bluuebunny/crossref_metadata_2025 huggingface dataset:
A QUANTITATIVE MICROIONTOPHORETIC ANALYSIS OF THE RESPONSES OF CENTRAL NEURONES TO NORADRENALINE: INTERACTIONS WITH COBALT, MANGANESE, VERAPAMIL AND DICHLOROISOPRENALINE
Authors: FREEDMAN R. , HOFFER B.J. , WOODWARD D.J.
Published: July 2012

A new experimental procedure has been devised for the study of pharmacological antagonism in the central nervous system using automated microiontophoresis to deliver pulses of agonists and computer‐generated histograms to quantify the neuronal response. The system allows study of potential antagonists having direct depressant effects and also of neurones with irregular or slow discharge rates.

The histogram analysis reveals the necessity for regular, periodic delivery of agonists during the assessment of agonist‐antagonist interactions. Without regular repetitive delivery, many agonists, such as noradrenaline, exhibit an apparent but artifactual decrease in inhibitory potency after an interruption of agonist pulses. Examples of this phenomenon are shown, using cerebellar Punkinje cells and cerebral cortical neurones in rats anaesthetized with halothane.

Preliminary results with these computer‐generated drug response histograms revealed manganese, cobalt, and verapamil to be generally ineffective as antagonists of noradrenaline, despite their direct depressant effects.

Conversely, dichloroisoprenaline (DCI), a β‐adrenoceptor antagonist, was effective in blocking noradrenaline‐induced depressions of firing in the cerebral cortex at doses which caused over 50% decrease in spontaneous discharge.
SOME PHARMACOLOGICAL EFFECTS OF p‐CHLOROPHENYLALANINE UNRELATED TO TRYPTOPHAN HYDROXYLASE INHIBITION
Authors: MARLEY E. , WHELAN JENNIFER E.
Published: July 2012

Experiments were performed on a variety of tissues from different species to establish whether or not the properties of p‐chlorophenylalanine methyl ester (PCPA) included a 5‐hydroxytryptamine (5‐HT)‐like action which might explain the soporific action of PCPA in chicks.

PCPA, like 5‐HT, contracted the rat fundal preparation (as did PCPA base), and in cats enhanced twitch tension of a lower limb flexor reflex, evoked adrenal medullary secretion and attenuated histamine‐induced gastric secretion; the effects on the rat fundal strip and the adrenal medulla were prevented by methysergide.

Like 5‐HT, PCPA elicited bronchoconstriction of guinea‐pig lungs, isolated or in vivo; this was not prevented by methysergide but reduced by polyphloretin and by indomethacin. Perfusate collected from the lungs during PCPA‐induced bronchoconstriction and applied to superfused isolated tissues contained a substance with prostaglandin‐like activity.

In contrast, the effect of PCPA on the guinea‐pig isolated ileum differed from that of 5‐HT, since it relaxed the ileum when contracted by transmural excitation, by acetylcholine, histamine or 5‐HT and contracted the ileum on wash‐out.
EFFECTS OF CHRONIC NICOTINE ADMINISTRATION ON THE DENERVATED RAT ADRENAL MEDULLA
Authors: SEIDLER F.J. , SLOTKIN T.A.
Published: July 2012

The effects of chronic nicotine administration (1 or 10 mg/kg, s.c., twice daily) were studied in intact and denervated rat adrenal glands to determine the relative roles of central input and direct actions on catecholamines.

Catecholamine depletion was obtained in the intact glands from 1–7 days of treatment with 10 mg/kg, with recovery by 14 days of treatment; catecholamines were not decreased in denervated adrenal glands.

Catecholamine depletion was accompanied by a decline in functional storage vesicles (determined by [3H]‐adrenaline uptake per gland) in the intact side, while no change was seen in the denervated side; the proportion of newly synthesized vesicles increased markedly during 1–7 days of treatment with 10 mg/kg in the intact side, while a much smaller increase of shorter duration was seen in the denervated adrenal gland.

Chronic nicotine administration at either dose level induced tyrosine hydroxylase in both intact and denervated glands, but the increase occurred more slowly in the denervated glands.

Dopamine β‐hydroxylase levels increased similarly in both sides during treatment with nicotine (10 mg/kg).

These studies suggest that although long‐term adrenal denervation eliminates the catecholamine depletion caused by chronic administration of nicotine, the mechanisms for induction of catecholamine synthesizing enzymes are still capable of responding to the drug.
CARDIOVASCULAR EFFECTS OF DIETHYLCARBAMAZINE CITRATE
Authors: ABAITEY A.K. , PARRATT J.R.
Published: July 2012

The cardiovascular effects of the anthelmintic drug diethylcarbamazine citrate (DECC) were examined in cats anaesthetized with pentobarbitone. There were two quite distinct haemodynamic responses, an initial transient hypotension (occurring within 10 s of an intravenous injection) and a pronounced secondary hypertension which reached a peak 30–60 s after the injection.

Within 10 s of an intravenous injection of DECC (2.5 to 10 mg/kg) there was hypotension, bradycardia and there were reductions in left ventricular and carotid artery dP/dt max. These effects were most pronounced following injections into the pulmonary artery; they were not observed after bilateral vagotomy or after injections into the lumen of the left ventricle. It is suggested that DECC, like nicotine, stimulates vagal receptors in the pulmonary vascular bed.

The secondary phase was characterized by marked systemic and pulmonary hypertension, by contractions of the nictitating membrane and by increases in left ventricular dP/dt (at fixed isovolumic pressures), in cardiac output and in myocardial blood flow. All these effects were prevented, or markedly reduced, following the administration of hexamethonium or bethanidine and the pressor response was prevented by phentolamine. It is concluded that, in doses similar to those used in therapeutics, DECC stimulates sympathetic ganglia and releases noradrenaline. The relevance of this finding to the reported side effects of the drug are discussed.

