bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of pre‐ and postjunctional inhibition by prostaglandin E2 of lipolysis induced by sympathetic nerve stimulation in dog subcutaneous adipose tissue in situ
Authors: FREDHOLM B. B. , HEDQVIST P.
Published: July 2012

Canine subcutaneous adipose tissue was isolated and autoperfused in situ after labelling of the noradrenaline stores by 3H‐(—)‐noradrenaline.

Prostaglandin E2 (10–200 ng/ml) increased blood flow and glucose uptake, and caused a dose‐dependent inhibition of lipolysis induced by sympathetic nerve stimulation (4 Hz). The actions of exogenous prostaglandin E2 are therefore similar to those of prostaglandin E1 in this tissue. There were no consistent effects of prostaglandin E2 on the vasoconstriction or on the 3H‐noradrenaline overflow induced by nerve stimulation.

Phenoxybenzamine (1·5–2 mg i.a.) caused a 5‐fold increase in 3H‐noradrenaline overflow and a 95% reduction of the vasoconstrictor response to nerve stimulation. The lipolytic response was similar to that of the control. Prostaglandin E2 (100–200 ng/ml) administered after phenoxybenzamine caused a 90% inhibition of lipolysis, while the vasoconstrictor response was enhanced to about 50% of control. Prostaglandin E2 inhibited 3H‐noradrenaline overflow by about 50% but it was still larger than that of the control.

It is suggested that exogenous prostaglandin E2 inhibits lipolysis induced by sympathetic nerve stimulation mainly by a postjunctional action in canine subcutaneous adipose tissue.
An assessment of sympathetic function in isolated tissues from mice given nerve‐growth‐factor antiserum and 6‐hydroxydopamine
Authors: HUGHES I. E. , KIRK JENNIFER A. , KNEEN BARBARA , LARGE B. J.
Published: July 2012

Experiments were done on isolated tissues from mice injected with 0·9% w/v NaCl solution (saline), 6‐hydroxydopamine (6‐OHDA), nerve‐growth‐factor antiserum (NGF‐As) or a combination of these agents (NGF‐As 4–6‐OHDA).

Fluorescence histochemistry of vasa deferentia showed clear differences between each of the treatments but no such distinction was possible in cardiac ventricle or intestine.

Compared with controls, the chronotropic responses of atria to field stimulation were reduced by all three treatments in the order NGF‐As<6‐OHDA<NGF‐As + 6‐OHDA. Supersensitivity to noradrenaline occurred in atria from all treated groups.

In contrast, vasa deferentia from NGF‐As‐treated mice responded almost identically with controls to both field stimulation and to exogenous noradrenaline. Considerable functional impairment and noradrenaline supersensitivity were obvious in both the 6‐OHDA and the NGF‐As + 6‐OHDA groups but no distinction could be made between them.

The relaxation of superfused ileum following nerve stimulation was reduced in the NGF‐As group, whilst preparations from the two groups given 6‐OHDA usually gave a motor response which was blocked by atropine.

None of the treatments employed in these experiments caused complete sympathectomy although 6‐OHDA alone or in combination with NGF‐As produced a more pronounced effect than NGF‐As alone and the relative ineffectiveness of the latter is discussed. The implications of the motor response after 6‐OHDA in ileum when the nerves were stimulated is considered in the light of the cholinergic link hypothesis.
Effects of drugs and of electrical stimulation on the muscularis mucosae of rabbit large intestine
Authors: GALLACHER MAUREEN , MACKENNA B. R. , McKIRDY H. C.
Published: July 2012

The muscularis mucosae of the rabbit large intestine shows spontaneous rhythmic contractions with an average frequency of about 11/minute.

The muscularis mucosae responds to acetylcholine, adrenaline and noradrenaline in a manner similar to that of whole segments of terminal large intestine.

The muscularis mucosae would seem to have a cholinergic motor innervation.
The effect of narcotic analgesics on the uptake of 5‐hydroxytryptamine and (—)‐metaraminol by blood platelets
Authors: AHTEE LIISA , SAARNIVAARA LAILA
Published: July 2012

The effects of narcotic analgesic and related drugs were studied on the uptake of 5‐hydroxytryptamine (5‐HT) and (—)‐metaraminol by blood platelets.

The most potent drug in inhibiting the uptake of 5‐HT (10 μm) by human platelets was methadone, followed by pentazocine>piminodine ˜ pethidine ˜ anileridine ˜ cyclazocine ˜ thebaine > dextropropoxyphene. Alphaprodine, papaverine, apomorphine, nalorphine, codeine, and morphine were almost without effect. Methadone was slightly less active than desipramine, and had 10% of the activity of imipramine under similar conditions. Naloxone did not antagonize the effect of methadone on 5‐HT uptake.

The most potent inhibitor of metaraminol (3 μm) uptake by human platelets was piminodine, followed by pentazocine>anileridine>cyclazocine=methadone > dextropropoxyphene ˜ thebaine > papaverine ˜ alphaprodine >pethidine>morphine. The activity of morphine was 1% of that of piminodine. Piminodine was more potent than desipramine and protriptyline under similar conditions. The order of potency of drugs studied in inhibiting the uptake of metaraminol by rabbit platelets was similar to that obtained with human platelets.

The effects of the analgesics studied on inhibiting uptake of monoamines did not correlate with their pain‐relieving properties.
Pharmacological analysis of the acute inflammatory process induced in the rat's paw by local injection of carrageenin and by heating
Authors: LEME J. GARCIA , HAMAMURA L. , LEITE M. P. , SILVA M. ROCHA E
Published: July 2012

Local injection of carrageenin in the rat's paw produced oedema and leakage of dye which had been administered previously by the intravenous route. A net dissociation between both parameters was observed: while oedema developed slowly, maximal intensity being attained after 4–5 h, dye‐leakage was maximum after 1 hour.

Anti‐inflammatory drugs such as acetylsalicylic acid and indomethacin were effective in reducing oedema and dye‐leakage when given before the injection of carrageenin, but much less effective when given 30 or 60 min after carrageenin. Hexadimethrine bromide was effective in reducing dye‐leakage also when given 1 h after the injection of carrageenin.

