bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of LM 5008, a selective inhibitor of 5‐hydroxytryptamine uptake, on blood pressure and responses to sympathomimetic amines
Authors: Ashkenazi R. , Finberg J.P.M. , Youdim M.B.H.
Published: July 2012

LM 5008 (4‐[2‐(3‐indolyl)ethyl]piperidine) (10, 20 and 50 mg kg−1) had no significant effect on pressor responses to noradrenaline or tyramine in rats anaesthetized with urethane. Desmethylimipramine (1 mg kg−1) blocked the response to tyramine but chlorimipramine (5 mg kg−1) had no significant effect on responses to noradrenaline or tyramine.

In the rabbit, anaesthetized with chloralose, LM 5008 (5 mg kg−1) had no effect on pressor responses to noradrenaline, tyramine or angiotensin II, while desmethylimipramine (0.25 mg kg−1) inhibited responses to tyramine and potentiated those to noradrenaline.

LM 5008 (10 mg kg−1) had no effect on resting blood pressure of conscious normotensive or DOCA‐saline hypertensive rats.

Tranylcypromine (5 mg kg−1) produced a fall in blood pressure in conscious normotensive and in DOCA hypertensive rats.

Treatment with a combination of LM 5008 (10 mg kg−1) and tranylcypromine (5 mg kg−1) resulted in the appearance of a behavioural hyperactivity syndrome, but blood pressure was not different from that of animals treated with tranylcypromine alone.

These results further demonstrate the selectivity of LM 5008 for 5‐hydroxytryptamine as opposed to catecholamine uptake.
Comparative effects of cotrimoxazole (trimethoprim‐sulphamethoxazole),pyrimethamine‐sulphadiazine and spiramycin during avirulent infection with Toxoplasma gondii (Beverley strain) in mice
Authors: Nguyen B.T. , Stadtsbaeder S.
Published: July 2012

The antitoxoplasm effects of cotrimoxazole (Ctx), spiramycin (Spir) and pyrimethamine‐sulphadiazine (Pmm‐Sdz) were compared during both proliferative and chronic phases of infection of mice with the Beverley (Bev) strain of Toxoplasma gondii of low virulence.

The therapeutic efficacy of the drugs was determined according to the following criteria: (i) specific antibody response; (ii) acquired resistance to lethal challenge with the virulent RH strain of Toxoplasma; and (iii) persistence of parasites in tissues (brain, liver, spleen) of treated mice.

The results indicated that Ctx, like Pmm‐Sdz, had a greater effect than Spir upon toxoplasma organisms during the proliferative phase of infection. In contrast, none of the three drugs tested was active against tissue cysts in chronically infected mice.
Effects of prostaglandin E2, propranolol and nitroglycerine with halothane, pethidine or pentobarbitone anaesthesia on arrhythmias and other responses to ligation of a coronary artery in rats
Authors: AU T.L.S. , Collins G.A. , Macleod B.A. , Walker M.J.A.
Published: July 2012

The effects of various cardiovascular drugs (prostaglandin E2 (PGE2), propranolol and nitroglycerine) and anaesthetic regimens (halothane, pethidine and pentobarbitone), upon the outcome of coronary artery ligation in acutely prepared rats were determined.

Effects upon arrhythmias, blood pressure, heart rate, mortality, ECG and the size of the occluded zone were determined for each drug in the presence of each anaesthetic.

PGE2 and nitroglycerine had no statistically significant effects on the outcome of ligation whatever the anaesthetic. Propranolol had limited antiarrhythmic actions.

The anaesthetic used had major effects upon the outcome of ligation, regardless of the cardiovascular drugs administered.

Pentobarbitone anaesthesia resulted in the highest mortality, and most arrhythmias.

Pethidine‐N2O anaesthesia was associated with fewer arrhythmias.

Halothane‐N2O anaesthesia markedly decreased the incidence and severity of arrhythmias, independent of the cardiovascular drug.