DECC (5 or 10 mg/kg) significantly inhibited prostaglandin F2α‐induced increases in peak inspiratory intra‐tracheal pressure without modifying its pulmonary hypertensive effect. The possible relevance of this finding to the use of DECC in asthma is discussed.
THE EFFECTS OF INTRA‐AMYGDALOID INJECTIONS OF 6‐HYDROXYDOPAMINE ON AVOIDANCE RESPONDING IN RATS
Authors: ASHFORD J. , JONES B.J.
Published: July 2012

The effects of bilateral intra‐amygdaloid injections of 6‐hydroxydopamine (6‐OHDA) on shuttle box avoidance acquisition, retention, and extinction, and passive avoidance acquisition were examined in rats.

Intra‐amygdaloid 6‐OHDA injections produced catecholamine depletion in and around the amygdalae but failed to reduce striatal dopamine concentrations.

Conditioned avoidance acquisition was markedly inhibited in 6‐OHDA‐treated rats whereas retention and extinction were only slightly impaired.

Passive avoidance acquisition was slightly but significantly improved in rats with amygdaloid 6‐ OHDA lesions.

Treated rats showed no motor abnormalities, they were not hypoactive in a photocell activity cage and they performed as well as controls on a rotating rod.

It is suggested that the conditioned avoidance acquisition deficit in rats with amygdaloid 6‐OHDA lesions may be related to an impairment of associative learning rather than to perceptual or motor disturbances.
RAT UTERUS RENIN‐LIKE ACTIVITY: EFFECT OF STIMULI AND HORMONES
Authors: GUTMAN Y. , MAZUR‐RUDER M.
Published: July 2012

The characteristics of renin‐like activity in rat uterus were studied. The optimum temperature was 50°C and optimum pH 4.0. Potassium (100 mM) enhanced this activity but sodium or calcium had no effect.

Uterine renin‐like activity was unchanged 24 h after bilateral nephrectomy.

Renin‐like activity in the uterus increased slowly from birth to 4 weeks of age and faster between the 4th and 8th week.

Ovariectomy caused a considerable fall in uterine renin‐like activity.

The following factors, known to affect renin secretion in the kidney, i.e., hypovolaemia, sodium loading, adrenalectomy, administration of desoxycorticosterone acetate and injection of isoprenaline, had no effect on uterine renin‐like activity.

Stilboestrol, an oestrogen, caused a significant increase of uterine renin‐like activity. Progesterone and testosterone had no significant effect on this activity but blocked the increase caused by stilboestrol.

During pregnancy there was a small but significant fall of renin‐like activity in the uterus in the first week and a continuous increase throughout the later period of pregnancy.

It is concluded that uterine renin‐like activity is independent of kidney renin and does not respond to stimuli affecting kidney renin. Uterine renin activity is hormone‐dependent and may be governed by the ratio, oestrogen: progesterone.
A METHOD FOR RECORDING SMOOTH MUSCLE AND VASCULAR RESPONSES OF THE BLOOD‐PERFUSED DOG TRACHEA In situ
Authors: HIMORI N. , TAIRA N.
Published: July 2012

A method is described for measuring responses of dog tracheal musculature and vasculature in situ.

The upper two thirds of the trachea was perfused with blood through both cranial thyroid arteries at a constant pressure. The blood flow through the arteries was measured with an electromagnetic flowmeter. The response of the tracheal musculature was measured as a change in pressure in a water‐filled cuff inserted into the trachea via the mouth. Drugs were injected close‐arterially.

Acetylcholine produced dose‐dependent increases in blood flow rate (vasodilatation) and in tracheal intraluminal pressure (tracheal constriction). These responses were antagonized by atropine.

Isoprenaline produced vasodilatation which was blocked by propranolol. Adrenaline and noradrenaline caused vasoconstriction which was blocked by phentolamine.

All three catecholamines produced a decrease in tracheal intraluminal pressure (tracheal dilatation). The tracheal dilatation in response to adrenaline and noradrenaline was converted to constriction by propranolol. The tracheal constriction thus unmasked was abolished specifically by phentolamine.

From these results it is concluded that the tracheal musculature and vasculature contain muscarinic receptors, and excitatory α‐ and inhibitory β‐adrenoceptors. In the tracheal musculature β‐adrenoceptors predominate over α‐adrenoceptors; the reverse is true in the tracheal vasculature.
A CHOLINOCEPTOR ANTISERUM: ITS PHARMACOLOGICAL PROPERTIES
Authors: BERTI F. , CLEMENTI F. , CONTI‐TRONCONI B. , FOLCO G.C.
Published: July 2012

Sera of rabbits immunized against a nicotinic receptor‐rich fraction, obtained from the electric organ of Torpedo marmorata, were tested for their pharmacological activity on different in vitro preparations.

Sera containing antibodies against the nicotinic receptor blocked neuromuscular transmission in the phrenic‐nerve hemidiaphragm preparation without affecting the muscle responses evoked by direct electrical stimulation. Complement inactivated sera were still active. Immune sera, incubated for 15 min with a receptor‐rich fraction, lost their activity.

The immune sera antagonized the responses elicited by acetylcholine on the frog rectus abdominis.

The immune sera tested in vitro decreased the compound action potential evoked in the superior cervical ganglion of the rat by electrical stimulation of the preganglionic nerve.

The sera did not show any activity on muscarinic receptors of the guinea‐pig ileum preparation.

It is concluded that in sera obtained from immunized rabbits a substance is present with curare‐like action, and that this activity is probably due to the presence of antibodies against the nicotinic receptor.
THE RELATIONSHIP BETWEEN CARDIOTOXICITY AND PLASMA DIGOXIN CONCENTRATION IN CONSCIOUS DOGS
Authors: CHAPPLE D.J. , HUGHES R. , JOHNSON B.F.
Published: July 2012

The tendency of a given oral dose of digoxin to induce cardiac dysrhythmia was determined indirectly at various times after its administration to eight conscious dogs by measurement of the intravenous dose of acetylstrophanthidin necessary to induce toxic changes in the ECG. Acetylstrophanthidin was used because its rapid elimination from the body permitted estimates to be made 45, 180 and 360 min after digoxin administration.

