bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of caffeine and isoprenaline on mammalian ventricular muscle
Authors: CLARK ANNE , OLSON CAMILLE B.
Published: July 2012

Caffeine, 0·6–20·0 mm, altered the duration of the action potential recorded from kitten papillary muscles; low concentrations shortened and high concentrations prolonged the action potential.

Caffeine, 20 mm, prolonged the action potential by delaying the final phase of repolarization.

Caffeine, 2·0–20·0 mm increased the tension developed and the duration of the isometric contraction.

When large stimulating electrodes were used, all concentrations of caffeine increased the duration of the action potential; this effect was probably due to the interactions of caffeine and released endogenous catecholamines.

Concentrations of caffeine and isoprenaline, which separately caused little change in the duration of the action potential, greatly prolonged the action potential when used together.

The effects of caffeine may be due to an increase in membrane calcium current in addition to an action on intracellular calcium stores.
Behavioural studies of the actions of cocaine, monoamine oxidase inhibitors and iminodibenzyl compounds on central dopamine neurones
Authors: CHRISTIE JANICE E. , CROW T. J.
Published: July 2012

Turning behaviour after unilateral lesions of the nigro‐striatal dopamine pathway in rats has been used to compare the actions of cocaine and desipramine on central dopamine‐containing neurones.

Administration of cocaine alone (5–20 mg/kg) resulted in no turning or minimal turning towards the lesioned side; the monoamine oxidase inhibitors nialamide and pargyline administered alone were also ineffective.

After pre‐treatment with nialamide (100 mg/kg) or pargyline (25 mg/kg) cocaine evoked high rates of turning towards the lesioned side.

Desipramine (1–100 mg/kg), either alone or in combination with nialamide did not evoke turning.

Turning evoked by the cocaine‐nialamide combination was abolished by pre‐treatment with α‐methyl‐p‐tyrosine (150 mg/kg).

Pre‐treatment with reserpine (5 mg/kg, 24 h previously) substantially diminished turning evoked by the cocaine‐nialamide combination but potentiated turning resulting from administration of methylamphetamine (5 mg/kg).

Cocaine (20 mg/kg) administered 15 min prior to (+)‐methylamphetamine (5 mg/kg) reduced the turning behaviour in the first hour after administration of the latter drug but prolonged the total duration of the effect.
Some effects of inhibiting endogenous prostaglandin formation on the responses of the cat spleen
Authors: FERREIRA S. H. , MONCADA S. , VANE J. R.
Published: July 2012

Cat isolated spleens release prostaglandins into the venous effluent in response to stimuli such as nerve stimulation, noradrenaline and angiotensin II.

The release of prostaglandins is abolished by pre‐treatment of the spleen with indomethacin (0·3–5 μg/ml).

The capsular and vascular responses to the different stimuli are augmented after inhibition of prostaglandin release.

The prevention of prostaglandin release, as well as the augmentation of vascular and capsular responses, are reversible after indomethacin treatment is stopped.

The role of prostaglandins as modulators of the responses to several stimuli is discussed.
Effect of single dose administration of diuretics on the blood sugar of alloxan‐diabetic mice or mice made hyperglycaemic by the acute administration of diazoxide
Authors: FOY J. M. , FURMAN B. L.
Published: July 2012

Frusemide produced hyperglycaemia in mice when administered together with diazoxide. The interaction between the drugs in elevating the blood sugar was shown to be additive.

The diuretic, natriuretic and kaliuretic effects of frusemide were very markedly attenuated by diazoxide.

Neither ethacrynic acid nor hydrochlorothiazide exerted any effect upon blood sugar when administered together with diazoxide.

Bilateral nephrectomy completely prevented the hyperglycaemic effect of frusemide in normal mice and in mice treated with diazoxide. Diazoxide itself still produced hyperglycaemia in nephrectomized mice.

Frusemide, ethacrynic acid and diazoxide, but not hydrochlorothiazide, each produced hyperglycaemia in alloxan‐diabetic mice, this being prevented by bilateral nephrectomy.
Further studies of binding of bromosulphthalein sodium by human serum albumin: effects of albumin concentration and buffer composition
Authors: THOMPSON J. M.
Published: July 2012

Binding isotherms of equilibrium solution concentration of bromosulphthalein (BSP) determined on the number of moles of BSP bound per mole of human serum albumin (HSA) in 310 ideal milliosmolar pH 7·4, Krebs—Henseleit and Krebs improved mammalian Ringer number 1 buffers at 37° C were determined using continuous diafiltration. The albumin concentration range was from about 10 to 30 g/litre.

The results indicate a competition between HSA polymerization and HSA binding BSP, confirming in more physiological conditions, the findings of Crawford, Jones, Thompson & Wells (1972) with pH 7·4 phosphate buffer.

The results in Krebs—Henseleit buffer were markedly different from those in Krebs mammalian Ringer buffer and it is suggested that the differences in ionic composition influence the HSA conformation and so affect the competition between HSA polymerization and HSA binding BSP.
Concentration of histamine in different parts of the brain and hypophysis of rabbit: effect of treatment with histidine, certain other amino acids and histamine
Authors: ABOU Y. Z. , ADAM H. M. , STEPHEN W. R. G.
Published: July 2012

Estimates have been obtained by biological assay of the histamine concentration in different parts of the rabbit brain and hypophysis.

Mean values (ng/g) for the brain were: hypothalamus, 660; central grey matter and medial thalamus, 275; tegmental region of mid‐brain, the hind‐brain and caudate nucleus, 140 to 170; hippocampus and cerebral cortex, 90 to 110; cerebellum (vermis), 60.