It was concluded that the anaesthetic used can have a major influence on ligation‐induced arrhythmias in acutely prepared anaesthetized rats.
Ligand binding to thromboxane receptors on human platelets: correlation with biological activity
Authors: Armstrong Roma A. , Jones R. L. , Wilson N. H.
Published: July 2012

The preparation of enantiomerically pure [3H]‐15 (S) 9, 11‐epoxymethano PGH2 (a thromboxane A2‐like agonist) has enabled the binding of ligands to the thromboxane receptor of the human platelet to be studied.

The binding of the radio‐ligand to washed human platelets has 3 components. One component is not displaceable by ‘cold’ 9, 11‐epoxymethano PGH2 and its concentration‐binding plot is roughly linear. The other 2 components are displaceable and saturable, and the larger of the two, which is sensitive to the stereochemistry of the C15 secondary alcohol, appears to represent the thromboxane receptor. About 1700 15(S)9, 11‐epoxymethano PGH2 molecules are specifically bound to a single platelet and 50% of this binding is achieved with a concentration of 75 nM.

Displacement of [3H]‐15(S)9, 11‐epoxymethano PGH2 is effected by (a) TXA2 and PGH2 and a number of bicyclic stable analogues (e.g. 9,11‐azo PGH2), all of which produce irreversible aggregation of human platelets; (b) analogues of PGF2α with potent thromboxane‐like activity (e.g. ICI 79939); (c) compounds with partial agonist activity on the platelet thromboxane system (e.g. CTA2); (d) Thromboxane/endoperoxide analogues which specifically antagonize thromboxane‐like actions on the human platelet (e.g. PTA2 and EP 045).

Displacement is not achieved with the natural prostaglandins PGE2, PGD2 and PGF2α. Neither the thromboxane‐synthetase inhibitor dazoxiben nor R(+)‐trimethoquinol have high displacing activity.

The correlation of radio‐ligand displacement with the biological activity of the competing ligands is discussed in relation to the nature of the thromboxane receptor on the human platelet.
Correlation of changes in α2‐adrenoceptor number and locomotor responses to clonidine following clorgyline discontinuation
Authors: Aulakh C.S. , Cohen R.M. , McLellan C. , Murphy D.L.
Published: July 2012

[3H]‐clonidine binding in vitro and the locomotor response to clonidine in vivo were studied over an eight week period following four weeks of treatment with the monoamine oxidase‐inhibiting antidepressant, clorgyline (1 mg kg−1 day−1). Long‐term clorgyline administration caused decreases in responsiveness to clonidine and in the number of α2‐adrenoceptors; these changes reverted towards pretreatment values very gradually over an eight week period following discontinuation of the drug. This study provides some of the first detailed evidence regarding the slow return of adaptional changes following discontinuation of an antidepressant drug in animals and has implications for understanding some delayed drug interactions associated with MAO‐inhibiting antidepressants in man.
Studies on the renin response to vasoactive intestinal polyeptide (VIP) in the conscious rabbit
Authors: Calam John , Dimaline Rodney , Peart W. Stanley , Unwin Robert
Published: July 2012

Vasoactive intestinal polypeptide (VIP) has been found within the renal cortex and is believed to be a neurotransmitter. Although it produces systemic vasodilatation and renin release, the exact mechanism of the latter response is uncertain. When infused into conscious rabbits, VIP elicits a rise in plasma renin activity (PRA) and an increase in heart rate. The rise in PRA is unaltered by pretreatment with propranolol, but is attenuated by indomethacin. The tachycardia is inhibited by propranolol, but unaffected by indomethacin. We conclude that the renin response to VIP is in part prostaglandin‐dependent and that the heart rate response is due to direct or reflex β‐adrènoceptor stimulation.
Studies in rabbits on the disposition and trypanocidal activity of the antitrypanosomal drug, diminazene aceturate (Berenil)
Authors: Gilbert Robert J.
Published: July 2012

After intramuscular injection of 3.5 mg kg−1 to rabbits, diminazene aceturate shows biphasic pharmacokinetics with maximum blood and interstitial fluid concentrations occurring after 15 min and 3 h respectively.

Seven days after treatment, 40–50% of the dose had been excreted in the urine and 8–20% in faeces.

