bluuebunny/crossref_metadata_2025 huggingface dataset:
THE INFLUENCE OF SODIUM AND POTASSIUM SUPPLEMENTS ON THE DIURETIC RESPONSES TO FRUSEMIDE ADMINISTRATION IN NORMAL SUBJECTS
Authors: BRANCH ROBERT A. , COLE EDWARD , HORTH CHARLES E. , JACKSON LYNNE , RAMSAY LARRY E. , SHELTON JOHN
Published: July 2012

Twelve normal subjects received (1) normal diet, (2) normal diet with 100 mmol supplementary sodium chloride and (3) normal diet with 96 mmol supplementary potassium chloride, each for 10 days, in a balanced cross‐over study according to a Latin Square design. At the end of each study period, the subjects received 80 mg frusemide orally. Each study period was separated from the other by 10 days.

Changes in urinary electrolyte excretion occurred within the first four days of each dietary period then remained constant, with significant differences in urinary Na/K ratio between the dietary regimes.

Between‐subject correlations, using the mean values over the three study periods, demonstrated significant associations between plasma uric acid and urinary Na/K ratio and between plasma prolactin and urinary potassium excretion.

Urinary potassium excretion and Na/K ratio following frusemide were influenced significantly by alteration of diet but there was no change in sodium excretion.

Between‐subject correlations of pretreatment variables with diuretic response, using the mean values over the three study periods, demonstrated significant associations between both pretreatment urinary Na/K ratio and plasma uric acid and respectively the urinary potassium excretion and urinary Na/K ratio in response to frusemide.

While the response to frusemide was altered by short‐term changes in dietary sodium and potassium, the difference was less than expected from observations in two populations with customary diets differing in similar manner.
EFFECTS OF SOMATOSTATIN ON GASTRIC ACID SECRETION AND ON LIPID AND CARBOHYDRATE METABOLISM IN THE RAT
Authors: LINSCHEER WILLEM G. , RAHEJA KRISHAN L.
Published: July 2012

Studies were conducted to examine the effects of somatostatin on pentagastrin‐induced gastric acid secretion, and on bile, plasma and liver lipid composition in the rat.

In addition, liver glycogen and plasma glucose concentrations were measured.

Somatostatin was administered intravenously as a bolus (100 ug) at the start of the experiment followed by a continuous infusion (50 ug/h) for 2 h.

Controls were infused with isotonic saline (1 ml/h) throughout the experiment. Gastric secretions and bile were collected during the infusions.

Somatostatin significantly decreased the volume of gastric secretion as well as total gastric acid output but it had no effect on bile flow or bile lipid composition.

Plasma and liver lipids were not affected. Plasma glucose concentrations were significantly elevated but liver glycogen was not changed.

Our results suggest that somatostatin probably decreases glucose uptake by peripheral tissue. The effect of somatostatin on bile composition and glucose levels in the rat is different from observations reported in other species.
ROLE OF 5‐HYDROXYTRYPTAMINE IN THE VASOCONSTRICTOR ACTION OF COMPOUND 48/80 IN THE RAT FEMORAL VASCULATURE
Authors: SAKAI K.
Published: July 2012

The effect of compound 48/80 on the rat femoral vasculature was examined by means of a cross‐circulation technique.

Intra‐arterial injection of increasing doses (1.5 to 15 ug) of compound 48/80 caused dose‐dependent vasoconstriction preceded by transient vasodilatation. The vasoconstriction was significantly reduced in reserpine‐treated preparations and converted to vasodilatation by methysergide.

When the vasoconstrictor response to a large dose (300 ug) of adenosine was abolished by repeated administration, the response to compound 48/80 remained unaltered.

The present results indicate that the femoral arterial vasoconstriction by compound 48/80 in the rat is mediated by the release of 5‐hydroxytryptamine (5‐HT); this 5‐HT may be liberated from a different storage site from that released by adenosine.
HYPERPOLARIZING ‘α2’‐ADRENOCEPTORS IN RAT SYMPATHETIC GANGLIA
Authors: BROWN D.A. , CAULFIELD M.P.
Published: July 2012

Receptors mediating catecholamine‐induced hyperpolarization of isolated superior cervical sympathetic ganglia of the rat have been characterized by means of an extracellular recording method.

(—)‐Noradrenaline (EC50, 1.7 ± 0.6 μm) produced an immediate low‐amplitude (<400 uV) hyperpolarization. The hyperpolarization was increased on removal of external Ca2+ or on reduction of external K+ from 6 to 2 mm. Hyperpolarization was unaffected by changing the temperature from 25° to 37°C.

Hyperpolarization was also produced by the following agonists (potencies relative to (—)‐noradrenaline): (—)‐noradrenaline 1; (±)‐isoprenaline 0.41; (—)‐phenylephrine 0.40; (+)‐noradrenaline 0.13; 2‐amino‐6,7‐dihydroxy tetrahydronaphthalene (ADTN) 0.25; dopamine 0.1; methoxamine 0.012; amidephrine 0.0015.

Responses were antagonized by phentolamine (1 μm) but not by (±)‐propranolol (1 μm), haloperidol (10 μm) or α‐flupenthixol (1 μm). This suggested that hyperpolarization was mediated solely throughα‐receptor stimulation not through stimulation of β‐receptors or dopamine‐receptors.

Dose‐ratio shifts produced by phentolamine varied with different agonists. The shift increased in inverse proportion to the ability of the agonists to inhibit [3H]‐(—)‐noradrenaline uptake, suggesting that uptake of agonists limited the dose‐ratio shift. Cocaine and nortriptyline reduced catecholamine‐induced hyperpolarization in concentrations (10 μm and 1 μm respectively) necessary to inhibit [3H]‐(—)‐noradrenaline uptake.

Clonidine (0.01 to 1 μm), oxymetazoline (0.01 to 1 μm) and ergometrine (0.1 to 10 μm) produced a persistent, low‐amplitude hyperpolarization, as though they were partial agonists. Responses to the agonists were blocked by yohimbine (1 μm) but not be prazosin (1 μm).

It is concluded that the adrenergic cell bodies in the ganglion were hyperpolarized through activation of the same type ofα‐receptor (‘α2‐receptors’) as those present at adrenergic nerve terminals.
PROSTAGLANDIN BIOSYNTHESIS BY GUINEA‐PIG SKELETAL MUSCLE in vitro AND THE EFFECT OF OESTRADIOL‐17β AND PROGESTERONE
Authors: KERRY P.J.
Published: July 2012

The effect of oestradiol and progesterone on prostaglandin biosynthesis by guinea‐pig skeletal muscle in vitro has been investigated.