Each dog underwent four studies in which doses of 0.05, 0.1, 0.2 and 0.4 mg/kg digoxin were used in a randomized sequence allowing at least ten days between each dose.

Digoxin reduced the amount of acetylstrophanthidin required to cause toxic changes in the ECG; this increase in cardiac sensitivity was dose‐dependent.

There was no correlation between plasma levels of digoxin and the tendency to dysrhythmia, since peak plasma concentrations of digoxin were reached at about 60 min after dosing whereas maximal sensitivity to acetylstrophanthidin was found 3 to 6 h after administration of digoxin.

These results suggest that there is little or no increased risk of cardiotoxicity during periods of transient increase in plasma levels of digoxin.
EFFECTS OF SOME PURINE DERIVATIVES ON THE GUINEA‐PIG TRACHEA AND THEIR INTERACTION WITH DRUGS THAT BLOCK ADENOSINE UPTAKE
Authors: COLEMAN R.A.
Published: July 2012

Adenosine, adenosine 5′‐triphosphate (ATP), adenine, inosine and guanosine all caused concentration‐dependent relaxations of guinea‐pig tracheal smooth muscle in vitro. The relative potencies in descending order were: adenine ≥ guanosine > inosine ≥ adenosine ≥ ATP

Responses to the purine compounds were unaffected by propranolol (1 μg/ml).

The spasmolytic potencies of adenosine and ATP were greatly enhanced in the presence of the adenosine uptake blocking drugs dipyridamole, hexobendine or Dilazep, whereas responses to adenine were unaffected and those to inosine and guanosine were reduced.

The spasmolytic potencies of noradrenaline, aminophylline, prostaglandin E2 and glyceryl trinitrate were unaffected by dipyridamole, hexobendine and Dilazep.

It is suggested that an adenosine uptake process may exist in the trachea of the guinea‐pig and that this process is inhibited by dipyridamole, hexobendine and Dilazep.
CONCENTRATION OF (±)‐PROPRANOLOL IN ISOLATED, PERFUSED LUNGS OF RAT
Authors: DOLLERY C.T. , JUNOD A.F.
Published: July 2012

The metabolism and the accumulation of (±)‐propranolol have been studied in isolated lungs of the rat, perfused with an artificial medium.

Little or no metabolism took place during the perfusion periods (up to 10 minutes).

Accumulation was observed with high tissue/medium ratios for substrate concentrations of 0.2 μm to 1 mm; there was evidence for saturability, but no real plateau could be seen. The presence of two binding sites with different affinities was established.

Cold greatly inhibited the accumulation process at low substrate concentrations, but had no effect at 1 mm propranolol.

Inhibition of accumulation was measured in the presence of imipramine, desmethylimipramine, nortryptiline, chlorpromazine and of Na+‐free medium. Cocaine, 5‐hydroxytryptamine and noradrenaline had no effect. Lidocaine enhanced the accumulation process. Release of previously bound propranolol was accelerated in the presence of propranolol and imipramine, unaffected by a Na+‐free medium and decreased by cold and by lidocaine.

Experiments on lung tissue slices yielded qualitatively similar results to those obtained with perfused lungs. Ouabain and KCN had no or little effect on propranolol accumulation.
TRYPTOPHAN METABOLISM IN THE ISOLATED PERFUSED LIVER OF THE RAT: EFFECTS OF TRYPTOPHAN CONCENTRATION, HYDROCORTISONE AND ALLOPURINOL ON TRYPTOPHAN PYRROLASE ACTIVITY AND KYNURENINE FORMATION
Authors: GREEN A.R. , WOODS H.F. , JOSEPH M.H.
Published: July 2012

The effect of tryptophan concentration on the rate of kynurenine appearance and tryptophan disappearance in the medium perfused through the isolated liver of the rat has been investigated. The effect of pretreatment of the rat with hydrocortisone or allopurinol was also examined, together with the effects of these treatments on liver tryptophan pyrrolase activity measured in vitro at the beginning and end of perfusion.

Hydrocortisone (5 mg/kg) injection 3 h before perfusion resulted in a four‐fold increase in kynurenine production by the liver during perfusion with a medium containing either 0.1 mmol/1 or 1.0 mmol/1 tryptophan. Injection of allopurinol (20 mg/kg) together with hydrocortisone and addition of allopurinol (4 mg/100 ml) to the medium abolished the hydrocortisone‐induced rise of kynurenine in the 0.1 mmol/1 tryptophan medium but not the 1.0 mmol/1 tryptophan medium.

Injection of cycloheximide (30 mg/kg) with hydrocortisone (5 mg/kg) 3 h before perfusion inhibited the hydrocortisone‐induced rise of kynurenine production and the increase in pyrrolase activity measured in vitro both before and at the end of perfusion with 1.0 mmol/1 tryptophan. This last result suggests that protein synthesis is involved not only in hydrocortisone induction of pyrrolase but also in substrate induction.

Kynurenine production in the 1.0 mmol/1 tryptophan medium was less in both saline‐ and hydrocortisone‐treate older rats (335–450 g) compared to younger rats (180–220 g). In agreement with a previous study, pyrrolase activity in vitro was also lower in both saline‐ and hydrocortisone‐treate older rats at the beginning of the perfusion although activity had risen equally in both young and older rats at the end of perfusion.

There was little correlation between the rate of tryptophan disappearance from the medium and the activity of tryptophan pyrrolase either as measured in vitro or as indicated by the rate of kynurenine production.

In general, the production of kynurenine in the medium at the end of the 60 min perfusion was indicative of in vitro pyrrolase activity at the start of the perfusion.