Highest diminazene residues were determined in liver: 7 days after dosage, residues of 40.53 ± 4.00 μg−1 were present, corresponding to 35–50% of the dose.

The recommended dose of 3.5 mg kg−1 was not curative for Trypanosoma congolense infections of rabbit but did cause the parasitaemia to become subpatent. A limited prophylactic effect was observed.
Increased 5‐HT2 receptor number in brain as a probable explanation for the enhanced 5‐hydroxytryptamine‐mediated behaviour following repeated electroconvulsive shock administration to rats
Authors: Green A. Richard , Johnson Pauline , Nimgaonkar Vishwajit L.
Published: July 2012

Following electroconvulsive shock (ECS) administration daily for 10 days there was an increase (35%) in 5‐hydroxytryptamine2 (5‐HT2) receptor number in rat frontal cortex 24 h after the last ECS, compared with handled controls. A similar increase was seen after intermittent ECS administration (5 ECS over 10 days) given during halothane anaesthesia, compared with halothane‐treated controls. The dissociation constant was also increased at this time. A single ECS had no effect.

Treatment of rats with pentylenetetrazol, p‐chlorophenylalanine or α‐methyl p‐tyrosine during the intermittent ECS administration abolished the increase in 5‐HT2 receptor binding.

Since enhanced 5‐HT‐mediated behavioural responses are seen after repeated ECS but not when the ECS is given with the drug treatments outlined above, it is suggested that ECS‐induced enhancement of 5‐HT‐mediated behaviour results from an increase in 5‐HT2 receptor number.
The effects of the antibiotic, primycin, on spontaneous transmitter release at the neuromuscular junction
Authors: Henderson F. , Marshall I.G.
Published: July 2012

The effects of primycin, a potent ionophore in biological membranes, have been studied at the neuromuscular junction of the garter snake.

Primycin in concentrations greater than 2 × 10−7m produced a time‐ and concentration‐dependent depolarization of twitch muscle fibres.

Primycin (10−7‐5 × 10−7m) produced an increased rate of quantal release of acetylcholine, which was not maintained, and a slight reduction in quantal size. Time to onset and to peak effect of primycin were concentration‐dependent whereas maximum frequency was not.

Absence of extracellular Ca2+ produced a significant delay in the time to onset and to peak effect of primycin, but did not affect the peak miniature endplate potential (m.e.p.p.) frequency.

Following 60 min exposure to primycin (5 × 10−7m), introduction of a high concentration of potassium (20 mm) produced no further increase in spontaneous release.

In cut muscle preparations, exposure to primycin (10−7‐5 × 10−7m) reduced peak endplate current (e.p.c.) amplitude until nerve stimulation resulted in failures or the release of one or two quanta. E.p.c. amplitude was not restored with prolonged washing.

The effects of primycin on the nerve terminal are considered to be consistent with its ability to increase the permeability of membranes to calcium ions resulting in an influx of extracellular calcium, an efflux of mitochondrial calcium and eventual depletion of synaptic vesicles.
Naloxone reduces diuretic responses induced by water, alcohol or congenital lack of vasopressin in rats
Authors: Guiol Chantai , Montastruc Jean‐Louis , Montastruc Paul
Published: July 2012

The effects of naloxone (2 and 10 mg kg−1 s.c.) were compared in several kinds of experimental polyuria: alcohol‐ or water‐loaded rats and Brattleboro rats (i.e. animals with congenital lack of vasopressin).

In normal rats, both water and alcohol increased urine flow and decreased urinary osmolality. Alcohol induced a more marked diuretic response than water.

In normally hydrated rats, naloxone (2 and 10 mg kg−1 s.c.) failed to modify urine flow, urinary osmolality, Ma+ and K+ urinary excretion, and urine creatinine concentration.

The two doses of naloxone decreased urine flow and increased osmolality in both water‐ and alcohol‐loaded rats.

In Brattleboro rats, naloxone (10 mg kg−1 s.c.) reduced urine flow and urinary creatine whereas the low dose (2 mg kg−1 s.c.) was without effect.