At high concentrations, oestradiol‐17β (100 μg/ml) and progesterone (500 μg/ml) increased prostaglandin E and prostaglandin F synthesis (measured by radioimmunoassay).

It is suggested that these steroids are unlikely to be found in vivo at levels sufficient to influence prostaglandin synthesis by skeletal muscle in physiological and pathological situations.
[3H]‐QUINUCLIDINYL BENZILATE BINDING TO MUSCARINIC RECEPTORS IN RAT BRAIN: COMPARISON OF RESULTS FROM INTACT BRAIN SLICES AND HOMOGENATES
Authors: GILBERT R.F.T. , HANLEY M.R. , IVERSEN L.L.
Published: July 2012

The binding of [3H]‐(+)‐quinuclidinyl benzilate ([3H]‐(±)‐QNB) to muscarinic sites in rat brain slice and homogenate preparations was compared.

Evidence is presented in support of the view that only the (—)‐enantiomer of QNB binds with high affinity to muscarinic sites.

The Kd value for [3H]‐(—)‐QNB binding in slices was eight times higher than that measured in homogenates.

Similarly, the potencies of various muscarinic ligands as inhibitors of [3H]‐(—)‐QNB binding were consistently lower in slices than in homogenates.

It is proposed that the results may reflect differences in the binding properties of muscarinic receptors in intact tissue slice and homogenate preparations.
ON THE MECHANISM OF PANCURONIUM‐INDUCED SUPER‐SENSITIVITYTO NORADRENALINE IN RAT SMOOTH MUSCLE
Authors: TOMLINSON D.R.
Published: July 2012

Pancuronium bromide (5 × 10−5m) caused super‐sensitivityto noradrenaline in the rat isolated vas deferens and hepatic portal vein. This super‐sensitivitywas manifest as a parallel leftward shift of the dose‐response curve for noradrenaline with no alteration of the maximum response to the agonist.

Pancuronium did not potentiate the response of the vas and portal vein to St 91, anα‐adrenocep‐tor agonist which is not a substrate for Uptake x.

Pancuronium did not potentiate the response of the vas to CaCl2.

In vasa deferentia made supersensitive to noradrenaline by treatment with cocaine (1 × 10−5m) pancuronium induced no further potentiation of the response to noradrenaline. However, the super‐sensitivityto noradrenaline induced by pancuronium alone was augmented by the addition of cocaine.

Histofluorescence studies showed that pancuronium inhibited neuronal uptake of α‐methyl noradrenaline in various noradrenergically‐innervated tissues from reserpine‐treated rats.

This study, with support from the literature, suggests that pancuronium induces noradrenaline super‐sensitivityby blockade of Uptake!.
STABILIZATION OF LYSOSOMES IN ANOXIC MYOCARDIUM BY PROPRANOLOL
Authors: WELMAN ELIZABETH
Published: July 2012

Isolated hearts of guinea‐pigs were perfused aerobically and anoxically for 60 min. (±)‐Propranolol was added to the perfusion medium in concentrations ranging from 10 ng to 10 μg/ml.

Lysosome stability was assessed by measurements of latent acid hydrolase activity in homogenates of left ventricular tissue.

In the absence of propranolol, the integrity of the myocardial lysosomes was considerably reduced after 60 min anoxia. Lysosome stability was enhanced by the presence of (±)‐propranolol. The optimal concentration was found to be 0.1 μg/ml. This concentration of the (+)‐isomer alone was less effective.

It was concluded that bT‐adrenoceptor blockade was the major mechanism by which lysosome disruption was prevented but that some direct membrane effect of propranolol may also be involved.
ACTION OF COLCHICINE AND CYTOCHALASIN B ON THE ACETYLCHOLINE RECEPTOR
Authors: ANWYL ROGER , NARAHASHI TOSHIO
Published: July 2012

The effects of colchicine and cytochalasin B have been investigated on the extrajunctional acetylcholine (ACh) receptors of rat muscle.

Colchicine and cytochalasin B each decreased the amplitude and rise time of the iontophoretic ACh potential. When the dose of ACh was increased in the presence of these agents, ACh potentials were produced with a biphasic waveform consisting of a fast initial phase and a second slow phase.

It is proposed that colchicine and cytochalasin B are acting through a mechanism other than the breakdown of microtubules and microfilaments.
POTENTIATION OF RESPONSES TO MONOAMINES BY ANTIDEPRESSANTS AFTER DESTRUCTION OF MONOAMINE AFFERENTS
Authors: JONES R.S.G. , ROBERTS M.H.T.
Published: July 2012

Stereotaxic lesioning and microiontophoretic techniques were used to study the effects of lesions of the medial forebrain bundle (MFB) on the potentiation by antidepressant drugs of responses to monoamines of cortical neurones.

Active uptake of noradrenaline (NA) and 5 hydroxytryptamine (5‐HT) by synaptosomes from the motor and somatosensory cortex was reduced to approximately 20%, 10 to 14 days following lesion of the MFB in rats.

Unilateral lesions of the MFB caused changes in responsiveness of neurones to NA and 5‐HT, applied by iontophoresis, in the cortex ipsilateral to the lesion. Excitatory responses to both amines were observed less frequently and depression was the predominant response. Excitatory responses on the lesioned side were significantly smaller than on the unlesioned side, but the size of depressant responses was unaltered.

Viloxazine strongly potentiated responses of cortical neurones to NA and 5‐HT on both sides of the brain of MFB‐lesioned rats. There were no significant differences in the potentiation of responses to monoamines on the lesioned or unlesioned sides of the brain.

Desipramine potentiated responses to NA of neurones in the cortex ipsilateral to MFB lesions.

Chlorimipramine potentiated responses to 5‐HT of neurones in the cortex ipsilateral to MFB lesions.

It is concluded that antidepressants can potentiate responses to monoamines despite a profound reduction in presynaptic terminals. The potentiation is unlikely to be the result of blockade of monoamine uptake into presynaptic terminals, and is probably a postsynaptic effect of the antidepressant drugs.
PROSTAGLANDIN E2, PROSTAGLANDIN I2 AND THE VASCULAR CHANGES OF INFLAMMATION
Authors: WILLIAMS T.J.
Published: July 2012

Plasma exudation and blood flow changes induced by intradermal injection of prostaglandins E2 (PGE2), I2 (PGI2), D2 (PGD2) and F2α (PGF2α) were measured in rabbit dorsal skin by the use of [131I]‐albumin and 133Xe.

