bluuebunny/crossref_metadata_2025 huggingface dataset:
Uptake kinetics and metabolism of 7–3H‐dopamine in the isolated perfused rat heart
Authors: HELLMANN G. , HERTTING G. , PESKAR B.
Published: July 2012

The isolated, perfused rat heart accumulates dopamine by two distinct uptake mechanisms characterized by different kinetic constants and different patterns of metabolite production (Uptake 1: Km 0.69 × 10−6M and Vmax (1.45 × 10−9 mol/g)/min; Uptake 2: Km 5.9 × 10−4M and Vmax (0.14 × 10−6 mol/g)/min).

The metabolic fate of dopamine taken up by the isolated, perfused rat heart depends on the concentration of dopamine in the perfusion medium. At a very low perfusion concentration (0.047 × 10−10 mol/ml) most of the radioactivity is stored as unchanged dopamine and the main metabolite is noradrenaline. With increasing perfusion concentrations deamination becomes the main metabolic pathway, deaminated metabolites accounting for more than 50% of the total radioactivity after perfusion with 2,614.4 × 10−10 mol/ml for 16 minutes. The O‐methylated, and the O‐methylated deaminated metabolites are of minor importance at all perfusion concentrations.

The resistance to wash out of the dopamine taken up by the isolated, perfused rat heart is dependent on the perfusion concentration used. At a concentration of 66.9 × 10−10 mol/ml, 50% of the total activity is washed out during an 8 min wash period. Within the same time interval there is no wash out when a perfusion concentration of 0.042 × 10−10 mol/ml is used.

It is concluded that the metabolic fate of dopamine taken up at various perfusion concentrations reflects the distribution of dopamine within intra‐ and extraneuronal compartments in the hearts.
In pursuit of the α‐adrenoceptor: a fine‐structural and electron autoradiographic study using 3H‐phenoxybenzamine and smooth muscle from the cat and guinea‐pig
Authors: GRAHAM J. D. P. , IVENS CAROLINE , LEVER J. D. , McOUISTON R. , SPRIGGS T. L. B.
Published: July 2012

Electron microscopical evaluation of sets of serial fine sections of pancreatic arteriolar muscle of the cat showed no significant difference between the number of pinocytotic vesicles per unit length of smooth muscle cell membrane in ‘synaptic’ and ‘non‐synaptic’ regions.

With high resolution autoradiography, 3H‐phenoxybenzamine was found to be distributed over the cytoplasm and nuclei of smooth muscle cell profiles of guinea‐pig vas deferens, although no localization in relation to discrete morphological organelles was evident.

‘Specific protection’ of α‐adrenoceptors using 606 μM noradrenaline resulted in a significant diminution in the binding of 3H‐phenoxybenzamine as evidenced by a decrease in silver grain concentrations over smooth muscle cell profiles in autoradiographs.

The significance of these findings in relation to the site and distribution of α‐adrenoceptors is discussed.
Effect of (±) dihydroxy ephedrine and (±) dihydroxy pseudoephedrine on adrenergic transmission in mesenteric arteries
Authors: MALIK K. U.
Published: July 2012

The effect of (±) dihydroxy ephedrine (DHE), (±) dihydroxy pseudoephedrine (DHPE) and isoprenaline on the vasoconstrictor responses of the perfused mesenteric arteries of the rat produced by stimulation of their periarterial sympathetic fibres, and in the responses to injected noradrenaline, has been studied.

DHE and DHPE inhibited the responses to nerve stimulation and increased the responses to injected noradrenaline.

Isoprenaline slightly decreased the basal perfusion pressure and reduced the responses to both nerve stimulation and injected noradrenaline. Since these effects of isoprenaline were abolished by propranolol, they are presumably mediated by β‐receptors.

The inhibitory effect of DHE and DHPE on the responses to nerve stimulation was not abolished by propranolol.

The results suggest that DHE and DHPE impair adrenergic transmission by partially replacing the adrenergic neurotransmitter, thereby acting as a false neurotransmitter.
Diffusion of labelled substances through isolated rat diaphragm
Authors: BROOKES N. , MACKAY D.
Published: July 2012

The rate of diffusion of [14C] sucrose through rat diaphragm muscle is dependent on the period of preliminary soaking of the muscle in Krebs solution at 36° C. The ratio of the length of the diffusion path through the diaphragm to its geometrical thickness appears to fall from 4.39 ± 0.38 (S.E. of the mean) to 2.23 ± 0.18 after about 6 h of soaking.

The area of the diaphragms available for diffusion is apparently constant at 0.3–0.4 of their total area.

The measured thickness of the diaphragms increases by about 20% on soaking.

Entry of [131I] iodide into the muscle fibres is detected as a fall in both steady state and non‐steady state rates of diffusion through the diaphragm.

Entry of [14C‐methyl] decamethonium into the muscle cells is not evident from such diffusion studies in normal Krebs solution.
Relationship between the anti‐inflammatory and irritant properties of inflammatory exudate
Authors: ATKINSON D. C. , HICKS R.
Published: July 2012

Using the rat paw oedema assay procedure a comparison was made between the anti‐inflammatory and irritant properties of the inflammatory exudate obtained from polyester sponges implanted subcutaneously in adrenalectomized rats. Where necessary, comparison was also made with a known counter‐irritant, carrageenin.

A significant correlation between the anti‐inflammatory and irritant properties of sponge exudate was observed when each parameter was determined in relation to dose. A similar result was obtained with carrageenin.

A comparison of the two activities of sponge exudate samples harvested at various times following sponge implantation did not give a significant correlation although in each case significant anti‐inflammatory activity was accompanied by marked irritation.