The mean value (ng/g) for the anterior lobe of the hypophysis was 650; for the posterior lobe, 400.

In conscious rabbits, intravenous infusion of histidine in the dose range 62 to 1,500 mg/kg, raised significantly (P < 0·01) the concentration of histamine in all regions of the brain examined, the pattern of distribution remaining unchanged. The largest increases occurred in the mid brain (90 to 320%) and in the hypothalamus (50 to 250%); in these areas the higher doses produced higher concentrations. Elsewhere in the brain the concentration rose in response to the lowest dose of histidine, but was not increased when higher doses were given. Concentrations in the anterior lobe of the hypophysis were unaltered.

The infusion of histidine, unlike that of amino acid precursors, of the monoamines, produced no obvious disturbance in the animals.

The rise in brain histamine after dosage with histidine persisted for several hours, depending on the dose; with 500 mg/kg, the rise was virtually unchanged after 16 hours.

Histamine (5 mg/kg by intravenous infusion) raised the concentration of histamine in the hypophysis but not in the brain.

After the infusion of DOPA, α‐methyldopa or 5‐hydroxytryptophan, the histamine concentration rose in the mid‐brain but not in other parts of the brain.

These amino acids, when infused singly with histidine, did not interfere with the histidine‐induced rise of brain histamine.
Monoamine oxidase in rat arteries: evidence for different forms and selective localization
Authors: COQUIL J. F. , GORIDIS C. , MACK G. , NEFF N. H.
Published: July 2012

Two forms of monoamine oxidase activity were differentiated in rat mesenteric and femoral artery by means of substrate and inhibitor specificities: one form deaminated tyramine, 5‐hydroxytryptamine and noradrenaline and was highly sensitive to pargyline and clorgyline but resistant towards carbonyl reagents. This form resembled type A monoamine oxidase previously described. The other deaminated tyramine but not 5‐hydroxytryptamine or noradrenaline and was inhibited by carbonyl reagents but not by clorgyline or pargyline.

About one third of the total monoamine oxidase in homogenates of rat mesenteric artery was recovered in a 105 g supernatant. Both forms were partially soluble, but relatively less of the type A activity was recovered in the soluble fraction.

Chemical sympathectomy with 6‐hydroxydopamine resulted in a loss of 59% of monoamine oxidase activity in the mesenteric artery. There was a selective loss of type A activity, as revealed by the 70% decrease in 5‐hydroxytryptamine deaminating ability and by the marked decrease in clorgyline sensitivity. The second monoamine oxidase species was resistant to 6‐hydroxydopamine. The soluble activity was not affected by chemical sympathectomy. Most of the transmitter‐specific monoamine oxidase of the arterial wall was localized within the adrenergic nerve endings. Our observations are consistent with the hypothesis that extraneuronal monoamine oxidase plays only a minor role in metabolizing noradrenaline in sympathetically innervated tissues.

Plasma amine oxidase might originate from the arterial wall since it has similar characteristics to that found in the mesenteric artery.
The oestrous cycle and monoamine oxidase activity
Authors: HOLZBAUER MARGARETHE , YOUDIM M. B. H.
Published: July 2012

During the oestrous cycle of the rat, monoamine oxidase (MAO) activity was studied in the uterus, the ovaries and the adrenal glands and also in 4 brain regions which are rich in monoamines. In all these structures the activity was lowest during the night between oestrus and metoestrus. High values were found in di‐oestrus, with the exception of the uterus in which the MAO activity reached its peak during metoestrus.

A stimulating effect of progesterone on uterine, ovarian and adrenal MAO activity was observed.

An index for the cyclic variations in progesterone production was obtained by measuring the adrenal and ovarian progesterone content at the same stages of the cycle as MAO activity.

The sum of the amounts of progesterone contained in the ovaries and adrenal glands was low in early oestrus but increased during late oestrus when MAO activity was at its minimum. Progesterone contents were high in met‐and di‐oestrus when MAO activity was also high.
Effects of intracoronary infusions of acetylcholine and nicotine on the dog heart in vivo
Authors: ROSS G.
Published: July 2012

In anaesthetized dogs intracoronary infusions of high doses of nicotine and acetylcholine increased myocardial contractile force and this could be prevented by pre‐treatment with desmethylimipramine or phenoxybenzamine.

The inotropic effect of nicotine was brief and subsided during the continuing infusion of the drug. The infusion of nicotine did not reduce the inotropic effects of cardiac sympathetic nerve stimulation.

The inotropic effect of intracoronary acetylcholine often fluctuated during prolonged infusions and was not altered by pretreatment with atropine. Acetylcholine infusions reduced the inotropic responses produced by cardiac sympathetic nerve stimulation and led to a substantial transient reduction in the associated pressor responses. Intracoronary acetylcholine also reduced the pressor and inotropic effect of intravenous noradrenaline. The attenuation of these adrenergic cardiovascular responses by acetylcholine was prevented by atropine.
Passage of gallamine from blood into the liquor space in man and in dog
Authors: HARANATH P. S. R. K. , KRISHNAMURTY A. , RAO L. N. , SESHAGIRIRAO K.
Published: July 2012

Patients receiving an intravenous injection of 2–3·8 mg/kg gallamine showed gallamine‐like activity in their lumbar c.s.f. collected 15 and 70–100 min after the injection. The activity assayed on acetylcholine contractions of frog rectus muscle was equivalent to between 0·1 and 0·75 μg/ml gallamine.

In anaesthetized dogs an intravenous injection as well as an intravenous infusion of gallamine led to the appearance of gallamine‐like activity in the cisternal c.s.f. and, on perfusion of the cerebral ventricles, in the effluent collected from the cisterna magna.