Since it is well known that the mechanism of water‐ or alcohol‐induced diuresis is an inhibition of vasopressin release, the present results suggest that naloxone could prevent this inhibition. They indicate that endogenous opioid peptides may exert an inhibitory control on vasopressin release.
Effects of clonidine and xylazine on body temperature in the rat
Authors: Livingston A. , Low J. , Morris B.
Published: July 2012

Clonidine and xylazine injected intraperitoneally both produced a dose‐dependent hypothermia in unanaesthetized, freely moving rats.

The α2‐antagonist yohimbine produced an antagonism of the xylazine‐induced hypothermia but a potentiation of the clonidine‐induced hypothermia.

The opioid antagonist naloxone had little effect on the xylazine hypothermia, but potentiated the clonidine hypothermia.

It is concluded that whilst the two α2‐agonists produce a similar hypothermic effect in the rat, they are acting by different mechanisms.
Thiopentone‐induced changes in the contraction pattern of vascular smooth muscle: the influence of albumin
Authors: Andreasen Frederik , Christensen Jørgen H.
Published: July 2012

The influence of thiopentone on (a) resting tension, (b) contractions evoked by exogenous noradrenaline (NA) and (c) contractions elicited by electrical field stimulation of rings of rabbit pulmonary artery was studied over a concentration range limited by the solubility of the drug.

At thiopentone concentrations from 3 × 10−5 to 1.4 × 10 −3 m in a protein‐free electrolyte solution (K‐H solution) a gradual increase in resting tension to 232% of the control value was observed. The concentration‐effect curve was displaced to the left in the presence of albumin (45 gl−1) at drug concentrations below 1.6 × 10 −4m. Above that concentration the curve was displaced to the right.

The maximal contractile response to exogenous NA in K‐H was reduced from 4.1 to 1.8 g by 5.6 × 10−4m thiopentone, but the effects of low concentrations of NA were potentiated by thiopentone. The concentration‐effect curve for exogenous NA was displaced to the right by albumin itself.

The contractions evoked by electrical field stimulation in K‐H solution were increased by thiopentone up to 2.4 × 10−4m where a maximum of 141 % of the control value was reached. Above that a gradual decrease was observed, the height of the contractions being reduced by 75% of the control value at 1.4 × 10−3m thiopentone. Thiopentone failed to potentiate electrically‐induced contractions in the presence of albumin K‐H, and the concentration‐effect curve for the inhibitory effect of thiopentone was displaced to the right.

From relationships between observed responses and free and total drug concentrations, a procedure was suggested to determine a biologically relevant expression for the thiopentone binding to albumin. The biologically determined albumin binding was always less than the binding determined by equilibrium dialysis, indicating that the fraction of thiopentone bound to albumin could not necessarily be considered biologically inactive.
Structure‐activity studies of homologues of short chain neurotoxins from Elapid snake venoms
Authors: Harvey A.L. , Hider R.C. , Hodges S.J. , Joubert F.J.
Published: July 2012

Three neurotoxin homologues (CM10 and CM12 from Naja haje annulifera and S5C10 from Dendroaspis jamesoni kaimosae) and two short neurotoxins (CM14 from Naja haje annulifera and erabutoxin b from Laticauda semifasciata)were examined by circular dichroism (c.d.) and tested for neuromuscular activity on chick biventer cervicis nerve‐muscle preparations.

All three homologues had acetylcholine receptor blocking activity, as they abolished responses to indirect stimulation, acetylcholine and carbachol but had no effect on responses to direct muscle stimulation. CM10 was only about 5 times less potent than the short neurotoxin CM14; S5C10 and CM12 were respectively 30 and 300 times less active. The block induced by the three homologues, but not by the neurotoxins, was readily reversed by washing.

CM10 and CM12 had virtually identical cd. spectra which were closely similar to those of the neurotoxins. The spectrum of S5C10 indicated changes in the environment of tyrosine‐25 and in the position of tryptophan‐29. These alterations could distort the 3‐dimensional arrangement of the residues postulated to form the receptor binding site.

