism of PGE2‐induced diarrhoea in the rat, since both normal animals and those with tied ileo‐caecal junctions exhibited almost the same incidence of diarrhoea.

Subcutaneous prostacyclin (PGI2) (2 mg kg−1 every 60 min) suppressed 16, 16‐dimethyl PGE2‐induced diarrhoea in normal rats and in those with tied ileo‐caecal junctions.

Colonic transit measured in rats with cannula preimplanted in their proximal colon indicated that 16, 16‐dimethyl PGE2 enhanced colonic transit and PGI2 suppressed this increase. Thus, PGI2 can inhibit diarrhoea in the rat caused by 16, 16‐dimethyl PGE2 by suppressing colonic transit exclusive of its effects on small intestinal transit and enteropooling.
The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion‐induced arrhythmias in anaesthetized rats
Authors: Fagbemi O. , Kane K.A. , McDonald F.M. , Parratt J.R. , Rothaul A.L.
Published: July 2012

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%.

When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg−1), prenylamine (0.5 mg kg−1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg−1) and cinnarizine (0.25, 0.5 and 1.0 mg kg−1) protected against these arrhythmias.

Higher doses of verapamil (0.1 and 0.5 mg kg−1), prenylamine (5 mg kg−1) and flunarizine (2.5 mg kg−1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine‐treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation.

Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine.

These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia‐induced arrhythmias, this protective effect may be limited to a narrow concentration range.
Leukotriene B4‐like material in scale of psoriatic skin lesions
Authors: Brain S.D. , Camp R.D.R. , Cunningham F.M. , Dowd P.M. , Greaves M.W. , Black A. Kobza
Published: July 2012

Acidic lipid extracts of scale from the lesions of the skin disease, psoriasis, were purified by straight phase high performance liquid chromatography (h.p.l.c). Assay of fractions by an agarose microdroplet chemokinesis method showed the presence of biologically active material that co‐eluted with standard leukotriene B4 (LTB4).

LTB4‐like chemokinetic activity was also detected in fractions collected on reversed phase h.p.l.c. of psoriatic scale extracts that were initially purified by straight phase h.p.l.c.

No LTB4‐like activity was detected after similar purification of scale obtained by abrasion of large areas of normal skin.

The LTB4‐like material found in extracts of psoriatic scale may play a role in the pathogenesis of the neutrophil infiltrate which characterizes psoriasis.
Ryanodine prolongs Ca‐currents while suppressing contraction in rat ventricular muscle cells
Authors: Mitchell Mary R. , Powell T. , Terrar D.A. , Twist V.W.
Published: July 2012

Ryanodine (1 μm) suppressed or abolished contraction in response to step depolarizations in voltage‐clamped cells isolated from adult rat ventricular myocardium. The step depolarizations evoked the second inward current, which is carried largely by Ca ions under these conditions, and there was little or no change in the amplitude of this current when contraction was reduced or abolished by ryanodine. The effects of ryanodine on contraction were, however, accompanied by a prolongation of the second inward current resulting from a slowing of the apparent inactivation of this current. It is suggested that ryanodine affects steps in excitation‐contraction coupling subsequent to the second inward current, perhaps Ca‐release from intracellular stores, and that this slows a Ca‐dependent inactivation of second inward current.
Enhanced responsiveness of rat isolated aorta to clonidine after removal of the endothelial cells
Authors: Eglème C. , Godfraind T. , Miller R.C.
Published: July 2012

With the endothelium present, the maximum response of rat isolated aorta to clonidine was much lower than that to noradrenaline. Removal of endothelium enhanced the response to both adrenoceptor agonists and the clonidine‐induced maximum contraction became almost equal to that produced by noradrenaline, although it was much more sensitive to inhibition by flunarizine and nifedipine. These results indicate that clonidine and noradrenaline activate receptors present in the endothelial cells and that these receptors are highly sensitive to clonidine.
Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5‐hydroxytryptamine involvement in muscimol's effect
Authors: Romandini Stefano , Samanin Rosario
Published: July 2012

The effect of morphine (3 mg kg−1 subcutaneously) on tail flick in the tail immersion test was studied in rats which had received a muscimol (100 ng) injection either in the nucleus raphé dorsalis (DR) or medianus (MR).