After an intravenous injection of 1 mg/kg the activity in the cisternal c.s.f. corresponded to between 0·2 and 1 μg/ml and in the effluent to between 130 and 175 ng/min during the first 15 min perfusion and then declined.

On intravenous infusion of gallamine at a rate of 10 (μg/kg)/min for 2 h the cisternal c.s.f. showed a uniform gallamine‐like activity corresponding to between 0·4 and 0·67 μg/ml during the infusion. In the cisternal effluent the gallamine‐like activity rose initially to between 20 and 90 ng/min but declined before the infusion was ended.

The intravenous injection of gallamine caused respiratory paralysis but did not affect arterial blood pressure; its intravenous infusion caused no respiratory paralysis and did not affect arterial blood pressure.
Predictions of the antimalarial activity of arylamidinoureas
Authors: GOODFORD P. J. , NORRINGTON F. E. , RICHARDS W. H. G. , WALLS L. P.
Published: July 2012

Regression equations were calculated relating the observed antimalarial potencies of arylamidinoureas to their predicted physicochemical properties.

A two‐parameter equation was used to forecast the antimalarial activity of more arylamidinoureas.

Thirteen compounds of the predicted type were synthesized, and their observed antimalarial potencies compared with the forecasts.
Morphine‐tolerant longitudinal muscle strip from guinea‐pig ileum
Authors: GOLDSTEIN A. , SCHULZ R.
Published: July 2012

Implantation of morphine pellets in guinea‐pigs produced a high degree of tolerance and dependence within 3 days.

The contractions of the longitudinal muscle induced by electrical stimulation of the myenteric plexus‐longitudinal muscle preparations obtained from tolerant animals were less depressed by morphine than the contractions evoked in preparations from non‐tolerant animals.

Naloxone did not alter the size of the evoked twitch but antagonized the depressant action of morphine in tolerant and in non‐tolerant animals. When given to tolerant guinea‐pigs, naloxone caused an increase in intestinal activity in vivo.

The contractile response of the longitudinal muscle to acetylcholine was the same in preparations obtained from tolerant and non‐tolerant animals. Electrically evoked contractions of the myenteric plexus‐longitudinal muscle preparations from tolerant animals showed reduced sensitivity to the depressant effects of adrenaline, isoprenaline, and particularly, dopamine.
Further studies regarding the structure activity relationships of β‐adrenoceptor antagonists
Authors: BAGWELL E. E. , WILLIAMS E. M. VAUGHAN
Published: July 2012

The ortho (M66,527) and para (M66,368) analogues of 1‐t‐butylamino‐3‐(methoxyphenoxy)‐2‐propanol and para substituted tertiary butylphenoxy‐1‐N‐isopropylamine‐3 propanol‐2 oxalate acid (L8429) were tested in dogs for their β‐adrenoceptor blocking activity.

M66,527, which contains a methoxy group in the ortho position of the benzene ring, was found to be comparable to propranolol in blocking cardiac and peripheral vascular responses to isoprenaline. Like propranolol, M66,527 was more potent on peripheral receptors.

Transference of the methoxy group to the para position (M66,368) reduced the overall potency; however, this compound was found to be relatively cardioselective in that it was 2 to 3·6 times more active in blocking cardiac responses to isoprenaline.

The cardioselective properties of the short chain para methoxy substituent were less than those reported for compounds with longer para substitutions (i.e. practolol, para oxprenolol and para alprenolol).

L8429, with a tertiary butyl group in the para position, was a weak β‐adrenoceptor antagonist without cardioselective properties. A longer, less bulky n‐butyl group may provide for a more potent and selective antagonist.

The results support the view that the size and site of the substituent on the benzene ring may be of importance in determining the cardioselective potency of β‐adrenoceptor antagonists.
Delayed manifestation of ultraviolet reaction in the guinea‐pig caused by anti‐inflammatory drugs
Authors: GUPTA N. , LEVY L.
Published: July 2012

Exposure of depilated skin of guinea‐pig to ultraviolet (u.v.) light for 20 s produces a prolonged inflammatory response.

The erythaema becomes evident within 15–30 min after the exposure and progressively increases in intensity reaching its maximum by 4–6 hours. The erythaema persists over 24 hours.

Increase in vascular permeability is biphasic with an early short‐lived rise peaking at 0·5 h and a prolonged secondary response peaking at 9–12 h and lasting over 48 hours.

In presence of aspirin, phenylbutazone and indomethacin, administered prior to u.v. exposure, the inflammatory reaction is partially suppressed, depending upon the dose. The drugs are ineffective in aborting or minimizing the response when given after the inflammation is established. Corticosteroids fail to influence the u.v. inflammation in this test. The significance of these findings is discussed.
A comparison of the effects of chemical sympathectomy by 6‐hydroxydopamine in newborn and adult rats
Authors: FINCH L. , HAEUSLER G. , THOENEN H.
Published: July 2012

The effects of chemical sympathectomy with 6‐hydroxydopamine (6‐OHDA) on the cardiovascular system of the rat were compared in, (a) 10‐week‐old rats treated during the first 14 days after birth with 150 μg/g subcutaneously, and (b) adult rats injected intravenously with 2 × 50 mg/kg on day 1 and 2 × 100 mg/kg on day 7 and the experiments performed on day 8.

Intravenous administration of 6‐OHDA to adult rats almost completely abolished the pressor responses to stimulation of the entire sympathetic outflow in the pithed rat, the contractions of the lower eyelid to stimulation of the cervical sympathetic trunk and the vasconstrictor responses produced by periarterial nerve stimulation of the isolated renal artery preparation. Pressor responses to physostigmine and to tyramine were markedly reduced or abolished in anaesthetized and pithed rat preparations, respectively.