Combined administration of benadryl and methysergide, before the injection of carrageenin caused only a slight reduction in oedema and dye‐leakage.

When the paws were heated (55° C for 30 s) as a noxious stimulus the dissociation between maximal oedema and maximal dye‐leakage was not observed, both phenomena running parallel. Pre‐treatment of the animals with indomethacin did not afford any protection.

These results suggest that the inflammatory reaction to mild stimuli (carrageenin in our experiments) develops through different phases: initially the increased vascular permeability involves extravasation of plasma proteins and that phase is followed by an increased permeability mainly to water. Stronger stimuli (heating in our experiments) produce an overlapping of both phases, probably by inflicting severe damage to the vascular bed of the affected area.

The anti‐inflammatory drugs employed affected chiefly the initial phase of the response.
Some observations on the β‐adrenoceptor agonist properties of the isomers of salbutamol
Authors: BRITTAIN R. T. , FARMER J. B. , MARSHALL R. J.
Published: July 2012

The pharmacological activities of the optical isomers of salbutamol have been examined. (–)‐Salbutamol was much more potent than (+)‐salbutamol on β‐adrenoceptors.

Both (–)‐ and (+)‐salbutamol showed high selectivity for β‐adrenoceptors in bronchial muscle compared to cardiac muscle, in this way resembling racemic salbutamol.

The use of isomeric activity ratio to detect differences between receptors was examined in the light of the results obtained with the isomers of salbutamol.
Microiontophoretic release of drugs from micropipettes: use of 24Na as a model
Authors: CLARKE G. , HILL R. G. , SIMMONDS M. A.
Published: July 2012

The use of 24Na+ of high specific activity allowed its iontophoretic release from multibarrelled glass micropipettes to be followed over short periods with low currents.

When a negative retaining current was passed to reduce diffusional efflux between the periods of positive current expulsion of 24Na+, the rate of release of 24Na+ during the expulsion period progressively increased during the first minute before becoming constant.

The currents employed were similar to those normally used to regulate the microiontophoretic release of potent drugs such as γ‐aminobutyric acid. It is therefore concluded that, during the usual period of response to such drugs, the rate of release of drug is not constant but increasing.

The implications of these observations for the construction of microiontophoretic dose‐response relationships is discussed.
Sleep induced by small doses of tubocurarine injected into cerebral ventricles of dog
Authors: HARANATH P. S. R. K. , SHYAMALAKUMARI S.
Published: July 2012

In unanaesthetized dogs, sleep with the typical sleep pattern in the E.E.G. was produced with (+)‐tubocurarine when injected in a small dose (500 ng) into, or perfused in low concentration (100 ng/ml) through the cerebral ventricles.
Elongation of oestrous cycle in the guinea‐pig following subcutaneous or intra‐uterine administration of indomethacin
Authors: HORTON E. W. , POYSER N. L.
Published: July 2012

Guinea‐pigs injected subcutaneously with 10 mg indomethacin twice daily, from day 7 of the oestrous cycle, had their oestrous cycles significantly lengthened (P < 0·001) by about 3 days.

When the indomethacin was incorporated into a slow‐release preparation and placed in the uterus (33 mg per horn), the oestrous cycle lengths of these guinea‐pigs were greatly prolonged and approached that produced by hysterectomy.

The measurement of corpora luteal size and progesterone levels in some of the guinea‐pigs autopsied on day 47 of the extended cycle showed functional corpora lutea to be present.

It was apparent that indomethacin had prolonged the life span of the corpus luteum. This would account for the increase in the length of the oestrous cycle.

Recent investigations suggest that normal corpora luteal regression, with the termination of the oestrous cycle, is induced by prostaglandin F2α released from the uterus on day 15. Since indomethacin prevents prostaglandin biosynthesis, it is probable in these experiments that this drug had prevented luteal regression by inhibiting the biosynthesis by, and release from, the uterus of prostaglandin F2α in luteolytic concentrations.

These results provide further evidence that the uterine luteolytic hormone in guinea‐pigs is prostaglandin F2α.
[3H]‐adenosine nucleotide and [3H]‐noradrenaline uptake by cold stored guinea‐pig taenia caecum; mechanical effects and release of [3H]‐adenosine nucleotide by noradrenaline, papaverine, and nitroglycerine
Authors: KUCHII M. , MIYAHARA J. T. , SHIBATA S.
Published: July 2012

Cold storage (2° C) treatment progressively reduced noradrenaline uptake by the taenia caecum of the guinea‐pig. After 15 days of cold treatment, [3H]‐noradrenaline uptake by tissue was reduced to about 10% of control. On the other hand, prolonged cold storage failed to decrease [3H]‐adenosine uptake by the taenia caecum.

Cocaine (10 μm) inhibited noradrenaline uptake by about 82% but nucleoside uptake was inhibited by 20%. Cocaine treatment failed to decrease the residual noradrenaline uptake in the cold stored strips (more than 10 days). Phenoxybenzamine (1 μm) or oligomycin (1 μg/ml) treatment decreased the tissue adenosine uptake to about 34% and 28% of the respective controls.

Based on thin layer chromatography, it was estimated that approximately 68% of [3H]‐adenosine was converted into and retained as [3H]‐ATP in the fresh tissues, a small fraction was accountable as [3H]‐adenosine (18%) but virtually no [3H]‐AMP, [3H]‐cyclic AMP or [3H]‐ADP was detected. Similar distribution of radioactivity of nucleotides was observed in tissues cold stored for 8 days.

The inhibition of the mechanical activity of taenia by noradrenaline (10 μm), papaverine (100 μm) and nitroglycerine (100 μm) was accompanied by [3H]‐adenine nucleotide but not [3H]‐noradrenaline release. Treatment with phentolamine and propranolol (both 1 μm) had no effect on the adenine nucleotide release elicited by nicotine and electrical field stimulation, whereas such treatment reduced the inhibitory action of both stimuli.