Little plasma exudation was produced by any of the prostaglandins when injected alone.

Both PGE2 and PGI2 were potent at increasing blood flow, whereas PGF2α and PGD2 produced an increase only at high doses.

All of the prostaglandins studied potentiated the plasma exudation induced by bradykinin. PGE2 and PGI2 had similar potent potentiating activity, whereas PGD2 and PGF2ae had activity at doses too high to be of biological significance.

Intradermal injections of arachidonate alone resulted in little plasma exudation but produced an increase in blood flow. Arachidonate potentiated bradykinin‐induced plasma exudation.

Locally‐injected indomethacin had no effect on basal blood flow and little effect on the exudation produced by bradykinin, but indomethacin did inhibit the vasodilatation and exudation potentiation produced by arachidonate.

PGE2 and PGI2 had similar potency in producing marked potentiation of plasma exudation induced by intradermal injection of zymosan.

In the reaction to zymosan, it is concluded that vasodilatation is the result of the release of arachidonate, which is subsequently converted to either PGE2 or PGI2. These substances regulate the plasma exudation induced by independently‐released vascular permeability‐increasing mediators.
EFFECTS OF DRUGS ON BEHAVIOUR OF AGGRESSIVE MICE
Authors: KRSIAK M.
Published: July 2012

The occurrence of 11 aggressive and non‐aggressive activities was observed in aggressive male mice treated with drugs in paired interactions with non‐aggressive males given water. Effects of chlordiazepoxide, diazepam, barbitone, chlorpromazine, imipramine, (‐h)‐amphetamine, lysergic acid diethylamide (LSD) all given orally and of intraperitoneal scopolamine were investigated.

Scopolamine (0.25 and 0.75 mg/kg), (+)‐amphetamine (0.25 and 1 mg/kg), chlorpromazine (2.5 mg/kg), diazepam (10 mg/kg) and chlordiazepoxide (50 mg/kg) reduced aggressive activities (attacks, aggressive unrest) without inhibiting walking across the cage or rearing in the aggressive mice. Thus, the inhibition of aggression induced by these drugs does not seem to be due to neuromuscular impairment and seems to this extent specific. On the other hand, imipramine lessened aggressive activities only at a dose (80 mg/kg) which also decreased walking across the cage and rearing. Barbitone or LSD did not change aggression at either dose tested (20 and 60 or 0.01 and 1 mg/kg, respectively). Aggressive activities were increased significantly only by chlordiazepoxide at a dose of 5 mg/kg.

(+)‐Amphetamine (0.25 mg/kg) and scopolamine (0.75 mg/kg) increased escapes and alert postures, respectively, in the aggressive mice.

Diazepam and chlordiazepoxide decreased tail rattling at 1 and 5 mg/kg, respectively, doses 10 times lower than those inhibiting attacks. The other drugs tested inhibited tail rattling only at doses reducing attacks. Tail rattling appears to be a convenient measure for testing effects of drugs on behavioural conflict.

Diazepam (5 and 10 mg/kg), chlordiazepoxide (20 and 50 mg/kg), barbitone (60 mg/kg) and scopolamine (0.25 and 0.75 mg/kg) increased sociable activities (sniffing, following partners and climbing over them) whereas (+)‐amphetamine, chlorpromazine, imipramine and LSD did not. Effects of the drugs on sociable activities in aggressive mice seem to correlate with their action on punished responding and other types of suppressed behaviour.
PHARMACOLOGY OF 5‐HYDROXYTRYPTAMINE RECEPTORS IN FROG SKIN EPITHELIUM
Authors: DALTON TERENCE
Published: July 2012

5‐Hydroxytryptamine (5‐HT) stimulates active sodium transport and decreases the passive mucosal to serosal chloride permeability across frog skin. The relative importance of the different regions of the 5‐HT molecule in the mediation of these responses has been studied using a range of structurally related compounds.

Substitution in the ethyl amine side chain of 5‐HT (5‐hydroxytryptophan) results in decreased receptor affinity and intrinsic activity; removal of the side chain (5‐hydroxyindole) abolishes activity. Methoxy substitution of the 5‐OH moiety of 5‐HT has no effect on intrinsic activity but reduces affinity; displacement of the hydroxyl group to position 6 diminishes intrinsic activity and affinity.

It is concluded that both of the 5‐HT‐induced physiological effects are mediated via a single receptor which is distinct from α‐ and β‐adrenoceptors.
THE ROLE OF CELL‐FIXED CALCIUM IN HISTAMINE RELEASE BY COMPOUND 48/80
Authors: GARLAND L.G. , PAYNE A.N.
Published: July 2012

Histamine release by compound 48/80 was substantially reduced in a time‐dependent manner (maximum at 30 min) by pre‐incubating mast cells in calcium‐free medium at 37°C but not at 2°C. This effect was optimal at pH 7.0 to 7.5.

The re‐introduction of calcium (0.1 to 3 mmol/1) restored histamine release to the control value; this effect was independent of temperature.

Strontium (1 to 30 mmol/1) partially reversed the effect of calcium deprivation but the same concentrations of barium and magnesium depressed histamine release even further. Magnesium (3 to 15 mmol/1) antagonized the effect of calcium replacement.

Results suggest that the level of cell‐fixed calcium involved in compound 48/80‐induced histamine release may be controlled by the combinaton of rapid passive influx and slow active efflux.
STIMULATION OF SPECIFIC [3H]‐OUABAIN BINDING TO MICROSOMAL PREPARATIONS FROM RAT HEART AND SKELETAL MUSCLE BY THYROID HORMONES: EFFECTS OF 6‐HYDROXYDOPAMINE
Authors: BANERJEE SHAILESH P. , SHARMA VIRENDRA K.
Published: July 2012

Surgical thyroidectomy decreased specific [3H]‐ouabain binding to heart ventricular microsomes by 43% and gastrocnemius muscle microsomes by 34%. Administration of triiodothyronine to euthyroid rats enhanced specific [3H]‐ouabain binding to heart and skeletal muscle membrane by 60% and 33% respectively.