Time‐effect curves of the two activities of sponge exudate showed a significant correlation over the time period examined. However, no such correlation was obtained using carrageenin.

Both activities of sponge exudate were retained following dialysis.

These findings are discussed in relation to a counter‐irritant mode of action for sponge exudate.
Interaction between prostaglandins E and F given intradermally in the rat
Authors: CRUNKHORN PEARL , WILLIS A. L.
Published: July 2012

Increases in permeability observed after intradermal injection of prostaglandins PGE1 or PGE2 (0.1 μg) into rats were greatly reduced when they were given in admixture with PGF2α. This effect was not seen with PGF1α at doses of 0.5–1 μg.

Effects of the histamine releasing agent compound 48/80 (25 ng) were inhibited by PGF2α (0.5 μg) but not by PGFlα (0.5 μg).

Responses to histamine (1 μg), 5‐hydroxytryptamine (0.1 μg) and brady‐kinin (1 μg), which have a direct action on the microvasculature, were not significantly altered by PGF2α (0.5 μg).

It is concluded that PGF2α probably acts by interfering with the release of mast cell histamine by PGEl, PGE2 and compound 48/80.
Investigations of the mode of action of a new antidysrhythmic drug, Kö 1173
Authors: SINGH B. N. , WILLIAMS E. M. VAUGHAN
Published: July 2012

Kö 1173, 1‐(2′,6′‐dimethyl‐phenoxy)‐2‐amino‐propane, was equal to lignocaine in potency as a local anaesthetic on stripped frog sciatic nerve at pH 7·5.

In anaesthetized guinea‐pigs in which ventricular fibrillation had been produced by an intravenous infusion of ouabain, intravenous administration of Kö 1173 caused reversion to sinus rhythm in ten out of ten animals. The mean dose of Kö 1173 required was 3·3 mg (15·3 μmol)/kg. When the ouabain infusion was continued, ventricular fibrillation did not recur, and the lethal dose of ouabain was greater than in controls.

Pretreatment with Kö 1173, however, did not influence the toxicity of ouabain infusion, implying great brevity of action.

Kö 1173 given intravenously caused a bradycardia which was maximal in 2–3 min, and which did not last more than 5 minutes.

Kö 1173 reduced the maximum driven frequency of isolated rabbit atria, raised electrical threshold, slowed conduction velocity and depressed contractions.

Kö 1173 reduced the maximum rate of depolarization of intracellularly recorded rabbit atrial and ventricular potentials, but did not affect the resting potential or the duration of the action potential.
Relationship between the chemical structure of prostaglandins and their vasoactivities in dogs
Authors: NAKANO J.
Published: July 2012

The relationship between the chemical structure and the direct vasoactivity of different prostaglandins administered intra‐arterially was studied in the dog hindlimb preparation.

All of the prostaglandins studied, except PGF1α and PGF2α, caused a dose related decrease in the femoral arterial perfusion pressure in dogs in which the femoral arterial blood flow was kept constant, indicating the direct vasodilator action of these prostaglandins.

Among the prostaglandins studied, PGE1 is the most potent vasodilator. Comparing the chemical structure and vasodilator action of PGE1 with those of different prostaglandins, the following conclusions can be made:

The formation of the Δ5 double bond in PGE1 causes no change in its vasodilator activity, whereas the saturation of the Δ13 double bond of PGE1 slightly reduces its activity.

The alterations in the orientation and length of the carboxyl and alkyl side chains reduce markedly the vasodilator action of PGE‐ and PGA‐compounds.

The presence of a carbonyl group at C9 is the most important requirement for the potent vasodilator action of PGE1. On the other hand, the presence and S‐configuration of a hydroxyl group at C15 are essential for the intrinsic action at the receptor sites in the vascular smooth muscle, but may not be responsible for the vasodilator action.

The esterification of PGE1 or PGE2 and a triple bond formation and the replacement of C7 with oxygen in prostaglandin appear to reduce or abolish their vasodilator action.
Clinical investigation of an antagonist at α‐ and β‐adrenoceptors‐AH 5158A
Authors: COLLIER J. G. , DAWNAY N. A. H. , NACHEV CH. , ROBINSON B. F.
Published: July 2012

The α‐ and β‐adrenoceptor blocking action of AH 5158A was investigated in man using the veins of the hand, the arterial bed of the forearm, and certain responses of the circulation as a whole.

In the veins, locally infused AH 5158A resulted in specific and competitive antagonism of the constrictor response to locally infused noradrenaline and of the dilator response to isoprenaline.

Brachial artery infusions of AH 5158A resulted in competitive antagonism of the arterial blood flow changes produced by local infusions of noradrenaline and isoprenaline.

Systemic infusion of AH 5158A (0·5–0·9 mg/kg) produced clear blockade of the heart rate response to systemic infusion of isoprenaline. It also attenuated the response to exercise at 80 watts for 4 min; mean arterial pressure during exercise was reduced by 16% and heart rate by 18%. Blockade lasted at least 1 hour.

AH 5158A caused small changes in arterial pressure and heart rate at rest supine, but had no effect on the response of pressure and rate to tilting.
Selective inhibition by glycine of some somatic reflexes in the cat
Authors: DHAWAN B. N. , SHARMA J. N. , SRIMAL R. C.
Published: July 2012

The effects of intracerebroventricular or intrathecal administration of glycine on some somatic reflexes in chloralosed cats were investigated.

Glycine produced marked inhibition of the flexor reflex (FR) and crossed extensor reflex (CER) at low doses (2·5–5·0 mg) but even large doses (up to 400 mg) had no effect on the facilitation or inhibition of the patellar reflex produced by stimulation of either the reticular formation or the sciatic nerve. The linguomandibular reflex (LMR) could be blocked by 10–20 mg glycine.