It is concluded that while in vitro pyrrolase assay does not give a quantitative index of kynurenine production, it does provide a qualitative index. Furthermore, if kynurenine production in the isolated perfused liver of the rat is indicative of in vivo pyrrolase activity, then hydrocortisone must induce pyrrolase activity in vivo.
THE EFFECT OF ASPIRIN ON 5‐HYDROXYTRYPTAMINE UPTAKE AND RELEASE BY HUMAN PLATELETS
Authors: RENDU F.
Published: July 2012

The influence of aspirin on 5‐hydroxytryptamine (5‐HT) uptake and storage by human blood platelets has been investigated. Uptake of 5‐HT was strongly inhibited. In 30 min aspirin released 50% of the 5‐HT that had been incorporated into the platelets prior to the addition of the aspirin. These results are discussed in terms of possible interference with a 5‐HT membrane receptor and the impairment of 5‐HT storage in the dense granules.
POTENTIATION BY DESIPRAMINE OF NEURONAL RESPONSES TO MESCALINE
Authors: BEVAN P. , BRADSHAW C.M. , SZABADI E.
Published: July 2012

The effect of desipramine on responses of single cortical neurones to mescaline was studied by the microelectrophoretic technique. Both potentiation and antagonism of responses to mescaline by desipramine were observed. The antagonism may be related to the α‐adrenolytic action of desipramine. The potentiation is unlikely to reflect the uptake blocking action of desipramine, since desipramine does not block the uptake of mescaline in the cerebral cortex. It is suggested that the potentiation may be due to a post‐synaptic action of desipramine.
THE EFFECT OF NANDROLONE, AN ANABOLIC STEROID ON PUTRESCINE METABOLISM IN THE MOUSE
Authors: HENNINGSSON S. , ROSENGREN ELSA
Published: July 2012

The catabolism of injected 14C‐putrescine was studied in mice treated with nandrolone phenpropionate, an anabolic steroid.

The putrescine was rapidly metabolized; almost 50% of the injected radioactivity was recovered within 2 h as 14CO2 in the expired air.

Considerable amounts of radioactive γ‐aminobutyric acid (GABA) and an unidentified compound were found in the kidney and in the urine in addition to radioactive putrescine, spermidine and spermine both in controls and nandrolone‐treated mice.

Nandrolone elevated the concentration of endogenous putrescine in the kidney and urine, eightfold and twentyfold, respectively, and the concentrations of spermidine and spermine were also increased.

After the injection of 14C‐putrescine the incorporation of 14C into spermidine was significantly increased in the kidney of mice receiving nandrolone.
FREQUENCY‐DEPENDENT CHANGES IN THE CARDIAC SARCOLEMMAL ATPASE
Authors: KHATTER J.C. , PRASAD K.
Published: July 2012

1Effects of various frequencies (0.25, 0.5, 1.0, 1.5 or 2.0 Hz) of stimulation for various durations (2, 5, 10 or 15 min) on the contractile force of trabecular or papillary muscles of dog myocardium were investigated.

2Effects of various frequencies (0, 0.25, 0.5, 1.0, 2.0 Hz) of various stimulus strengths (0.5, 1, 10 V) for various durations (2, 5, 10 or 15 min) on the Mg2+‐dependent Na+‐K+‐adenosinetriphosphatase (ATPase) of isolated sarcolemmal fraction of dog myocardium were determined.

3There was a frequency‐dependent increase in the contractility and inhibition of the Na+‐K+‐ATPase within 2 minutes.

4Frequency‐dependent increase in the contractility and inhibition of Na+‐K+‐ATPase decreased as the duration of stimulation was increased.

5The diminution in the inhibition of ATPase was associated with a decrease in the contractility with prolonged stimulation.

6These results suggest that the frequency‐dependent increase in the myocardial contractility might be mediated through an inhibition of the sarcolemmal ATPase.
EFFECTS OF THYROIDECTOMY AND l‐THYROXINE ON ADRENALINE AND NORADRENALINE CONCENTRATIONS IN THE ADRENAL GLANDS AND PLASMA OF RATS DURING THE PRO‐OESTROUS PHASE OF THE OESTROUS CYCLE AND PREGNANCY
Authors: ISMAHAN G. , PARVEZ H. , PARVEZ S. , YOUDIM M.B.H.
Published: July 2012

1The influence of thyroidectomy upon the adrenaline and noradrenaline content of adrenal glands and plasma in mature female rats in pro‐oestrus and in pregnant rats was studied.

2Adrenal adrenaline and noradrenaline declined significantly after thyroidectomy in pro‐oestrous and pregnant females but the effects were more marked in pregnant females.

3Plasma adrenaline increased by 160% after thyroidectomy in pro‐oestrous females but similar treatment resulted in 85% decrease in plasma adrenaline of pregnant rats. The loss of thyroid increased plasma noradrenaline significantly in both groups of females.

4The administration of l‐thyroxine to thyroidectomized females increased adrenal noradrenaline stores of both the groups. The effects of l‐thyroxine in pro‐oestrous females resulted in decreased adrenaline stores of the adrenals but the pregnant group showed an increase. Plasma noradrenaline increased after treatment of pro‐oestrous and pregnant‐thyroidectomized females with l‐thyroxine.

5The thyroidectomized females in pro‐oestrous phase receiving l‐thyroxine showed a return to the control values for plasma adrenaline but in pregnant females whose plasma adrenaline had declined after thyroidectomy no such change occurred.

6Considering the variations in total catecholamines in plasma and adrenals, it was observed that the loss of thyroid hormones results in an increase in total catecholamine storage and output in the blood. The results provide evidence that the thyroid‐catecholamine interrelation is significantly affected by pregnancy.
A POSSIBLE ROLE FOR CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE IN THE REGULATION OF ACID SECRETION IN THE ISOLATED STOMACH OF GUINEA‐PIG
Authors: CANFIELD S.P. , CURWAIN B.P. , SPENCER JAN
Published: July 2012

1The rate of acid secretion and mucosal cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) content have been measured on the same guinea‐pig isolated stomach preparation in response to histamine, theophylline and ICI 63197, a potent phosphodiesterase inhibitor.