In corresponding experiments, 10‐week‐old rats treated as newborns with 6‐OHDA showed a marked reduction in the stimulation‐induced pressor responses and contractions of the lower eyelid, but completely normal vasoconstrictor responses to periarterial nerve stimulation of the isolated perfused renal artery were obtained. The pressor responses to physostigmine were slightly reduced but the tyramine responses were unchanged.

Treatment with 6‐OHDA at birth caused an almost complete and long‐lasting noradrenaline depletion in the heart, spleen, salivary glands and ileum but only a partial depletion in the mesentery from 10‐week‐old rats. These low noradrenaline levels showed no recovery in rats up to an age of 4 months. The tyrosine hydroxylase activity in both the cervical and stellate ganglia from 10‐week‐old rats was markedly reduced by treatment with 6‐OHDA after birth.

Injections of 6‐OHDA after birth produce an almost complete and permanent sympathectomy of various adrenergically innervated organs in the rat. The vascular system represents a major exception, exhibiting a surprisingly high resistance to this type of chemical adrenergic denervation.
Interaction of bretylium and guanethidine on the relaxations of the rat isolated fundal strip preparation, evoked by indirect stimulation
Authors: GAITONDÉ B. B. , NIMBKAR A. Y.
Published: July 2012

Isolated rat stomach fundal strip bathed in Krebs solution containing atropine (1 μg/ml), responded to indirect stimulation by a relaxation which was frequency dependent. These responses were blocked by phenoxybenzamine (6 ftg/ml) or phentolamine (8 μg/ml).

Strips obtained from rats previously treated with reserpine did not show relaxation to indirect stimulation. These responses were therefore adrenergic in nature.

Bretylium (0·1–100 μg/ml) failed to block the relaxations produced by indirect stimulation, in fact relaxations were potentiated by the drug.

Guanethidine (10 μg/ml) blocked the relaxations induced by indirect stimulation.

Guanethidine may be taken up by adrenergic nerves actively since its action is not seen at 12° C.

Bretylium (10 μg/ml) prevented the actions of guanethidine at 37° C.
The release of spasmogenic substances from human chopped lung tissue and its inhibition
Authors: PIPER PRISCILLA J. , WALKER JOYCE L.
Published: July 2012

Human lung tissue, passively sensitized with reaginic antibodies, released prostaglandins E1, E2 and F2α in addition to histamine and slow reacting substance (SRS‐A), when exposed to the appropriate antigen. No rabbit aorta contracting substance (RCS) was detected.

Experiments with rats and guinea‐pigs showed that the release of RCS is not confined to anaphylactic reactions mediated by non‐reaginic antibodies but may be a feature of anaphylaxis in guinea‐pigs alone.

Human lung tissue gently agitated with a blunt nylon rod liberated an E‐type prostaglandin and RCS in addition to histamine and SRS‐A.

Human isolated bronchial muscle was contracted by RCS.

Disodium cromoglycate antagonized the release of prostaglandins during anaphylaxis but not during agitation of human lung tissue, whereas indomethacin blocked the release of prostaglandins during agitation and anaphylaxis.

The release of an E‐type prostaglandin during anaphylaxis in human lung tissue, which inhibits the further release of histamine could be another example of the regulatory role of prostaglandins in body functions.
The removal of noradrenaline in the pulmonary circulation of rat isolated lungs
Authors: ALABASTER VALERIE A. , BAKHLE Y. S.
Published: July 2012

Removal of noradrenaline by isolated lungs of the rat, perfused via the pulmonary artery with Krebs bicarbonate solution has been studied.

A constant removal (40·2%) was observed over a concentration range of 2–50 ng noradrenaline/ml (12–300 nM). At 100 ng/ml (600 nM), the removal is significantly reduced to 33·5%.

The removal of noradrenaline was inhibited by cocaine (1 μm), but not by normetanephrine (5 μm), metaraminol (10 μm), phenoxybenzamine (10 μm) and 5‐hydroxytryptamine (110 and 560 nM).

We conclude that the removal of noradrenaline in the lungs does not involve an uptake process comparable with those previously described for this amine. The uptake process for noradrenaline in the lung is similar to that for 5‐hydroxytryptamine and may be unique to this tissue.
The inhibitory effect of manganese on transmitter release at the neuromuscular junction of the toad
Authors: BALNAVE R. J. , GAGE P. W.
Published: July 2012

Manganese, at low concentrations (0·5–2·0 mm), blocks neuromuscular transmission in toads. Endplate potentials (e.p.ps) are reduced in amplitude but the amplitude of miniature endplate potentials (m.e.p.ps) is, if anything, increased.

The release of transmitter by an action potential is reduced in solutions containing Mn, but is still well described by the Poisson equation.

Log‐log plots of e.p.p. quantal content (m) against [Ca] have a mean gradient of 3·73, and a model based on the co‐operative action of four calcium ions in excitation‐secretion coupling, and competitive inhibition by Mn, was constructed. The model, with its exponent of 4, is shown in fact to predict gradients of less than four for log‐log plots of m against [Ca].

The assumption of competitive inhibition by Mn was supported by modified Lineweaver‐Burk plots of m−¼ against 1 / [Ca]. The mean dissociation constants for Ca and Mn were 1·3 mm and 015 mm respectively. From the model, an upper estimate of the density of calcium* receptor sites' of 30 per square micron of nerve terminal was obtained.