These results suggest that the nucleotide release after application of electrical and chemical stimulation may be from an extraneurogenic source. Thus, we conclude that ATP or a related nucleotide is not the chemical transmitter of the non‐adrenergic inhibition in the taenia caecum of the guinea‐pig.
Tolerance pattern of the anorexigenic action of amphetamine in rats
Authors: GHOSH M. N. , PARVATHY S.
Published: July 2012

When food intake in fasted male rats was recorded daily for two consecutive 2 h periods it revealed a characteristic pattern.

In the control rats the food intake was greater during the first than the second 2 h period. Following (±)‐amphetamine 5 mg/kg s.c. 30 min before food for 7 days there was a reversal of this normal food pattern. The rats consumed much less during the first 2 h period but progressively more during the second 2 h period.

The first 2 h food intake remained low throughout the treatment period and there was no evidence of development of tolerance despite continuation of treatment.

The second 2 h food intake steadily increased, contributing to the appearance of tolerance when only total 4 h food intake was recorded.

On withdrawal of amphetamine, there was immediate recovery of the first 2 h food intake. The second 2 h food intake, though decreased, remained high compared to the pretreatment level and may be responsible for the production of the ‘rebound’ phenomenon following withdrawal of amphetamine.
Effects of suramin on complement, blood clotting, fibrinolysis and kinin formation
Authors: EISEN V. , LOVEDAY C.
Published: July 2012

The inhibition by suramin of complement components, and of blood clotting, fibrinolytic, and plasma kinin forming factors depended on the conditions of the assay and on the substrates used.

Haemolysis by complement was more effectively inhibited in red blood cell suspensions, than in agarose gel plates. In esterolytic tests, the activation of component 1 (C1) to C1 esterase was significantly inhibited by 0·1–0·3 mm suramin, and the activity of C1 esterase by 0·5 mm suramin.

Part of the anticoagulant effect of suramin is due to inhibition of the action of thrombin on fibrinogen.

Suramin did not inhibit fibrin degradation by the fibrinolytic system in plasma. In esterolytic tests, the activation of plasminogen was more potently inhibited than the activity of plasmin.

Activation of plasma kallikrein, measured either by kinin formation or by esterolysis, was inhibited by 0·1–0·3 mm suramin. Active plasma kallikrein was inhibited by 0·3–0·5 mm suramin. Pancreatic kallikrein was weakly inhibited, and urinary kallikrein not at all.
DEPOLARIZING ACTIONS OF γ‐AMINOBUTYRIC ACID AND RELATED COMPOUNDS ON RAT SUPERIOR CERVICAL GANGLIA IN VITRO
Authors: BOWERY N.G. , BROWN D.A.
Published: July 2012

Potential changes in rat superior cervical ganglia were recorded in vitro with surface electrodes.

γ‐aminobutyric acid (GABA) produced a transient, low‐amplitude ganglion depolarization at rest, and a transient hyperpolarization in ganglia depolarized by carbachol. Depolarization was not prevented by preganglionic denervation. The log dose‐response curve for depolarization was sigmoid with a mean ED50 of 12.5 μm.

The ganglion was depolarized in similar manner by the following compounds (mean molar potencies relative to GABA (=1) in brackets): 3‐aminopropane sulphonic acid (3.4), γ‐amino‐β‐hydroxybutyric acid (0.27), β‐guanidino‐propionic acid (0.12), guanidinoacetic acid (0.057), δ‐aminovaleric acid (0.048), β‐alanine (0.01), 2,4‐diaminobutyric acid, γ‐guanidinobutyric acid, taurine and N‐methyl‐GABA (all <0.01). The following compounds did not depolarize the ganglion at 10 mm concentrations: α‐ and β‐amino‐n‐butyric acids, α‐amino‐iso‐butyric acid, glycine and glutamic acid.

Depolarization declined in the continued presence of GABA. Ganglia thus ‘desensitized’ to GABA showed a diminished response to other amino acids but not to carbachol.

The effect of GABA was not antagonized by hyoscine and hexamethonium in combination, in concentrations sufficient to block responses to carbachol.

Responses to GABA were blocked more readily than those to carbachol by bicuculline (IC50, 14 μm) and picrotoxin (IC50, 37 μm). Strychnine (IC50, 73 μm) was a relatively weak and less selective GABA‐antagonist.

It is concluded that sympathetic ganglion cells possess receptors for GABA and related amino acids which are (a) different from the acetylcholine receptors and (b) similar to GABA receptors in the central nervous system.
EFFECTS OF VINBLASTINE ON NORADRENERGIC AXONS
Authors: HANBAUER I. , JACOBOWITZ D.M. , KOPIN I.J.
Published: July 2012

The effects of vinblastine and 6‐hydroxydopamine (6‐OHDA) on various parameters of adrenergic neurone functions in the rat were examined and compared.

During the first 12 h after injection of vinblastine, although the concentration of cardiac noradrenaline was unaltered, the turnover rate of the catecholamine in the heart was reduced to 40 ng g−1 h−1 compared to a rate of 66 ng g−1 h−1 in the hearts of animals treated with 0.9% w/v NaCl solution.

The uptake of noradrenaline by rat atria in vitro was inhibited by vinblastine (2.5 × 10−4 m) or 6‐OHDA (5 × 10−5 m), but only the inhibitory effect of vinblastine was readily reversible. The in vitro uptake of noradrenaline by atria of vinblastine‐ or 6‐OHDA‐treated rats was found to be impaired two days after injection of the drugs. After 14 days, however, the noradrenaline uptake was 71% of control values after vinblastine and 91% after 6‐OHDA.