2Unstimulated control tissues had a spontaneous rate of acid secretion of 74.41 ± 9.06 μmol H+/g wet wt. of mucosa per hour (s.e. mean, n=20) and a cyclic AMP content of 0.517 ± 0.058 nmol/g wet weight.

3Each of the three drugs caused an increase in both the mucosal cyclic AMP content and the rate of acid secretion. These increases were linearly related to the logarithm of drug concentration for each drug.

4There were no statistically significant differences between the three regression coefficients obtained for acid on drug and for cyclic AMP on drug.

5There was a significant correlation between the rate of acid secretion and mucosal cyclic AMP content in stimulated preparations (P>0.001) and also in control preparations which received no drug (P<0.05).

6These results are discussed in relation to the possible role of cyclic AMP in the mediation of acid secretory responses in the mammalian stomach.
MODIFICATION OF CARDIOVASCULAR RESPONSES TO HISTAMINE BY DITHIOTHREITOL
Authors: CARROLL P.R. , GLOVER W.E.
Published: July 2012

1Histamine produced dose‐dependent contractile responses on both isolated perfused ear arteries and aortic strips of the rabbit. These responses were blocked by mepyramine and potentiated by both metiamide and dithiothreitol.

2In the presence of maximum potentiation by metiamide, dithiothreitol still potentiated the contractile response to histamine of both preparations.

3In the presence of mepyramine, histamine produced dose‐dependent reductions in the contractile response to noradrenaline. This vasodilator action of histamine was abolished by metiamide but was unaffected by dithiothreitol.

4The vasodilator action of histamine on the human isolated perfused temporal artery and the positive inotropic effect of histamine on the isolated spontaneously beating atria of the rabbit were blocked by metiamide but unaffected by dithiothreitol.

5It is concluded that the rabbit aorta, like the ear artery, contains both H1 and H2 histamine receptors and that dithiothreitol potentiates cardiovascular responses mediated by H1‐receptors but not by H2‐receptors.
THE EFFECTS OF BRADYKININ AND PROSTAGLANDIN E1 ON RAT CUTANEOUS AFFERENT NERVE ACTIVITY
Authors: CHAHL LORIS A. , IGGO A.
Published: July 2012

1The activity produced by intra‐arterial bradykinin and prostaglandin E1 was investigated in multifibre strands dissected from the saphenous nerves of anaesthetized rats.

2Bradykinin (0.5‐10 μg) alone produced little activity in nerve strands but produced considerable activity following a 10 min infusion, but not a single injection, of prostaglandin E1 (5‐100 ng).

3Prostaglandin E1 alone produced a few large height spikes but following several injections of bradykinin smaller height spikes were also produced by prostaglandin E1.

4It was concluded that the presence of a low concentration of prostaglandin E1 is required for bradykinin to manifest its action and that bradykinin and prostaglandin E1 are mutually potentiating in their effects on afferent nerve terminals.
INFLUENCE OF NEUROGLIAL TRANSPORT ON THE ACTION OF γ‐AMINOBUTYRIC ACID ON MAMMALIAN GANGLION CELLS
Authors: BROWN D.A. , GALVAN M.
Published: July 2012

1The effect of inhibiting the transport of γ‐aminobutyric acid (GABA) by neuroglial cells on the depolarizing action of exogenous amino acids on isolated superior cervical ganglia of the rat was studied.

2Transport (measured by uptake of [3H]‐GABA) was inhibited by (a) reducing external [Na+] from 143 to 2 mm and (b) administering alternative carrier‐substrates, 3‐amino‐n‐butyric acid (β‐amino‐butyric acid, BABA) and (±)‐nipecotic acid at a concentration of 1 mm.

3All three procedures enhanced the depolarization produced by low concentrations of GABA (<10 μm) but did not alter the maximum response, nor the response to 3‐aminopropanesulphonic acid (a gabamimetic with low affinity for the neuroglial carrier).

4It is concluded that the neuroglial uptake process can limit the action of exogenous GABA upon neurones, by reducing the interstitial GABA concentration.
THE EFFECTS OF BRADYKININ AND THE BRADYKININ POTENTIATING PEPTIDE BPP5a ON THE ELECTRICAL AND MECHANICAL RESPONSES OF THE GUINEA‐PIG TAENIA COLI
Authors: AARSEN P.N.
Published: July 2012

By means of the double sucrose‐gap technique, the effects of bradykinin and the bradykinin potentiating peptide BPP5a were compared on the guinea‐pig taenia coli under a number of experimental conditions.

In normal Krebs solution the response to bradykinin was mostly a slight stimulation, characterized by a depolarization, an increase in spontaneous spike activity and a contraction. If BPP5a caused any effect at all, it was stimulation of the spike activity but without depolarization. Since the effect of bradykinin was little affected by an increase in dose, a potentiating effect of BPP5a could not be determined.

Spontaneous spikes with a 5 to 7 s rhythm and prepotentials at their base were inhibited by bradykinin, whereas they were stimulated by BPP5a.

Oscillatory potentials (slow waves) induced by a calcium and magnesium‐free medium were also suppressed by bradykinin and stimulated by BPP5a. This effect of bradykinin was accompanied by a depolarization and a decrease in membrane resistance, phenomena not found after administration of BPP5a.

The amplitude of spontaneous spikes induced by potassium‐depolarization was suppressed by bradykinin, even though the membrane resistance and potential had been decreased. BPP5a produced either no effect or a small stimulatory effect without influencing the membrane resistance.

Reduction of the calcium concentration to 0.25 mM enhanced the stimulatory responses to both bradykinin and BPP5a, especially the spike activity and depolarization. In this case the membrane resistance was increased by bradykinin as well as BPP5a. These effects, especially those of BPP5a, were inhibited by reduction of the sodium concentration to 15.5 mM. Reduction of the chloride concentration to 9.7 mM decreased rather than increased the stimulatory effects of both bradykinin and BPP5a. Under these conditions bradykinin did not decrease the membrane resistance.

