bluuebunny/crossref_metadata_2025 huggingface dataset:
A new dopamine‐β‐hydroxylase inhibitor: effects on the noradrenaline concentration and on the action of L‐DOPA in the spinal cord
Authors: ANDÉN N.‐E. , FUXE K.
Published: July 2012

The dopamine‐β‐hydroxylase inhibitor bis(4‐methyl‐1‐homopiperazinyl‐thiocarbonyl) disulphide (FLA‐63; 25 mg/kg i.p.) caused within 4 h a 65% loss of noradrenaline throughout the intact rat spinal cord and also cranial to a transection of the cut spinal cord. Caudal to the lesion, there was only an insignificant depletion of 17% indicating the importance of nerve impulses for the disappearance of noradrenaline.

Dopamine accumulated in the spinal cord after treatment with FLA‐63 although the amounts were not sufficient to replace the missing noradrenaline. Even after treatment with l‐3,4‐dihydroxyphenylalanine (l‐DOPA), the catecholamine store was incompletely replenished by dopamine.

After a large depletion of the noradrenaline stores, induced by repeated doses of FLA‐63 or by reserpine plus FLA‐63, the l‐DOPA‐induced increase in flexor reflex activity of the hind limbs of spinal rats was inhibited much more than after pretreatment with α‐methyl‐tyrosine or reserpine. FLA‐63 blocked the formation of noradrenaline but not of dopamine from l‐DOPA.

The increase in flexor reflex activity induced by the noradrenaline receptor stimulating agent clonidine was not changed by FLA‐63, indicating that the noradrenaline receptor sensitivity was not influenced.

After depletion of the noradrenaline stores, the small formation of noradrenaline from l‐DOPA may be of greater functional significance for the noradrenaline receptor stimulation than the greater formation of dopamine, but the dopamine formed also has a slight action. With intact noradrenaline stores, displacement of endogenous noradrenaline by newly formed dopamine contributes, at least after monoamine oxidase inhibition, to the increase in the flexor reflex activity caused by l‐DOPA.
Lack of relationship between myocardial cyclic AMP concentrations and inotropic effects of sympathomimetic amines
Authors: BENFEY B. G.
Published: July 2012

Sympathomimetic amines which increase the contractility of the isolated heart were tested for effects on cyclic AMP concentrations in rabbit heart slices and on adenyl cyclase activity in rabbit heart homogenate.

Noradrenaline, as expected, stimulated adenyl cyclase activity and increased cyclic AMP concentrations, but dopamine and phenylephrine were ineffective.

This result does not support the concept that cyclic AMP plays an essential role in the inotropic effect of sympathomimetic amines.
Preferential secretion of adrenaline or noradrenaline by the cat adrenal in vivo in response to different stimuli
Authors: FEUERSTEIN GIORA , GUTMAN YEHUDA
Published: July 2012

The concentrations of adrenaline and noradrenaline in the adrenal vein and the adrenal gland of the cat were studied in response to different stimuli leading to increased catecholamine (CA) secretion.

Haemorrhage and hypoglycaemia, but not acute exposure to cold or intravenous administration of cocaine, induced considerable increases in total catecholamine secretion.

The ratio of the concentration of adrenaline to noradrenaline in adrenal vein plasma during the control period was higher than the ratio in the adrenal gland itself.

Haemorrhage increased noradrenaline secretion considerably more than adrenaline secretion so that the ratio of the concentration of adrenaline to noradrenaline in adrenal vein plasma was significantly lower than in the adrenal gland itself.

Hypoglycaemia induced by insulin increased catecholamine secretion, with the adrenaline to noradrenaline ratio significantly higher than in the adrenal gland itself.

Hypothermia resulted in a fall of the initial high ratio of adrenaline to noradrenaline, to a value similar to that in the adrenal gland.

Neither cocaine nor changes in adrenal plasma flow affected the adrenaline to noradrenaline ratio in adrenal vein blood.

It is concluded that preferential release from the adrenal gland of either adrenaline or noradrenaline is possible in vivo in response to different stimuli.
Modification by choline of adrenergic transmission in rat mesenteric arteries
Authors: MALIK K. U. , McGIFF J. C.
Published: July 2012

The action of choline on the vasoconstrictor responses of the perfused mesenteric arteries of the rat to sympathetic nerve stimulation and to injected noradrenaline has been investigated.

The infusion of choline (500 μg/ml), for periods of 15 s, increased the response to sympathetic nerve stimulation, whereas the infusion of the same concentration for 20 min greatly reduced the response to nerve stimulation. Choline (up to 500 μg/ml), infused either for short or long periods, did not alter the response to injected noradrenaline.

The inhibitory action of choline on the response to nerve stimulation was abolished either by an increase in the calcium concentration from 1·8 to 5·4 mm or by simultaneous infusion of (+)‐amphetamine or atropine.

The results suggest that choline in concentrations of 500 μg/ml has the same effect on adrenergic transmission in mesenteric arteries as acetylcholine at concentrations of 5 ng/ml.
Differences in the uptake, storage and metabolism of (+)‐ and (—)‐noradrenaline
Authors: IVERSEN L. L. , JARROTT B. , SIMMONDS M. A.
Published: July 2012

The rate of uptake of (+)‐ and (—)‐noradrenaline was measured in isolated perfused hearts of reserpine treated rats, mice and guinea‐pigs by fluorimetric analysis of the removal of catecholamine from the perfusion medium. In rat and mouse heart (—)‐noradrenaline was taken up significantly more rapidly than (+)‐noradrenaline, but no stereochemical specificity was found for noradrenaline uptake in guinea‐pig hearts.