In addition to intensely fluorescent nerve trunks in epicardial connective tissue septa, a decrease in the number of fluorescent adrenergic terminals in the atria and ventricles could be observed two days after vinblastine injection. It is suggested that intravenous vinblastine treatment, like 6‐OHDA, results in the destruction of adrenergic nerve terminals.
ABSORPTION, METABOLISM AND DISTRIBUTION OF [14C]‐O‐METHYLDOPA AND [14C]‐l‐DOPA AFTER ORAL ADMINISTRATION TO RATS
Authors: RIVERA‐CALIMLIM LEONOR
Published: July 2012

The absorption, tissue distribution, and metabolism of [14C]‐O‐methyldopa were compared with those of [14C]‐l‐DOPA after oral administration to rats.

Total radioactivity in the plasma and brain of rats treated with [14C]‐O‐methyldopa was significantly higher (2 fold and 30–50 fold, respectively) than that of rats treated with [14C]‐l‐DOPA.

Total radioactivity in the gut washings and intestinal tissue 2 h after oral administration was significantly higher in rats treated with [14C]‐l‐DOPA than in rats treated with [14C]‐O‐methyldopa. The reverse was observed in the stomach tissues.

Peripheral metabolism of [14C]‐O‐methyldopa was much lower than that of [14C]‐l‐DOPA; the major metabolite of [14C]‐O‐methyldopa in the plasma is l‐DOPA, whereas l‐DOPA is mainly metabolized to phenylcarboxylic acids.
EFFECT OF ETHANOL ON THE OXIDATIVE METABOLISM OF TRYPTAMINE BY RAT LIVER HOMOGENATE
Authors: ASAAD M.M. , BARRY H. , CLARKE D.E. , DIXIT B.N.
Published: July 2012

The effect of a wide range of ethanol concentrations (v/v) on indoleacetic acid (IAA) formation from the oxidative deamination of tryptamine was studied in vitro, in rat whole liver homogenate.

IAA production was inhibited progressively by ethanol in concentrations between 0.01% to 0.2%, but the inhibition declined when the ethanol concentration was increased further to 6%.

Ethanol‐induced inhibition of IAA formation was only partially reversed by excess aldehyde dehydrogenase, whereas reductions in IAA formation were completely prevented by pyrazole or ethanol (6% and 10%) itself.

Excess nicotinamide adenine dinucleotide failed to alter the inhibitory effect of ethanol and no evidence was obtained for inhibition of monoamine oxidase by ethanol or its metabolite, acetaldehyde.

We conclude that ethanol indirectly inhibits IAA production as a result of oxidation of ethanol by alcohol dehydrogenase, during which the oxidative metabolism of tryptamine is shifted towards the reductive pathway, thus favouring the formation of tryptophol in place of IAA.
HYPERPOLARIZATION OF RABBIT SUPERIOR CERVICAL GANGLION CELLS DUE TO ACTIVITY OF AN ELECTROGENIC SODIUM PUMP
Authors: LEES G.M. , WALLIS D.I.
Published: July 2012

The mechanisms underlying the hyperpolarization which follows depolarization of rabbit superior cervical ganglion cells by acetylcholine, have been investigated and compared with the mechanisms responsible for the hyperpolarizations induced by orthodromic stimulation of the ganglion.

The amplitude of the drug‐induced hyperpolarization (after‐hyperpolarization) was diminished when [Na+]o and the duration of the preceding depolarization were reduced.

In K+‐free solutions, the amplitude of the after‐hyperpolarization was often diminished and its rate of development was reduced. In 12.5 mm K=+‐Krebs solutions, the amplitude and rate of development of the after‐hyperpolarization were increased; the potential was still present when the resting potential was at or close to EK.

Ouabain (10 μm) prevented or greatly diminished the after‐hyperpolarization. The rates of onset and decay of the after‐hyperpolarization were reduced in glucose‐free solutions.

It is, therefore, concluded that the after‐hypolarization is due to the activity of an electrogenic sodium pump.

The positive after‐potential associated with the ganglionic action potential was increased in K+‐free solutions and diminished when the resting potential approached EK, indicating that it is due to a period of increased K+ conductance. In the presence of high concentrations of hexamethonium (276 μm), the P wave was not selectively depressed by ouabain and has been shown by other workers to be due to a mechanism not involving an increased potassium conductance. It is concluded, therefore, that the positive after‐potential, the P wave and the after‐hyperpolarization are due to different mechanisms.
HYPERGLYCAEMIA PRODUCED BY THE POLYAMINES SPERMINE AND SPERMIDINE
Authors: ANDERSON D.J. , SHAW G.G.
Published: July 2012

Intravenous injection of rabbits with the polyamines spermine (10–30 mg/kg) and spermidine (50–90 mg/kg) produced hyperglycaemia.

Given by intraventricular injection, spermine and spermidine gave rise to hyperglycaemia in doses 250–500 times smaller than those effective intravenously.

Intraventricular injections of the polyamines also produced hyperglycaemia in rats. Adrenal demedullation abolished the response.

In the rabbit, the hyperglycaemia resulting from intraventricular injection of polyamines was abolished in reserpine‐treated animals. Anaesthesia had no effect on the response unless accompanied by anoxia, when the response was potentiated.

Intracisternal injections of the polyamines in rabbits were less effective than intraventricular injections in that doses about four times larger were required to elicit an equivalent response.
EFFECT OF SELECTIVE PROTEOLYSIS ON THE ACCUMULATION OF 5‐HYDROXYTRYPTAMINE BY INTACT RAT BLOOD PLATELETS
Authors: SNEDDON J.M. , WILLIAMS K.I.
Published: July 2012

The effect of perturbation of intact blood platelets with proteolytic enzymes was studied with respect to 5‐hydroxytryptamine (5‐HT) transport, adenine transport and intracellular Na+ and K+ levels.

Leucine aminopeptidase and thrombin reduced 5‐HT transport, released 5‐HT from pre‐labelled platelets and disturbed the gradient to monovalent cations. Leucine aminopeptidase, but not thrombin, inhibited adenine transport.

α‐Chymotrypsin and carboxypeptidases A and B were without effect on the parameters studied.

Trypsin selectively reduced 5‐HT transport. It did not release 5‐HT from blood platelets or inhibit adenine transport.