Glycine antagonized strychnine‐induced facilitation of FR, CER and LMR and was 5–6 times as active as γ‐aminobutyric acid in this respect.

The possibility of glycine being a transmitter in spinal pathways is discussed.
Effects of a focal penicillin lesion on responses of rabbit cortical neurones to putative neurotransmitters
Authors: CLARKE G. , HILL R. G.
Published: July 2012

Epileptogenic foci were generated in rabbit cerebral cortex by the topical application of penicillin.

Responses to iontophoretically applied putative neurotransmitters were compared in cortical neurones firing spontaneously with those driven by applied excitant substances, both before and after establishing the penicillin focus.

In the presence of the spiking focus, currents of γ‐aminobutyric acid, which normally produced 100% depression of neuronal firing, were ineffective.

In the same situation, currents of (±)‐homocysteic acid, glutamate and acetylcholine produced predominantly depolarization block responses, and hence depression of firing.

It is concluded that an epileptogenic focus can alter the responses of rabbit cortical neurones to microiontophoretically applied neurotransmitter substances. Possible mechanisms for the spread of seizure activity are discussed.
Interaction of prostaglandin E1 and calcium in the guinea‐pig myometrium
Authors: EAGLING ELIZABETH M. , LOVELL H. G. , PICKLES V. R.
Published: July 2012

Prostaglandin E1 (PGE1) increased the responses of guinea‐pig myometrium in a low calcium medium to added Ca2+, acetylcholine, vasopressin, Ba2+ and Sr2+. The concentration of PGE1 used (50 pg/ml) was clearly below the threshold for direct spasmogenesis. In the presence of PGE1 the doses necessary for half‐maximal contractions were decreased by factors of 2·6 for Ca2+, 2·4 for acetylcholine, and 3·7 for vasopressin. The responses to Ba2+ or Sr2+, though studied less extensively, were found to be affected in much the same manner.

The K+ depolarized myometrium in a low Ca2+ medium contracts in response to added Ca2+. These responses also were increased by low concentrations of PGE1, but the effective concentration of PGE1 was indistinguishable from that for direct spasmogenesis.

Possible mechanisms for the interaction of PGE1 and Ca2+ in the myometrium are discussed. It is tentatively suggested that these findings may be relevant to the physiological control of human myometrium.
Distribution and excretion of N‐[14C]‐methyl labelled m‐hydroxybenzyltrimethylammonium ions in mice
Authors: BARLOW R. B. , READING H. W. , YATES CELIA M.
Published: July 2012

Radioactivity in the plasma, livers, and brains of mice was measured at intervals of 10 min to 24 h after the intraperitoneal injection of 14C labelled m‐methoxy‐ and m‐hydroxy‐ benzyltrimethylammonium ions.

Well over 10% of the dose of either of these quaternary compounds was found in the liver and plasma within 10 min of the injection, but they were rapidly excreted or metabolized, having a half life of between 1 and 2 hours.

Small amounts of radioactivity were detectable in brain, and were not due to contamination of brain samples by blood, after doses of 14–16 μmol/kg (approximately 4 mg iodide/kg) and upwards. After doses of 4–6 μmol/kg (approximately 1 mg iodide/kg), however, radioactivity in the brain was barely detectable.

Any behavioural effects reported to occur in mice treated with these lower doses of m‐hydroxybenzyltrimethylammonium, which include improved performance in a test of avoidance learning, are unlikely to be due to an action within the central nervous system. Learning may be more influenced by the peripheral effects of drugs than has hitherto been appreciated.
Effects of the inhibition of noradrenaline uptake and synthesis on the maintenance of the response to continuous nerve stimulation in the central artery of the rabbit ear
Authors: KALSNER STANLEY
Published: July 2012

. The central artery of the rabbit ear was perfused through its lumen in vitro, with a constant pressure technique, and stimulated continuously via its periarterial sympathetic nerves at the physiological frequency of 5 Hz.

. The vasoconstrictor response, which led initially to an almost complete cessation of intraluminal flow, deteriorated steadily over a period of hours. The involvement of presynaptic mechanisms in this effect was indicated by the finding that noradrenaline, administered extraluminally, produced a similar response before the onset of continuous stimulation and at a late stage when the constriction had decreased markedly. In addition, the noradrenaline precursor DOPA, restored the depressed responses towards their original values, indicating that failure involved depletion of mediator for release.

. Responses to continuous stimulation declined significantly faster after inhibition of tyrosine hydroxylase with α‐methyl‐p‐tyrosine. However, inhibition of the uptake of noradrenaline with cocaine did not enhance the decline of the response, even when the sensitization produced by the compound was taken into account.

. It is concluded that synthesis, along with the mobilization of stored mediator, rather than uptake and re‐use of noradrenaline maintain the effector response in the central artery of the rabbit ear stimulated continuously at a frequency within the physiological range.
The release of prostaglandins and rabbit aorta contracting substance (RCS) from rabbit spleen and its antagonism by anti‐inflammatory drugs
Authors: GRYGLEWSKI R. , VANE J. R.
Published: July 2012

. Slices of rabbit spleen generate rabbit aorta contracting substance (RCS) and a prostaglandin of the E series when they are vibrated or stirred.

. The release of both substances is increased by arachidonic acid and inhibited by aspirin‐like drugs.

. When the spleen effluent containing RCS and prostaglandin E is incubated for a further 3 min, the prostaglandin concentration increases and the RCS concentration declines.

