bluuebunny/crossref_metadata_2025 huggingface dataset:
THE STIMULATORY EFFECTS OF NEUROTENSIN AND RELATED PEPTIDES IN RAT STOMACH STRIPS AND GUINEA‐PIG ATRIA
Authors: QUIRION R. , REGOLI D. , RIOUX F. , ST‐PIERRE S.
Published: July 2012

The stimulatory effects of neurotensin (NT) and several NT fragments were evaluated in two pharmacological preparations: rat stomach strips and isolated spontaneously beating atria of guinea‐pigs.

In rat stomach strips, NT elicited a dose‐dependent contractile effect in concentrations varying between 1.3 × 10−9 and 5.4 × 10−7 M.

The contractile effect of NT (1.3 and 5.4 × 10−8 m) in this tissue was not modified by atropine (3.4 × 10−7 m), methysergide (2.0 × 10−6 m), a mixture of cimetidine (8.0 × 10−6 m) and diphenhydramine (7.8 × 10−6 m), indomethacin (1.4 × 10−5 m), 8‐Leu‐angiotensin II (1.0 × 10−6 m), glucagon (2.0 × 10−6 m) or somatostatin (3.0 × 10−7 m).

Rat stomach strips desensitized by bradykinin (6.1 × 10−6 m) or substance P (7.4 × 10−6 m) maintained their sensitivities to NT (1.3 and 5.4 × 10−8 m).

In guinea‐pig atria, NT produced a dose‐dependent positive inotropic action in concentrations varying between 5.4 × 10−10 and 2.7 × 10−7 m.

The inotropic effect of NT (2.7 × 10−9 m) was not influenced by methysergide (2.8 × 10−6 m), atropine (3.4 × 10−7 m), practolol (1.5 × 10−5 m), 8‐Leu‐angiotensin II (1.0 × 10−6 m), or indomethacin (1.4 × 10−5 m), but it was reduced by 37% by cimetidine (4.0 × 10−5 and 2.0 × 10−4 m). A combination of cimetidine (4.0 × 10−5 m) and diphenhydramine (3.9 × 10−6 m) did not produce a greater inhibition of NT than cimetidine alone.

Atria desensitized by bradykinin (6.1 × 10−6 m) or glucagon (2.0 × 10−6 m) maintained their sensitivities to NT (2.7 × 10−9 m). Substance P was inactive both as an agonist or antagonist of NT.

These results suggest the existence of specific NT receptors in rat stomach strips and guinea‐pig atria.

The data derived from our structure‐activity study suggest that the minimum structure required for the full stimulation of NT receptors in these two preparations is H‐Arg9‐Pro10‐Tyr11‐Ile12‐Leu13‐OH. The sequence PyroGlu1‐Leu2‐Tyr3‐Glu4‐Asn5‐Lys6‐Pro7‐Arg8‐ and the amino acids Ile12 and Leu13 appear to contribute mainly to the affinity or binding of NT to its receptor. The chemical groups responsible for the full activation (intrinsic activity) of NT receptors seem to be located in the sequence ‐Arg9‐Pro10‐Tyr11.
A COMPARISON OF RATES OF DEPLETION AND RECOVERY OF NORADRENALINE STORES OF PERIPHERAL AND CENTRAL NORADRENERGIC NEURONES AFTER RESERPINE ADMINISTRATION: IMPORTANCE OF NEURONAL ACTIVITY
Authors: WAKADE ARUN R.
Published: July 2012

The noradrenaline (NA) content of various peripheral sympathetic neuroeffector organs and brain was measured at various times after different doses of reserpine administered to the rat.

About a 25% reduction in the NA content of the heart was observed 24 h after 0.005 mg/kg reserpine. Two to ten times more reserpine was needed to obtain an approximately similar degree of depletion in the salivary gland and vas deferens; 0.1 mg/kg produced almost complete depletion in the heart and salivary gland, whereas 5 mg/kg was needed to deplete the vas deferens of its NA content.

The NA content of the brain and superior cervical ganglion was lowered by 20 to 30% in 24 h only when the reserpine dose was raised to 0.1 mg/kg, and 5 to 10 mg/kg was required to obtain over 95% depletion.

The rates of recovery of cardiac and salivary gland NA stores, after about 80 to 100% depletion by low and high doses of reserpine, were almost identical. About 50% restoration occurred in 7 to 15 days after a single dose of 0.1 mg/kg reserpine.

The superior cervical ganglion, the NA content of which was fully depleted by 10 mg/kg, showed almost complete recovery in about 7 days.

Transmural stimulation of the left atrium of the guinea‐pig for 30 min (5 Hz for 30 s/min), or exposure of the atrium to reserpine (5 μg/ml) for 30 min, caused modest but statistically insignificant reduction in tissue NA content. However, stimulation in the presence of reserpine 5 μg/ml for 30 min produced about 50% depletion of NA.

In vitro reduction in NA content caused by reserpine plus transmural stimulation, was even more pronounced after treatment of the isolated vas deferens of the rat with tetraethylammonium.

It is suggested that different rates of depletion following in vivo administration of reserpine are mainly due to variation in neuronal activity of different sympathetic neuroeffector organs.
REMOVAL OF INTERNALLY DEPOSITED GOLD BY 2,3‐DIMERCAPTOPROPANE SODIUM SULPHONATE (DIMAVAL)
Authors: GABARD B.
Published: July 2012

Orally administered 2,3‐dimercaptopropane sodium sulphonate (DMPS, Dimaval) reduced the concentration of gold in rats treated with Auro‐Detoxin and increased the urinary excretion of the metal.

In a long‐term experiment, DMPS decreased significantly the concentration of gold in the kidneys and in the skin and increased it in plasma.

DMPS appears to be of interest as a possible antidote to gold, which could replace the more toxic 2,3‐dimercaptopropanol (BAL).
A NEW METHOD FOR STUDYING THE RELATIONSHIP BETWEEN HEPATIC UPTAKE OF DRUGS AND THEIR PHARMACODYNAMIC EFFECTS IN ANAESTHETIZED CATS
Authors: AGOSTON S. , HOUWERTJES M.C. , SALT P.J.
Published: July 2012

A new in vivo experimental method is described whereby the liver can be temporarily excluded from the general circulation by means of a portocaval shunt operation. The influence of this manoeuvre upon the effects of pancuronium and Org 6368 was investigated using the tibialis muscle preparation of anaesthetized cats.