The action of proteolytic enzymes is discussed in terms of proteins localized in the external membrane that may function in part as membrane carriers.
FAILURE OF CHRONIC DENERVATION TO ALTER THE SENSITIVITY OF THE RAT DIAPHRAGM TO LOCAL ANAESTHETICS OR QUINIDINE
Authors: HARVEY S.C. , RANG H.P.
Published: July 2012

The actions of procaine, nupercaine and quinidine on the membrane resting and action potentials of the normal and chronically denervated rat diaphragm were studied in vitro.

The degree of suppression of the rate of rise of the action potential by any of the drugs was the same in denervated as in normal muscle.

The degree of suppression of the rate of rise of the action potential by procaine in denervated muscle was about the same in the presence and absence of tetrodotoxin.

Three possible interpretations of the lack of effect of denervation on the response to these drugs are discussed:

In the sodium channel, the structural alteration that confers resistance to tetrodotoxin is quite limited and does not affect groups which interact with local anaesthetics.

Local anaesthetics are non‐selective in their binding so that alteration in membrane structure around the channel has little influence on the efficiency of the local anaesthetic.

Denervation may affect the outer surface of the membrane, where acetylcholine and tetrodotoxin act, more than the intracellular surface, where local anaesthetics appear to act.

The slope of the log concentration‐effect line for quinidine was steeper than that for procaine or nupercaine.
MORPHINE ANALGESIA AND THE BULBOSPINAL NORADRENERGIC SYSTEM: INCREASE IN THE CONCENTRATION OF NORMETANEPHRINE IN THE SPINAL CORD OF THE RAT CAUSED BY ANALGESICS
Authors: SHIOMI H. , TAKAGI H.
Published: July 2012

Administration of an analgesic dose (10 mg/kg, s.c.) of morphine increased the concentration of a noradrenaline metabolite, normetanephrine (NM) in the spinal cord of normal rats. The time course of the change in the NM concentration corresponded approximately to that of the morphine analgesia. The concentration of noradrenaline was not affected.

A similar effect on the NM concentration was also observed after the administration of pentazocine (30 mg/kg, s.c.) and nalorphine (20 mg/kg, s.c.).

The NM increasing effect of morphine, pentazocine and nalorphine was found in the dorsal half of the spinal cord but not in the ventral half.

The increase in the concentration of NM induced by morphine, pentazocine or nalorphine was completely suppressed by naloxone (1 mg/kg, s.c.) given 5 min before the administration of these drugs.

When the spinal cord was transected at C1, the NM increasing effect of morphine disappeared, yet when the brain stem was transected at the inter‐collicular level, the effect remained.

In morphine‐tolerant rats, the concentration of NM in the spinal cord was almost the same as that observed in normal rats, but the increase in the concentration of NM in the spinal cord after the acute administration of morphine did not take place.

The NM concentration in the spinal cord of normal rats was not modified by aminopyrine (75 mg/kg, s.c.), chlorpromazine (10 mg/kg, s.c.), mephenesin (100 mg/kg, i.p.) or naloxone (25 mg/kg, s.c.).

The possible relation between morphine analgesia and the descending noradrenergic neurones in the spinal cord of rats is discussed.
THE EFFECT OF ETHACRYNIC ACID ON THE GUINEA‐PIG AND RAT ISOLATED VAS DEFERENS
Authors: KHOYI M.A. , POUSTI A. , ZARRINDAST M.R.
Published: July 2012

The effect of ethacrynic acid (EA) was studied on guinea‐pig and rat vas deferens in vitro.

EA contracted the guinea‐pig but not the rat vas deferens in a dose‐dependent manner (50–800 μg/ml). Tyramine caused contraction in 10 out of 18 guinea‐pig vas deferens; EA caused contraction in 17 of the preparations which did not respond to tyramine. Repeated doses of EA produced tachyphylaxis, but there was no cross tachyphylaxis to tyramine.

The contractions produced by EA were prevented by phentolamine or reserpine pretreatment and potentiated by cocaine. A low concentration of desipramine (3 ng/ml) potentiated and higher concentrations (0.6 and 3.0 μg/ml) inhibited the response of vas deferens to EA.

Hexamethonium (100 μg/ml) or atropine (0.1 μg/ml) did not inhibit the effect of EA, excluding the nicotinic and muscarinic receptors as the sites of action.

The effect of noradrenaline (NA) on the guinea‐pig and rat vas deferens was enhanced by EA pretreatment, which may be due to inhibition of NA uptake.

It is concluded that EA releases NA from guinea‐pig vas deferens. The mechanism of release seems to be different from that of tyramine.
EFFECT OF DRUGS ON RAT PAW OEDEMA INDUCED BY MERCURY
Authors: JINDAL M.N. , KELKAR V.V. , VAISHNAV U.H.
Published: July 2012

Metallic mercury (0.04 ml) injected into the foot pad of rats induced a consistent inflammatory reaction, which at 4 h showed oedema but no cellular infiltration or vascular changes. The lesions exhibited lymphocytic infiltration, vasodilatation and haemorrhages at 24 and 48 h, and often became cystic after 2–3 weeks, before healing. The oedema volume at 4 h was used to test anti‐inflammatory activity of drugs.

Cortisone, phenylbutazone, indomethacin, acetylsalicylic acid, flufenamic acid and propranolol exhibited potent, dose‐related anti‐inflammatory activity. Aminopyrine, chloroquine and chlorpromazine were only moderately effective. Dimercaprol, adrenaline, and to some extent, mepyramine also inhibited mercury‐induced oedema.

This simple model of acute inñammation may be useful for preliminary tests of anti‐inflammatory activity.
THE ACTION OF NITROGLYCERINE AND DIPYRIDAMOLE IN NORMAL AND ISCHAEMIC DOG HEART
Authors: GRAYSON J. , SCOTT C.
Published: July 2012

Network and post‐network resistances were measured together with heat clearance and heat production in the myocardium.

Nitroglycerine dilated all resistance vessels but was twice as effective on network as compared with post‐network vessels.