. RCS may therefore be an unstable intermediate in the biosynthesis of prostaglandins.
Degradation of angiotensin II by plasmin
Authors: DUDEK G. , LATALLO Z. S. , PROKOPOWICZ J. , WOROWSKI K.
Published: July 2012

. Synthetic angiotensin II (Hypertensin, Ciba, Basel) was incubated with a water‐insoluble preparation of plasmin (E.C. 3.4.4.14) and the resulting products analysed by paper chromatography and N‐terminal amino‐acid analysis.

. Only the N‐terminal asparagine was split off from the peptide. This indicates that plasmin attacks the Asn‐Arg but not the Arg‐Val in angiotensin II molecule.
Some evidence of the active uptake of noradrenaline in the guinea‐pig isolated trachea
Authors: FOSTER R. W. , O'DONNELL STELLA R.
Published: July 2012

. Guinea‐pig isolated trachea immersed in a low concentration (50 nm) of (—)‐3H‐noradrenaline accumulates radioactive material against an apparent concentration gradient.

. Compartmental analysis based on the decay curve of radioactive material content during washout and its comparison with that of 14C‐sorbitol shows that some extracellular noradrenaline is adsorbed. A considerable mass exists in a slowly exchanging compartment, i.e. is retained. This retention is inversely concentration dependent.

. Over a 25‐fold range of concentration the entry of either total radioactive material or noradrenaline followed Michaelis‐Menten kinetics.

. The uptake of radioactive material was sodium‐dependent and ouabainsensitive.

. The uptake was susceptible to metabolic poisons which deprive the tissue of all available energy but it was not exclusively associated with either oxidative or glycolytic energy supply.

. Although net uptake could not be distinguished from exchange with endogenous amine, other evidence has been obtained for an active noradrenaline transport system with properties similar to neuronal uptake.
Actions of levodopa on the blood pressure of conscious rabbits
Authors: CALNE D. B. , REID J. L.
Published: July 2012

. In conscious rabbits, the rapid intravenous injection of levodopa alone does not have any significant effects on the blood pressure in doses up to 10 mg/kg.

. After inhibition of monoamine oxidase, levodopa induces a sustained pressor response.

. This response can be blocked by inhibition of extracerebral decarboxylase.

. Possible mechanisms for these interactions are discussed, together with their therapeutic implications in Parkinsonism.
β‐Adrenoceptor blocking properties and cardioselectivity of M & B 17,803A
Authors: BASIL B. , JORDAN R. , LOVELESS A. H. , MAXWELL D. R.
Published: July 2012

. The β‐adrenoceptor blocking properties of (±)‐1‐(2‐acetyl‐4‐n‐butyramidophenoxy)‐2‐hydroxy‐3‐isopropylaminopropane hydrochloride (M&B 17,803A) have been compared with those of practolol and propranolol in the guinea‐pig, cat and dog.

. Following either intravenous or oral administration in the cat or dog, M&B 17,803A and practolol had similar potency in antagonizing isoprenaline‐induced tachycardia and both showed cardioselectivity, but both were less potent than propranolol.

. M&B 17,803A and practolol had approximately one hundredth the intravenous potency of propranolol in increasing the severity of anaphylactic bronchospasm in the conscious sensitized guinea‐pig.

. M&B 17,803A possessed less marked intrinsic sympathomimetic activity than practolol but, like propranolol, it had significant local anaesthetic properties and increased the refractory period of rabbit isolated atria.
Modification of the responses of brain stem neurones to transmitter substances by anaesthetic agents
Authors: BRADLEY P. B. , DRAY A.
Published: July 2012

. The effects of microiontophoretic applications of acetylcholine (ACh), (—)‐noradrenaline ((—)‐NA) and 5‐hydroxytryptamine (5‐HT) have been investigated on spontaneously active brain stem neurones in decerebrate unanaesthetized rats and in rats anaesthetized wih either tribromoethanol, urethane or pentobarbitone.

. Four types of responses to both (—)‐NA and 5‐HT were seen. These were: simple excitation; excitation preceded by a short‐lasting inhibition; short‐lasting inhibition and prolonged inhibition. Three types of responses to ACh were seen: an excitation with long latency of onset; excitation with short latency of onset, resembling the response to an excitant amino acid, and a short‐lasting inhibitory response.

. The types of responses to microiontophoretically applied ACh, (—)‐NA or 5‐HT in anaesthetized and unanaesthetized animals were similar.

. The number of ACh excitatory responses with short latency of onset were significantly reduced in the pentobarbitone‐anaesthetized group and a small but significant increase in the number of 5‐HT inhibitory effects were observed in each anaesthetized group of animals.

. A significantly greater proportion of slower firing neurones (less than 10 spikes/s) were found in the pentobarbitone‐anaesthetized animals.

. The effects of microiontophoretically applied and i.v. administered pentobarbitone were studied on spontaneously active neurones which responded consistently to ACh and a control agonist.

. Pentobarbitone administered by either route reduced the firing rate of most neurones studied and was shown to antagonize specifically the excitation of neurones by exogenously applied ACh.

. It is suggested that postsynaptic antagonism of endogenously released ACh may be a contributing factor in the mechanism of action of pentobarbitone.
Acetylcholine release from the rabbit isolated superior cervical ganglion preparation
Authors: DAWES P. M. , VIZI E. S.
Published: July 2012

. The rabbit isolated superior cervical ganglion preparation has been used to measure the release of acetylcholine from the tissue at rest and during preganglionic nerve stimulation.