Bradykinin can have both inhibitory and stimulatory effects on the taenia coli whereas BPP5a has only a stimulatory effect. Since under certain conditions both responses to bradykinin are accompanied by a sodium‐dependent depolarization and decrease in membrane resistance, not influenced by lanthanum to any extent, it is suggested that bradykinin induces an increase in sodium conductance of the membrane. Under all the conditions investigated, except in low calcium, BPP5a did not affect the membrane potential and resistance. Thus, the underlying cause of its stimulatory effect is probably different from that of bradykinin.
THE CONTRIBUTION OF PROSTAGLANDINS IN THE MUSCLE OF HUMAN ISOLATED SMALL INTESTINE TO NEUROGENIC RESPONSES
Authors: BENNETT A. , STOCKLEY HELEN L.
Published: July 2012

In strips cut parallel to the longitudinal or circular muscle, indomethacin (2‐10 μg/ml) usually lowered the tone, thus probably accounting for the reduction of nerve‐mediated relaxations to electrical field stimulation.

In longitudinal muscle strips, indomethacin enhanced contractions which occurred during electrical stimulation, probably because tone fell, but antagonized after‐contractions. By contrast, in the circular muscle indomethacin reduced initial contractions but enhanced after‐contractions.

Prostaglandin E2 counteracted all of the effects of indomethacin in the longitudinal muscle and most of those in the circular muscle; prostaglandin F2α restored circular muscle tone.

The results suggest that prostaglandins affect the muscle directly and contribute to the regulation of tone. They may also mediate non‐cholinergic contraction in longitudinal muscle and suppress contractility in the circular muscle.
THE INFLUENCE OF VASOACTIVE SUBSTANCES ON BLOOD FLOW AND CONTRACTILE RESPONSES OF CAT GASTROCNEMIUS
Authors: HUDLICKA O. , REIT E.
Published: July 2012

The effects of several vasoactive substances have been studied on blood flow and acetylochline‐induced contraction of the vascularly isolated gastrocnemius of the cat. All substances, including acetylcholine, were administered intra‐arterially to the muscle. Blood flow and contractile tension were monitored simultaneously.

All substances which increased blood flow, enhanced the contractile responses to acetylcholine; angiotensin, which decreased blood flow, attenuated them.

Histamine was typical of the vasodilators in doses up to 1 μg (9 nmol), but in a dose tenfold higher it produced only a small and transient increase in blood flow and little or no enhancement of the acetylcholine‐induced contractions. These paradoxical effects were brought about by that portion of the high dose of histamine which re‐entered the cat's systemic circulation.

The order of potency of the vasodilators was the same for their potentiating effect on the acetylcholine‐induced contractile responses as for their enhancing effect on muscle blood flow: bradykinin >histamine>papaverine>NaH2PO4 >KCl. Median effective doses (ED50s) determined only for bradykinin, histamine and papaverine were, respectively, 20.5, 49.8, and 3,352 pmol as potentiators, and 13.4, 199.8 and 85,000 pmol as vasodilators.

In general, the effect of a given vasoactive substance on the contractile response to acetylcholine was dose‐dependent and correlated well with its effect on muscle blood flow at the moment the acetylcholine was injected. Two important exceptions were, firstly, that the highest dose of papaverine was only moderately effective as a potentiator even though highly effective as an increaser of muscle blood flow; and, secondly, that histamine produced its greatest potentiating effect 10 s after it was injected, at which time its effect on muscle blood flow was quite small.

It is suggested that these exceptions and, indeed, the much greater potentiating effectiveness of histamine and bradykinin versus papaverine may be due to the ability of histamine and bradykinin to increase the permeability of the muscle's capillaries as well as increasing blood flow through them, thus facilitating much better than mere vasodilators the access of bloodborne acetylcholine to its receptors on the muscle fibres.
THE ROLE OF EXTRACELLULAR CALCIUM IN THE CONTRACTIONS PRODUCED BY ACETYLCHOLINE IN CHRONICALLY DENERVATED MUSCLE
Authors: HALL MOIRA T. , MALEQUE M.A. , WADSWORTH R.M.
Published: July 2012

Acetylcholine‐induced contractions of the isolated chronically denervated soleus muscle of the mouse consist of two phases, but both phases are equivalent to the contracture phase seen in vivo.

Low [Ca2+]o (0.5‐1.5 mM) augmented peak tension, as well as the rate of relaxation, of the first phase, but inhibited the second phase. Ethyleneglycol‐bis‐(β‐aminoethyl ether)‐N,N'‐tetraacetic acid (EGTA) or La3+ (2 mM) also inhibited the second phase, but not the first.

It was concluded that the first phase requires Ca2+ release from the sarcoplasmic reticulum, and is terminated by inactivation of the contractile process. The second phase is caused by the entry of activator Ca2+ from the extracellular space.

Increasing [Ca2+]o to 5 or 10 mM after the addition of acetylcholine caused a contraction, starting after a delay of about 50 seconds. EGTA or La3+ added during the second phase of the acetylcholine contraction caused relaxation after a much shorter lag time.

It is concluded that most of the Ca2+ entering from the extracellular fluid is taken up by the sarcoplasmic reticulum.

The acetylcholine second phase was augmented in low (25 mM) [Na+]o. It is concluded that Na+ and Ca2+ compete for the acetylcholine controlled ionic channels.

Isolated chronically denervated diaphragm muscles were less sensitive to acetylcholine and the contraction usually consisted of a first phase only.

It is concluded that sequestration of Ca2+ entering from the extracellular fluid is more complete in the diaphragm.
COMPARATIVE POTENCIES OF AMPHETAMINE, FENFLURAMINE AND RELATED COMPOUNDS IN TASTE AVERSION EXPERIMENTS IN RATS
Authors: BOOTH D.A. , PILCHER C.W.T. , D'MELLO G.D. , STOLERMAN I.P.
Published: July 2012

Rats failed to drink a flavoured solution when its consumption had been followed by injection of amphetamine (conditioned taste aversion).