Treatment of thyroidectomized rats with triiodothyronine increased specific [3H]‐ouabain binding by 44% in skeletal muscle membrane preparation and 428% in cardiac microsomes.

Specific [3H]‐ouabain binding decreased by 55% in heart and 53% in gastrocnemius muscle preparations following chemical sympathectomy with 6‐hydroxydopamine.

Treatment with triiodothyronine of euthyroid rats which had been sympathectomized did not significantly alter specific [3H]‐ouabain binding to heart or skeletal muscle membrane preparations.

Administration of triiodothyronine to thyroidectomized and sympathectomized rats increased specific [3H]‐ouabain binding by 80% in heart and 83% in skeletal muscle membrane preparations.

These results suggest that triiodothyronine may influence specific [3H]‐ouabain binding to thyroid hormone nonresponsive tissue such as sympathetic nerve endings. Therefore, the present observations are incompatible with the hypothesis that induction of (Na+ 4‐ K+)‐adenosine triphosphatase of skeletal muscle membrane is the molecular mechanism for the calorigenic actions of thyroid hormones.
EFFECTS OF VERAPAMIL, DANTROLENE AND LANTHANUM ON CATECHOLAMINE RELEASE FROM RAT ADRENAL MEDULLA
Authors: COHEN JACKIE , GUTMAN YEHUDA
Published: July 2012

The release of catecholamines (CA) from rat adrenal incubated in vitro in Locke solution was studied.

Acetylcholine‐induced release of CA and CA release by 56 mm KC1 were inhibited by verapamil and lanthanum chloride which block calcium permeability.

CA secretion induced by salbutamol or by theophylline was unaffected by either verapamil or lanthanum chloride.

Dantrolene‐sodium inhibited the CA secretion induced by theophylline but only partially reduced potassium‐induced release of CA.

Verapamil enhanced the secretion of CA induced by salbutamol (in a calcium‐free medium).

Tyramine‐induced secretion of CA was unaffected by lanthanum chloride, verapamil or dantrolene‐sodium.

It is suggested that cyclic adenosine 3′,5′‐monophosphate‐mediated CA secretion (induced by theophylline or salbutamol) depends on release of calcium from intracellular stores, and that CA secretion induced by tyramine is independent of intra‐ or extracellular calcium.
INHIBITION OF NEURONAL FIRING BY OPIATES: EVIDENCE AGAINST THE INVOLVEMENT OF CYCLIC NUCLEOTIDES
Authors: KARRAS P.J. , NORTH R.A.
Published: July 2012

Extracellular recordings were made in vitro from single neurones of the myenteric plexus of the guinea‐pig ileum.

Neuronal firing was inhibited by morphine and normorphine (10 nM to 1 μm). Cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) (100 μm to 1 mm) also inhibited the firing of the majority of the neurones. Prostaglandin E2 usually caused a short‐lasting excitation of myenteric neurones and the phosphodiesterase inhibitor 3‐isobutyl‐l‐methylxanthine was usually without effect on firing rate.

The inhibition of neuronal firing by normorphine was unaffected by prior and/or concurrent administration of cyclic AMP, dibutyryl cyclic adenosine 3′,5′‐monophosphate, prostaglandin E2 or 3‐isobutyl‐l‐methylxanthine. As these four treatments might be expected to elevate intracellular levels of cyclic AMP, the results lend no support to the notion that a reduction in intracellular cyclic AMP is essential to the inhibition of firing produced by morphine.
INVESTIGATION OF THE ROLE OF CALCIUM IN THE SUPER‐SENSITIVITYPRODUCED BY COCAINE IN CAT SPLEEN STRIPS
Authors: SUMMERS R.J. , TILLMAN JANET
Published: July 2012

Cocaine (2 × 10−6m and 10−5m) produced 2 and 7 fold shifts to the left of the dose‐response curve to (—)‐noradrenaline recorded isotonically in isolated splenic capsular strips of the cat.

The same concentrations of cocaine also produced increases in the maximum response of the tissue to 117% and 126.7% of control.

Desmethylimipramine (DMI, 10 −7 to 10−6m) produced no significant potentiation of the response of cat spleen strips to (—)‐noradrenaline. At 10−5 M DMI decreased the maximum response.

Cocaine (10−5m) produced a 3.3 fold shift to the left of the dose‐response curve whereas DMI (10−6m) had no effect on the dose‐response curve to oxymetazoline in cat splenic capsular strips.

Cocaine (10−5m) in the presence of phentolamine (10−6m) produced a shift to the left and an increase in the maximum response to K+, an agonist which is believed to produce muscle contraction by increasing the membrane calcium flux.

Cocaine (10−5m) had no effect on the dose‐response curve to angiotensin which is believed to contract vascular muscle by releasing calcium from intracellular storage sites.

The potentiating effect of cocaine (10−5m) on responses of spleen strips to (—)‐noradrenaline was blocked by the calcium flux inhibitor SKF 525A (2.65 × 10−5m).

It is concluded that the results are compatible with the view that cocaine enhances the influx of calcium across the cell membrane during responses to agonists that utilize the extracellular pool of calcium and that this effect is responsible for a large part of the potentiation of the response.
EVIDENCE FOR DOPAMINERGIC VASODILATOR INNERVATION OF THE CANINE PAW PAD
Authors: BELL CHRISTOPHER , LANG WILLIAM J.
Published: July 2012

In chloralose‐anaesthetized dogs pretreated with guanethidine and pancuronium, electrical stimulation (0.2 to 5 Hz) of the peripheral end of the cut tibial nerve caused a frequency‐dependent increase in femoral blood flow which was restricted to the paw pads.

This neurogenic vasodilatation was not attenuated by atropine, mepyramine plus burimamide, indomethacin or propranolol. It was, however, attenuated in a dose‐dependent manner by intra‐arterial administration of the dopamine receptor antagonist, ergometrine (0.05 to 0.5 mg).

The effect of ergometrine could not be explained by non‐specific effects on axonal conduction or transmission or by vasospasm of the blood vessels of the paw‐pads.

In dogs with intact tibial nerves, a pharmacologically similar dilator response localized to the paw‐pads could be elicited by electrical stimulation of loci in the ipsilateral diencephalon and midbrain. This response was not due to inhibition of adrenergic vasomotor tone and was abolished by systemic ganglion blockade or by tibial nerve section as well as by femoral arterial administration of ergometrine.