Dipyridamole dilated network and post‐network vessels equally.

Nitroglycerine had no effect on heat clearance or heat production in ischaemic myocardium.

Dipyridamole increased heat clearance in normal but not in ischaemic myocardium.

Dipyridamole depressed heat production in normal and ischaemic myocardium.

That the clinical effectiveness of nitroglycerine does not depend entirely on its coronary vasodilator properties is confirmed.

It is suggested that the action of dipyridamole in depressing myocardial heat production may be due to an action on the efficiency of oxygen utilization during cardiac contraction.
THE EFFECT OF VARIOUS AMINE‐DEPLETING DRUGS ON THE FEVER RESPONSE EXHIBITED BY RABBITS TO BACTERIAL OR LEUCOCYTE PYROGEN
Authors: METCALF G. , THOMPSON J.W.
Published: July 2012

The concentration of noradrenaline, dopamine and 5‐hydroxytryptamine (5‐HT) in the rabbit brainstem was measured during fevers produced by either an injection of bacterial pyrogen (BP) or continuous infusion of leucocyte pyrogen (LP).

Both procedures had little effect on the concentration of noradrenaline in the preoptic/hypothalamic area but significantly (P < 0.001) lowered the concentration of noradrenaline in the midbrain and pons/medulla.

BP significantly (P < 0.01) lowered the concentration of 5‐HT in the preoptic/hypothalamic area but had no effect in the midbrain or pons/medulla, whereas LP significantly (P < 0.01) lowered the concentration of 5‐HT in the midbrain and pons/medulla but had little effect in the hypothalamus.

The concentration of dopamine throughout the brainstem was little affected by either BP or LP fevers. However the concentration in the midbrain was significantly reduced by LP (P < 0.001).

α‐Methyltyrosine (200 mg/kg) pretreatment diminished the pyrogenic response to both BP and LP whilst p ‐chlorophenylalanine (300 mg/kg) slightly enhanced the response to both forms of challenge.

Reserpine (1 mg/kg) diminished both types of fever whilst a combination of α‐methyltyrosine and p ‐chlorophenylalanine slightly enhanced the fevers produced by either BP or LP.

The results obtained are discussed in relation to the mechanisms involved in the production of fever and to the possible function of noradrenaline and 5‐HT as thermoregulatory transmitters.
THE PREVENTION BY SULPHYDRYL COMPOUNDS OF THE TOXICITY IN THE CAT OF 2,6‐DIMETHOXYPHENOL AND ITS MORPHOLINOPROPIONYL ESTER
Authors: LOVELESS A.H. , MAXWELL D.R.
Published: July 2012

Intravenous (—)‐2,6‐dimethoxyphenyl‐2‐morpholinopropionate hydrochloride (M&B 16,573) produced anaesthesia of short duration in the mouse, rat, rabbit, cat, dog and monkey. In the cat but not in other species, a severe and usually fatal toxic reaction was seen 1‐2 h after administration.

This toxic reaction but not the anaesthetic properties of M&B 16,573 was prevented by the intravenous administration of cysteine or N‐acetylcysteine. Cysteamine or dimercaprol were ineffective.

Intravenous administration of 2,6‐dimethoxyphenol or 2,6‐dimethoxyquinol in the cat produced a response similar to the delayed toxic effects of M&B 16,573 but not preceded by anaesthesia. The toxic effects of these compounds were prevented by cysteine.

Intravenous 4‐allyl‐2,6‐dimethoxyphenyl‐2‐morpholinoprop*ionate hydrochloride produced anaesthesia in the cat without the delayed toxic effects seen after M&B 16,573.

The acute toxicity of 2,6‐dimethoxyquinol in mice was reduced by the administration of cysteine or N‐acetylcysteine.

It is postulated that the delayed effects produced by M&B 16,573 in the cat are due to the formation of 2,6‐dimethoxyquinol and 2,6‐dimethoxybenzoquinone in this species, the toxicity of the latter being reduced by sulphydryl compounds.
EFFECT OF ANTI‐INFLAMMATORY DRUGS ON THE MEMBRANE POTENTIAL OF VASCULAR ENDOTHELIAL CELLS in vitro
Authors: NORTHOVER B.J.
Published: July 2012

Cells of the aortic endothelium isolated from the guinea‐pig and bathed at 37° C with a calcium‐free superfusion fluid had membrane potentials of −41 ± 7 mV (mean ± s.e. mean).

Depolarization was produced by addition of potassium (50‐200 mM) or certain other monovalent metal cations to the superfusion fluid. Depolarization was rapidly reversed on return to the original superfusate.

Several divalent metal cations, notably calcium (16 mM), caused depolarization which was only slowly and incompletely reversed on return to the original calcium‐free superfusate.

Repolarization after exposure to calcium was accelerated and made more complete by addition of indomethacin (0.25 mM) to the superfusate.

The trivalent cations of lanthanum, aluminium or iron (0.1 mM) inhibited the depolarizing effect of calcium (16 mM).

Exposure to histamine (100 μg/ml) or heating to 45° C for 1 h caused depolarization in the presence but not in the absence of calcium. Subsequent removal of histamine or cooling again to 37° C in the continued presence of calcium permitted only slow and partial repolarization. However, repolarization was more rapid and complete in the presence of indomethacin (0.25 mM).

Heating to 45° C for 5 h in the presence of calcium caused progressive and almost complete depolarization. Lanthanum, cinchocaine, indomethacin, flufenamic, meclofenamic and salicylic acids, phenylbutazone and aminopyrine each reduced the depolarization, but hydrocortisone, chloroquine, benzindamine, isoprenaline and aminophylline did not.
THE EFFECTS OF BURIMAMIDE AND METIAMIDE ON BASAL GASTRIC FUNCTION IN THE CAT
Authors: HARRIS D. W. , SMY J.R. , REED J.D. , VENABLES C.W.
Published: July 2012

Burimamide injected intravenously in the anaesthetized or conscious cat produced significant increases in gastric acid secretion: in the anaesthetized cat it produced increased gastric mucosal blood flow.