Using radioactively labelled (+)‐14C‐noradrenaline and (—)‐3H‐noradrenaline, the kinetic constants for uptake into noradrenaline‐containing and dopamine‐containing synaptosomes from rat brain were determined. The uptake by noradrenaline terminals in the hypothalamus had a higher affinity for (—)‐noradrenaline than for the (+)‐isomer, but no differences in affinity were found for uptake into dopamine terminals.

When equal amounts of labelled (+)‐ and (—)‐noradrenaline were injected in vivo in double isotope experiments, the (+)‐isomer disappeared more rapidly than the (—)‐isomer from rat heart and spleen, but no significant differences were found between the rates of disappearance of the two isomers from rat brain or in the whole mouse.

Analysis of the radioactive metabolites of the two isomers of noradrenaline after administration of mixed doses of the labelled substances showed that a significantly higher proportion of (+)‐noradrenaline was metabolized to normetanephrine than of (—)‐noradrenaline, in the whole mouse, rat heart and rat brain.
The effects of dipyridamole on coronary post‐occlusion hyperaemia and on myocardial vasodilatation induced by systemic hypoxia
Authors: PARRATT J. R. , WADSWORTH R. M.
Published: July 2012

. The arterial pO2 of anaesthetized cats was reduced to 33 mmHg by supplying a mixture of oxygen and nitrogen as the respiratory gas. This produced vasodilatation in the myocardial bed which was not increased after the injection of dipyridamole (1 mg/kg).

. Reactive hyperaemia was observed following occlusion of the left anterior descending coronary artery for 10–120 seconds. The duration of the period of reactive hyperaemia was increased after the injection of dipyridamole. This effect of dipyridamole was most pronounced when the longest periods of occlusion were used.

. These results support the hypothesis that myocardial reactive hyperaemia is at least partly caused by adenosine released from hypoxic myocardial cells. The vasodilatation occurring during systemic hypoxia, on the other hand, is probably mediated via a different mechanism.
The effect of bradykinin on denervated tongue
Authors: RADMANOVIĆ B. , TORRES SONIA H.
Published: July 2012

. The contractile response of the chronically denervated tongue of the cat to chorda stimulation, and to close arterial injections of bradykinin, acetylcholine (ACh) and other drugs was examined.

. Bradykinin in doses of 50 ng‐20 μg injected close arterially always produced a contractile response of the denervated tongue. Sodium nitrite (1 mg i.a.) and isoprenaline (3–200 ng i.a.) also produced contracture; histamine (40–100 ng i.a.) evoked an increase in tension in only 2 out of 5 experiments.

. Tubocurarine in doses of 0·25–1 mg injected intra‐arterially, produced a large and long‐lasting contracture of the denervated tongue. When the contracture was over, the effect of bradykinin was reduced to about half; the effects of ACh and chordo‐lingual nerve stimulation were markedly reduced (over 80%), and those of sodium nitrite and isoprenaline were transiently abolished. Gallamine only slightly reduced the effect of bradykinin.

. Close intra‐arterial injection of physostigmine (100 μg) potentiated the effect of ACh and chordo‐lingual nerve stimulation, but did not increase the response to bradykinin.

. Cocaine (1 mg/kg i.v.) deeply depressed the response to bradykinin, and moderately reduced the responses to ACh (41%) and to chorda stimulation (66%).

. In 2 out of 7 experiments, close arterial injections of bradykinin (100–500 ng) to the denervated tibialis anterior muscle of the cat, produced a contractile response. Bradykinin in small doses (200–250 ng) injected immediately before ACh potentiated its effect. On the other hand, the effect of ACh was depressed when given immediately after a big dose of bradykinin (10–15 μg).

. The possible mechanism of action of bradykinin and other substances on denervated muscle is discussed.
Actions of the selective inhibitor of cholinesterase tetramonoisopropyl pyrophosphortetramide on the rat phrenic nerve‐diaphragm preparation
Authors: HEFFRON P. F.
Published: July 2012

. Tetramonoisopropyl pyrophosphortetramide (iso‐OMPA) added for 15 min to the rat isolated phrenic nerve‐diaphragm in a concentration of 30 μm, produced a complete selective and stable inhibition of cholinesterase. A concentration of 3 μm produced near complete inhibition of cholinesterase, and a concentration of 300 μm also inhibited acetylcholinesterase marginally.

. Inhibition of cholinesterase was associated with a sustained increase in the neuromuscular blocking action of exogenous butyrylcholine but not of exogenous acetylcholine. Iso‐OMPA, 300 μm, in addition caused transient increases in the sensitivity of the rat diaphragm to exogenous acetylcholine and butyrylcholine. In the same concentration, it had a curare‐like action on the frog rectus abdominis muscle preparation.

. Iso‐OMPA, 30 μm, caused reversible increases in the amplitude of the twitch response and tetanic responses, which were of a similar magnitude in the indirectly stimulated preparation and the directly stimulated curarized preparation. Caffeine had a similar effect on the twitch response and its effectiveness was increased by iso‐OMPA, and vice‐versa. Amongst anticholinesterases, octamethyl pyrophosphortetramide and tetraethylpyrophosphate also enhanced the amplitude of the tetanic response, but paraoxon, dyflos, and mipafox did not.

. It is concluded that iso‐OMPA, in concentrations (3 and 30 μm) which in 15 min give near maximal or maximal selective inhibition of cholinesterase, has no effect on the transmission of nerve impulses at the neuromuscular junction, but enhances reversibly the amplitude of the contractile response to stimulation by a direct action upon the muscle fibre, which involves a mechanism related to but not identical with that by which caffeine potentiates twitch tension. In higher concentrations, iso‐OMPA has a curare‐like action at the neuromuscular junction.
Effects of clozapine on cerebral catecholaminergic neurone systems
Authors: BARTHOLINI G. , HAEFELY W. , JALFRE M. , KELLER H. H. , PLETSCHER A.
Published: July 2012

. Clozapine, a dibenzodiazepine derivative claimed to possess antipsychotic properties in man without producing extrapyramidal disorders, greatly increased the turnover of cerebral dopamine in the rat.