It is suggested that the vasculature of the canine paw pads is innervated by a population of autonomic axons which utilize dopamine or a related substance as a transmitter substance and activation of which causes vasodilation.
DOPAMINE AGONISTS AND COBALT‐INDUCED EPILEPSY IN THE RAT
Authors: FARJO I.B. , McQUEEN JUDITH K.
Published: July 2012

Electrocorticogram (ECoG) recordings were made from conscious rats which had cortical implants of cobalt. The epileptiform spike activity was then assessed by means of an automated technique, based on peak angle measurements.

Apomorphine (0.5, 1.0 and 2.0 mg/kg i.p.) and lisuride (0.1, 0.25, 0.5 and 1.0 mg/kg i.p.) inhibited spike activity in established primary and secondary foci in a dose‐dependent manner. Bromocryptine (10 and 20 mg/kg i.p.) and CF 25–397 (40 mg/kg i.p.) had a similar effect but only after a latent period of several hours. Chronic administration of bromocryptine (20 mg/kg i.p. daily) attenuated the normal development of the foci following implantation.

Pimozide (1 mg/kg i.p.) potentiated cortical epileptic activity in cobalt‐implanted rats and blocked the antiepileptic effects induced by the dopamine agonists.

Intrastriatal administration of dopamine (25 μg) or apomorphine (60 μg) suppressed epileptiform spikes in the cortex. Destruction of striatal catecholamine terminals by 6‐hydroxydopamine increased the spike activity.

It is concluded that the striatum may play an essential part in mediating the anti‐epileptic effects of dopamine and its agonists in this model of epilepsy.
THE SUBDIVISION OF β‐ADRENOCEPTORS IN THE CARDIOVASCULAR SYSTEM OF THE RAT
Authors: IMMS F.J. , NEAME R.L.B. , POWIS D.A.
Published: July 2012

The antagonism by the β‐adrenoceptor blocking drugs, propranolol (non‐selective) and practolol (β‐selective), of the cardiovascular actions of isoprenaline has been investigated in the rat.

All doses of practolol (0.1, 1 and 3 mg/kg) blocked the cardio‐accelerator action of isoprenaline but only the largest dose blocked the vasodilator effect.

All doses of propranolol (0.01, 0.03 and 0.1 mg/kg) blocked the vasodilator effect of isoprenaline but only the largest dose diminished the tachycardia.

It is concluded that in the rat, as in other species, β‐adrenoceptors may be subdivided into β1 (cardiac) and β2 (peripheral vascular) types.
THE EFFECTS OF IONS ON THE BINDING OF AGONISTS AND ANTAGONISTS TO MUSCARINIC RECEPTORS
Authors: BIRDSALL N.J.M. , BURGEN A.S.V. , HULME E.C. , WELLS J.W.
Published: July 2012

There are no selective effects of Na+, K+, Ca2+, Mg2+ or Cl− on the binding of antagonists or agonists to muscarinic receptors in rat brain. A decrease in affinity related to ionic strength is found for all these ions.

Larger effects were produced by T+, La3+, and some transition metal ions.
DIFFERENT EFFECTS OF CURRENT STRENGTH ON INHIBITORY RESPONSES OF THE MOUSE VAS DEFERENS TO METHIONINE‐ AND LEUCINE‐ENKEPHALIN
Authors: HART S.L. , KITCHEN I. , WADDELL P.R.
Published: July 2012

The inhibitory potency of methionine (Met)‐enkephalin on the field‐stimulated mouse vas deferens was greatly increased by a reduction in current strength whilst that of leucine (Leu)‐enkephalin increased only slightly. All currents were submaximal and all muscle twitches were neuronally evoked. These results suggest that inhibitory effects of Met‐ and Leu‐enkephalin in the mouse vas deferens are not commonly mediated and provide a rapid method for ascertaining heterogeneity of enkephalin extracts.
NALOXONE INHIBITS THE ANTI‐DIARRHOEAL ACTIVITY OF LOPERAMIDE
Authors: PIERCEY M.F. , RUWART M.J.
Published: July 2012

Subcutaneous prostaglandin E2 (2.5 mg/kg) produces profuse diarrhoea in fed rats.

Pretreatment of rats with subcutaneous loperamide (1.0 mg/kg) completely prevents prostaglandin‐induced diarrhoea. If naloxone is administered prior to loperamide injections the activity. of the antidiarrhoeal compound is completely destroyed.

These data provide strong evidence that the antidiarrhoeal activity of loperamide is mediated via the opiate receptor.
INVOLVEMENT OF SRS‐A IN THE SCHULTZ‐DALE RESPONSE OF THE GUINEA‐PIG SMALL INTESTINE
Authors: HERMAN A.G. , LAEKEMAN G.M. , VAN BEEK H.A.
Published: July 2012

The anaphylactic reaction of the guinea‐pig ileum, the so called Schultz‐Dale reaction, shows a biphasic response: a short rapid contraction followed by a partial relaxation and a slow contractile response.

Dose‐response curves with ovalbumin as an antigen were obtained for the quick and slow contraction of this anaphylactic reaction.

Mepyramine (1 μg/ml) blocked the rapid first contraction, but failed to abolish the slow one in about 50% of the animals studied.

The SRS‐A antagonist, FPL 55712, significantly depressed the slow sustained contraction during the Schultz‐Dale reaction. Disodiumcromoglycate was without effect on both phases when it was added 5 min before addition of the antigen. However, when added simultaneously with the antigen it produced a 30% suppression of the slow phase in the highest concentration used.
5‐HYDROXYTRYPTAMINE UPTAKE INHIBITORS BLOCK para‐METHOXYAMPHETAMINE‐INDUCED 5‐HT RELEASE
Authors: TSENG LIANG‐FU
Published: July 2012

Activation of myoclonic twitch activity (MTA) of suprahyoideal muscle after p‐methoxyamphetamine (PMA) administration in rats anaesthetized with urethane has previously been reported to be due to brain 5‐hydroxytryptamine (5‐HT) release. Increased MTA caused by PMA was blocked by chlorimipramine (0.1 to 1 mg/kg) and fluoxetine (0.3 to 3 mg/kg) but not by desipramine (3 mg/kg).

The 5‐hydroxytryptophan‐induced increase of MTA of suprahyoideal muscle in rats pretreated with pargyline was not blocked by chlorimipramine but was blocked by methysergide.