The procedure also allowed intraportal injections of the drugs to be made so that the effect of first‐passage uptake by the liver could be compared with hepatic exclusion in the same animal.

Hepatic exclusion greatly increased the duration of action of both drugs. Whereas intraportal injection did not significantly alter the effect of pancuronium on the tibialis muscle, the effect of Org 6368 was greatly diminished when given by this route.

The liver appears to tolerate short periods of hepatic exclusion and it is concluded that this technique may become a useful tool for studying the handling of drugs by this organ.
CHEMOKINESIS OF RAT POLYMORPHONUCLEAR LEUCOCYTES AND THE EFFECT OF CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE
Authors: BRADSHAW D. , GIROUD J.P. , ROCH‐ARVEILLER M.
Published: July 2012

The chemotactic and chemokinetic properties of various substances were studied using rat polymorphonuclear leucocytes (PMN) in Boyden chambers.

Casein and the exudate from a carrageenan‐induced pleurisy possessed both chemotactic and chemokinetic properties, whereas erythrocyte lysates and albumin showed only chemokinetic activity.

Dibutyryl cyclic adenosine 3′,5′‐monophosphate (db cyclic AMP) had little or no effect on the migration towards casein and the inflammatory exudate, but stimulated the migration towards erythrocyte lysates and albumin.

It appears therefore that db cyclic AMP is able to increase a chemokinetic response initiated by other substances. The lack of effect of this compound on cell migration towards substances possessing both chemotactic and chemokinetic properties probably results from the equilibrating effect of a simultaneous stimulation of chemokinesis and inhibition of chemotaxis.

These results suggest that studies designed to investigate the effect of anti‐inflammatory drugs on cell migration should include the separate assessment of their ability to influence both chemotaxis and chemokinesis.
STRUCTURE‐ACTIVITY STUDIES ON AN EXCITATORY RECEPTOR FOR GLUTAMATE ON LEECH RETZIUS NEURONES
Authors: JAMES VICTORIA A. , WALKER R.J. , WHEAL H.V.
Published: July 2012

Intracellular recordings were made from Retzius cells from the segmental ganglia of Hirudo medicinalis and Haemopis sanguisuga. Glutamate had a direct excitatory effect on the leech Retzius cells.

l‐Glutamate was 25 times more potent than d‐glutamate.

l‐Glutamate was approximately equipotent with ibotenic acid and 11.2 times more potent than l‐aspartic acid.

Quisqualic acid and kainic acid were both approximately 100 times more potent than l‐glutamate. dl‐1‐Amino‐cis‐1,3‐dicarboxycyclopentane was approximately 5 times more potent than l‐glutamate, while the trans isomer was 105 times less potent.

α‐NH2‐pimelic acid and β‐CH3‐glutamic acid reduced the response to l‐glutamate.

It is suggested that glutamic acid may interact with the Retzius cell glutamate receptor in an extended conformation.
RELATIONSHIP BETWEEN THE (−)‐[3H]‐DIHYDROALPRENOLOL BINDING TO β‐ADRENOCEPTORS AND TRANSMEMBRANE 86Rb EFFLUX OF THE BC3H1 NONFUSING MUSCLE CELL LINE
Authors: MAUGER JEAN‐PIERRE , WORCEL MANUEL
Published: July 2012

We have studied the binding properties of the β‐adrenoceptor antagonist [3H]‐dihydroalprenolol ([3H]‐DHA) on a membrane preparation of the non‐fusing muscle cells BC3H1.

[3H]‐DHA appears to bind to two classes of sites. The first site has a high affinity (KD = 0.53 nm) and a low capacity (Bmax = 58 fmol/mg of protein). The second site has a low affinity (KD =110 nm) and a high capacity (Bmax = 1100 fmol/mg of protein).

The pharmacological properties of the high affinity low capacity site correspond to the known properties of the β2‐adrenoceptors since the agonists inhibit [3H]‐DHA binding following the series isoprenaline > adrenaline > noradrenaline > phenylephrine and the antagonists following the series alprenolol ≃ propranolol > butoxamine > practolol > phentolamine.

The binding properties of the β‐adrenoceptors were correlated with the effect of β‐adrenoceptor agonists and antagonists on 86Rb efflux rate from BC3H1 cells.

There is very good correlation between the dissociation constants obtained by inhibition of [3H]‐DHA binding by the antagonists alprenolol and propranolol, and the inhibition constants calculated from their antagonism of the 86Rb efflux rate stimulation by adrenaline. The ratio of the dissociation constants obtained by inhibition of [3H]‐DHA binding by agonists and their EC50, calculated from 86Rb efflux curves, is higher than 1. This high KD/EC50 ratio indicates a high coupling efficiency between receptor occupancy by agonists and the biological effect measured.
METERGOLINE AND CYPROHEPTADINE SUPPRESS PROLACTIN RELEASE BY A NON‐5‐HYDROXYTRYPTAMINERGIC, NON‐DOPAMINERGIC MECHANISM
Authors: BESSER G.M. , DELITALA G. , GROSSMAN A. , YEO T.
Published: July 2012

A dispersed rat anterior pituitary cell system has been used to investigate the effects of cyproheptadine and metergoline on prolactin secretion. Both drugs were potent inhibitors of prolactin secretion. However, the inhibition was not antagonized by either 5‐hydroxytryptamine or a variety of dopamine antagonists. We conclude that both drugs act through mechanisms that are neither 5‐hydroxytryptaminergic nor dopaminergic.
OXOTREMORINE DOES NOT ENHANCE ACETYLCHOLINE RELEASE FROM RAT DIAPHRAGM PREPARATIONS
Authors: GUNDERSEN CAMERON B. , JENDEN DONALD J.
Published: July 2012

We have reinvestigated the dramatic effect of oxotremorine on acetylcholine release from the rat diaphragm reported by Das, Ganguly & Vedasiromoni (1978), using a rigorous gas chromatographic mass spectrometric/isotope dilution method for identification and measurement of acetylcholine and choline. Oxotremorine (10 μm) causes no significant change in the spontaneous or evoked (1 or 10 Hz) release or in the tissue levels of acetylcholine or choline.
TYPE OF ADRENOCEPTORS INVOLVED IN INDUCTION BY ADRENALINE OF HEPATIC ALKALINE PHOSPHATASE IN MICE in vivo
Authors: MARY P.L. , RAO J. PRAKASA
Published: July 2012