The results with CM 10 and CM 12 highlight a role for the first loop (residues 6–16) in the binding of neurotoxins to acetylcholine receptors, in addition to the previously postulated reactive site.
Maintained contractions of rat uterine smooth muscle incubated in a Ca2+‐free solution
Authors: Mironneau C. , Mironneau J. , Savineau J.P.
Published: July 2012

The effects of acetylcholine (10−4m), prostaglandin E2 (10−6m), vanadate (5 × 10−4m) and fluoride (10−2m) have been studied on the mechanical and electrical activities of rat myometrial strips perfused in Ca2+‐free EGTA‐containing solutions.

All four substances produced maintained contractions which could be initiated repeatedly after exposure to Ca2+‐free solution for more than 1 h, without a significant decrease. The largest contractions were obtained with vanadate and the smallest ones with acetylcholine. The tension was usually 7–30% of the control contraction triggered by an action potential in Ca2+ containing solution.

Maintained contractions induced by fluoride were unaffected by isoprenaline while those induced by acetylcholine, prostaglandin E2 and vanadate were completely relaxed.

Prostaglandin E2 ‐and vanadate‐induced contractions were slightly reduced by Na+ removal or by adding Ca2+ antagonists. In contrast, contractions induced by acetylcholine were suppressed in Na+‐free solution and largely inhibited in the presence of Ca2+ antagonists.

The depolarization induced by acetylcholine in Ca2+‐free solution was strongly dependent on the external Na+ concentration. The relationship between the size of the acetylcholine‐induced depolarization and the membrane potential (shifted by constant currents) was linear, giving an apparent reversal potential for acetylcholine close to zero potential.

In Ca‐free solutions and in the presence of atropine, Na+ action potentials of long duration can be evoked which produced contractions of the same order of magnitude as those initiated by acetylcholine‐induced depolarizations.

These results are consistent with the hypothesis that the maintained contractions in Ca2+‐free solutions induced by several stimulants could be related to Ca2+‐independent mechanisms (fluoride) or Ca2+ release from an intracellular store. This latter mechanism would include both pharmacomechanical (prostaglandin E2, vanadate) and electromechanical (acetylcholine) coupling.
Antagonism of fenfluramine‐induced hyperthermia in rats by some, but not all, selective inhibitors of 5‐hydroxytryptamine uptake
Authors: Sugrue M.F.
Published: July 2012

The injection of fenfluramine (7.5 mg kg−1, i.p.) to rats housed at 27–28°C was associated with an elevation of core body temperature which peaked at approximately 1 h post‐injection.

One h pretreatment with Citalopram (20 mg kg−1, i.p.), chlorimipramine (10 mg kg−1, i.p.), femoxetine (10 mg kg−1, i.p.) and fluoxetine (20 mg kg−1, i.p.) resulted in an attenuated response to fenfluramine. In contrast, Org 6582 (20 mg kg−1) and zimelidine (20 mg kg−1) were devoid of an effect on fenfluramine‐induced hyperthermia. The response to fenfluramine was also blocked by i.p. injections of metergoline (0.2 mg kg−1), methysergide (5 mg kg−1) and mianserin (0.5 mg kg−1). Rectal temperature was unaltered by both the 5‐hydroxytryptamine (5‐HT) uptake inhibitors and the 5‐HT receptor antagonists.

The IC50 values (nm) for in vitro inhibition of [3H]‐5‐HT uptake into rat hypothalamic synaptosomes were for Citalopram 2.4, chlorimipramine 8.8, femoxetine 14, fluoxetine 16, Org 6582 75 and zimelidine 250. The injection of all six compounds (20 mg kg−1, i.p.) 1 h before death was associated with an inhibition of [3H]‐5‐HT uptake into rat hypothalamic synaptosomes which ranged from 47.2% for chlorimipramine to 83.3% for Citalopram.

Rat hypothalamic 5‐HT levels were decreased by approximately 50% 3 h after the injection of fenfluramine (15 mg kg−1, i.p.). This effect was blocked by a 1 h pretreatment with fluoxetine, Org 6582 and zimelidine (all 20 mg kg−1, i.p.).