In contrast to its inhibitory effect on evoked release, Mn increases the spontaneous release of transmitter. It is suggested that Mn may increase m.e.p.p. frequency by releasing Ca from an intracellular store.
Mechanism of potentiation by amines of non‐equilibrium blockade of the α‐adrenoceptor
Authors: KALSNER S.
Published: July 2012

The mechanism by which sympathomimetic and certain other amines enhance blockade of the α‐adrenoceptors by the non‐equilibrium antagonist N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ) in strips of rabbit aorta was examined.

Non‐equilibrium blockade of the 5‐hydroxytryptamine receptors by EEDQ was not increased by sympathomimetic amines and was decreased by 5‐hydroxytryptamine.

Low concentrations of reversible competitive antagonists appeared to protect selectively against the additional blockade by EEDQ which develops in the presence of an amine.

Phenoxybenzamine potentiated EEDQ blockade of the α‐receptors but not of the 5‐hydroxytryptamine receptors.

Augmentation of EEDQ blockade was also detected in a variety of other tissues, but not in segments of rabbit intestine where α‐adrenoceptors mediate an inhibitory response.

It was concluded that EEDQ acts at two sites in antagonizing α‐receptor mediated responses, and that one of these sites (site II) is separate from the site of action of agonists and phenoxybenzamine (site I). Amines which enhance blockade appear to exert their action by combining with a third site (site III), which may induce a conformational alteration at site II.

It appears that the α‐adrenoceptor may have multiple sites for drug interaction.
Effects of quazodine (MJ 1988) on contractions of the isolated hemidiaphragm of the rat and the biventer cervicis muscle of the chick
Authors: NOTT M. W. , WINSLOW EILEEN
Published: July 2012

The effects of quazodine and theophylline have been studied on the rat hemidiaphragm and chick biventer cervicis preparations in vitro.

Theophylline and quazodine enhanced maximal twitches and contractural responses to acetylcholine and carbachol.

These actions on contractility were exerted directly upon the muscle fibres and were dependent upon the concentration of calcium ions in the bathing solution.

In addition, quazodine enhanced the neuromuscular blocking activity of tubocurarine, probably by a prejunctional action.

Theophylline potentiated acetylcholine to a greater extent than it potentiated carbachol thus suggesting that theophylline possesses anticholinesterase activity.
Response of the rat ileum, uterus and vas deferens to carbachol and acetylcholine following repeated daily administration of a cholinesterase inhibitor
Authors: FOLEY D. J. , McPHILLIPS J. J.
Published: July 2012

Daily i.p. administration, for eight days, of the cholinesterase inhibitor disulfoton to rats produced mild to moderate signs of intoxication (tremors, incontinence and diarrhoea) but no deaths.

Segments of ileum taken from the treated rats were subsensitive to carbachol but the vas deferens and the uterus did not exhibit any change in sensitivity to carbachol.

The sensitivity to acetylcholine was increased in the ileum and vas deferens but not in the uterus.

Acetylcholinesterase activity was 60–70% inhibited in all three tissues.
Correlation between desipramine levels and (—)‐noradrenaline uptake and chronotropic effect in isolated atria of rats
Authors: BABULOVA A. , BAREGGI S. R. , BONACCORSI A. , GARATTINI S. , MORSELLI P. L. , PANTAROTTO C.
Published: July 2012

The uptake of unlabelled and [14C]‐desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 μg/ml. The uptake was found to be dose‐ and time‐dependent. Equilibrium was not reached after 2–3 h of incubation unless concentrations of desipramine higher than 1 μg/ml were used.

The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration.

The binding appeared to be at non‐specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6‐hydroxydopamine accumulated the drug at the same rate as control atria.

The inhibition of (—)‐noradrenaline uptake and the potentiation of the chronotropic response to (—)‐noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 001 to 1 μg/g. Higher tissue levels show less potentiation of the effect of (—)‐noradrenaline or even inhibition of the maximal response to (—)‐noradrenaline. These concentrations of desipramine (> 7 μg/g) markedly depressed the atrial rate.

The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.
The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by NaF
Authors: KATZ S. , TENENHOUSE A.
Published: July 2012

A method for measuring the rate of production of 14C‐labelled adenine nucleotides, including cyclic adenosine 3′,5′monophosphate (cyclic AMP), from [14C]‐adenosinetriphosphate (ATP) was developed and used to study the effects of ATP, adenosine diphosphate (ADP) and adenosine 5′‐monophosphate (AMP) on the rate of accumulation of cyclic AMP in cell‐free preparations of adenyl cyclase from rat brain.

The mechanism by which NaF increases cyclic AMP accumulation was studied by comparing its effect on adenine nucleotide metabolism with that of an ATP regenerating system.

ADP and ATP are potent inhibitors of phosphodiesterase (PDE) and it is the sum of the concentrations of these two nucleotides which controlled the rate of destruction of cyclic AMP. The effect of these nucleotides was significant even in the presence of 6·7 mm theophylline; theophylline itself inhibited PDE only 50–60%.

Fluoride ion had no direct effect on PDE but it inhibited the rate of hydrolysis of ADP and ATP and thus indirectly inhibited PDE. The effect of fluoride ion on cyclic AMP accumulation can be explained, at least in part, by this indirect inhibition of PDE.

Studies on a more purified preparation of adenyl cyclase clearly demonstrated a direct action of NaF on adenyl cyclase.
The relation of adenyl cyclase to the activity of other ATP utilizing enzymes and phosphodiesterase in preparations of rat brain; mechanism of stimulation of cyclic AMP accumulation by adrenaline, ouabain and Mn++
Authors: KATZ S. , TENENHOUSE A.
Published: July 2012

The mechanism of stimulation of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) accumulation by adrenaline and ouabain and the effect of Mn++substitution for Mg++ as the metal ion requirement of this system was studied in cell‐free preparations of adenyl cyclase from rat brain.