Study of adrenoceptor agonist drugs in hepatic alkaline phosphatase induction in mice in vivo revealed that β‐receptors are involved in this process. Use of selective blocking drugs showed that β2‐receptors may be responsible for the induction.
GENDER DIFFERENCES IN PROSTAGLANDIN RECEPTORS OF RAT AORTA
Authors: KARANIAN J.W. , MORAN F.M. , RAMEY E.R. , RAMWELL P.W.
Published: July 2012

The maximal contractile response to the prostaglandin endoperoxide H2 analogue U46619, prostaglandins E2, D2 and F2α and the sensitivity of the superfused aorta preparation to these drugs (except PGF2α) is greater in the male than the female rat. In contrast, gender differences were not observed in the response to noradrenaline or 5‐hydroxytryptamine. In previous studies, testosterone unlike oestrogen or progesterone, increased the response of both rabbit and rat aorta to U46619. We conclude that prostaglandin receptors in rat thoracic aorta may be hormonally regulated.
ACTIVE SITE‐DIRECTED ALKYLATION OF Na+‐K+‐ATPase BY DIGITALIS SULPHONATE DERIVATIVES OF DIFFERENT LIPOPHILICITY
Authors: FRICKE UWE , KLAUS WOLFGANG , ROGATTI MICHAEL
Published: July 2012

Sulphonate derivatives of k‐strophanthidin and digitoxigenin were tested as active site‐directed labels of Na+‐K+‐adenosine triphosphatase (Na+‐K+‐ATPase) from guinea‐pig heart.

Lipophilicity ranged between P = 93 for strophanthidin‐3‐tosyloxy‐acetate (STA) and P = 3028 for digitoxigenin‐3‐tosyloxy‐acetate (DTA).

Although the alkylating moiety of STA and DTA was identical, the reversibility of Na+‐K+‐ATPase inhibition varied appreciably (82% and 35% respectively).

It is concluded that lipophilicity contributes considerably to the irreversible binding of alkylating cardiotonic steroids to myocardial Na+‐K+‐ATPase.
SOME in vitro AND in vivo ACTIONS OF THE NEW HISTAMINE H2‐RECEPTOR ANTAGONIST, RANITIDINE
Authors: DALY M.J. , HUMPHRAY JANET M. , STABLES R.
Published: July 2012

Ranitidine has been investigated as an antagonist of the H2‐receptor‐mediated responses to histamine of guinea‐pig atrium and rat uterus in vitro and as an inhibitor of gastric acid secretion in the rat.

Ranitidine competitively antagonized histamine‐induced increases in contraction frequency of the guinea‐pig isolated right atrium. Ranitidine had a pA2 of 7.2 and was 7.9 and 4.5 times more potent than metiamide and cimetidine respectively.

Ranitidine competitively antagonized histamine‐induced relaxations of the rat isolated uterine horn. Ranitidine had a pA2 of 6.95 and was 3.6 and 5.9 times more potent than metiamide and cimetidine respectively.

Ranitidine, even at high concentrations, did not affect responses of the guinea‐pig isolated atrium or rat isolated uterus to (−)‐isoprenaline. Similarly it was without effect on either histamine or bethanechol‐induced contractions of guinea‐pig isolated ileum.

Ranitidine inhibited histamine‐ and pentagastrin‐induced gastric acid secretion in the perfused stomach preparation of the anaesthetized rat. Ranitidine was 5.2 and 7.0 times more potent on a molar basis than metiamide and cimetidine respectively, as an inhibitor of histamine‐induced gastric acid secretion.

It is concluded that ranitidine is a potent, competitive and selective antagonist of histamine at H2‐receptor sites and an effective inhibitor of gastric acid secretion in vivo.
SPURIOUS EFFECTS OF COMMERCIAL PREPARATIONS OF OXYTOCIN ON THE ISOLATED VAS DEFERENS OF THE RAT
Authors: BOTTING J.H.
Published: July 2012

The inhibitory effect of a commercial preparation of oxytocin (Syntocinon) was studied on the isolated vas deferens of the rat.

The inhibition of contractions to agonists and to field stimulation obtained were mimicked by appropriate dilutions of chlorbutol, a preservative present in Syntocinon.

Preservative‐free synthetic oxytocin had no inhibitory effect on the tissue and slightly potentiated contractions evoked by field stimulation.

It is concluded that inhibitory effects of Syntocinon on the vas deferens are due to chlorbutol, not oxytocin.
INACTIVATION OF HERPES SIMPLEX VIRUS BY A PREGNENE DERIVATIVE (TX 3047)
Authors: PERBAL BERNARD
Published: July 2012

Two strains of independently purified Herpes simplex virus type 1 were irreversibly inactivated after incubation with the pregnene derivative methyl‐p‐toluene sulphonate of diethylamino‐3‐β‐ethoxy‐20‐hydroxy‐pregn‐5‐ene (TX 3047) in vitro.

RNA and DNA synthesis (both cellular and viral) were studied in the presence of TX 3047. Viral and cellular DNA synthesis but not viral RNA synthesis was reduced.

Formation of infectious particles was not affected by TX 3047 if the parental virus was adsorbed to the cell before it was incubated with TX 3047. This suggests that TX 3047 acts at the level of the membrane.
PHARMACOLOGICAL CHARACTERIZATION OF THE EXCITATORY INNERVATION TO THE GUINEA‐PIG URINARY BLADDER in vitro: EVIDENCE FOR BOTH CHOLINERGIC AND NON‐ADRENERGIC‐NON‐CHOLINERGIC NEUROTRANSMISSION
Authors: KRELL ROBERT D. , McCOY JEAN L. , RIDLEY PETER T.
Published: July 2012

Field stimulation of strips of guinea‐pig isolated urinary bladder with 5 s trains at 0.1 to 15 Hz resulted in frequency‐dependent, reproducible contractions.

At concentrations of 1 and 4× 10−7M and 1 × 10−6M, atropine produced a variable, partial inhibition of contractions at all frequencies but was most effective at frequencies of 3 Hz or more.

Tetrodotoxin (TTX), 5 × 10−7M, inhibited contractions at all frequencies by 80 to 90%.

Physostigmine, 2 × 10−6M, significantly enhanced the contractile response to frequencies of less than 10 Hz but did not enhance responses resistant to inhibition by atropine. Hexamethonium, 1 × 10−4M, slightly enhanced the contractile response to frequencies of 4 Hz or greater.