Ki values for displacement of specifically bound [3H]‐5‐HT (1 nm) to rat hypothalamic membranes were for metergoline 26 nm, methysergide 1.1 μm, mianserin 3.6 μm, chlorimipramine 9.2 μm and fluoxetine 32.7 μm. Values for Citalopram, femoxetine, Org 6582 and zimelidine were in excess of 65.4 μm.

Fenfluramine‐induced hyperthermia in rats is blocked by Citalopram, chlorimipramine, femoxetine and fluoxetine but not by Org 6582 and zimelidine. This dichotomy cannot be explained in terms of differences in 5‐HT uptake, storage and release mechanisms in the rat hypothalamus. Moreover, antagonism of fenfluramine‐induced hyperthermia cannot be attributed to blockade of central, postsynaptic 5‐HT receptors. The involvement of an indoleamine other than 5‐HT is discussed.
An increase in sensitivity of rat cingulate cortical neurones to substance P occurs following withdrawal of chronic administration of antidepressant drugs
Authors: Jones Roland S.G. , Olpe Hans‐Rudolf
Published: July 2012

The sensitivity of neurones in the cingulate cortex of the rat to iontophoretically applied substance P (SP) was tested one hour after a single dose of various antidepressant drugs and also 1 day following the termination of a chronic dosing schedule (14 once daily injections) of the same agents.

One hour after a single injection of desipramine (DMI), chlorimipramine (CMI), trimipramine (TMI) or zimelidine (ZIM) (all at 10 mg kg−1 i.p.) there was no change in the mean size of excitatory responses to SP compared to those before the injection. There was a tendency towards a decrease in the TMI group.

One day following the last of 14 consecutive daily injections (10 mg kg−1 i.p.) of the above agents there was a significant increase in the size of excitatory responses to SP compared to those in rats receiving daily saline injections. However, 14 days of treatment with DMI did not alter the responses to l‐glutamate.

Similar chronic dosing schedules with either diazepam (5 mg kg−1) or fluphenazine (5 mg kg−1) did not affect the responses to SP.

Thus chronic but not acute administration of antidepressant drugs results in an increase in the sensitivity of neurones, in the cingulate cortex of the rat, to SP.
Pharmacological actions of some cyclic analogues of choline
Authors: Hemsworth B.A. , Shreeve S.M. , Veitch G.B.A.
Published: July 2012

Two cyclic choline analogues (3‐hydroxy‐N,N‐dimethylpiperidinium and 2‐hydroxymethyl‐N,N‐dimethylpiperidinium) and two cyclic homocholine analogues (4‐hydroxy‐N,N‐dimethylpiperidinium and 3‐hydroxymethyl‐N,N‐dimethylpiperidinium) have been studied with regard to their actions at the cholinergic synapse.

All the analogues had some direct depolarizing activity on the frog rectus abdominis muscle but they were less potent in this respect than acetylcholine. Compared to physostigmine, the analogues were weak inhibitors of Cholinesterase enzymes.

All the analogues were found to have a presynaptic blocking action on the rat phrenic nerve‐hemidiaphragm preparation, which was reversed by choline. In addition, they all inhibited the high affinity transport of choline into synaptosomes but only the cyclic choline analogues were found to be acetylated by soluble choline acetyltransferase in vitro.

We conclude that the hydroxypiperidinium analogues caused the presynaptic block seen at the neuromuscular junction by inhibiting acetylcholine synthesis.
Genetic heterogeneity of histamine H2‐receptors in the mouse vas deferens
Authors: Calvete J. A. , Donegan J.L.M. , Hayes R.J. , Oates N.S. , Sloan T.P.
Published: July 2012

The ability of histamine to inhibit the overall contractile (‘twitch’) response of the isolated vas deferens of the mouse to electrical field stimulation (64 V pulse, 1 ms pulse width, frequency 0.2 Hz) was studied in nine inbred mouse strains. The strains were also characterized in terms of the potency of the histamine H2‐receptor antagonist cimetidine in its inhibition of histamine‐mediated effects. An apparently bimodal inter‐strain variation (8−10 fold) in both characteristics was encountered, with three strains (SWR, A2G and C57BL/10ScSn) relatively sensitive (S) to both agonist and antagonist actions, and six (C3H, A, C57/BL6, DBA/2, Balb/C and 129/Sv) relatively insensitive (IS).