There was very little difference between the potencies of (+)‐ and (‐)‐amphetamine.

p‐Chloromethamphetamine was a more potent aversive agent than methamphetamine.

Strong taste aversions were also conditioned with other congeners of amphetamine. The rank order of potency was: fenfluramine > chlorphentermine >p‐hydroxyamphetamine.

Cocaine induced only moderate taste aversions, even at high doses.

Aversive potency did not appear to be correlated with known neurochemical actions of the drugs or with behavioural stimulation, but appeared to be a central action which may have been linked to anorexigenic potency or time course of action.
AN ESTIMATE OF THE EQUILIBRIUM DISSOCIATION CONSTANT FOR CALCIUM AS AN ANTAGONIST OF EVOKED ACETYLCHOLINE RELEASE: IMPLICATIONS FOR EXCITATION‐SECRETION COUPLING
Authors: SILINSKY E.M.
Published: July 2012

The equilibrium dissociation constant (Kd) for Ca2+ as an antagonist of evoked acetylcholine (ACh) release was determined in the hope of distinguishing whether divalent cations control excitation‐secretion coupling selectively (by binding with high affinity to an external membrane site) or non‐selectively (by screening fixed negative charges on the external surface of the nerve terminal). ACh release was detected electrophysiologically by means of conventional intracellular recording techniques at frog motor endplates. Ba2+ was used as the agonist to support the asynchronous release of ACh by repetitive motor nerve impulses. Despite its dispersed nature, release mediated by Ba2+ occurs through the same conductance pathway as synchronous release mediated by Ca2+. Ca2+ was found to be a potent antagonist of Ba2+‐dependent release with a Kd = 0.12 ± 0.02 mM (mean ± s.e. mean, n = 5). This value is 30‐50 times lower than the Kd for Mg2+ as an antagonist of the same release process. It is suggested that antagonism of release by Ca2+ is likely to be exerted at the same external site that binds other divalent cation antagonists, a site that appears essential for the agonist behaviour of Ca2+. The high affinity (low Kd) of Ca2+ as an antagonist of ACh release suggests that a selective, binding model appears to be the most appropriate single description of the action of divalent cations at the external surface of the motor nerve ending.
ACTIONS OF 16‐ARYLOXY ANALOGUES OF PROSTAGLANDIN F2α ON PREPARATIONS RESPONSIVE TO PROSTAGLANDIN ENDOPEROXIDES
Authors: JONES R.L. , MARR C.G.
Published: July 2012

On four prostaglandin endoperoxide‐sensitive preparations, namely human platelets in vitro, rabbit aortic strip, guinea‐pig tracheal chain and pig blood pressure, ICI 79939 and its 11‐oxo analogue mimicked the actions of 11,9‐(epoxymethano) prostaglandin H2, and were considerably more active than either prostaglandin F2α or ICI 81008. It is suggested that this activity of ICI 79939 may contribute to its toxicity in experimental animals.
PROSTAGLANDIN F2α REDUCES THE ALGESIC EFFECT OF BRADYKININ BY ANTAGONIZING THE PAIN ENHANCING ACTION OF ENDOGENOUSLY RELEASED PROSTAGLANDIN E
Authors: JUAN H. , LEMBECK F.
Published: July 2012

The isolated perfused ear of the rabbit connected to the body only by its nerve, was used to investigate the influence of prostaglandin F2α on the algesic effect of bradykinin and acetylcholine.

Bradykinin and acetylcholine, following intra‐arterial injection into the isolated perfused ear elicited a dose‐related reflex fall in blood pressure due to stimulation of paravascular pain receptors (=algesic effect).

Infusion of prostaglandin F2α (0.1 to 1 ng/ml) into the rabbit ear reduced the algesic effect of bradykinin but not that of acetylcholine.

The onset of the reflex fall in blood pressure by bradykinin but not that by acetylcholine was delayed by infusion of prostaglandin F2α into the ear.

Infusion of prostaglandin E1 into the rabbit ear led to an enhancement of the algesic effect of bradykinin and acetylcholine. Enhancement of both effects was abolished by infusion of prostaglandin F2α.

During inhibition of the endogenous synthesis of prostaglandins (mainly E‐type) by indomethacin, a low concentration of prostaglandin F2α no longer reduced the algesic effect of bradykinin. However, a high concentration of F2α continued to enhance the effect of bradykinin and acetylcholine.

Prostaglandin F2α influenced neither the brief reduction in venous outflow produced by bradykinin nor the brief increase in venous outflow caused by acetylcholine.

The results suggest that prostaglandin F2α does not directly reduce the effect of bradykinin but inhibits the enhancement of its algesic effect produced by prostaglandin E that is released endogenously by bradykinin. That the algesic effect of acetylcholine is not reduced by prostaglandin F2α is in keeping with its releasing very little endogenous prostaglandin E.
BRAIN AND VASCULAR MONOAMINE OXIDASE ACTIVITY IN THE DEOXYCORTICOSTERONE‐SALT HYPERTENSIVE RAT
Authors: LAI F.M. , SPECTOR S.
Published: July 2012

The role of monoamine oxidase (MAO) in the maintenance of deoxycorticosterone‐sodium chloride (DOCA‐salt) hypertension was investigated by assaying the MAO activity both in central as well as peripheral blood vessels and in brain tissue.

The results suggest that the activity of MAO in the DOCA‐salt hypertensive rat is similar to the activity present in the normotensive rat.
EFFECTS OF D‐600 AND ITS OPTICAL ISOMERS ON FORCE OF CONTRACTION IN CAT PAPILLARY MUSCLES AND GUINEA‐PIG AURICLES
Authors: LUDWIG C. , NAWRATH H.
Published: July 2012

(−)‐D‐600 and (+)‐D‐600 exerted concentration‐dependent negative inotropic effects in papillary muscles from cats, the potency of (−)‐D‐600 being about 100 times greater than that of (+)‐D‐600. The action was more pronounced at high than at low frequencies of stimulation. Time to peak force, relaxation time and therefore also total duration of contraction were not significantly affected by the drugs.