(±)‐Propranolol (5 × 10−6m), guanethidine (1 × 10−6m), phentolamine (5 × 10−6m) and clonidine (3 × 10−8m) each enhanced the contractile response to field stimulation.

Contractile responses obtained in the presence of atropine (4×10−7m) and guanethidine (1 × 10−6M) increased with time and were inhibited 60 to 80% by TTX (5 × 10−7m).

It is concluded that the cholinergic nervous system contributes, in part, to electrically‐induced excitatory contractions of the isolated urinary bladder of the guinea‐pig. Concomitant sympathetic stimulation appears to serve an inhibitory role. In addition, a major portion of the contractile response appears to be due to a non‐cholinergic non‐adrenergic, as yet unidentified, substance.
ELECTROMECHANICAL EFFECTS OF ANTHOPLEURIN‐A (AP‐A) ON RABBIT VENTRICULAR MUSCLE: INFLUENCE OF DRIVING FREQUENCY, CALCIUM ANTAGONISTS, TETRODOTOXIN, LIDOCAINE AND RYANODINE
Authors: KODAMA ITSUO , SHIBATA SHOJI , TOYAMA JUNJI , YAMADA KAZUO
Published: July 2012

Anthopleurin‐A (AP‐A 5×10−9m, 1 × 10−8m) caused a prolongation of action potential duration (APD) and an increase of contractile force in rabbit isolated ventricular muscle preparations

The prolongation of APD and the positive inotropic effect of AP‐A (1 × 10−8m) were augmented by lowering the driving frequency from 2.0 to 0.2 Hz, resulting in an apparent negative staircase of contractile force in this frequency range. When the preparation was driven at an extremely low frequency (0.017 Hz), AP‐A did not increase the contractile force, but caused a considerable prolongation of APD

Verapamil (1 × 10−6m) and nifedipine (1 × 10−6m) had no apparent influence on the APD prolongation by AP‐A (5 × 10−9M, 1 × 10−8m). The positive inotropic effect of AP‐A was also relatively well maintained even in the presence of these calcium antagonistic drugs when the preparation was driven at a lower frequency (0.2 Hz)

Tetrodotoxin (TTX 2 × 10−6m) and lidocaine (1 × 10−4m) markedly inhibited both the APD prolongation and the positive inotropic effect of AP‐A (l×l 0−8 m)

In the presence of ryanodine (2 × 10−6m), an agent which is known to interfere with calcium release from the intracellular activator pool, AP‐A (l×l 0−8 m) failed to cause its positive inotropic effect in spite of the marked prolongation of APD

These results suggest that the effects of AP‐A on cardiac muscle are primarily mediated by the fast sodium inward current. Thus, delayed inactivation of sodium inward current may cause APD prolongation, and probably induces an alteration of intracellular calcium kinetics reflected by an increase of contractile force.
SEXUAL DIMORPHISM AND THE EFFECTS OF THE X‐LINKED Tfm LOCUS ON HEXOBARBITONE METABOLISM AND ACTION IN MICE
Authors: KING DOROTHY K. , SHAPIRO BERNARD H.
Published: July 2012

Normal males of the testicular feminized strain of mice (Tfm) had longer hexobarbitone‐induced sleeping times than females, and hepatic hexobarbitone hydroxylase activity differed in that the Km was higher and the Vmax lower in the male

Castration and androgen replacement studies indicated that testicular androgens were responsible for the sexual differences in drug metabolism found in this mouse strain

Hepatic hexobarbitone metabolism and action were feminized in the intact, androgen‐insensitive, genetically male Tfm mouse. Furthermore, hexobarbitone hydroxylase activities were less responsive to large doses of testosterone in Tfm mice than in normal males

The Tfm mouse with a deficiency in androgen receptors responded to the enzyme‐inductive effects of phenobarbitone and softwood bedding, indicating that these inducers do not act through the androgen receptors.
EFFECTS OF AMILORIDE ON CONTRACTIONS AND THE RELEASE OF TRITIUM FROM RAT VAS DEFERENS PRELOADED WITH [3H]‐NORADRENALINE
Authors: AKHTAR‐KHAVARI FARZANEH , KHOYI M.A. , REZAEI EFFAT
Published: July 2012

The effect of amiloride was studied on contractions and tritium release from rat vas deferens preloaded with [3H]‐noradrenaline

Amiloride had no effect on the resting tension and maximal contractile force of the vas deferens and did not alter the ED50 of noradrenaline

Amiloride (10−4‐10−3m) decreased the response of vas deferens to electrical stimulation dose‐dependently without inhibiting the response to KC1 (60 mm)

The effect of amiloride was not prevented by preincubation of the tissue with phentolamine, propranolol, atropine or indomethacin

Amiloride did not alter the spontaneous outflow of radioactivity from [3H]‐noradrenaline labelled vasa deferentia

Amiloride decreased the release of tritium induced by electrical stimulation or nicotine but did not inhibit the release of radioactivity induced by KC1 or tyramine. 7 It is concluded that amiloride may inhibit the contractions of rat vas deferens by inhibiting the release of noradrenaline.
THE EFFECTS OF MORPHINE AND METHIONINE‐ENKEPHALIN ON THE RELEASE OF PURINES FROM CEREBRAL CORTEX SLICES OF RATS AND MICE
Authors: STONE T.W.
Published: July 2012

Slices of cerebral cortex from Wistar rats, TO mice or C57 mice were preincubated with [3H]‐adenosine, and labelled purines were subsequently released by electrical stimulation or by perfusing with ouabain, 100 μM

Electrically‐evoked purine release was substantially reduced when the Ca2+ concentration in the medium was lowered from 2.4 to 0.1 mM. In both rats and mice, the electrically‐evoked release was increased by morphine and methionine‐enkephalin (Met‐enkephalin), 10 μm and in rats and TO mice by morphine 1 μm, both drug effects being prevented by naloxone

Purine release evoked by ouabain was also increased by morphine 1 and 10 μm, though not by Met‐enkephalin, from slices of rat cortex. Ouabain‐induced release from TO mice was reduced by morphine, and from C57 mice was unchanged

The enhancement by morphine of electrically‐evoked purine release may indicate that purines mediate some effects of morphine in the CNS.
PRE‐ AND POSTJUNCTIONAL EFFECTS OF CLONIDINE‐ AND OXYMETAZOLINE‐LIKE COMPOUNDS IN GUINEA‐PIG ILEAL PREPARATIONS
Authors: MALTA E. , RAPER C. , TAWA PAULINE E.
Published: July 2012

Noradrenaline and 28 imidazolidine (clonidine‐like) and imidazoline (oxymetazoline‐like) compounds with various phenyl ring substituents have been examined for their ability to inhibit responses to transmural stimulation and exogenous acetylcholine in ileal preparations from reserpine‐treated guinea‐pigs.