. In the presence of physostigmine, the resting release of acetylcholine was 013+001 (nmol/g)/min (10 experiments) and that during stimulation with 300 shocks at 10 Hz was 3·1 ± 0·4 (pmol/g)/volley in 4 experiments (means ± s.e.m.). The volley output was independent of the frequency of stimulation over the range 1 to 10 Hz but was higher at 0·3 Hz.

. Tetrodotoxin, 0·8 μm, had no effect on the resting release of acetylcholine but reduced the stimulated release below detectable levels (2 pmol). Lowering the temperature of the bathing fluid to 5° C reduced to below detectable levels both the resting release and that produced by nerve stimulation.

. The resting release of acetylcholine was increased by a potassium‐rich (49·4 mm K+) bathing solution and by replacing the sodium chloride in the solution with lithium chloride (113 mM Li+).

. (—)‐Noradrenaline bitartrate, 3 μm, and (±)‐adrenaline bitartrate, 1·5 μm, reduced by 70% the output of acetylcholine induced by stimulation at 0–3 Hz, but failed to reduce the resting release or that evoked by stimulation at 10 Hz. The inhibition was reversed by phentolamine.

. It is concluded that the rabbit superior cervical ganglion in vitro is a suitable preparation for studying transmitter release and that the ganglion blocking effect of catecholamines is due to a reduction in transmitter release.
The effect of salicylate on the biliary excretion of 14C‐bishydroxycoumarin in rat
Authors: BUTTAR H. S. , COLDWELL B. B. , THOMAS B. H.
Published: July 2012

. The effect of intravenous sodium salicylate on the biliary excretion of 14C‐bishydroxycoumarin (14C‐BHC) was studied in rats.

. Salicylate (88·9 mg/kg) increased the biliary excretion of 14C‐radioactivity from a control value of 12·3±2·7% to 29·3±2·5% of the administered dose in 6 h after injection.

. During the 6 h period, 11% of the dose of radioactivity underwent biliary recycling in the salicylate‐treated rats compared to only 6% in the absence of salicylate.

. About 15·3% of the radioactivity excreted in the bile of rats given BHC alone was detected as unchanged BHC, 8·6% was present as BHC‐conjugate, conjugates of BHC metabolites accounted for 30·9%, and the remainder consisted of unidentified metabolites.

. Salicylate treatment did not significantly alter the excretory pattern of unchanged BHC and its metabolites.
Effects of prostaglandin E1 on acid secretion, mucosal histamine content and histidine decarboxylase activity in rat stomach
Authors: HÅKANSON R. , LIEDBERG G. , OSCARSON J.
Published: July 2012

Prostaglandin E1 inhibits basal and pentagastrin‐stimulated gastric acid secretion. The mechanism of this action is not clear. One possible explanation might be that prostaglandin E1 interferes with the local release or synthesis of histamine which has been proposed as the mediator of the effects of gastrin on the parietal cell.

A single injection of prostaglandin E1 did not affect mucosal histamine content or histidine decarboxylase activity in the rat stomach. Pentagastrin lowered the histamine content and activated the histidine decarboxylase to the same extent in prostaglandin E1‐pretreated and in control rats. We conclude therefore that the inhibitory effect of prostaglandin E1 on basal and pentagastrin‐stimulated acid secretion is not caused by inhibition of histamine release or histamine synthesis.

Repeated injections of prostaglandin E1 resulted in a significant elevation of the gastric histidine decarboxylase activity in normal but not in antrectomized rats. Conceivably, this increase in enzyme activity is secondary to prostaglandin E1‐induced inhibition of acid secretion, which will stimulate release of gastrin due to the rise in intragastric pH.
The uptake of 3H‐γ‐aminobutyric acid by the retina
Authors: GOODCHILD MARGARET , NEAL M. J.
Published: July 2012

The accumulation of 3H‐γ‐aminobutyric acid (GABA) by the isolated rat retina has been measured.

When retinae were incubated at 37° C in a medium containing 3H‐GABA, tissue:medium ratios of about 25:1 were attained after a 30 min incubation.

After incubations of 40 min at 37° C, almost all (98%) the radioactivity in the tissue was present as unchanged 3H‐GABA.

The process responsible for 3H‐GABA uptake showed many of the properties of an active uptake system: it was temperature‐sensitive, required the presence of sodium ions in the external medium, was inhibited by anoxia, dinitrophenol and ouabain, and showed saturation kinetics.

The estimated Km value of GABA was 4·0 × 10−5M, and Vmax was 0·167 (μmoles/min)/g retina.

The uptake of 3H‐GABA was not affected by the presence of large molar excesses of glycine, l‐glutamate, l‐aspartate, l‐alanine, l‐proline, or l‐histidine, but was inhibited by dl‐γ‐amino‐β‐hydroxybutyrate, β‐guanidinopropionate, and l‐2,4‐diaminobutyrate.

The retina was capable of achieving a large net uptake of GABA, indicating that the accumulation of 3H‐GABA by the tissue was not due only to an exchange process with the endogenous GABA pool.

The uptake of 3H‐GABA occurred only in tissue from the central nervous system. Thus, retina and cerebral cortex rapidly accumulated radioactivity, but slices of cornea, posterior wall of the eye, and liver achieved tissue: medium ratios of approximately one.

There was a rapid efflux of radioactivity from retinae placed in fresh medium and after 60 min, 90% of the radioactivity was lost from the tissue. The radioactivity released into the medium was present largely as 3H‐acidic and neutral metabolites. When the metabolism of GABA was inhibited by the presence of amino‐oxyacetic acid in the medium, only about 10% of the radioactivity was lost from the tissue during a similar 60 min incubation, and the radioactivity released was present largely as unchanged 3H‐GABA.