. The drug itself was virtually devoid of cataleptigenic activity in rats; however, it antagonized prochlorperazine‐induced catalepsy.

. It is proposed that clozapine causes a blockade of striatal dopamine receptors which is of the surmountable type in contrast to that produced by cataleptigenic neuroleptics. In addition, clozapine may also increase the turnover of cerebral noradrenaline.
Responses of the isolated, perfused human spleen to sympathetic nerve stimulation, catecholamines and polypeptides
Authors: AYERS A. B. , DAVIES B. N. , WITHRINGTON P. G.
Published: July 2012

The responses of the smooth muscle of the capsule and blood vessels of the isolated, perfused human spleen to sympathetic nerve stimulation, adrenaline, noradrenaline, angiotensin, oxytocin, vasopressin, isoprenaline and acetylcholine have been investigated and compared with those of dog spleen.

Stimulation of the postganglionic sympathetic nerves to the human spleen at frequencies of 3–10 Hz evoked graded vasoconstriction but very small changes in spleen volume.

The injection of adrenaline and noradrenaline in doses of 0·25–25 μg to the human spleen produced graded increases in splenic vascular resistance with very small decreases in spleen volume.

Administration of the α‐adrenoceptor blocking drug phenoxybenzamine completely abolished or considerably reduced the vascular responses of the human spleen to sympathetic nerve stimulation or the injection of noradrenaline.

The vascular action of adrenaline was often reversed to elicit a vasodilatation after phenoxybenzamine suggesting the presence of β‐adrenoceptors in the vascular bed. This was confirmed by the administration of isoprenaline which induced a marked reduction in vascular resistance of the human spleen.

The polypeptides angiotensin and vasopressin induced a marked vasoconstriction in the human spleen without changes in the spleen volume. These effects were uninfluenced by the administration of phenoxybenzamine.

The polypeptide oxytocin caused a slight vasodilatation in the human spleen, an effect almost exactly mimicked by the preservative chlorobutanol.

Preliminary experiments suggest that noradrenaline is the transmitter released by the postganglionic nerves to the human spleen.

These results provide direct evidence that the normal human spleen, unlike that of the dog, does not have a reservoir function. It is suggested that contractions of the enlarged human spleen may occur in various pathological conditions.
Fluorometric estimation of 4‐hydroxy‐3‐methoxyphenylethyleneglycol sulphate in brain
Authors: MEEK JAMES L. , NEFF NORTON H.
Published: July 2012

A simple, sensitive, and selective method was developed for the fluorimetric estimation of 4‐hydroxy‐3‐methoxyphenylethyleneglycol sulphate (MOPEG‐SO4) in rat brain.

MOPEG‐SO4 was isolated on a DEAE Sephadex column. Fluorescence was measured at 465 nm (excitation at 320 nm) after heating the column eluate with acid and reheating after adding ethylene diamine.

The concentration in brain of MOPEG‐SO4 increased after blockade of its transport from brain by treatment with probenecid and decreased after inhibiting its synthesis by treatment with α‐methyltyrosine or pargyline.

Our studies suggest that measurement in changes in the rate of formation of MOPEG‐SO4 may be a useful index of noradrenaline turnover.
Pharmacology of AH 5158; a drug which blocks both α‐ and β‐adrenoceptors
Authors: FARMER J. B. , KENNEDY I. , LEVY G. P. , MARSHALL R. J.
Published: July 2012

AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both α‐ and β‐adrenoceptors.

AH 5158 is 5–18 times less potent than propranolol in blocking β‐adrenoceptors. It resembles propranolol in its non‐selective blockade of β1‐cardiac and β2‐vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity.

AH 5158 is 2–7 times less potent than phentolamine in blocking α‐adrenoceptors. AH 5158 itself is more active on β‐ than α‐adrenoceptors.

Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose‐dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. ‘Self‐limiting’ blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of ‘self‐limiting’ blockade is discussed.

In doses higher than those required for either α‐ or β‐adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane‐stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea‐pig left atrial strips, as a negative chronotropic action in syrosingopine pre‐treated dogs, and as an increase in the effective refractory period of guinea‐pig left atrial strips. AH 5158 was 3–11 times less potent than propranolol in these tests.

In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to β‐adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent β‐adrenoceptor blocking doses. These differences are attributable to the α‐adrenoceptor blocking actions of AH 5158.

In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine and ouabain‐induced arrhythmias. Orally administered AH 5158 lowered systolic arterial pressure in conscious renal hypertensive dogs.

These results show AH 5158 to possess a novel profile of activity. Possible uses of the drug in cardiovascular disorders such as hypertension, angina pectoris and cardiac arrhythmias are discussed.
The effect of certain β‐adrenoceptor antagonists on overdrive suppression
Authors: KELLIHER G. , LUOTO JOANNE , ROBERTS J.
Published: July 2012

Propranolol, as the racemate and the (+)‐ and (–)‐isomers (400 μg/l.) and practolol (50 mg/l.) were tested for their effects on atrial and ventricular rates and on the duration of overdrive suppression (ODI) in isolated perfused cat hearts with surgically‐induced heart block.

Racemic propranolol and the (+)‐ and (–)‐isomers prolonged ODI and slowed the rate of the ventricular pacemaker; the (+)‐ and (–)‐isomers also reduced the rate of the atrial pacemaker. Practolol shortened ODI and increased the rate of the atrial and ventricular pacemakers.

The (+)‐ and (–)‐isomers were more potent than the racemate; the (–)‐isomer was more potent than the (+)‐isomer. The results suggest there is a stereospecific mechanism involved in the biological distribution of propranolol.