The bathing solution contained propranolol, mepyramine, cimetidine and desipramine to preclude interference with the responses by other than the α‐receptor‐mediated actions of the compounds.

In transmurally stimulated preparations the inhibitory response to noradrenaline is due to a combination of prejunctional α‐adrenoceptor stimulation and a postjunctional depressant effect that does not involve adrenoceptor activation.

Of the 28 imidazolidines and imidazolines studied, 21 inhibited transmurally elicited responses. In the various compounds studied this effect involved actions at pre‐ or postjunctional sites as indicated by (a) the frequency‐dependence of the inhibitory response, (b) its susceptibility to blockade by α‐receptor antagonists and (c) the relative concentrations required to inhibit responses to transmural stimulation and exogenous acetylcholine.
VESICULAR NORADRENALINE STORES IN PERIPHERAL NERVES OF THE RAT AND THEIR MODIFICATION BY TRANYLCYPROMINE
Authors: FILLENZ M. , STANFORD S.C.
Published: July 2012

Vesicular noradrenaline stores were compared in the heart, salivary gland and vas deferens of the rat.

Noradrenaline storage vesicles in nerve terminals of different organs differed with respect to the amount of noradrenaline they contain in the endogenous store (content), the amount of exogenous noradrenaline they can take up from the circulation (uptake) and the amount of noradrenaline they contain when they are saturated (total storage capacity).

The data suggest that the vesicles in the salivary gland and vas deferens are almost completely filled with transmitter while, in the heart, the vesicular store is filled to only 55% of its total capacity.

The monoamine oxidase inhibitor, tranylcypromine, was found to increase not only the size of the endogenous store but also the size of the unfilled store.
PARTIAL AGONIST BEHAVIOUR OF ADENOSINE 5′O‐(2‐THIODIPHOSPHATE) ON HUMAN PLATELETS
Authors: CUSACK N.J. , HOURANI S.M.O.
Published: July 2012

The effects of an adenosine diphosphate (ADP) analogue, adenosine 5′‐O‐(2‐thiodiphosphate) (ADP‐β‐S), in which a terminal phosphate oxygen has been replaced by sulphur, were studied on human platelets.

ADP‐/3‐S induced platelet aggregation and inhibited prostaglandin E 1 (PGE 1)‐stimulated adenylate cyclase but in both cases was less potent than ADP and did not achieve the same maximal effects.

Both actions of ADP could be inhibited by the simultaneous addition of ADP‐β‐S (50 μm).

Aggregation induced by 11α, 9α‐epoxymethano prostaglandin H2 (a stable endoperoxide analogue) was not inhibited by simultaneous addition of ADP‐β‐S (50 μm).

The behaviour of ADP‐β‐S towards human platelets was consistent with it being a partial agonist.
OPIATE‐LIKE ANALGESIC ACTIVITY IN GENERAL ANAESTHETICS
Authors: LAWRENCE D. , LIVINGSTON A.
Published: July 2012

The interaction of naloxone with various anaesthetics was studied both in vivo and in vitro.

Naloxone (10 mg/kg) did not significantly alter the anaesthetic duration of halothane, diethylether, ketamine, pentobarbitone or Althesin.

Naloxone (10 mg/kg) reduced the analgesic activity of nitrous oxide, ketamine and morphine in the rat tail‐flick test. With the exception of pentobarbitone and Althesin, the other anaesthetic agents also induced analgesia but were not antagonized by naloxone. 4 Specific [3H]‐dihydromorphine binding was displaced by the opiates naloxone (IC50=7.6nM), methionine‐enkephalin (Met‐enkephalin, IC50=40nM) and morphine (IC50=54nM). Similarly, displacement was observed with xylazine (IC50=9μ,m), ketamine (IC50 = 130μm) and Althesin (IC50 = 150 μm); other anaesthetics agents tested were inactive in mM concentrations.

Ketamine (IC50 =200 μm) and xylazine (IC50 =9.5 μ,m) were also capable of displacing specific [3H]‐D‐Ala2‐enkephalin (D‐Leu) binding, as were morphine (IC50 = 95 nM) and Met‐enkephalin (IC50 = 40nM).

On the stimulated guinea‐pig ileum, Met‐enkephalin and morphine inhibited the contractions, the IC50 values were 30 nM and 50 nM respectively. The anaesthetics ketamine (IC50 = 10μm) and Althesin (IC50 = 8μ,m) were active. Xylazine (IC50 = 12nM) exhibited considerable potency in inhibiting the contractions on this preparation. Naloxone 0.5 μ,M produced a 1000 fold shift in the opiate dose‐response curve but the anaesthetic responses showed only slight sensitivity to antagonism by naloxone.

The activity of Althesin was found to be due to the vehicle in which this anaesthetic is solubilised.

Whilst several anaesthetic agents showed analgesic activity, specific dihydromorphine binding displacement or guinea pig ileum inhibiting activity, these effects showed variable sensitivity to naloxone.
CLONIDINE DEPENDENCE IN THE GUINEA‐PIG ISOLATED ILEUM
Authors: COLLIER HARRY O.J. , CUTHBERT NIGEL J. , FRANCIS DAVID L.
Published: July 2012

Compared with the response of preparations incubated in solutions without clonidine, a three to four fold increase in the magnitude of the contracture of the longitudinal muscle to challenge with phentolamine (1.0 μm) was induced by incubating the guinea‐pig isolated ileum at 22°C for 24 h with clonidine (1.0 μm) in Krebs solution containing hexamethonium (70μm). Incubation of the ileum with clondine (1.0 μm) for 0.5 h at 37°C did not increase responsiveness to phentolamine.

The increase in responsiveness to phentolamine was directly related to the clonidine concentration in the incubation fluid over the range 0.01 to 1.0 μm.

The magnitude of the contracture to phentolamine of ilea incubated with clonidine (1.0 μm) (withdrawal contracture) was directly related to the challenge dose of phentolamine over the range 0.3tol.0μM.