The levels of 5‐hydroxyindoleacetic acid (5‐HIAA) were measured in the hippocampus and striatum of muscimol‐injected animals.

Muscimol injections in the DR reduced 5‐HIAA concentrations in the striatum but not in hippocampus, whereas in animals which had received muscimol in the MR a selective decrease in hippocampal 5‐HIAA levels was found.

Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR.

An injection of 5,7‐dihydroxytryptamine (6 μg in 3 μl) in the DR did not change the effect of morphine or muscimol.

These findings indicate that muscimol‐sensitive neurones in the DR, which are probably not 5‐hydroxytryptaminergic, are involved in the effect of morphine on tail flick in tail immersion. The muscimol‐sensitive neurones involved in this effect of morphine do not seem to exist in the MR.
Lymphocytes sensitize rat isolated atria to the inotropic and chronotropic effects of sodium arachidonate
Authors: Borda Enri S. , de Bracco María M. , Finiasz Marta , Sterin‐Borda Leonor
Published: July 2012

Normal human lymphocytes (4 × 105 ml−1) incubated with sodium arachidonate (8 × 10−7m) (NaA‐L) induced a strong enhancement of the tension and frequency of spontaneously beating rat atria. Normal human lymphocytes (L) or NaA alone at 8 × 10−7m did not modify this contractile activity.

Between 2 × 10−6m to 1 × 10−5m NaA alone increased the tension of the atria without effect on the rate. In the presence of L (4 × 105 ml−1) the dose‐response curve to NaA shifted to the left, the potency and the efficiency of NaA were enhanced and the chronotropic action was triggered.

Inhibitors of cyclo‐oxygenase (indomethacin 1 × 10−6m or acetylsalicylic acid (ASA) 1.8 × 10−4m) completely blocked the positive inotropic effect induced by NaA alone. Inhibitors of lipoxygenase/s (nordihidroguaiaretic acid (NDGA) 1 × 10−5m or 5,8,11,14‐eicosatetraynoic acid (ETYA) 1 × 10−7 m did not modify this effect.

Indomethacin and ASA did not block the positive inotropic and chronotropic effects of the lower concentration of NaA‐L and significantly reduced the inotropic effect of the higher ones.

NDGA and ETYA shifted to the right the inotropic and chronotropic dose‐response curve to NaA‐L. FPL‐55712 (1 × 10−7m), the slow reacting substance of anaphylaxis (SRS‐A) antagonist, significantly reduced the overall inotropic and chronotropic effect of NaA‐L.

Direct contact of NaA‐L with the atria was not necessary. Cell‐free supernatants of L exposed to NaA increased the tension and the frequency of beating rat atria.

The stimulatory effect of NaA‐L supernatants did not occur if rat atria had been previously incubated with NDGA 1 × 10−5 m. On the other hand, the generation of stimulatory products from NaA‐L was not prevented by preincubating L with 1 × 10−5 m NDGA. Hence SRS‐A and/or other oxidative metabolites of arachidonic acid were produced by the atria.

These results suggest that NaA‐L react in vitro with spontaneous beating rat atria, inducing inotropic and chronotropic effects. Moreover, the stimulatory action of NaA itself was potentiated by L. These reactions involved a balance between cyclo‐oxygenase and lipoxygenase oxidative products with a central role for SRS‐A.
Antimuscarinic action of quinidine on the heart? A study in myocardial preparations from cat hearts
Authors: Nawrath Hermann , Sack Ulrich , Xian‐Gang Zong
Published: July 2012

Quinidine exerts anticholinergic effects which have been ascribed to atropine‐like properties of the drug. We have examined the effects of acetylcholine on the force of contraction in isolated heart muscle preparations from cats and compared the inhibitory effects of atropine with those of quinidine.