It is suggested that the GABA uptake process may represent a possible mechanism for the inactivation of GABA if this amino acid is released at inhibitory synapses in the retina.
Uptake kinetics and ion requirements for extraneuronal uptake of noradrenaline by arterial smooth muscle and collagen
Authors: GILLESPIE J. S. , TOWART R.
Published: July 2012

The ionic requirements for noradrenaline uptake into vascular smooth muscle cells were studied by perfusing rabbit isolated ear arteries with noradrenaline (10−3M) either in Krebs solution or in Krebs solution modified by altering the concentration of one or more ion. Noradrenaline uptake was measured by quantitative microphotometry.

Some uptake into smooth muscle continued in isotonic sucrose in the absence of all ions. Omission of Na+ from the Krebs solution partially inhibited uptake as did high (100 mm) K+. Omission of K+, Ca++ or Mg++ had no effect on uptake. Lithium was able completely to substitute for Na+.

Alteration in ion concentration did not affect the binding of noradrenaline to collagen.

The kinetics of uptake of noradrenaline into smooth muscle were analysed and found to be saturable with a Km of 4·9 × 10−4M.

It is concluded that the ionic requirements of the transport mechanism for the uptake of noradrenaline by vascular smooth muscle show a relatively low specificity.
The accumulation and metabolism of (—)‐noradrenaline by cells in culture
Authors: POWIS G.
Published: July 2012

Cultured bovine embryonic tracheal cells, EbTr (NBL‐4) possess a process for the intracellular accumulation of (—)‐noradrenaline with the characteristics generally ascribed to extraneuronal uptake by cardiac and smooth muscle cells in the body. It has a Km of 2·6 × 10−4M.

The accumulation process is inhibited competitively by normetanephrine, but only at relatively high concentrations, IC50 = 2·1 × 10−4M. Inhibition also occurs with 17‐β‐oestradiol, IC50 = 1·3 × 10−5M.

The noradrenaline metabolites, 3,4‐dihydroxy‐mandelic acid and 3,4‐dihydroxy‐phenylglycol potentiate accumulation and reduce intracellular levels of normetanephrine in a similar manner to known inhibitors of catechol‐O‐methyl transferase.

It is suggested that intracellular, rather than extracellular, normetanephrine may exert feedback inhibition upon noradrenaline accumulation by combining with the transport process at the inner surface of the cell membrane.
The effects of pargyline on overflow of transmitter and uptake of noradrenaline in the cat spleen
Authors: BLAKELEY A. G. H. , POWIS G. , SUMMERS R. J.
Published: July 2012

Twenty minutes after the addition of pargyline (5 × 10−4M) to blood perfusing the isolated spleen of the cat, the overflow of transmitter resulting from stimulation of the sympathetic nerves increased 2–3–3‐fold. Lower doses of pargyline did not significantly affect overflow.

Monoamine oxidase activity, measured with either radioactively labelled tyramine or noradrenaline as substrate, was almost completely inhibited by doses of pargyline in the range of 10−4M to 5 × 10−4M. Inhibition of enzyme activity was not correlated with the effect on overflow. Pargyline had only a slight inhibitory effect on catechol‐O‐methyl transferase.

Uptake of a 1 μg injection (pulse) of labelled noradrenaline, following pargyline (5×10−4M), was increased to 199·1% of that found in control experiments.

Pargyline significantly reduced the vascular responses to nerve stimulation but had no significant effect on capsular responses.

The inhibitor had no effect on resting overflow of labelled noradrenaline from the spleen but doubled the overflow of labelled noradrenaline following nerve stimulation.

It is suggested that the effect of pargyline on overflow is due to increased release of transmitter during nerve stimulation.

The possible clinical significance of these findings is discussed.
Acetylcholine release from guinea‐pig ileum by parasympathetic ganglion stimulants and gastrin‐like polypeptides
Authors: VIZI E. S.
Published: July 2012

The release of acetylcholine by parasympathetic ganglion stimulants from the nerve terminals of the guinea‐pig longitudinal muscle strip was studied. The acetylcholine released was collected in the presence of physostigmine sulphate.

Nicotine and 1,1‐dimethyl‐4′‐phenylpiperazinium iodide (DMPP) released acetylcholine. Tetrodotoxin (50 ng/ml) and hexamethonium completely prevented their action on acetylcholine release, indicating that their effect is on nicotinic receptors of cell bodies. Noradrenaline (1 μg/ml), excess magnesium, and calcium withdrawal inhibited the acetylcholine release induced by nicotine or by DMPP.

There was rapid tachyphylaxis to the acetylcholine releasing action of both nicotine and DMPP.

The octapeptide amide of cholecystokinin and caerulein (10−9M) enhanced the acetylcholine release without producing tachyphylaxis. Tetrodotoxin completely inhibited acetylcholine release. However, hexamethonium or desensitization with 5‐hydroxytryptamine did not prevent their action. In the early phase of nicotine action the polypeptides studied failed to increase acetylcholine release. However, a few minutes later the tissue became sensitive to polypeptides despite the fact that the tissue was still exposed to nicotine. These data suggest the presence in the parasympathetic ganglion cells of separate gastrointestinal hormone‐sensitive receptors.

Noradrenaline inhibited the acetylcholine releasing action of polypeptides. This effect was mediated via α‐adrenoceptors since phentolamine prevented its action.

Excess magnesium (9·3 mm) also reduced the acetylcholine release in response to the polypeptides.
Effect of phospholipase C on calcium release from epithelia treated with antidiuretic hormone
Authors: CUTHBERT A. W. , WONG P. Y. D.
Published: July 2012

Addition of antidiuretic hormone (ADH) to the bladders of toads (Bufo marinus) preloaded with 45Ca causes an increase in the rate of calcium efflux.