These strain differences were independent of extracellular calcium concentration in the range 1.25−5 mm, and also independent of the frequency of tissue stimulation over the range 0.2−6.4 Hz.

Representative S (SWR and A2G) and IS (DBA/2 and C3H) mouse vasa were also characterized in terms of their sensitivity to the agonist actions of dimaprit and the antagonist actions of tiotidine. In the S strain tissues, dimaprit produced 50% inhibition of the twitch response at 4.6−1.8 μm (mean ± s.d.) and was able to elicit complete inhibition of the twitch response at concentrations greater than 100 μm, whereas 48.7 ± 11.9 μm dimaprit was required to produce 50% inhibition of the twitch response in tissues from IS mice. In addition, the agonist actions of dimaprit were incomplete in the latter tissues, the drug eliciting no more than 75% inhibition of the twitch response at concentrations in the range 300−1000 μm. Tiotidine produced competitive antagonism of the actions of both histamine and dimaprit, the strain differences being of the same magnitude as those observed for cimetidine.

Mating of a representative S (SWR) and IS (129/Sv) strain produced F1 mice with intermediate histamine and cimetidine sensitivities relative to the parental strains. A backcross of male F1 to female IS mice produced progeny displaying a range of histamine and cimetidine sensitivities representative of those seen in tissues from F1 and IS parental animals, however, the data were not bimodal. Thus, the backcross data provided no evidence to support single gene inheritance of histamine sensitivity and might suggest that more than one gene is responsible for these differences between S and IS mice.
Release of endogenous dopamine from rat isolated striatum: effect of clorgyline and (−)−deprenyl
Authors: Hársing L.G. , Vizi E.S.
Published: July 2012

High performance liquid chromatography with electrochemical detection was used to measure the release and content of dopamine and dihydroxyphenylacetic acid (DOPAC) from rat isolated striatum. The effects of the monoamine oxidase (MAO) inhibitors clorgyline and (−)−deprenyl on dopamine and DOPAC release and contents, and the IC50 values of these compounds for inhibition of dopamine deamination in rat striatum were determined.

Dopamine release was significantly increased by elevated KCl (22 mm) in a Ca2+‐dependent manner, and by ouabain (20 μm), whereas the release of DOPAC remained constant. The loss in striatal dopamine content during the incubation period (67% of initial content) was far greater than the amount of dopamine recovered in the incubation fluid (16% of initial content), suggesting that much of the DOPAC, released during incubation originated from the conversion of dopamine to DOPAC within the striatum.

A concentration‐dependent decrease in DOPAC efflux, both during rest and stimulation periods, was observed in the presence of clorgyline (10−8m‐10−7m) and (−)−deprenyl (10−5m‐10−4m).

Higher concentrations of clorgyline (10−7m) and (−)−deprenyl (10−4m), which inhibited dopamine deamination by 85–90%, enhanced both the resting and KCl‐induced release of dopamine.

The total amount of dopamine plus DOPAC that was released in the presence of clorgyline or (−)−deprenyl did not differ from control values, suggesting that the increase in dopamine release elicited by MAO inhibitors might result from reduced degradation of dopamine to DOPAC.

The IC50 values of clorgyline (5 × 10−9m) and (−)−deprenyl (5 × 10−6m) for inhibition of dopamine deamination indicate that dopamine is a substrate for type A MAO in rat striatum.
Comparison of the biphasic excitatory junction potential with membrane responses to adenosine triphosphate and noradrenaline in the rat anococcygeus muscle
Authors: Byrne N.G. , Large W. A.
Published: July 2012

The effects of field stimulation and ionophoretic application of adenosine triphosphate (ATP) and noradrenaline were studied in the rat anococcygeus by means of an intracellular micro‐electrode.

Field stimulation at room temperature produced three types of electrical membrane response: (a) a ‘fast’ excitatory junction potential (e.j.p.) which had a latency of less than 100 ms and a time to peak of 300 ms; (b) a ‘slow’ e.j.p. which had a latency of several hundred ms and a time to peak of 1–2 s, and (c) an inhibitory junction potential (i.j.p.) which had a time to peak of about 1.5 s. All three responses were blocked by tetrodotoxin.