Yohimbine (1.0 μm) or piperoxane (1.0 μm) elicited a response comparable to that elicited by phentolamine but propranolol (1.0 μm) was inactive.

Addition of phentolamine (1.0 μm) to clonidine (1.0 μm) in the incubation fluid abolished the increased response of the preparation to subsequent challenge with phentolamine. 6 Addition of hyoscine (0.5 μm) immediately after challenge with phentolamine restored the tension of the withdrawal contracture to its resting level.

Tetrodotoxin (3.0 μm) given before challenge, prevented phentolamine from eliciting a withdrawal contracture. 8 Ileal segments incubated with clonidine (1.0 μm) were unresponsive to challenge with naloxone (100 nM); and segments incubated with normorphine (1.0 μm) were unresponsive to phentolamine (1.0 μm), although responsive to naloxone.

Normorphine (1.0 μm) restored to resting level the tension of the clonidine withdrawal contracture; and clonidine (0.1 μm) restored to resting level the tension of the contracture to naloxone in ileal segments incubated with normorphine.

These experiments indicate that incubation with clonidine induces, in the final cholinergic motor neurones of the myenteric plexus of the isolated ileum, a dependence the withdrawal from which is expressed as a contracture in response to α‐adrenoceptor antagonists.

Although opiate receptors are not involved in clonidine dependence nor α‐adrenoceptors in opiate dependence, the findings that normorphine suppresses the clonidine withdrawal‐contracture and that clonidine suppresses the contracture of opiate‐dependent ileum to naloxone, suggest that the withdrawal effect studied in both clonidine and normorphine dependence in this preparation is mediated by release of acetylcholine from the final motor neurone.
THE EFFECTS OF SUBSTANCE P AND RELATED PEPTIDES ON α‐AMYLASE RELEASE FROM RAT PAROTID GLAND SLICES
Authors: BROWN C.L. , HANLEY M.R.
Published: July 2012

The effects of substance P and related peptides on amylase release from rat parotid gland slices have been investigated.

Supramaximal concentrations (1 μ) of substance P caused enhancement of amylase release over the basal level within 1 min; this lasted for at least 40 min at 30°C.

Substance P‐stimulated amylase release was partially dependent on extracellular calcium and could be inhibited by 50% upon removal of extracellular calcium.

Substance P stimulated amylase release in a dose‐dependent manner with an ED50 of 18 nM.

All C‐terminal fragments of substance P were less potent than substance P in stimulating amylase release. The C‐terminal hexapeptide of substance P was the minimum structure for potent activity in this system, having 1/3 to 1/8 the potency of substance P. There was a dramatic drop in potency for the C‐terminal pentapeptide of substance P or substance P free acid. Physalaemin was more potent than substance P (ED50 = 7 nM), eledoisin was about equipotent with substance P (ED50 = 17 nM), and kassinin less potent than substance P (ED50 = 150 nM).

The structure‐activity profile observed is very similar to that for stimulation of salivation in vivo, indicating that the same receptors are involved in mediating these responses.

All the fragments of substance P tested were capable of eliciting a full amylase release response. This indicates that the apparent partial agonist action of the C‐terminal nonapeptide fragment on in vivo salivation is not explicable at the receptor level.
CONVULSANT AND POSSIBLE ANTICHOLINERGIC ACTIONS OF DENDROTOXIN IN THE AMPHIBIAN SPINAL CORD
Authors: COLLIER B. , PADJEN A.L. , QUIK M. , SMITH P.A.
Published: July 2012

Dendrotoxin (DTOX)6, 6a and 5,6‐1, fractions of the venom isolated from the green mamba (Dendroaspis viridis) promoted both spontaneous and stimulus‐coupled rhythmic activity and antagonized the cholinergically mediated ventral root‐dorsal root potential (VR‐DRP) of frog spinal cord. The different time course and reversibility of these two effects indicates that the toxin has two entirely separate sites of action on the frog spinal cord.

Since DTOX 6 neither blocked nor enhanced responses of ventral and dorsal roots to glutamate, γ‐aminobutyric acid (GABA), β‐alanine, glycine or aspartate, it is unlikely that its convulsant action resulted from an alteration of the postsynaptic actions of inhibitory or excitatory amino acids.

An alteration in the threshold for action potential generation could perhaps contribute to the convulsant action of DTOX 6, although other mechanisms such as blockade of the release of unspecified inhibitory substances cannot be excluded.

In addition to the lack of effect on amino acid responses, DTOX failed to block the polysynaptic DR‐VRP or DR‐DRP pathways, which are mediated at least in part by amino acid neurotransmitters. Although this would be consistent with a specific action of DTOX at the cholinergic synapse of the VR‐DRP pathway, this site of action has not yet been demonstrated unequivocally. Other possible mechanisms whereby DTOX could block VR‐DRP are discussed.
ANTIBIOTIC‐ASSOCIATED COLITIS: AN in vitro INVESTIGATION OF THE EFFECTS OF ANTIBIOTICS ON INTESTINAL MOTILITY
Authors: LEES G.M. , PERCY W.H.
Published: July 2012

Nine antibiotic compounds in common use were studied to determine their ability to affect intestinal motility in vitro, in the guinea‐pig ileum and rabbit colon.

Ampicillin, doxycycline, mecillinam and metronidazole were without effect over a concentration range which included typical serum levels found when these drugs are used therapeutically.

Clindamycin, gentamicin, kanamycin, pivmecillinam and trimethoprim were all found to inhibit evoked and reflex responses of the guinea‐pig ileum but only clindamycin and trimethoprim also affected evoked responses of the rabbit colon.

Kanamycin and gentamicin appeared to have a predominantly prejunctional action, pivmecillinam and trimethoprim a predominantly post‐junctional action. Clindamycin had a prejunctional action at low concentrations and long exposure times, and a post‐junctional action at high concentrations and short exposure times.

The concentration of each antibiotic required to inhibit the peristaltic reflex of the guinea‐pig ileum was less than that required to inhibit its responses to electrical stimulation or exogenous acetylcholine or histamine but greater than the serum levels associated with their respective use in therapeutic doses.