In the rat cerebral cortex preparation, substitution of Mn++for Mg++significantly increased cyclic AMP accumulation while significantly inhibiting adenosine triphosphate (ATP) and adenosine diphosphate (ADP) hydrolysis and adenosine 5′‐monophosphate (AMP) accumulation. In the synaptic membrane preparation, in the absence of NaF, the highest amount of ATP hydrolysis was obtained in tissue prepared with Mn++and incubated with Mg++; under these conditions cyclic AMP accumulation was equal to that produced under any other condition and significantly higher than that observed in the presence of Mg++prepared and Mg++incubated tissue.

Preparation and/or incubation of tissue with Mn++significantly reduced phosphodiesterase (PDE) activity compared to that observed in Mg++prepared tissue.

Adrenaline and ouabain both significantly increased cyclic AMP accumulation in the rat cerebral cortex preparation but did not inhibit ATP or ADP hydrolysis. In the synaptic membrane preparation, in the presence of 001 mm Ca++, adrenaline but not ouabain significantly increased cyclic AMP accumulation. Phenoxybenzamine (0·1 mm) and pronethalol (01 mm) significantly inhibited adrenaline‐induced cyclic AMP accumulation in both these preparations.

Ouabain and adrenaline both failed to stimulate cyclic AMP accumulation in the presence of Mn++prepared and/or incubated tissue.

Ouabain and adrenaline had no effect on PDE activity in either of these preparations.

It was concluded that Mn++increased cyclic AMP accumulation in part by indirect inhibition of ATP and ADP hydrolysis which provides inhibitors of cyclic AMP destruction, by direct stimulation of adenyl cyclase and by inhibition of cyclic AMP destruction in a way unrelated to nucleotide inhibition of PDE. Adrenaline and ouabain appeared to stimulate cyclic AMP accumulation in a more direct manner.
Pentobarbitone inhibition of catecholamine secretion
Authors: HOLMES J. C. , SCHNEIDER F. H.
Published: July 2012

The perfused isolated cow adrenal gland was used to investigate the effect of barbituric acid, phenobarbitone and pentobarbitone on catecholamine secretion.

Pentobarbitone reduced catecholamine secretion induced by a number of drugs which cause exocytosis. The concentration of pentobarbitone which caused a 50% inhibition of catecholamine secretion was for acetylcholine 5·6 × 10−5m, for carbachol 6·3 × 10−5m, for histamine 1·6 × 10−4m, for (+)‐amphetamine 4·4 × 10−5m and for potassium chloride 1·5 × 10−4m. The degree of inhibition by pentobarbitone was not dependent on the concentration of the secretagogue.

Pentobarbitone (up to 10−3m) did not inhibit the catecholamine release that was induced by acetyldehyde or by calcium chloride; it inhibited slightly (34%) the catecholamine secretion induced by tyramine.

Catecholamine release induced by carbachol was also inhibited by phenobarbitone (50% inhibition at 2·8 × 10−4m (n = 7)) but was unaffected by barbituric acid.

Pentobarbitone had no effect on spontaneous or on (+)‐amphetamine‐ or tyramine‐induced release of catecholamines from isolated chromaffin vesicles of cow adrenal medulla.

It is concluded that pentobarbitone inhibits catecholamine release by preventing a configurational change in the structure of the membrane of the chromaffin cell which is a necessary link between receptor activation and catecholamine release.
Release of rabbit aorta contracting substance (RCS) and prostaglandins induced by chemical or mechanical stimulation of guinea‐pig lungs
Authors: PALMER M. A. , PIPER PRISCILLA J. , VANE J. R.
Published: July 2012

Rabbit aorta contracting substance (RCS) and prostaglandins were released from guinea‐pig isolated perfused lungs by gentle massage and also by infusion of Prosparol.

RCS and prostaglandins were also released by infusion into the pulmonary artery of bradykinin, arachidonic and dihomo‐γ‐linolenic acids or shock perfusate (containing RCS‐releasing factor).

Arachidonic and dihomo‐γ‐linolenic acids caused a prolonged release of RCS and prostaglandins whereas bradykinin and shock perfusate gave a short‐lasting output.

RCS and prostaglandins, together with histamine were released when super‐fused chopped lung tissue was agitated.

Challenge of sensitized guinea‐pigs in vivo led to the release of an RCS‐like substance into the carotid arterial blood.

Intravenous injection of bradykinin into guinea‐pigs also released an RCS‐like substance.

The release of RCS and prostaglandins was inhibited by aspirin or indomethacin in all experiments.

RCS contracted all vascular tissues investigated and also rat stomach strip.

The half‐life of RCS was estimated as 1–2 minutes.
Decreased synthesis of DNA in regenerating rat liver after the administration of reserpine
Authors: ĆIHÁK A. , VAPTZAROVA K.
Published: July 2012

Reserpine given to rats before the enhanced synthesis of DNA begins 14h after partial hepatectomy markedly depresses thymidine uptake into DNA at 24 hours.

At this time decreased activity of liver thymidine kinase but unchanged thymidine 5′‐nucleotidase were observed.

Reserpine has no effect on DNA synthesis when administered simultaneously with the labelled thymidine 2 h before killing.

With depressed DNA synthesis after reserpine administration there is no significant decrease of liver RNA synthesis.
[3H]‐adenine nucleotide and [3H]‐noradrenaline release evoked by electrical field stimulation, perivascular nerve stimulation and nicotine from the taenia of the guinea‐pig caecum
Authors: KUCHII M. , MIYAHARA J. T. , SHIBATA S.
Published: July 2012

The release of [3H]‐noradrenaline and adenine nucleotide evoked by electrical field stimulation (20–60 V, 30 Hz), perivascular nerve stimulation (20–80 V, 60 Hz) and nicotine (10, 100 μm) was studied in the taenia of the guinea‐pig caecum under various conditions.