Metiamide, in doses which inhibited pentagastrin‐stimulated acid secretion, produced no increase in gastric acid secretion in conscious animals, or gastric acid secretion or gastric mucosal blood flow in the anaesthetized cat.

Metiamide did not influence the amount of acid which diffused out of the stomach when instilled at pH values between 1.5 and 6.0.

The possible mode of action of burimamide in increasing basal gastric secretion is discussed.
THE FAILURE OF p‐CHLOROPHENYLALANINETO AFFECT VOLUNTARY ALCOHOL CONSUMPTION IN RATS
Authors: HOLMAN R.B. , HOYLAND VALERIE , SHILLITO ELIZABETH E.
Published: July 2012

The effects of p‐chlorophenylalanine (PCPA) administered orally and intraperitoneally on rat brain 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) content were compared. The depletion of brain 5‐HT and 5‐HIAA following PCPA (316 mg/kg) injected intraperitoneally every third day was not significantly different from that following the administration of PCPA (316 mg/kg) by stomach tube on eight consecutive days.

Rats tested for alcohol preference before, during and after treatment with PCPA on two intraperitoneal dose regimens (either 316 mg/kg then 100 mg/kg four days later or 316 mg/kg three times at intervals of three days) showed no reduction in voluntary alcohol consumption.

The results indicated that depletion of brain 5‐HT and 5‐HIAA is not responsible for the reduction of voluntary alcohol intake which has been reported to follow chronic oral administration of PCPA to the rat (Myers & Veale, 1968). The possibility of a learned aversion to alcohol due to an association with PCPA administration is discussed.
PROSTAGLANDIN RELEASE FROM CAT AND DOG SPLEEN
Authors: BEDWANI J.R. , MILLAR G.C.
Published: July 2012

The output of prostaglandins from the spleens of cats and dogs was studied. Comparison is made between the results found in the two species.

The release of prostaglandins was investigated in isolated saline‐perfused spleens and in incubates of spleen slices. Release in response to nerve stimulation, and exposure to adrenaline or noradrenaline was compared with resting release.

A resting release of prostaglandins was found in the dog but not in the cat spleen.

Whereas stimulated dog spleens released microgram quantities of prostaglandins E2 and F2α, prostaglandin output from the cat spleen under similar conditions was undetectable or barely detectable.

The identity of the prostaglandins released from the dog spleen (prostaglandins E2 and F2α) was confirmed by mass spectrometry.

The species difference in prostaglandin output from the spleen is discussed in relation to the hypothesis that endogenous prostaglandins modify the responses of this organ to nervous stimuli.
DISPLACEMENT BY METIAMIDE OF THE DOSE‐RESPONSE CURVES TO PENTAGASTRIN AND METHACHOLINE IN THE CONSCIOUS RAT
Authors: LUNDELL L.
Published: July 2012

The effect of a specific histamine H2‐receptor antagonist, metiamide, on the acid dose‐response curves for pentagastrin or methacholine was studied in rats provided with Heidenhain pouches.

Metiamide induced a shift to the right of the dose‐response curve to pentagastrin and lowered the maximal secretion.

In contrast, metiamide only increased the ED50 for methacholine but did not alter the calculated maximal response.

The effect of metiamide on pentagastrin and methacholine‐induced secretion is in agreement with the previously suggested difference in the part played by mucosal histamine in the mode of action of the two stimulatory agents.
DUAL EFFECT OF α‐ADRENOCEPTOR ANTAGONISTS IN RAT ISOLATED VAS DEFERENS
Authors: JURKIEWICZ A. , JURKIEWICZ N.H.
Published: July 2012

In rat isolated vas deferens, the isotonic contractile responses to low doses of noradrenaline or adrenaline were antagonized, and those to high doses were potentiated, by yohimbine, piperoxan, phentolamine and tolazoline. Effects due to intermediate doses were not affected, or were potentiated within about 30 min, following an initial inhibition.

The α‐adrenoceptor blockers thus caused a shift to the right and an increase of the maximum height of log dose‐response curves of α‐adrenoceptor stimulants. For a given dose of antagonist, the onset was slower for the potentiating than for the blocking effect.

The shift to the right induced by piperoxan and yohimbine on dose‐response curves of noradrenaline and adrenaline was analysed with the Schild plot, and the slopes obtained, around 0.3, were lower than expected from receptor theory. When cocaine was used to block neuronal uptake, the slopes were close to 1.0.

The increase in maximum response to noradrenaline and adrenaline induced by α‐adrenoceptor blockers was dependent on the time of incubation, on the dose of antagonist, and on the initial height of responses to the agonist. A less pronounced potentiation was also obtained when acetylcholine was used as agonist.

The findings are explained in terms of receptor theory as being due to a dual effect of α‐adrenoceptor antagonists; competitive antagonism proper, which may be disclosed after blockade of neuronal uptake, and an interaction at a different locus, which results in potentiation of the effects of noradrenaline and adrenaline.
A COMPARISON OF THE TIME COURSE OF EXCITATION AND INHIBITION BY IONTOPHORETIC DECAMETHONIUM IN FROG ENDPLATE
Authors: ADAMS P.R.
Published: July 2012

The depolarization of frog endplate by a brief iontophoretic application of decamethonium was slower in time course than the inhibition of a long carbachol response produced by the same decamethonium pulse, or than the excitation produced by a brief equipotent carbachol pulse.

The delay between the peak inhibition and peak excitation produced by decamethonium, about 50 ms, is too great to be explained by slow receptor activation kinetics, since Katz & Miledi (1973) have shown that the lifetime of decamethonium‐activated receptors is only 0.25 milliseconds.

If doses of carbachol and decamethonium are adjusted to give response amplitudes in the ratio corresponding to the ratio of their presumed maximum responses, then there is little difference in the time courses of the responses.

This observation, together with the finding that increasing the dose applied slows the decamethonium response much more than the carbachol response, suggests that a decamethonium response contains contributions from a much wider area of receptive membrane than does a carbachol response of equal amplitude.