Pretreatment of the serosal surfaces of bladders with phospholipase C prevents the action of ADH on calcium efflux.
Structure‐activity relationships in some series of 2‐alkyl‐1,2,3,‐benzotriazinium compounds
Authors: CULL GERALDINE A. G. , SCOTT N. C.
Published: July 2012

The potencies of four series of N‐alkyl‐1,2,3‐benzotriazinium iodides have been estimated on the frog rectus abdominis and chick biventer cervicis preparations.

The partition coefficients between chloroform and water were measured for all of the compounds, as well as the ionization constants for some members of two of the series.

The potencies of the compounds increased with the number of carbon atoms in the N‐alkyl side chain up to a maximum at the n‐butyl homologue while partition coefficients increased up to the n‐pentyl homologue, and there may be some association between the lipid solubilities of the compounds and their biological activity.

The responses of the tissues to the benzotriaziniums were not abolished by tubocurarine, indicating that the site of action was not at acetylcholine receptors.

The similarity between the actions of the benzotriaziniums and those of quinine and quinidine is discussed.
Effect of chronic l‐DOPA administration on catecholamine metabolism in the rat
Authors: LANCASTER JULIE , SAWYER P. R. , SHEPHERD D. M. , TURNBULL M. J.
Published: July 2012

l‐DOPA was administered to rats by twice daily intraperitoneal injection for a period of eleven days. The daily dose was gradually increased from 250 mg/kg to 1 g/kg. The animals were killed 12 h after the last injection and tissue catechol‐O‐methyl transferase, DOPA‐decarboxylase and monoamine oxidase activity determined.

Catechol‐O‐methyl transferase activity was reduced in the liver (46%) and red blood cells (38%) but was approximately doubled in the heart.

Liver DOPA‐decarboxylase activity was reduced by approximately 25%.

l‐DOPA administration did not significantly affect the activity of any of the enzymes studied in brain tissue.
Role of brain monoamines in the fatal hyperthermia induced by pethidine or imipramine in rabbits pretreated with a monoamine oxidase inhibitor
Authors: GONG S. N. C. , ROGERS K. J.
Published: July 2012

The intravenous infusion of pethidine or imipramine, in doses of 5 mg/kg, caused fatal hyperpyrexia in rabbits premedicated with pargyline.

The drug interaction was not antagonized when either reserpine or α‐methyl‐p‐tyrosine were administered with pargyline. Neither reserpine nor α‐methyl‐p‐tyrosine prevented the rise in brain stem 5‐hydroxytryptamine content following monoamine oxidase inhibition, although the increase in catecholamines normally produced by pargyline was prevented.

The development of fatal hyperthermia was completely prevented when rabbits were treated with p‐chlorophenylalanine prior to pargyline premedication. In these animals, the concentration of brain stem catecholamines, but not 5‐hydroxytryptamine, was increased.

The results indicate that the hyperthermia evoked by pethidine or imipramine in combination with monoamine oxidase inhibitors can take place only in the presence of raised concentrations of 5‐hydroxytryptamine in the brain stem.
Effect of depletion of cerebral monoamines on the concentration of glycogen and on amphetamine‐induced glycogenolysis in the brain
Authors: HUTCHINS D. A. , ROGERS K. J.
Published: July 2012

An increase in the concentration of glycogen occurs in the mouse brain after depletion of cerebral catecholamines by alpha methyl‐p‐tyrosine methylester (H44/68), diethyldithiocarbamate, or reserpine.

Depletion of cerebral 5‐hydroxytryptamine with parachlorophenylalanine (PCPA) does not result in a change in the concentration of brain glycogen.

When H44/68 is administered together with reserpine to inhibit the synthesis and storage of cerebral catecholamines, and thus bring about their total depletion from the brain, the cerebral glycogenolytic effect of amphetamine is abolished.

Amphetamine‐inducing glycogenolysis is only partially antagonized if only one of the catecholamine‐depleting agents H44/68, diethyldithiocarbamate, or reserpine is injected prior to the amphetamine. The persistence of this glycogenolytic effect of amphetamine is possibly due to the presence of residual stores of catecholamines available for release by the stimulant drug.

Depletion of cerebral 5‐hydroxytryptamine by PCPA does not result in any antagonism of amphetamine‐induced glycogenolysis.

The results suggest that amphetamine depletes brain glycogen by the release of central catecholamines rather than by a direct action at receptors.
Action of drugs on denervated myoepithelial cells of salivary glands
Authors: EMMELIN N. , THULIN A.
Published: July 2012

The pressure in the ducts of the two submaxillary glands was recorded in anaesthetized dogs in which either the superior cervical ganglion had been removed or the chorda‐lingual nerve had been cut on one side, 17–30 days earlier. Noradrenaline, adrenaline, phenylephrine, acetylcholine and methacholine were injected to produce pressure rises attributed to contraction of myoepithelial cells.

After sympathectomy increased pressure responses were obtained with all the drugs, but particularly with noradrenaline. Cocaine increased the effect of noradrenaline on the normal gland but slightly less than sympathectomy.

Parasympathetic decentralization increased the pressure effects of acetylcholine and methacholine, and in most cases also increased those of the sympathomimetic drugs.