Twenty‐four hours after reserpine treatment (5 mg/kg, i.p.) practolol continued to increase the rate of the atrial and ventricular pacemakers but did not shorten ODI.

The mechanism by which these agents affect myocardial excitability and automaticity is discussed.
Further studies on nitrofurantoin excretion in dog hepatic bile
Authors: CONKLIN J. D. , SOBERS R. J. , WAGNER D. L.
Published: July 2012

. Results obtained with a dog donor‐recipient model indicate that following intravenous administration of nitrofurantoin sodium, nitrofurantoin is subjected to enterohepatic cycling. At least one‐third of the nitrofurantoin originally excreted in the donors' bile after a nitrofurantoin dose of 3 mg/kg is reabsorbed intestinally in the recipients within 3 hours.

. After intraduodenal administration of a nitrofurantoin suspension to dogs at doses ranging from 2 to 12 mg/kg, about 10% of the dose is recovered in bile as nitrofurantoin within 6 hours. A hydrocholeretic effect was also observed which correlated with the amount of drug administered. Both biliary drug excretion and the related hydrocholeresis appeared linearly related over the drug dose range.

. The hydrocholeresis observed in dogs within 3 h after intravenously administered nitrofurantoin sodium, equivalent to 3 mg/kg nitrofurantoin, was at least ten times that seen following the intravenous administration of an equimolar dose of dehydrocholic acid given as its sodium salt.
Alterations in the activities of ornithine and histidine decarboxylases provoked by testosterone in mice
Authors: GRAHN B. , HENNINGSSON S. S. G. , KAHLSON G. , ROSENGREN ELSA
Published: July 2012

The urinary excretion of putrescine has been determined in female mice before and during repeated injections of testosterone.

Testosterone administration effected a striking increase in the excretion of free putrescine.

Ornithine decarboxylase (l‐ornithine carboxy‐lyase; E.C. 4.1.1.17) and histidine decarboxylase (l‐histidine carboxy‐lyase; E.C. 4.1.1.22) activities of mouse kidney and liver were examined. In the kidney, following testosterone administration, ornithine decarboxylase activity was found to be substantially elevated, whereas that of histidine decarboxylase was depressed. In the liver, by contrast, the activity levels of these enzymes were not significantly altered by testosterone treatment.

The possibility of a functional interrelation between putrescine and histamine, via the two enzyme activities investigated, is discussed.
Anaphylaxis in the guinea‐pig isolated heart: selective inhibition by burimamide of the positive inotropic and chronotropic effects of released histamine
Authors: CAPURRO NORINE , LEVI R.
Published: July 2012

Anaphylaxis was induced in the isolated heart of the guinea‐pig in the presence of burimamide at concentrations of 4 × 10−5M and 2·7 × 10−4M.

Burimamide did not affect the immunological release of histamine; however, it selectively antagonized the positive inotropic and chronotropic effects of released histamine. The antagonism of the positive chronotropic effect was concentration‐dependent.

Neither the negative dromotropic effect nor the decrease in coronary flow rate occurring during anaphylaxis were inhibited by burimamide.

The results are in agreement with the double histamine receptor theory and suggest that, in the heart of the guinea‐pig, H2‐receptors are involved in the positive inotropic and chronotropic effects of released histamine, and H1‐receptors in the negative dromotropic effect.
The determination of dopamine by a modification of the dihydroxyindole fluorimetric assay
Authors: ATACK C. V.
Published: July 2012

A simplified sensitive fluorimetric assay for dopamine based on the hydroxyindole principle is described. Oxidation of dopamine by ferricyanide and subsequent tautomerization both occur in the same, strongly alkaline, ethanolic solution in the presence of metabisulphite. The reaction is self‐regulating, and since times of additions of reagents are relatively unimportant and the final fluorescence is very stable, a large number of samples can be assayed together.

The method was developed for assaying dopamine in n‐ethanolic (50%)–HCl eluates, after purification on a strongly acidic cation exchange column as previously described (Atack & Magnusson, 1970). Portions, up to 1 ml volume, of the 3·5 ml eluate can be taken. No preliminary, time‐consuming, neutralization step is required before oxidation. Fluorescence intensity shows a linear relation with concentration for 1–5,000 ng of dopamine per 1·6 ml of final solution, both in pure solutions and in column eluates.

Fluorescence readings from biological material are given, with evidence for their reproducibility. These, together with other data, demonstrate the relative accuracy of the ‘tissue blank’ and indicate that amounts of dopamine greater than 3 ng per column can confidently be detected, and amounts greater than 10 ng can be measured quantitatively.

Fluorescence spectra are presented for the fluorophore derived from authentic dopamine, and from suspected dopamine extracted from spinal cord of normal rats and rats treated with reserpine plus an inhibitor of synthesis. Values for the concentration of dopamine of 20 and <3 ng/g, respectively, were obtained.
Cardiovascular and respiratory effects of cannabis in cat and rat
Authors: GRAHAM J. D. P. , LI D. M. F.
Published: July 2012

In anaesthetized rats, intravenous administration of cannabis extract (10 mg/kg), Δ1‐tetrahydrocannabinol (THC) (0·5 mg/kg) and Δ6‐THC (0·5 mg/kg) caused a reduction in systemic blood pressure, pulse rate and respiratory rate.

Neither cannabinol (1 mg/kg, i.v.) nor cannabidiol (1 mg/kg, i.v.) had any observed effects on the cardiovascular and respiratory systems of the rat.

Pretreatment of rats with atropine (1 mg/kg, i.v.) reduced the hypotension and bradycardia caused by Δ1‐THC or the extract.