Electrical stimulation at high intensity (60 V) caused the release of [3H]‐adenine nucleotide; however, the inhibitory action of electrical stimulation was proportional to [3H]‐noradrenaline release.

The intensity of the inhibitory effect of stimulation of the perivascular nerves was directly related to [3H]‐noradrenaline release and not associated with the release of [3H]‐nucleotide.

Cold storage for more than 8 days, cooling (19° C) or tetrodotoxin treatment (1 μg/ml) abolished the inhibitory responses to electrical stimulation and to nicotine. After these treatments, nicotine and electrical stimulation elicited only contractions; the release of [3H]‐noradrenaline, but not that of [3H]‐adenine nucleotide, was inhibited.

The dissociation of the inhibitory effects of electrical stimulation and nicotine from [3H]‐nucleotide release does not support the hypothesis that ATP or a related nucleotide is the humoral transmitter of the non‐adrenergic inhibition in the taenia of the guinea‐pig caecum.
Inhibition by diuretics of cyclic 3′,5′‐AMP‐dependent protein kinase from toad bladder epithelium
Authors: FERGUSON D. R. , TWITE B. R.
Published: July 2012

A cAMP‐dependent protein kinase enzyme has been isolated from toad bladder epithelium.

This enzyme catalyses the phosphorylation of histones; a reaction stimulated by 0·1 μm cAMP.

Activity of this enzyme in the presence of 01 μm cAMP was significantly inhibited by 100 μm mercuderamide, bumetanide and frusemide. A small, though statistically insignificant inhibition was seen with the same concentrations of hydrochlorothiazide and ethacrynic acid.

The half maximal inhibition was achieved with mercuderamide, 5 μm, and with frusemide and bumetanide 600 μm.
Interaction of (+)‐amphetamine with cerebral dopaminergic neurones in two strains of mice, that show different temperature responses to this drug
Authors: CACCIA S. , CECCHETTI G. , GARATTINI S. , JORI A.
Published: July 2012

(+)‐Amphetamine sulphate elicits a dose‐dependent hyperthermia in NMRI mice but it does not significantly increase the body temperature of C3H mice.

When low doses of (+)‐amphetamine are given, the body temperature of C3H mice decreases.

(+)‐Amphetamine decreases the noradrenaline concentration in the brainstem and increases the homovanillic acid concentration (HVA) in the striatum of NMRI mice, but only slightly reduces the noradrenaline concentration and does not change the HVA concentration in the brains of C3H mice.

The two strains appear to show a difference in the metabolism of dopamine in the striatum. The rates at which dopamine disappears from the tissue after blocking catecholamine synthesis with α‐methyltyrosine and the rates at which HVA accumulates after blocking the active transport of this metabolite out of the brain with probenecid suggest that the turnover of dopamine is lower in C3H mice than in NMRI mice.
The role of sodium pump in the inhibition of smooth muscle responsiveness to agonists during potassium restoration
Authors: BOSE D. , INNES I. R.
Published: July 2012

Isometric contractions of cat splenic capsular smooth muscle in response to noradrenaline and histamine were recorded.

Removal of potassium from the bathing medium did not change the resting tension or the responsiveness to noradrenaline. Restoration of potassium inhibited responses to noradrenaline or histamine only if the muscles were stimulated with an agonist while in the K‐free medium.

This inhibition of responses to the agonists due to potassium was reversed rapidly by removing the ion or reversed slowly by prolonged exposure to the ion. The inhibition was also blocked by procedures or agents which block the sodium pump (ouabain, substitution of NaCl by LiCl), inhibit active processes (low ambient temperature) or prevent intracellular accumulation of sodium (substitution of choline for sodium).

It is proposed that under special circumstances such as when there is an increase in internal sodium concentration, the sodium pump is probably electrogenic and causes relaxation when activated by external potassium. In the normal muscle the pump is probably electrically neutral.
The effects of drugs on the sensitivity of the rat anococcygeus muscle to agonists
Authors: GIBSON A. , POLLOCK D.
Published: July 2012

The effects of cocaine, 6‐hydroxydopamine (6‐OHDA), reserpine and 17‐β‐oestradiol on the sensitivity of the rat anococcygeus muscle to noradrenaline (NA), acetylcholine (ACh) and KCl were investigated.

Cocaine (10−5m) increased the sensitivity of the anococcygeus to NA (100‐fold) but not to ACh or KCl.

6‐OHDA treatment, whether discontinuous over 6 days or continuous for 12 days, also produced a specific increase in sensitivity to NA (50‐fold).

Reserpine ((1 mg/kg)/day) produced a small increase in sensitivity of the muscle to NA and ACh but not to KCl, after 6 days and 12 days treatment.

17‐β‐Oestradiol (10–5m) had no effect on the sensitivity of the anococcygeus to NA or ACh, but reduced the sensitivity to KCl and the possible mechanism of this effect is discussed.

Cocaine increased, while reserpine, 6‐OHDA and 17‐β‐oestradiol decreased, the maximum response of the muscle to KCl. The response to KCl was shown to consist of at least three components; a direct action on the muscle, an effect due to release of NA, and an inhibitory action, probably due to release of the unknown inhibitory transmitter.
Mechanisms contributing to barbiturate intolerance in rats
Authors: ASTON R.
Published: July 2012

Female rats, 3 weeks after pretreatment with 200 or 400 (mg/kg)/day barbitone for 2 or 30 days, exhibited a prolonged sleeping time and a reduced awakening barbiturate brain level when challenged with either barbitone or pentobarbitone. After 3 additional weeks, the latter responses had returned, or were returning to, control values.