A sequence of events whereby antibiotic‐induced alterations in gastro‐intestinal motility could lead to the development of pseudomembranous colitis is proposed.
DOES CYCLIC 3′,5′‐ADENOSINE MONOPHOSPHATE ACT AS SECOND MESSENGER IN A VOLTAGE‐DEPENDENT RESPONSE TO 5‐HYDROXYTRYPTAMINE IN Aplysia?
Authors: PELLMAR TERRY C.
Published: July 2012

The possibility that cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) mediates a voltage‐dependent inward current elicited by 5‐hydroxytryptamine (5‐HT) in RB and LB cells of the abdominal ganglion of Aplysia was tested.

Intracellular injection of cyclic AMP elicited an inward current with a similar time course, potential dependence and ionic sensitivity as the response to 5‐HT.

Intracellular injection of guanylyl imidodiphosphate (GMP‐PNP), which activates adenylate cyclase, neither mimicked nor enhanced the 5‐HT‐evoked current. On the contrary, it reduced the current.

The phosphodiesterase inhibitors, Ro20–1724, isobutyl methylxanthine (IBMX) and theophylline, each antagonized the voltage‐dependent response to 5‐HT. To varying degrees they each induced an inward current.

The adenylate cyclase antagonist, dithiobisnitrobenzoic acic (DTNB), had no effect on the response to 5‐HT when applied either intracellularly or extracellularly. Intracellular injection of the phosphodiesterase activator imidazole also had no effect.

Tubocurarine and neostigmine did not reduce the voltage‐dependent inward current evoked by 5‐HT; methysergide elicited an inward current.

Although the observation that cyclic AMP and 5‐HT can evoke similar voltage‐dependent inward currents in RB and LB neurones of Aplysia might suggest a second messenger role for the cyclic nucleotide, the pharmacological data are inconsistent with this hypothesis.
THE BINDING OF [3H]‐PROSTACYCLIN TO MEMBRANES OF A NEURONAL SOMATIC HYBRID
Authors: BLAIR I.A. , MACDERMOT J.
Published: July 2012

[3H]‐prostacylin bound to a washed membrane preparation of the NCB‐20 neuronal hybrid cell line.

Kinetic analysis of [3H]‐prostacyclin binding suggested a simple, non‐cooperative bimolecular interaction between the ligand and a single receptor population. The equilibrium dissociation constant was 16.6 nm, and binding at a saturating [3H]‐prostacyclin concentration enabled the receptor density of 2.57 × 105 receptor molecules per cell to be calculated.

At 20°C the rate constant for the forward reaction (k+1) was 2.26 × 105 m−1 s−1, and the rate constant for the dissociation of the ligand‐receptor complex (k‐1) was 3.85 × 10−3 s−1. Thus the dissociation constant (k‐1/k+1) was 17.0 nm.

Prostaglandin E1 and prostacyclin compete for a single receptor in these cells, and comparison of other prostaglandins as inhibitors of [3H]‐prostacyclin binding revealed some of the structural requirements for high‐affinity occupation of prostacyclin receptors.
LEUKOTRIENE B4: A MEDIATOR OF VASCULAR PERMEABILITY
Authors: BRAY M.A. , CUNNINGHAM F.M. , FORD‐HUTCHINSON A.W. , SMITH M.J.H.
Published: July 2012

Intradermal injection of leukotriene B4 (LTB4) or prostaglandin E2 (PGE2), 1 to 100 ng per skin site produced little or no change in plasma exudation in the rabbit, guinea‐pig and rat.

Intradermal injection of LTB4 together with PGE2 produced a significant increase in plasma exudation in the rabbit, guinea‐pig and rat.

Intradermal injection of LTB4 or PGE2 together with bradykinin (500 ng) resulted in a significant potentiation of the plasma exudation produced by bradykinin alone in the rabbit and guinea‐pig.

LTB4 (1 to 10 ng) had no effect on blood flow in the rabbit skin, in contrast to PGE2 which was a potent vasodilator in this species.

It is concluded that LTB4 is a mediator of vascular permeability and that this effect can only be observed in the presence of a vasodilator such as PGE2.
FAILURE OF ACETALDEHYDE OR ACETATE TO MIMIC THE SPLANCHNIC ARTERIOLAR OR VENULAR DILATOR ACTIONS OF ETHANOL: DIRECT in situ STUDIES ON THE MICROCIRCULATION
Authors: ALTURA BURTON M. , GEBREWOLD ASEFA
Published: July 2012

The effects of acetaldehyde and sodium acetate on rat mesenteric arterioles (17–25 μm i.d.) and muscular venules (35–50 μm i.d.) were examined in situ, at the microcirculatory level, by use of a high‐resolution closed circuit television microscope recording system. Local, intravenous or intra‐arterial administration of acetaldehyde (1.8–3600 μmol) and sodium acetate (0.25–250 μmol) to mesenteric arterioles and muscular venules of the anaesthetized rat induced dose‐dependent vasoconstriction. Systemic administration of a variety of pharmacological antagonists (i.e., phentolamine, diphenhydramine, methysergide, atropine and indomethacin) did not attenuate or prevent the dose‐dependent vasoconstrictor actions of these metabolites of ethanol. Our findings do not support the concept that some or all of the peripheral vasodilator actions of ethanol can be attributed to its metabolites, acetaldehyde and acetate.
THE EFFECT OF ANAESTHETICS ON THE UPTAKE AND RELEASE OF γ‐AMINOBUTYRATE AND D‐ASPARTATE IN RAT BRAIN SLICES
Authors: MINCHIN M.C.W.
Published: July 2012

The effect of various concentrations of thiopentone, pentobarbitone, methohexitone, hydroxydione, alphaxalone/alphadolone, ketamine, α‐chloralose and urethane on the transport of radiolabelled γ‐aminobutyric acid (GABA) and D‐aspartate was investigated.

Uptake of the amino acids was weakly inhibited, if at all, by the anaesthetics and it is unlikely that such effects contribute significantly to their physiological function.

The spontaneous efflux of GABA and D‐aspartate was not detectably altered by any of the drugs tested.

Thiopentone, pentobarbitone, methohexitone and hydroxydione inhibited K+‐stimulated GABA and D‐aspartate release. The other anaesthetics had no effect on K+‐stimulated amino acid release.

The rank order of potency of the inhibitors of K+‐stimulated amino acid release did not correlate with their anaesthetic potency. Furthermore not all inhibitors appeared to be very effective at anaesthetic concentrations.