The effects of acetylcholine were antagonized competitively in the presence of atropine. The Schild‐plot yielded a straight line; the slope was not significantly different from unity.

In the presence of quinidine, the concentration‐response curve of acetylcholine was shifted to the right as with atropine, however, the Schild‐plot yielded a regression line which was not linear; the slope was statistically different from unity.

The negative inotropic response to acetylcholine in cat ventricular heart muscle (revealed in the presence of the phosphodiesterase inhibitor, papaverine) was antagonized by atropine but not influenced by quinidine.

We conclude that the inhibitory action of quinidine on the effects of acetylcholine in atrial heart muscle is not merely antimuscarinic. The antagonistic effects of acetylcholine and quinidine on atrial heart muscle may also be due to the opposite effects of the drugs on potassium conductance of the myocardial cell membrane.
Uptake of [3H]‐nicotine and [3H]‐noradrenaline by cultured chromaffin cells
Authors: Ceña V. , García A.G. , Montiel C. , Sánchez‐García P.
Published: July 2012

Three day‐old cultured bovine adrenal chromaffin cells incubated at room temperature with Krebs‐HEPES solution containing different concentrations of [3H]‐nicotine, took up and retained increasing amounts of the drug by a mechanism that did not saturate.

Concentrations of cold nicotine as high as 100 μm did not alter the amount of [3H]‐nicotine retained by cells.

Imipramine, cocaine, tetracaine or mecamylamine, at concentrations (10 μm) that blocked the catecholamine secretory effects of nicotine completely, did not modify the uptake of [3H]‐nicotine.

Both imipramine and cocaine drastically inhibited [3H]‐noradrenaline uptake by cells in a concentration‐dependent manner (IC50s of 0.08 and 1 μm, respectively).

These data indicate that the secretory effects of nicotine are not coupled to its previous uptake into cells, and are evidence in favour of a site of action for nicotine located in or at the surface of the chromaffin cell membrane.
The regulation of δ‐opiate receptor density on 108CC15 neuroblastoma × glioma hybrid cells
Authors: Moses Margaret A. , Snell Christopher R.
Published: July 2012

The effect of exogenous substances on the expression of opiate receptors on 108CC15 neuroblastoma × glioma hybrid cells has been studied.

Cell differentiation by culture in the presence of N6‐O2‐dibutyryl adenosine 3′,5′‐cyclic monophosphate induced a three fold increase in opiate receptor density.

When the cells were grown in the presence of 10−5 m morphine hydrochloride for up to 23 days, opiate receptor densities were reduced by only 30% when compared with matched controls.

Culture in the presence of 10−7md‐Ala2‐d‐Leu5‐enkephalin produced opiate receptor down regulation of 73% compared to controls after only 4 h of treatment.

The down regulation process could be inhibited by continued exposure to d‐Ala2 d‐Leu5‐enkephalin at concentrations greater than 4 nm; below this concentration down regulation was rapid and irreversible.

A model to explain these observations is described.
A new in vivo method for the measurement of repetitive anaphylactic responses in the guinea‐pig
Authors: Bottomley Kevin M.K. , Lewis Stevan , Rising Trevor J. , Steward Alan
Published: July 2012

The established Konzett‐Rossler bronchorespiratory model has been combined with a unique ovalbumin sensitization procedure to give a novel method to measure anaphylaxis in the anaesthetized guinea‐pig.

Following antigen challenge, up to eight equal bronchoconstrictor responses to the same dose can be generated from a single animal over a 120 min period.

Total inhibition of the anaphylactic response can be elicited by four different classes of compound, namely salbutamol, mepyramine, theophylline and dimaprit. Cromoglycate failed to cause any inhibition.

The method is discussed with particular reference to the antigen sensitization procedure, which differs substantially from other regimens previously employed and gives rise to heat labile antibody.