Barbitone pretreatment schedules had no residual effect upon in vitro hepatic pentobarbitone‐metabolizing activity measured 3 or 6 weeks later, except in one instance, when hepatic enzyme activity was significantly enhanced 3 weeks after 30 daily doses of 200 mg/kg barbitone. In this case, however, an enhanced barbiturate sleeping time, together with a reduced awakening barbiturate brain level, were observed.

It is concluded that barbitone administered intraperitoneally in doses of 200 to 400 (mg/kg)/day for 2 or 30 days induces a non‐hepatogenic intolerance to barbiturates, related to an increased sensitivity of the central nervous system to these drugs. This central intolerance is seen 3 weeks, but not 6 weeks, after pretreatment. Furthermore, this central intolerance has been observed to co‐exist with an hepatic tolerance, a situation which could result in a reduced LD50 coupled with an increase in ED50.
A STUDY OF THE FACTORS AFFECTING THE SLEEPING TIME FOLLOWING INTRACEREBROVENTRICULAR ADMINISTRATION OF PENTOBARBITONE SODIUM: EFFECT OF PRIOR ADMINISTRATION OF CENTRALLY ACTIVE DRUGS
Authors: STEVENSON I.H. , BULL M.J. TURN
Published: July 2012

Injection of pentobarbitone sodium into a lateral cerebral ventricle of rats produced a loss of righting reflex. The duration of anaesthesia was dose‐dependent.

The optimum dose of pentobarbitone to allow study of the factors affecting the sleeping time was considered to be 650 μg injected in 25 μl water.

In a study of the effect of age and sex on the sleeping time, the youngest rats used (88 g body weight) were found to be the most sensitive to barbiturate. Female rats were more sensitive than male animals.

The duration of anaesthesia was not affected by induction or inhibition of hepatic drug‐metabolizing enzyme activity.

Prior administration (acute) of central nervous system depressant drugs shortened the latent period and prolonged the duration of sleep. Prior administration of stimulant drugs antagonized the effect of pentobarbitone.

Animals withdrawn following chronic administration of a number of drugs, barbitone, barbitone/bemegride mixture, Mandrax (methaqualone: diphenhydramine; 10: 1), chlordiazepoxide, nitrazepam, chlorpromazine or ethanol, exhibited a significant tolerance to intracerebroventricularly administered pentobarbitone.

Withdrawal of amphetamine, morphine, methyprylon or diazepam did not result in tolerance to intracerebroventricularly administered pentobarbitone.

Chronic administration of all drugs except amphetamine and morphine induced a tolerance to intraperitoneally administered hexobarbitone (100 mg/kg).

The usefulness of sleeping time determination following intracerebroventricular administration of pentobarbitone as an assessment of central nervous system excitability is discussed. It is concluded that this method gives a valid indication of the sensitivity of the central nervous system to barbiturate and of the level of excitability in general. The method is particularly applicable in situations where the activity of hepatic drug‐metabolizing enzyme activity may be altered.
DISTRIBUTION OF α‐ AND β‐ADRENOCEPTORS IN HUMAN URINARY BLADDER
Authors: AWAD S.A. , BRUCE A.W. , CARRO‐CIAMPI G. , DOWNIE J.W. , LIN M. , MARKS G.S.
Published: July 2012

The distribution of α‐ and β‐adrenoceptors in isolated preparations of human bladder neck and detrusor muscle has been studied.

Adrenaline caused contraction of the bladder neck which was blocked by phenoxybenzamine but unaltered by propranolol.

Isoprenaline caused relaxation of the bladder neck which was blocked by propranolol. High concentrations caused contraction which was enhanced by propranolol but blocked by phenoxybenzamine.

Detrusor muscle was relaxed by isoprenaline and this effect was blocked by propranolol. Phenylephrine caused relaxation of detrusor which was unaffected by phenoxybenzamine; in some cases contraction was produced in the presence of propranolol.

It is concluded that the bladder neck contains mainly α‐receptors and the detrusor mainly β‐receptors but both regions possess both types of adrenoceptor.
INHIBITION BY NON‐STEROID ANTI‐INFLAMMATORY AGENTS OF RABBIT AORTA CONTRACTING ACTIVITY GENERATED IN BLOOD BY SLOW REACTING SUBSTANCE C
Authors: FERREIRA S.H. , VARGAFTIG B.B.
Published: July 2012

A crude and a partially purified preparation of slow reacting substance C (SRS‐C) as well as arachidonic acid decreased resistance to perfusion of the dog hind paw. This effect was suppressed by treatment with non‐steroid anti‐inflammatory drugs.

Injections of SRS‐C or of arachidonic acid induced marked and reproducible contractions of strips of rabbit aorta and a rat stomach which were bathed in blood from an anaesthetized dog. The effect on the rabbit aorta is attributed to formation of a rabbit aorta contracting substance (RCS). The contractions were suppressed when the dog was treated with a non‐steroid anti‐inflammatory drug.

Incubation of blood or of platelet‐rich plasma with SRS‐C or arachidonic acid resulted in the formation of similar materials. This formation was suppressed by anti‐inflammatory drugs.

SRS‐C, linoleic, linolenic, and arachidonic acids are suitable substrates for soybean lipoxidase for the generation of RCS.

It is suggested that RCS and prostaglandin are formed within platelets, when SRS‐C or arachidonic acid are injected into animals or added in vitro. Non‐steroid anti‐inflammatory drugs suppress these effects, possibly by inhibiting prostaglandin synthetase.