It is concluded that the myoepithelial cells of this gland normally receive motor impulses from both divisions of the autonomic nervous system, and that many, if not all, of the cells are innervated by both. Disconnecting the gland from the central nervous system by either pathway causes supersensitivity of the classical post‐junctional type, and sympathetic ganglionectomy causes in addition a pre‐junctional sensitization.
Prostaglandin E1 causes sedation and increases 5‐hydroxytryptamine turnover in rat brain
Authors: HAUBRICH D. R. , PEREZ‐CRUET J. , REID W. D.
Published: July 2012

Administration of prostaglandin E1 (1 mg/kg, i.p.) to rats induced sedation and a decrease in muscular tone. Prostaglandin E1‐induced sedation was accompanied by the low voltage—high frequency E.E.G. pattern characteristic of the waking animal.

Administration of prostaglandin E1 also increased the turnover rate of 5‐hydroxytryptamine and raised the concentration of acetylcholine in brain.

The behavioural effects of prostaglandin were blocked by prior administration of p‐chlorophenylalanine or pargyline, drugs which lowered the brain concentration of 5‐hydroxyindoleacetic acid (5‐HIAA), and was potentiated by pretreatment with probenecid, which elevated the 5‐HIAA concentration. Pretreatment with atropine sulphate failed to alter prostaglandin E1‐induced sedation.

The results are compatible with the possibility that prostaglandin E1 induces a state resembling paradoxical sleep through an action on 5‐hydroxytryptamine metabolism in brain.
Effects of vinblastine on catecholamine‐biosynthetic enzymes in heart, sympathetic ganglion and adrenal glands of rats
Authors: HANBAUER I. , KOPIN I. J. , MAENGWYN‐DAVIES GERTRUDE D. , THOA N. B. , WEISE VIRGINIA K.
Published: July 2012

The effect of vinblastine on the activities of dopamine‐β‐hydroxylase (DBH) in heart, superior cervical ganglion and adrenal glands of rats and tyrosine hydroxylase (TH) and phenylethanolamine‐N‐methyl transferase (PNMT) in adrenal glands was examined.

In the superior cervical ganglion and heart, DBH activity decreased within hours, reached a minimum in 3 to 5 days and slowly returned towards normal over the next 2 weeks.

There was an increase in the activities of TH, DBH and PNMT in adrenal glands which was prevented by adrenal denervation.

When the same total dose of vinblastine was administered subdivided over a period of 5 days, enzyme activities in heart, superior cervical ganglion or adrenal glands remained unchanged.
Interaction of benzilylcholine mustard, benzilylcholine and lachesine with the histamine receptor in the longitudinal muscle of guinea‐pig ileum
Authors: REASBECK P. G. , YOUNG J. M.
Published: July 2012

The histamine receptors of longitudinal muscle strips from guinea‐pig ileum were inactivated on extended exposure to concentrations of benzilylcholine mustard (BCM) above 10−6M. These concentrations are 3 orders of magnitude greater than those required for inactivation of the muscarinic receptors. Mepyramine (3 × 10−8M) afforded complete protection for the histamine receptor against the effects of BCM.

Recovery from block at 30° C was very slow with a first‐order rate constant of approximately 10−7 s−1.

The rate constant, k2, for the alkylation reaction in which the reversible BCM‐receptor complex is converted into an irreversible complex is much greater than the rate constant, k–1, for dissociation of the reversible complex. The value of the rate constant, k1, for formation of the reversible complex was 1·1 ± 0·2 × 103 M−1 s−1.

These observations suggested that k1 was probably not much greater than for BCM acting on the muscarinic receptor, even though the value of k1 was reduced by more than 2 orders of magnitude. This effect has been established for benzilylcholine and lachesine, reversible analogues of BCM. For both drugs k1 for the histamine receptor was approximately 3 orders of magnitude less than for the muscarinic receptor, whereas k‐1 was greater by a factor of only 6.
Role of inorganic nitrite in methaemoglobin formation after nitrate ester administration to the rat
Authors: CLARK D. G. , LITCHFIELD M. H.
Published: July 2012

Methaemoglobin is rapidly formed during the incubation of rat red cells with inorganic nitrite, whereas ethylene glycol dinitrate at a higher concentration has little effect.

The concentrations of blood inorganic nitrite in the rat after ethylene glycol dinitrate or glyceryl trinitrate injection can be reproduced by the infusion of nitrite. The methaemoglobin formed after ethylene glycol dinitrate or glyceryl trinitrate injection is equivalent to that produced from nitrite infusions simulating its formation from the nitrate esters.

It is concluded that methaemoglobin arising from nitrate ester administration is formed principally by the action of the metabolite inorganic nitrite.
A comparative study of some convulsant substances as γ‐aminobutyric acid antagonists in the feline cerebral cortex
Authors: HILL R. G. , SIMMONDS M. A. , STRAUGHAN D. W.
Published: July 2012

By the use of microiontophoretic techniques, quantitative estimates were obtained of the depressant effects of γ‐aminobutyric acid (GABA) on single feline cortical neurones.

Picrotoxin, bicuculline, strychnine, (+)‐tubocurarine, penicillin and leptazol were also applied microiontophoretically to single neurones. Sequential GABA applications were made before, during and after the microiontophoresis of these substances and any effects on the time course of the GABA depression were measured as an estimate of antagonism or potentiation of GABA.

(+)‐Tubocurarine was found to be a potent GABA antagonist. Picrotoxin and bicuculline were rather less potent and strychnine and penicillin only weakly active as GABA antagonists. Leptazol appeared to be inactive against GABA depressions.

In addition, bicuculline and strychnine were found to be capable of potentiating the depressant action of GABA. This property was not shared by the other substances studied.

All the substances studied produced changes in neuronal firing rate that did not correlate with GABA antagonism.

In conclusion, several potent convulsants have been shown to be capable of GABA antagonism. It is not yet clear that this effect, rather than a direct effect on neuronal excitability, is the prime mechanism behind their convulsant properties.