[3H]‐5‐HT was injected intraventricularly 30 min before the beginning of ventricular perfusion with artificial cerebrospinal fluid in urethane anaesthetized rats. PMA (2 mg/kg i.v.) increased the release of [3H]‐5‐HT in the perfusate after injection. Chlorimipramine (0.1 to 1 mg/kg) and fluoxetine (0.1 to 1 mg/kg), injected 10 min before the PMA injection, caused a dose‐related blockade of the increased release of [3H]‐5‐HT induced by PMA. Desipramine at 3 mg/kg slightly inhibited the increased release of [3H]‐5‐HT caused by PMA but was inactive at 1 mg/kg.

It is proposed that these 5‐HT uptake inhibitors block the increased MTA caused by PMA by preventing the PMA‐induced release of 5‐HT in the central nervous system.
CHARACTERIZATION OF ULTRAVIOLET LIGHT‐INDUCED RELAXATION OF THE ISOLATED DUODENUM OF THE RAT
Authors: DAVE K.C. , JINDAL M.N. , KELKAR V.V. , TRIVEDI H.D.
Published: July 2012

Isolated duodenum of the rat, exposed to ultraviolet (u.v.) light in the presence of NO2 ions, responded with reversible relaxation.

The photorelaxation response did not seem to involve any known receptor mechanisms and was independent of any ganglionic or neuronal influences.

Changes in the ionic environment of the tissue showed that Na+ and Ca2+ were essential for the photorelaxation. K+ depolarized‐tissue did not show the photoresponse.

The presence of the metabolic inhibitors, iodoacetic acid, 2,4‐dinitrophenol, sodium fluoride, sodium azide or potassium cyanide, abolished the photorelaxation response.

It is proposed that the photorelaxation of the tissue resulted from the liberation of metabolic energy following NO2 ion‐dependent absorption of u.v. light energy, which in turn, interfered with the Na+ ion movement across the cell membrane.
AN ANALYSIS OF THE NEGATIVE INOTROPIC ACTION OF SOMATOSTATIN
Authors: QUIRION R. , REGOLI D. , RIOUX F. , ST‐PIERRE S.
Published: July 2012

Somatostatin (SS) was evaluated as a chronotropic and inotropic agent in isolated spontaneously beating auricles of rats, rabbits and guinea‐pigs.

SS was completely inactive in rat and rabbit auricles but exerted a dose‐dependent, negative inotropic effect in guinea‐pig auricles in concentrations between 1.5 × 10−8 to 1.2 × 10−6 m.

The negative inotropic effect of SS (6.0 × 10−8 and 3.0 × 10−7 m) was not inhibited by a mixture of antagonists containing practolol (7.9 × 10−6 m), phentolamine (3.5 × 10−7 m), methysergide (2.8 × 10−7 m), diphenhydramine (3.9 × 10−5 m), cimetidine (4.0 × 10−5 m) atropine (3.4 × 10−7 m) and indomethacin (1.4 × 10−5 m).

The negative inotropic effect of SS was greatly potentiated by reduction in the Ca2+ concentration of the medium from 5.0 to 1.25 mm.

On a molar basis, SS was equipotent with acetylcholine (ACh) as a negative inotropic agent in the guinea‐pig auricles.

SS (6.0 × 10−8 and 6.0 × 10−7 m) was found to inhibit selectively the positive inotropic action of neurotensin (NT) in guinea‐pig but not in rat auricles.

The inhibitory action of SS against NT was independent of its negative inotropic action.

These results suggest that SS produces its negative inotropic action by interacting with specific receptors presumably located in the cell membrane of guinea‐pig atria. The interaction between SS and its receptor may cause a decreased Ca2+ diffusion and/or transport into the atrial cells. The physiological and pharmacological significance of these results is discussed.
RAPID ABSORPTION FROM THE URINARY BLADDER OF A SERIES OF n‐ALKYL CARBAMATES: A ROUTE FOR THE RECIRCULATION OF DRUGS
Authors: BRIDGES J.W. , SARGENT N.S.E. , UPSHALL D.G.
Published: July 2012

The rate of loss of a series of n‐alkyl carbamates from the lumen of the urinary bladders of female rats has been studied.

The rate of loss obeys first order kinetics and was not affected by water flux across the bladder wall nor by binding of the carbamates to it.

The rate of loss of octyl carbamate was reduced by about 76% by the presence of 5% Tween 80. Histological evidence indicates that this may be due to the formation of a thin luminal lining which may be adsorbed Tween 80 or mucopolysaccharide material.

The absorption rate of the carbamates was limited by their hydrophilicity but reached a plateau for the more lipophilic homologues with a half life for loss of approximately 10 min.

The implications of these results with regard to the recirculation of unmetabolized drugs and hydrolysed conjugates of drugs, the systemic absorption of intravesically applied cancer chemotherapeutic agents and bladder wall permeability to carcinogens are discussed.
THE EFFECT OF POTASSIUM ON FROG STOMACH MUSCLE
Authors: BAYSAL F. , ÖNDER S. , ÖZGÜL M. , TOYGAR A.
Published: July 2012

KCl relaxed strips of frog stomach muscle. Usually, the effect was biphasic, i.e. contraction followed by relaxation at a concentration of 137 mm.

The effect was mimicked by K2SO4.

Ouabain (5 and 10 μg/ml) blocked the relaxations and reversed them to contractions. The tension of strips was not affected.

Phenoxybenzamine (1 μg/ml) and procaine (20 μg/ml) inhibited the relaxations, potentiated the contractile component and lowered the tone of the muscle.

The relaxation and the tone were inhibited by papaverine (5 μg/ml) but the contractile component was unaffected.

It is suggested that potassium‐induced relaxations are mediated through the activation of the sodium pump.
RELAXANT RESPONSE OF GOAT TRACHEA TO 5‐HYDROXYTRYPTAMINE MEDIATED BY D‐TRYPTAMINE RECEPTORS
Authors: CHAND N. , DeROTH L. , EYRE P.
Published: July 2012

Goat isolated trachea contracted in response to carbachol, histamine and 2‐pyridylethylamine (an H1‐receptor agonist) and relaxed after application of isoprenaline, 5‐hydroxytryptamine (5‐HT) and phenylephrine.

Mepyramine, a selective H1‐receptor antagonist, blocked histamine‐ and 2‐pyridylethylamine‐induced contractions. In high doses it also exhibited some nonspecific antagonism to carbachol. After H1‐receptor blockade, 4‐methylhistamine and dimaprit (specific H2‐agonists) relaxed the carbachol‐contracted trachea.