In anaesthetized cats with autoperfused hindquarters, cannabis extract (10 mg/kg, i.v.) and Δ1‐THC (0·2 mg/kg, i.v.) caused hypotension, bradycardia, depression of respiratory rate and reduction of hindlimb perfusion pressure.

Both cannabis extract and Δ1‐THC potentiated reflex vasodilatation and direct vasoconstriction in the hindlimb induced by intravenous noradrenaline in the cat; they reduced reflex hindlimb vasoconstriction elicited by histamine, acetylcholine or bilateral carotid occlusion.

Tolerance to these cardiovascular and respiratory effects of cannabis extract developed in rats which had been treated i.p. with the extract at (50 mg/kg) per day for 14 days.
Cardiovascular responses to injections of cholinomimetic drugs into the cerebral ventricles of unanaesthetized dogs
Authors: LANG W. J. , RUSH M. L.
Published: July 2012

The cardiovascular and behavioural effects of cholinomimetic drugs injected through a cannula chronically implanted into a lateral cerebral ventricle were examined in unanaesthetized dogs.

Acetylcholine (ACh) (10–20 μg) produced an increase in arterial pressure and heart rate, the dogs became more alert, moved their heads, licked and swallowed and then became drowsy.

The responses to ACh were potentiated by intraventricular physostigmine (5 μg), were abolished by intraventricular atropine (100 μg) but were unaffected by intraventricular mecamylamine (250 μg). The responses to ACh were reproducible on any one day if injections were given again after a 30 min interval but tolerance developed when ACh was injected repeatedly over periods of several days.

Methacholine (40 μg) produced similar behavioural and cardiovascular effects to ACh but of a longer duration. The responses to methacholine were abolished by intraventricular atropine (100 μg).

Nicotine (20–60 μg) produced a biphasic cardiovascular response of an initial brief pressor response and tachycardia followed by a secondary increase in arterial pressure and heart rate which was greater in magnitude and duration. The secondary cardiovascular effects were associated with restlessness and vomiting.

The responses to nicotine were abolished by prior injection of mecamylamine (250 μg) but were unaffected by atropine (100 μg). The responses to nicotine were not reproducible if injections were repeated on the same day but could be again produced if a few days were allowed to elapse between injections.

An increased heart rate occurred during the pressor response to the cholinomimetic drugs but when a comparable pressor response was produced by intravenous infusion of noradrenaline in the same unanaesthetized dogs pronounced reflex bradycardia resulted.

The results indicate that the activation of both muscarinic and nicotinic cholinergic mechanisms leads to cardiovascular and behavioural effects in the conscious dog although the site of action and peripheral mechanisms have not been determined.
Selective blockade of β‐adrenoceptors by 1‐(p‐allylphenoxy)‐3‐isopropylamino‐2 propanol hydrochloride (H 64/52) in the anaesthetized dog
Authors: LEVY B.
Published: July 2012

The β‐adrenoceptor blocking properties of l‐(p‐allylphenoxy)‐3‐isopropylamino‐2‐propanol hydrochloride (H 64/52) on the cardiovascular and broncho‐motor responses to isoprenaline have been determined in the anaesthetized dog.

H 64/52 selectively blocked the isoprenaline‐induced increase in heart rate, contractile force and reduction in airway pressure in the same dose range.

H 64/52 produced a minimal blockade of vascular β‐adrenoceptors which was apparent only when the isoprenaline‐induced fall in diastolic pressure was considered. No significant vascular β‐adrenoceptor blockade with H 64/52 could be shown with the femoral arterial flow or hind‐limb perfusion studies.

These results further support the hypothesis that several different β‐adrenoceptor subtypes exist in the dog. The β‐adrenoceptors subserving cardiac stimulation and bronchodilation appear to be similar and both differ from the β‐adrenoceptor subserving vasodilatation.
On the pharmacology of ascending, descending and recurrent postsynatic inhibition of the cuneo‐thalamic relay cells in the cat
Authors: KELLY J. S. , RENAUD L. P.
Published: July 2012

In cats decerebrated or anaesthetized with pentobarbitone, cells of the middle third of the cuneate nucleus that were excited by tactile stimulation of the ipsilateral forelimb (responding to displacement of hairs, skin or joints) and inhibited by electrical stimulation of the contralateral pyramid, were invariably inhibited by electrical stimulation of the ipsilateral forepaw and the contralateral forelimb nerves.

In 50% of the cats, the cells were more fully identified by placing electrodes stereotaxically in the contralateral medial lemniscus. Recurrent inhibition was always a concomitant of the antidromic action potential.

The intensity and the duration of inhibition evoked by all of these pathways was totally resistant to iontophoretic and intravenous strychnine in doses at least 5 times that required to block completely the response of the same cells to iontophoretic glycine and was extremely sensitive to either iontophoretic bicuculline or picrotoxin.

Although the inhibition was invariably sensitive to intravenous picrotoxin, no significant change occurred in the duration or intensity of the inhibition when bicuculline was administered intravenously (5 or 6 times) as repeated doses of 0·2 mg/kg.

Postsynaptic inhibition in the cuneate may be mediated by γ‐aminobutyric acid released from the nerve terminals of a common pool of interneurones shared by ascending, descending and recurrent pathways. Since the receptors involved in this pathway are resistant to intravenous bicuculline, they may well be distinct from those responsible for changes in the primary afferent terminal excitability, usually believed to be associated with presynaptic inhibition.
Lithium kinetics in man: effect of variation in dosage pattern
Authors: BERGNER P‐E. E. , BERNIKER K. , COOPER T. B. , GRADIJAN J. R. , SIMPSON G. M.
Published: July 2012

Utilizing a general stochastic theory of drug kinetics we have demonstrated that from the serum concentration curve derived from a single dose of lithium, it is possible to predict the steady state concentration, the time required to reach steady state, the dependency of these quantities on the time interval between drug administrations and the fluctuations in plasma level under steady state conditions.