The negative inotropic effects of both drugs were not reversible after washing in drug‐free solution for 60 min at all concentrations tested.

The same negative inotropic effects were seen in guinea‐pig left auricles with the racemic mixture of both isomers.

Uptake measurements of D‐600‐[nitrile‐14C] in isolated left auricles of guinea‐pigs showed the drug to be accumulated in the myocardial tissue; tissue‐medium ratios from 1.25 to 6.0 were found at exposure times from 1 to 100 minutes. Preparations which were loaded first with D‐600‐[nitrile‐14C] for 100 min and then washed in drug‐free solution for different times lost up to about 80% of the initial radioactivity, whereas the depression of force of contraction was not reversible.

The results show that there are marked quantitative differences between the actions of (−)‐D‐600 and (+)‐D‐600 on isometric force of contraction in cat papillary muscles. Although the time course of the uptake of D‐600‐[nitrile‐14C] and the development of the negative inotropy in guinea‐pig left auricles were reasonably well related, the magnitude of the negative inotropy does not seem to be dependent on the total tissue concentration once the negative inotropic effect has been fully developed.
INHIBITION BY GLUCOCORTICOIDS OF PROSTAGLANDIN RELEASE FROM ADIPOSE TISSUE in vitro
Authors: CHANG J. , LEWIS G.P. , PIPER PRISCILLA J.
Published: July 2012

When rabbit chopped adipose tissue was incubated with a lipolytic agent (adrenocorticotrophic hormone, ACTH1–24, 0.1 μg/ml) in Krebs solution, prostaglandin E2 was formed in the tissue and about the same amount was found in the medium.

In the presence of indomethacin (1 μg/ml) the appearance of prostaglandin E2 was almost abolished both in the tissue and in the medium.

When the incubation was carried out in the presence of hydrocortisone or betamethasone (1–10 μg/ml) the concentration of prostaglandin E2 leaking or carried into the medium was significantly reduced, whereas that remaining in the tissue was significantly increased. This action of the steroids was not reversed by increasing substrate (arachidonic acid) concentration in the medium.

The steroids did not affect lipolysis, nor did they influence prostaglandin metabolism since such activity was not detectable in the adipose tissue.

Anti‐inflammatory steroids therefore did not reduce prostaglandin formation but increased the tissue/medium ratio, which supports the view that they inhibit the release of prostaglandins after these have been synthesized.
BEHAVIOURAL AND PHARMACOKINETIC STUDIES IN THE MONKEY (Macaca mulatta) WITH DIAZEPAM, NORDIAZEPAM AND RELATED 1,4‐BENZODIAZEPINES
Authors: CURRY S.H. , WHELPTON R. , NICHOLSON A.N. , WRIGHT CATHERINE M.
Published: July 2012

Behavioural activity (delayed differentiation and spatial delayed alternation) and pharmacokinetics of diazepam and its metabolites, N‐desmethyldiazepam (nordiazepam), 3‐hydroxydiazepam (temazepam) and 3‐hydroxy‐N‐desmethyldiazepam (oxazepam), and of dipotassium clorazepate (clorazepate), were studied in the monkey (Macaca mulatta). Diazepam and its metabolites (1.8 and 3.0 mg/kg) and clorazepate (2.6 and 4.3 mg/kg) were given by intraperitoneal injection.

Hydroxylation of diazepam (temazepam and oxazepam) led to a loss of, or a considerable reduction in, behavioural activity, whereas activity was preserved, though modified, by demethylation (nordiazepam). It was not possible to establish change in behaviour at specific time intervals after clorazepate, but combined performance data revealed an effect.

The maximum mean plasma concentrations of diazepam, temazepam, oxazepam and clorazepate were observed at 0.5 h, and the maximum mean plasma concentration of nordiazepam was observed at 1 hour. Plasma concentrations of nordiazepam were the highest and decreased monoexponentially. Plasma concentrations of the other drugs declined rapidly at first but more slowly later, and these data were analysed as biexponential models. In the analysis for metabolites, nordiazepam reached measurable levels after the injection of diazepam and clorazepate.

It is suggested that differences in the effects of closely related benzodiazepines may not be due solely to their plasma pharmacokinetic properties, but may arise from differences in their intrinsic activity.
A PRESYNAPTIC SITE OF ACTION WITHIN THE MESENCEPHALIC RETICULAR FORMATION FOR (+)‐AMPHETAMINE‐INDUCED ELECTROCORTICAL DESYNCHRONIZATION
Authors: CANDY J.M. , KEY B.J.
Published: July 2012

Changes induced in the electrocorticogram by the bilateral perfusion of (+)‐amphetamine into the mesencephalic reticular formation (MRF) have been studied in cat encéphale isolé preparations.

(+)‐Amphetamine, applied for 5 min in the MRF, mimicked the electrocortical desynchronization induced by the perfusion of (−)‐noradrenaline (NA) or (−)‐α‐methylnoradrenaline (AMNA) into the same sites.

Perfusion of 6‐hydroxydopamine (6‐OHDA) also induced desynchronization but, over the 1 h perfusion period, slow wave activity gradually returned to the electrical record.

Following the application of 6‐OHDA the effect of (+)‐amphetamine was abolished or significantly attenuated, whereas the effect of NA or AMNA was not affected.

The electrocortical desynchronization induced by (+)‐amphetamine could be restored if its application was preceded by perfusion with NA or AMNA.

Fluorescence studies using AMNA indicated that 6‐OHDA depleted noradrenergic nerve terminals near the cannulae tips. However, the terminals were still capable of taking up exogenously applied AMNA.

These results suggest that (+)‐amphetamine has a presynaptic action on noradrenergic nerve terminals within the MRF.