Propranolol, a β‐adrenoceptor blocker, antagonized relaxation in response to isoprenaline and phenylephrine. In high doses, it produced a reversal of the phenylephrine response.

Indomethacin enhanced contractions in response to carbachol and histamine.

Relaxation to 5‐HT was not affected by propranolol, indomethacin, metiamide or cimetidine (H2‐blockers). These findings appear to exclude the involvement of adrenergic, prostaglandinergic and H2‐histaminergic mechanisms in the mediation of this response.

Atropine potentiated 5‐HT‐induced relaxations. This suggests the participation of a ‘masked’ excitatory cholinergic mechanism.

Methysergide, dibenamine and dibenzyline selectively antagonized or reversed 5‐HT‐induced relaxation. Dibenamine and dibenzyline enhanced relaxations to isoprenaline.

This investigation showed (i) a relaxant response of goat trachea to 5‐HT, mediated via D‐muscular tryptamine receptors; (ii) a small population of excitatory M‐neuronal tryptamine and α‐adrenoceptors; and (iii) predominance of H1‐histamine receptors in the goat trachea.
CHARACTERIZATION OF VASCULAR HISTAMINE RECEPTORS IN THE RAT
Authors: POWELL JAMES R. , SHAMEL L. BLAIR
Published: July 2012

In the rat the decrease in blood pressure caused by histamine involves activation of both H1‐ and H2‐receptors. Since arterial pressure measurements alone do not permit the separation of responses into cardiac and vascular components, the following experiments were undertaken to study vascular histamine receptors.

Vascular responses were studied in the autoperfused hindquarters of anaesthetized rats. Intra‐arterial histamine caused vasodilatation which was only partially attenuated by treatment with mepyramine, an H1‐receptor antagonist. Treatment with metiamide, the H2‐receptor antagonist, did not affect vasodilatation caused by histamine but did attenuate vasodilatation which persisted after mepyramine.

Intra‐arterial 4‐methylhistamine, an H2‐receptor agonist, caused vasodilatation which was reduced by metiamide. The H1‐receptor agonist, 2‐(2‐pyridyl)ethylamine also caused vasodilatation which was blocked by mepyramine.

It is concluded that in the rat, histamine causes vasodilatation mediated by both H1‐ and H2‐receptors.
THE RELEASE OF PROSTAGLANDIN E2 FROM THE SKIN OF THE PLAICE, Pleuronectes platessa L.
Authors: ANDERSON A.A. , FLETCHER THELMA C. , SMITH G.M.
Published: July 2012

A fungal extract which produces a cutaneous hypersensitivity reaction in the plaice, Pleuronectes platessa L., was incubated in vitro with the skin of this teleost fish. Samples of incubation media were assayed for smooth muscle stimulating activity.

Prostaglandin E2 was identified by bioassay, thin‐layer chromatography, ultraviolet absorption spectroscopy and gas chromatography‐mass spectrometry. Release from challenged skin was maximum after 60 min incubation.

Analysis of the fatty acid composition of plaice skin showed that although arachidonic acid was present (3% of total fatty acids), the precursor of prostaglandin E3, eicosapentaenoic acid contributed 9% of total.

Indomethacin (50 mg/kg i.p.) did not inhibit the erythema induced by the fungal extract, whilst a dose of 1 mg/kg maximally inhibited prostaglandin release from skin on incubation in vitro.

It is concluded that prostaglandins do not have an exclusive role in the mediation of the hypersensitivity reaction.
BACKWARD WALKING AND CIRCLING: BEHAVIOURAL RESPONSES INDUCED BY DRUG TREATMENTS WHICH CAUSE SIMULTANEOUS RELEASE OF CATECHOLAMINES AND 5‐HYDROXYTRYPTAMINE
Authors: CURZON G. , FERNANDO J.C.R. , LEES A.J.
Published: July 2012

The roles of catecholamine and 5‐hydroxytryptamine (5‐HT) release in mediating backward walking and circling were studied in rats.

These behaviours occurred in animals given 15mg/kg intraperitoneally of (+)‐amphetamine (which predominantly releases catecholamines) or either p‐chloroamphetamine or fenfluramine (which predominantly release 5‐HT). They also occurred when smaller doses of (+)‐amphetamine (5mg/kg) and either p‐chloroamphetamine (2–5 mg/kg) or fenfluramine (5 mg/kg) were given together.

Characteristic dopamine‐dependent behaviours (rearing, licking, gnawing) resulting from (+)‐amphetamine injection were greatly reduced by p‐chloroamphetamine or fenfluramine.

Characteristic 5‐HT‐dependent behaviours (wet dog shake, hind limb abduction) resulting from injection of either p‐chloroamphetamine or fenfluramine were unaffected by (+)‐amphetamine.

Fragmentary backward walking and circling resulting from levallorphan injection (50 mg/kg s.c.) were decreased by (+)‐amphetamine at low dosage.

Results in general strengthen previous evidence that backward walking and circling are mediated by simultaneous dopamine and 5‐HT release.

The possible relevance of the above findings to hallucinogenic activity, amphetamine psychosis, schizophrenia and abnormal movements due to l‐DOPA treatment is discussed.
THE INHIBITORY EFFECTS OF PRESYNAPTIC α‐ADRENOCEPTOR AGONISTS ON CONTRACTIONS OF GUINEA‐PIG ILEUM AND MOUSE VAS DEFERENS IN THE MORPHINE‐DEPENDENT AND WITHDRAWN STATES PRODUCED in vitro
Authors: GILLAN MAUREEN G.C. , KOSTERLITZ H.W. , ROBSON LINDA E. , WATERFIELD ANGELA A.
Published: July 2012

Isolated ilea from guinea‐pigs implanted with morphine pellets were stimulated coaxially, either with or without morphine present in the bath fluid, and the longitudinal contractions recorded.

In the absence of morphine the inhibitory effects of the presynaptic α‐adrenoceptor agonists, clonidine and oxymetazoline were much reduced and the dose‐response curve was flat. This state of ‘withdrawal’ was readily reversed by morphine and levorphanol but not its inactive (+)‐isomer, dextrorphan.

The κ‐agonists, ketazocine and ethylketazocine, also restored the effects of clonidine as did the opioid peptides Tyr‐d‐Ala‐Gly‐Phe‐d‐Leu, acting preferentially on δ‐receptors, and Tyr‐d‐Ala‐Gly‐MePhe‐Met(O)‐ol, acting mainly on μ‐receptors.