It has been shown in general that the more frequently the drug is administered the higher is the steady state level, the shorter is the time required to reach steady state, and the smaller are the fluctuations.
EFFECTS ON PLASMA AND BRAIN TRYPTOPHAN IN THE RAT OF DRUGS AND HORMONES THAT INFLUENCE THE CONCENTRATION OF UNESTERIFIED FATTY ACID IN THE PLASMA
Authors: CURZON G. , KNOTT P.J.
Published: July 2012

The effects on tryptophan distribution and metabolism of drugs altering plasma unesterified fatty acid (UFA) concentration were investigated in the rat.

UFA and plasma free (i.e. ultrafilterable) tryptophan altered in the same direction.

Catecholamines and l‐DOPA increased both plasma UFA and free tryptophan. l‐DOPA also increased brain tryptophan and 5‐hydroxyindoleacetic acid (5‐HIAA) but decreased brain 5‐hydroxytryptamine (5‐HT).

Aminophylline increased plasma UFA and free tryptophan and also brain tryptophan, 5‐HT and 5‐HIAA. Food deprivation had qualitatively similar effects.

Insulin decreased plasma UFA and free tryptophan in both fed and food‐deprived rats. However, while in fed rats these changes were associated with small decreases of brain indoles, in food‐deprived animals small increases occurred.

Nicotinic acid had only small effects in fed rats but it opposed both the UFA and indole changes in food‐deprived animals. Total plasma tryptophan increased in nicotinic acid treated, food‐deprived rats.

There was a tendency towards inverse relations between changes of plasma free and total tryptophan.

The results suggest that drugs which influence plasma UFA through actions on cyclic AMP thereby alter the binding of tryptophan to plasma protein and that this leads to altered distribution and metabolism of tryptophan.
RELEASE OF PROSTAGLANDINS FROM THE RABBIT PERFUSED KIDNEY: EFFECTS OF VASOCONSTRICTORS
Authors: GAGNON D.J. , GAUTHIER R. , REGOLI D.
Published: July 2012

The rat stomach strip was used to assay prostaglandin E2‐like material released by a rabbit isolated kidney perfused with Krebs solution.

Doses of noradrenaline and angiotensin II producing similar vasoconstrictor effects released equivalent amounts of prostaglandins from the kidney.

8‐Leu‐angiotensin II, a specific inhibitor of the natural octapeptide, blocked the action of angiotensin II on perfusion pressure and the release of prostaglandins, while the action of noradrenaline on both parameters was unaffected.

Indomethacin, a specific inhibitor of prostaglandin biosynthesis, blocked the effects of both vasoconstrictors on prostaglandin release while their action on perfusion pressure was significantly enhanced.

In the kidney effluent, amounts of prostaglandin E2‐like material increased linearly with the rise in perfusion pressure induced by increasing doses of angiotensin II. These results indicate that prostaglandin output from the isolated kidney follows the rise in perfusion pressure.
INTERACTION OF CANNABIS AND GENERAL ANAESTHETIC AGENTS IN MICE
Authors: CHESHER G.B. , JACKSON D.M. , STARMER G.A.
Published: July 2012

A cannabis extract (I) (in a concentration equivalent to 10 mg Δ9‐tetrahydrocannabinol(THC)/kg) prolonged pentobarbitone anaesthesia in mice maximally 20 min to 2 h after medication. The effect was still significant after 8 h, but less than at 2 hours.

The cannabis extract (I) (equivalent to 10 mg Δ9‐THC/kg) prolonged both pentobarbitone and ether anaesthesia in mice when administered 20 min before the anaesthetic. After eight consecutive daily doses of cannabis, the pentobarbitone anaesthesia was still significantly longer than a control group, while ether anaesthesia was not significantly prolonged.

A second cannabis extract (II) with a different ratio of cannabinoids (also administered in dosage equivalent to 10 mg Δ9‐THC/kg) failed to affect pentobarbitone anaesthesia in mice. This extract presented about 4% the dose of cannabidiol as extract I.

Δ8‐THC, Δ9‐THC and cannabidiol prolonged pentobarbitone anaesthesia with cannabidiol being generally more active than Δ9‐THC. Cannabinol (10 mg/kg) was inactive.

The effects of cannabidiol and Δ9‐THC were found to be additive, and there was a consistent trend for cannabinol to reduce the effectiveness of Δ9‐THC and cannabidiol when given in combination.

Premedication with phenoxybenzamine, phentolamine, propranolol, iproniazid, protriptyline, desipramine, reserpine, α‐methyl tyrosine or parachlorophenylalanine did not affect the extract I‐induced prolongation of pentobarbitone anaesthesia.

It is concluded that cannabis may affect pentobarbitone and ether anaesthesia in mice at least partially by a direct depressant effect, and that the cannabis‐induced prolongation of anaesthesia is probably unrelated to any effect on central 5‐hydroxytryptamine or catecholamine neurones.
DISTRIBUTION OF LOCAL ANAESTHETICS: ACCUMULATION IN SOME ENDOCRINE POLYPEPTIDE‐HORMONE PRODUCING CELL SYSTEMS
Authors: HAMMARSTRÖM L. , SLANINA P. , TJÄLVE H. , ULLBERG S.
Published: July 2012

After the injection of labelled procaine and lidocaine in mice, the location and concentration of radioactivity was demonstrated by autoradiographical methods.

An accumulation in some endocrine cells such as the pancreatic islets, the hypophysis, the adrenal medulla and certain cells of the thyroid (probably representing the calcitonin‐producing parafollicular cells) was shown.

After the injection of [14C]‐procaine in chicks, an accumulation of radioactivity was observed in the ultimobranchial gland (which produces calcitonin in birds), but not in the thyroid.