Simulation shows that these geometrical effects are sufficient to account for the rapidity of inhibition compared to excitation without postulating slow receptor kinetics.

It is pointed out that similar effects may account for certain results obtained in iontophoretic studies of desensitization.
MECHANISM OF THE INDIRECT SYMPATHOMIMETIC EFFECT OF 5‐HYDROXYTRYPTAMINE ON THE ISOLATED HEART OF THE RABBIT
Authors: FOZARD J.R. , MWALUKO G.M.P.
Published: July 2012

Rabbit isolated hearts, perfused by the Langendorff technique, were used to investigate the indirect sympathomimetic effects of 5‐hydroxytryptamine (5‐HT). Comparisons were made with noradrenaline and with two indirectly acting sympathomimetic agents with entirely different mechanisms of action, tyramine and dimethylphenylpiperazinium (DMPP).

The cardiac stimulant effects of 5‐HT, tyramine and DMPP were inhibited by propranolol and practolol and the pA2 values obtained were similar to those obtained with noradrenaline as the agonist.

Responses to 5‐HT, tyramine and DMPP were greatly reduced on hearts from rabbits pretreated with 6‐hydroxydopamine. Such hearts had less than 7% of their normal catecholamine concentration and no fluorescence characteristic of noradrenaline in the cardiac sympathetic nerves could be demonstrated.

Rapid, reversible and selective tachyphylaxis to 5‐HT was demonstrated during perfusion with 5‐HT. In hearts desensitized to DMPP by perfusion with DMPP, responses to 5‐HT were also reduced.

Perfusion of hearts with colchicine inhibited stimulant responses to 5‐HT and DMPP but had little effect on responses to noradrenaline or tyramine.

Desmethylimipramine enhanced cardiac stimulant responses to noradrenaline and to a lesser extent, those to 5‐HT and DMPP. Responses to tyramine were consistently inhibited by desmethylimipramine.

Tetrodotoxin abolished responses of the heart to electrical nerve stimulation but left responses to noradrenaline, 5‐HT and DMPP unaffected.

5‐HT, tyramine and DMPP evoked 3H‐release from hearts whose neuronal noradrenaline stores had been labelled by perfusion with [3H]‐(–)‐noradrenaline. The pattern of release evoked by 5‐HT was similar to that of DMPP but differed from that of tyramine.

Reducing the calcium concentration in the Tyrode solution from 3.6 to 0.2 mEq/1 did not affect 3H‐overflow after tyramine but greatly inhibited that evoked by 5‐HT and DMPP.

The results confirm that the stimulant effects of 5‐HT on the rabbit isolated heart are the result of noradrenaline release. They further suggest that the site of the release is the terminal sympathetic nerve network. The mechanism of release shows more similarities to that of DMPP (calcium‐dependent depolarization and exocytosis) than to that of tyramine (neuronal uptake and stoichiometric displacement).
EVIDENCE CONCERNING THE INVOLVEMENT OF 5‐HYDROXYTRYPTAMINE IN THE LOCOMOTOR ACTIVITY PRODUCED BY AMPHETAMINE OR TRANYLCYPROMINE PLUS l‐DOPA
Authors: GREEN A.R. , KELLY P.H.
Published: July 2012

Pretreatment of rats with p‐chlorophenylalanine (PCPA; 2 × 200 mg/kg) decreased the concentration of 5‐hydroxytryptamine (5‐HT) in the brain. It also decreased the locomotor activity produced by tranylcypromine plus l‐DOPA administration 24 h after the second dose of PCPA.

Pretreatment with p‐chloroamphetamine, which produced a similar decrease in brain 5‐HT concentrations did not decrease the locomotor response to tranylcypromine and l‐DOPA.

PCPA pretreatment decreased the rise in the concentration of DOPA and dopamine in the brain following tranylcypromine and l‐DOPA, suggesting its effect on the dopamine‐induced locomotor activity was the result of this drug diminishing dopamine formation in the brain, probably by inhibiting l‐DOPA uptake.

The locomotor activity produced by tranylcypromine and L‐DOPA was not decreased by pretreatment 6 h earlier with disulfiram (400 mg/kg). This argues against the locomotor activity being due to noradrenergic stimulation.

PCPA pretreatment did not alter amphetamine‐induced stereotypy or the circling behaviour in unilateral nigro‐striatal lesioned rats.
THE INHIBITORY EFFECT OF GALLAMINE ON MUSCARINIC RECEPTORS
Authors: CLARK A.L. , MITCHELSON F.
Published: July 2012

The inhibitory effect of gallamine (1.1 μM‐1.1 mM) on negative inotropic responses to acetylcholine (ACh) or carbachol (CCh) was investigated in isolated electrically stimulated atria of the guinea‐pig. Gallamine caused parallel rightward shifts of the dose‐response curves to the agonists, with no depression of the maximal response.

Gallamine (0.11‐1.1 mM) produced a greater degree of antagonism towards CCh than towards ACh. With either agonist, the degree of antagonism produced by gallamine in high concentrations was less than that expected for a competitive antagonist.

Similar findings were made when either negative inotropic or chronotropic responses were recorded in spontaneously beating guinea‐pig atria. The inhibitory effect of gallamine against the negative inotropic response to cholinomimetics in electrically stimulated atria was not altered either in the presence of propranolol (17 μM) or in atria obtained from guinea‐pigs pretreated with diisopropylphosphorofluoridate (DFP) (12.5 μmol/kg, in divided doses over 3 days).

When ACh was used as the agonist, combination of gallamine with atropine (0.05‐0.4 μM) produced dose‐ratios which were less than expected for combination of two competitive antagonists. The same phenomenon was observed in atria obtained from guinea‐pigs pretreated with DFP.

It is suggested that the antagonism produced by gallamine is a type of non‐competitive inhibition, which has been termed ‘metaffinoid antagonism’. An antagonist of this type allosterically alters the affinity of the agonist for its binding site, rather than changing the effectiveness of the agonist‐receptor interaction.