It is concluded that although it is possible that inhibition of excitatory transmitter release may be involved in the anaesthetic action of some anaesthetics, for many of the substances tested in this study such a mechanism does not appear to be implicated.
CHOLINE ACETYLTRANSFERASE ACTIVITY IN THE SYMPATHETIC NERVES OF THE RABBIT EAR ARTERY
Authors: FLORENCE VERENA M. , HUME W.R. , MATSUNAGA MARSHA L.
Published: July 2012

No statistically significant difference in the activity of choline acetyltransferase (ChAT) was detected between sympathetically denervated and control rabbit ear artery (REA) tissue. This was interpreted as evidence against the hypothesis that endogenous acetylcholine plays an obligatory role in sympathetic postganglionic neurotransmission.

The values obtained for ChAT activity in the extraneuronal REA tissue were very low, but were greater than the boiled blank values.

Treatment with a specific inhibitor of ChAT did not reduce the REA values, while it did for rabbit iris. Addition of acetylcholinesterase to the REA assay reduced the activity of the collectable product to a markedly lesser degree than was observed with other tissues.

The specificity of the enzyme assay at the very low yield levels observed in the extraneuronal REA tissue was therefore questioned.
THE ROLE OF THE LOCAL ANAESTHETIC PROPERTIES OF β‐ADRENOCEPTOR BLOCKING AGENTS IN ANTAGONIZING CaCl2‐INDUCED ARRHYTHMIAS IN THE RAT
Authors: EVANGELISTA S. , MAGGI C.A. , MELI A.
Published: July 2012

Eight β‐adrenoceptor blocking agents were compared for their ability to antagonize arrhythmias induced by bolus injections of CaCl2 in rats.

Only those β‐blockers possessing local anaesthetic properties were effective in antagonizing this type of arrhythmia and there was a highly significant correlation between antiarrhythmic and local anaesthetic properties.

Effects on adrenoceptors seem to play only a minor role in the genesis of this type of arrhythmia.
DUAL EFFECTS OF CATECHOLAMINES ON PRE‐ AND POST‐JUNCTIONAL MEMBRANES IN THE DOG TRACHEA
Authors: ITO YUSHI , TAJIMA KIKUO
Published: July 2012

Effects of noradrenaline or isoprenaline on the membrane and contractile properties of the smooth muscle cell, or on the excitatory neuro‐effector transmission in the dog trachea, in vitro, were observed by use of microelectrodes and double sucrose gap methods.

Noradrenaline (<5 × 10−6 m) or isoprenaline (< 5 × 10−7 m) modified neither the membrane potential nor the membrane resistance. Increased concentrations of noradrenaline (> 5 × 10−5 m) depolarized and isoprenaline (> 5 × 10−7 m) hyperpolarized the membrane, and these actions were suppressed by phentolamine and propranolol respectively. Both catecholamines reduced the membrane resistance.

Noradrenaline (5 × 10−6 m) or isoprenaline (5 × 10−7 m) reduced the resting tension, raised the mechanical threshold required to produce the contraction and suppressed the amplitude of phasic contractions evoked by electrical depolarization of the membrane.

The action potential evoked by an outward current pulse in the presence of tetraethylammonium (TEA) was not affected by 5 × 10−6m isoprenaline, while the mechanical response was markedly suppressed.

The excitatory junction potential (e.j.p.) evoked by electrical field stimulation was blocked by atropine. Noradrenaline (5 × 10−7 m) or isoprenaline (5 × 10−8 m) suppressed the amplitude of e.j.p. with no change in the membrane potential or input membrane resistance. Depression in the amplitude of e.j.ps produced by noradrenaline or isoprenaline reduced the amplitude of phasic contractions evoked by e.j.ps.

These inhibitory actions of the catecholamines on mechanical responses and on e.j.ps were suppressed by pretreatment with propranolol (4 × 10−6 m).

Dog tracheal smooth muscles are innervated by cholinergic excitatory and adrenergic inhibitory systems. Electrical field stimulation produced excitation of both cholinergic and adrenergic nerve fibres, and propranolol (4 × 10−6 m) enhanced the amplitude of e.j.p. generated by excitation of cholinergic nerves when repetitive stimulation (10 stimuli at 20 Hz) was used, but not the amplitude of the e.j.p. evoked by a single stimulus.

5‐Hydroxytryptamine (6 × 10−6 m) produced a tonic contracture of the dog trachea. After pretreatment with atropine (4 × 10−6 m), field stimulation (50 μs in duration and repetitive stimuli at 20 Hz) induced reversal of the contracture induced by 5‐hydroxytryptamine and this was abolished by propranolol (5 × 10−6 m).

These results indicate that endogenous or exogenous catecholamines, in relatively low concentrations, predominantly activate β‐adrenoceptors in the pre‐ and post‐junctional membrane in the dog trachea, and induce muscle relaxation.
ROLE OF CENTRAL β‐ADRENOCEPTORS IN THE CONTROL OF PENTYLENETETRAZOL‐INDUCED CONVULSIONS IN RATS
Authors: LOUIS W.J. , PAPANICOLAOU JENNY , SUMMERS R.J. , VAJDA F.J.E.
Published: July 2012

The role of central β‐adrenoceptors in the anticonvulsant effect of β‐adrenoceptor antagonists has been examined.

Oral administration of (−)‐and (+)‐propranolol (0.05–1 mg/kg) and (±)‐pindolol (0.025–0.5 mg/kg) produced a dose‐dependent decrease in duration of convulsions produced by pentylenetetrazol (PTZ 50 mg/kg, i.p.) in rats.

At the EC5+ level, (−)‐propranolol is seven times more effective than the (+)‐isomer.

Oral administration of (−)‐, (+)‐or (±)‐practolol (1–10 mg/kg) or (−)‐or (+)‐timolol (1–10 mg/kg), two β‐adrenoceptor antagonists that do not penetrate the blood brain barrier, had no significant effect on the duration of PTZ‐induced convulsions.

Intracerebroventricular administration of (−)‐propranolol (0.5 μg/kg) or (−)‐timolol (0.25 μg/kg) produced highly significant anticonvulsant effects whereas the (+)‐isomers at the same dose level were ineffective. (±)‐Pindolol (0.25 μg/kg) was also much more effective given by this route than when given orally. The (+)‐and (−)‐isomers of the β1‐adrenoceptor selective antagonist practolol (10 μg/kg) exerted only weak anticonvulsant effects.

This study provides evidence that β‐adrenoceptor antagonists exert an anticonvulsant effect through central β2‐adrenoceptors. At high dose levels, additional anticonvulsant activity is associated with membrane stabilization in those antagonists which possess this property.