Radioactivity was also shown to be strongly concentrated in structures containing melanin, such as the pigment of the eye, skin and hair and in some organs involved in the metabolism and excretion of these drugs.
ELECTROPHORESIS OF ISOLATED SECRETORY GRANULES FROM GUINEA‐PIG SUBMAXILLARY GLAND
Authors: BHOOLA K.D. , COGDELL R.
Published: July 2012

The nature of the surface charge on secretory granules from the submaxillary gland of the guinea‐pig has been studied by electrophoresis of the isolated granules. The granules suspended in buffered sucrose solutions move to the anode.

Divalent ions reduce the anodal movements of the granules. Calcium and magnesium neutralize the net surface charge of the granules. This result supports the hypothesis that the electrostatic surface charge which can be reduced by calcium ions may be a major factor in controlling the fusion of secretory granules to the cell membrane, before release by exocytosis.

The mechanisms which couple membrane events with enzyme or hormone release from secretory glands are considered.
ACTIONS OF SOME ESTERS OF 3,3‐DIMETHYLBUTAN‐1‐OL (THE CARBON ANALOGUE OF CHOLINE) ON THE GUINEA‐PIG ILEUM
Authors: BARLOW R.B. , TUBBY JULIA H.
Published: July 2012

Estimates were made of the affinity constants for postganglionic acetylcholine receptors of the guinea‐pig ileum of the esters of 3,3‐dimethylbutan‐1‐ol with benzilic, (±)‐cyclohexylphenylglycollic, (±)‐mandelic, and diphenylacetic acids.

Attempts were made to check the competitive nature of the antagonism by using as wide a range of concentrations of antagonist as possible, consistent with their limited solubility, and by testing some of the compunds in the presence of a known competitive antagonist.

By comparing the affinities with those of the corresponding quaternary nitrogen compounds, the contribution made by the positive charge in the onium group to the binding by receptors may be assessed and has been found to be variable. The carbon analogue of benziloylcholine has about one‐tenth of its affinity, that of (±)‐cyclohexylphenylglycolloylcholine has only about one‐sixtieth of its affinity, but that of (±)‐mandelylcholine has slightly higher affinity than that of (±)‐mandelylcholine itself.

3,3‐Dimethylbutylacetate appeared to be a partial agonist with an affinity constant of about 2.6 × 103. The contribution made by the positive charge to the binding of acetylcholine at these receptors therefore seems likely to lie within the range observed with antagonists and there is no reason to believe that there is necessarily greater intimacy of association by agonists than by antagonists.

Although the C—C and N—C bonds in —CMe3 and —NMe3 are similar in length, the groups do not occupy the same volume in solution in water.
MANGANESE IONS AND SYNAPTIC TRANSMISSION IN THE SUPERIOR CERVICAL GANGLION OF THE CAT
Authors: KOSTIAL KRISTA , LANDEKA M. , ŠLAT B.
Published: July 2012

In the perfused superior cervical ganglion of the cat manganese ions (2.7 − 4.6 mm) caused a block of synaptic transmission and reduced the output of acetylcholine.

Calcium ions (8.4–10.5 mm) relieved the synaptic block produced by manganese and partially restored the acetylcholine output.

The presence of manganese also reduced the sensitivity of ganglion cells to injected acetylcholine.

Both effects of manganese were completely reversible.
INFLUENCE OF SKF‐525A CONGENERS, STROPHANTHIDIN AND TISSUE‐CULTURE MEDIA ON DESENSITIZATION IN FROG SKELETAL MUSCLE
Authors: TERRAR D.A.
Published: July 2012

Microelectrodes have been used to follow changes in membrane potential at end‐plate regions of frog skeletal muscle fibres exposed to carbachol; the depolarizing drug was applied to narrow strips of muscle in a rapidly flowing solution containing relatively impermeant anions rather than chloride.

During prolonged applications of carbachol (10 to 20 μm), the depolarization caused by the drug showed a gradual decline which was attributed to desensitization.

Desensitization was little if at all affected by supplementing the external solution with factors present in tissue‐culture media, or by treating the muscle with strophanthidin (25 μm).

The rate of repolarization in the presence of carbachol (10 to 20 μm) was greatly increased by the SKF‐525A congeners pipenzolate bromide (10 μm) and adiphenine hydrochloride (1 μm). The desensitization‐enhancing action of these compounds is discussed.
EFFECT OF 6‐HYDROXYDOPAMINE ON [3H]‐ADENINE NUCLEOTIDE AND [3H]‐NORADRENALINE RELEASE FROM THE GUINEA‐PIG TAENIA CAECUM EVOKED BY ELECTRICAL FIELD STIMULATION, NICOTINE AND PERIVASCULAR NERVE STIMULATION
Authors: KUCHII M. , MIYAHARA J.T. , SHIBATA S.
Published: July 2012

The effects of pretreatment of guinea‐pigs with 6‐hydroxydopamine (6‐OHDA) on the release of [3H]‐noradrenaline and [3H]‐adenine nucleotide following electrical field, nicotine and perivascular nerve stimulation of guinea‐pig taenia caecum were studied.

High frequency electrical field stimulation (15,30 Hz) released both [3H]‐noradrenaline and [3H]‐adenine nucleotide but low frequency (0.5, 5 Hz) stimulation, producing comparable muscle relaxation led only to [3H]‐noradrenaline release.

6‐OHDA (50–200 mg/kg) pretreatment inhibited the muscle relaxation and, [3H]‐noradrenaline release with electrical stimulation or with nicotine in isolated taenia but did not affect the release of [3H]‐nucleotide.

A low dose of 6‐OHDA (50 mg/kg), completely inhibited the muscle relaxation and [3H]‐noradrenaline release elicited by perivascular nerve stimulation.