The inhibitory effects of adrenaline and adenosine 3′,5′‐diphosphate were reduced at low but not at high concentrations.

In contrast, the inhibitory effect of clonidine on the electrically evoked contractions of vasa deferentia from mice implanted with morphine pellets was not abolished by the lack of morphine in the bath fluid or by addition of naloxone.

A possible explanation is suggested for the loss of the inhibitory effects of presynaptic α‐adrenoceptor agonists in the withdrawn state of the dependent ileum.
ANTI‐AGGREGATORY EFFECT OF PROSTACYCLIN (PGI2) in vivo
Authors: BAYER B.‐L. , BLASS K.‐E. , FORSTER W.
Published: July 2012

Prostacyclin (PGI2) when infused intravenously reduced the mortality of rabbits given high intravenous doses of arachidonic acid (AA). Prostaglandins E1 and D2 were ineffective. Indomethacin pretreatment abolished the toxic AA effect. Since the lethal effect of AA is partly due to the formation of platelet aggregates it is concluded that PGI2 is a most potent antiaggregatory prostaglandin in vivo.
ACETYLCHOLINE RECEPTORS IN THE CILIARY GANGLION AND IN THE IRIS MUSCLE OF THE CHICK: SPECIFIC BINDING AND EFFECT ON THE SYNAPTIC TRANSMISSION OF THE NEUROTOXIN FROM Naja naja siamensis
Authors: CONTI‐TRONCONI B. , GOTTI C. , PAGGI P. , ROSSI A.
Published: July 2012

A specific binding of Naja naja siamensis neurotoxin was found both in the iris and in the ciliary ganglion of the chick.

Naja‐toxin (125 nm) caused a complete block of the iris muscle contraction induced by carbamyl‐choline.

Naja‐toxin had a different effect on the two neuronal populations present in the ganglion: it blocked the synaptically evoked response of the ciliary cells, while the response of the choroid ones was only slightly reduced. The effects were the same in a wide range of concentrations (125 to 2500 nm).

The results obtained in the iris show the existence of an acetylcholine receptor population similar to the nicotinic receptor of the skeletal muscle.

In the ciliary ganglion the results confirm the existence of different acetylcholine receptors on the two cell types.
EFFECTS OF Δ9‐TETRAHYDROCANNABINOL, 2.4‐DINITROPHENOL AND PENTOLINIUM TARTRATE ON BEHAVIOURAL THERMOREGULATION IN MICE
Authors: PERTWEE R.G. , TAVENDALE R.
Published: July 2012

A new apparatus in which mice are allowed to shuttle between the warm and cool parts of a continuous oval tunnel has been designed for the measurement of drug effects on behavioural thermoregulation.

The length of time that untreated mice spent in the warmer part of the apparatus (tunnel wall temperature 38°C) was found to be inversely related to the temperature of the cooler part (wall temperature 18c, 24c or 30°C).

Mice treated with 2,4‐dinitrophenol at a dose known to be hyperthermic at an ambient temperature of 32 C (20 mg/kg s.c.) spent an increased length of time in the cooler part of the apparatus (wall temperature 18°C) and did not exhibit any change in rectal temperature.

Mice treated with pentolinium tartrate at a dose known to be hypothermic at room temperature (5.0 mg/kg i.v.) spent a decreased length of time in the cooler part of the apparatus (wall temperature 24 C) and did not exhibit any change in rectal temperature.

It is concluded from the above results that the apparatus can be used to measure drug effects on behavioural thermoregulation.

In experiments of 30 min duration, mice treated with Δ9‐tetrahydrocannabinol (A9‐THC) at doses known to be hypothermic and to lower oxygen consumption at room temperature (20 mg/kg i.p. or 2.0 mg/kg i.v.) spent a longer time in the warmer part of the apparatus between 15 and 30 min after injection. Rectal temperatures measured 30 min after injection were only slightly less than those of control mice. In these experiments the wall temperature of the cool tunnel was 24C.

In experiments of 15 min duration, mice treated with A9‐THC (20 mg/kg) and then placed in the apparatus spent more time in the cooler part of the apparatus (wall temperature 24 C) and exhibited a large fall in rectal temperature.

It is concluded that immediately after injection of A9‐THC the mice do not attempt to oppose drug‐induced falls in deep body temperature by moving into a warm environment and that only later do the animals demonstrate a preference for a warm environment.
A POSSIBLE ROLE FOR LIPOXYGENASE PRODUCTS AS REGULATORS OF AIRWAY SMOOTH MUSCLE REACTIVITY
Authors: ADCOCK J.J. , GARLAND L.G.
Published: July 2012

The size of guinea‐pig isolated tracheal contractions induced by histamine was substantially augmented by pretreatment with the cyclo‐oxygenase inhibitor, indomethacin. However, compounds which inhibit both the cyclo‐oxygenase and lipoxygenase pathways of arachidonic acid metabolism not only did not augment histamine‐induced contractions of the guinea‐pig trachea, but also completely reversed the increased reactivity to histamine produced by indomethacin. The SRS‐A (slow reacting substance of anaphylaxis) antagonist, FPL55712, and the Antiallergic drug, cromoglycate, had no effect on the augmentation of histamine‐induced contractions by indomethacin.
POST‐TETANIC POTENTIATION IN GANGLIA WHICH ARE BLOCKED WITH HEXAMETHONIUM
Authors: CHRIST DARYL
Published: July 2012

Post‐tetanic potentiation (p.t.p.) of the compound action potential in the presence of hexamethonium was observed in the isolated stellate ganglion of the hamster using extracellular postganglionic recordings.

The magnitude of the p.t.p. was small (less than a 20% increase) in the control solution, but increased as the depth of blockade with hexamethonium was increased.

The magnitude of the p.t.p. was frequency‐dependent between 1 and 40 Hz.

Atropine partially blocked the p.t.p.

McN‐A‐343, a muscarinic agonist, potentiated ganglionic transmission which had been partially blocked by hexamethonium.

Repetitive stimulation in the presence of hexamethonium potentiated the discharges induced by DMPP, a nicotonic agonist. The potentiation was blocked by atropine.

It was concluded that the p.t.p. in the presence of hexamethonium has the same characteristics as p.t.p. in the control solution. There appears to be both a muscarinic component and a presynaptic component of the p.t.p.