Both tissue noradrenaline content and [3H]‐noradrenaline uptake were decreased to the same extent by low as well as high doses of 6‐OHDA: noradrenaline content was reduced to 20% and uptake to 30% of the control value.

Catecholamine fluorescence disappeared from tissue layers of the taenia after treatment with a high dose of 6‐OHDA.

In these experiments the inhibitory action of electrical stimulation and nicotine on the taenia can be correlated better with noradrenaline than with nucleotide release.
THE EFFECTS OF INDOMETHACIN AND EICOSA‐5,8,11,14‐TETRAYNOIC ACID ON THE RESPONSE OF THE RABBIT PORTAL VEIN TO ELECTRICAL STIMULATION
Authors: GREENBERG R.
Published: July 2012

The effects of indomethacin and eicosa‐5,8,11,14‐tetraynoic acid (ETYA) on the contractile response of the transmurally stimulated rabbit portal vein were studied in vitro.

When the veins were stimulated for 240 pulses at 1 and 2 Hz, the responses were potentiated by indomethacin and ETYA. However, responses to 4 and 8 Hz were not potentiated. The responses to continuous electrical stimulation at 2 Hz were also potentiated by indomethacin and ETYA. This potentiating effect was attenuated when the veins were pretreated with α‐methyl‐p‐tyrosine. The responses of the veins to noradrenaline were not altered by either indomethacin or ETYA.

Prostaglandin E2 inhibited the responses of the portal vein to electrical stimulation. The magnitude of this inhibition was inversely related to the frequency of stimulation. The responses of the vein to noradrenaline were not altered by prostaglandin E2.

It is concluded that potentiation by indomethacin and ETYA of the response of the isolated portal vein is due to an increased release of newly synthesized noradrenaline as a result of inhibition of prostaglandin synthesis.
EFFECTS OF FASTING, STRESS AND DRUGS ON GASTRIC GLYCOPROTEIN SYNTHESIS IN THE RAT
Authors: DEKANSKI J.B. , MACDONALD A. , SACRA P. , PARKE D.V.
Published: July 2012

The relationship between gastric mucosal damage and synthesis of gastric glycoproteins, as measured by the rate of incorporation of N‐acetyl‐[3H]glucosamine, was investigated in rats after fasting and restraint stress and a single administration of aspirin (200 mg/kg, orally), phenylbutazone (200 mg/kg, orally), prednisolone (200 mg/kg, orally), or adrenaline (2 mg/kg, i.p.). In one experiment, the effects of aspirin and phenylbutazone on carbohydrate content of the glycoproteins were also determined.

Restraint stress, phenylbutazone and aspirin resulted in acute gastric mucosal erosions in some of the rats. Adrenaline produced severe sub‐mucosal haemorrhage, but no erosions or ulceration, while prednisolone and fasting gave no gross pathology.

The rate of incorporation of N‐acetyl‐[3H]glucosamine into glycoproteins was decreased after all treatments except adrenaline. In the groups receiving restraint stress, aspirin or phenylbutazone, the decreases were more marked in rats which developed erosions than in those with no gastric pathology.

Aspirin and phenylbutazone also produced changes in the carbohydrate content of the glycoproteins, the effects again being greater in the rats which developed erosions.

The results are discussed in the context of a possible association between erosion formation and glycoprotein synthesis and it is proposed that inhibition of mucus glycoprotein biosynthesis may be one mode of action of stress and drugs in causing gastric mucosal damage.
RESPONSE OF RAT LUNG TO HUMORAL MEDIATORS OF ANAPHYLAXIS AND ITS MODIFICATION BY DRUGS AND SENSITIZATION
Authors: CHURCH M.K.
Published: July 2012

The effects of humoral mediators of anaphylaxis on the bronchial function of the pithed rat have been assessed and compared with their effects in the guinea‐pig and man.

5‐Hydroxtryptamine, acetylcholine and bradykinin were bronchoconstrictor. Slow reacting substance in anaphylaxis and prostaglandin F2α caused only slight constriction at high doses and histamine was not active.

Bradykinin was less active in the rat than in the guinea‐pig and its effects were not antagonized by anti‐inflammatory analgesic drugs.

β‐Adrenoceptor blockade potentiated the activity of bradykinin but not that of 5‐hydroxytryptamine or acetylcholine.

Dexamethasone reduced the activity of bradykinin but not that of 5‐hydroxytryptamine or acetylcholine.

Sensitization with Nippostrongylus brasiliensis did not increase the sensitivity of the rat lung to the effects of mediators.
ADENOSINE AND DIPYRIDAMOLE ACTIONS AND INTERACTIONS ON ISOLATED CORONARY ARTERY STRIPS OF CATTLE
Authors: KALSNER S.
Published: July 2012

The actions and interactions of adenosine and dipyridamole were investigated on isolated strips of coronary arteries of beef cattle. It was found that small diameter arteries (about 0.5‐1.0 mm o.d.), raised to a moderate level of tone with potassium, responded with relaxation to low concentrations of adenosine.

Dipyridamole, over a broad concentration range (6.0 × 10−8‐2.0 × 10−5 M), enhanced these responses, shifting the adenosine concentration‐response curve (3.7 × 10−8‐1.1 × 10−4 M) considerably to the left. In contrast, inhibitory concentration‐response curves to sodium nitrite and to noradrenaline were not materially altered by dipyridamole.

Studies of the uptake of [3H] ‐adenosine revealed a rapid uptake of the nucleoside by coronary artery strips, which was inhibited by dipyridamole (6.0 × 10−8‐2.0 × 10−5 M); but this may not be sufficient to account fully for the observed sensitization.

It is concluded that the regulation of adenosine responses and the action of dipyridamole in the heart involve a more direct association with coronary vascular tissue than has been previously appreciated.