The ionophoretic application of ATP produced both monophasic and biphasic depolarizations; these responses had a latency of less than 30 ms and a time to peak of 150–300 ms. In contrast, ionophoretically‐applied noradrenaline produced a depolarization which had a mean latency of 471 ms and a time to peak of 861 ms.

The ‘slow’ e.j.p. and the noradrenaline‐induced depolarization were blocked by prazosin whereas the ‘fast’ e.j.p. and the ATP responses were resistant to this antagonist and also to atropine.

These results are further evidence that the ‘fast’ e.j.p. in some smooth muscle tissues is mediated by ATP.
Reduction by phentolamine of the hypotensive effect of methionine enkephalin in anaesthetized rabbits
Authors: Eulie P.J. , Rhee H.M.
Published: July 2012

In intact rabbits anaesthetized with pentobarbitone, methionine enkephalin (Met enkephalin, 1−1,000 μg kg−1 i.v.) produced a dose‐dependent bradycardia and hypotension.

The bradycardia and hypotension were antagonized by naloxone hydrochloride (1 mg kg−1), but not by naloxone methobromide (1.3 mg kg−1).

Phentolamine (1 and 4 mg kg−1 i.v.) blocked both the hypotension and bradycardia produced by Met enkephalin.

The inhibitory effect of phentolamine was not due to a simple hypotensive action of this drug per se because a similar degree of hypotension induced by nitroprusside (15 μg kg−1, i.v.) caused a further reduction of pressure when Met enkephalin was added.

Atropine (2 mg kg−1) reduced the bradycardia but not the hypotensive response to Met enkephalin.

Met enkephalin did not antagonize the vasopressor effect of exogenous noradrenaline (2–8 μg kg−1, i.v.).

Met enkephalin had no significant effects in superfused thoracic aortic strips and in isolated perfused hearts of rabbits.

It is concluded that the cardiovascular effects of Met enkephalin are more probably due to an action on the central nervous system, although a peripheral site of action cannot be completely excluded.
A comparison of analgesia and suppression of oxytocin release by opiates
Authors: Clarke G. , Wright D.M.
Published: July 2012

The potency of opiates for suppressing oxytocin release relative to their potency as analgesics was tested in lactating rats.

Oxytoxin release was evoked by the sucking of the young in urethane‐anaesthetized and unanaesthetized rats, and was detected by the characteristic behaviour of the young and milk yield respectively.

The tail‐flick test, using noxious radiant heat, was used to assess analgesia.

Intraperitoneal injection of morphine (1 mg kg−1 and 5 mg kg−1) significantly reduced milk yield in unanaesthetized rats.

Urethane‐anaesthetized rats displayed a pattern of reflex milk‐ejection responses similar to that found in conscious rats. This reflex was significantly inhibited in a dose‐related, naloxone‐reversible manner by buprenorphine (ED50 0.18 mg kg−1), meptazinol (ED50: 14.0 mg kg−1), morphine (ED50: 0.67 mg kg−1), pentazocine (ED50: 15.0 mg kg−1) and pethidine (ED50: 7.9 mg kg−1).

Although intraperitoneal injection of morphine (5 mg kg−1) abolished the increase in intramammary pressure occurring at reflex milk‐ejection, that evoked by intravenous oxytocin (0.5−1 mu) was unaffected.

Each opiate also caused significant, dose‐related, naloxone‐reversible increases in tail‐flick latency. The ED50 doses were buprenorphine (ED50: 0.14 mg kg−1), meptazinol (ED50: 12.5 mg kg−1), morphine (ED50: 5.0 mg kg−1), pentazocine (ED50: 12.5 mg kg−1) and pethidine (ED50: 6.1 mg kg−1).

The order of potency for analgesia and for suppression of oxytocin release were identical, namely: buprenorphine > morphine > pethidine > meptazinol > pentazocine.

The results obtained with lactating rats suggest that secretion of the hormone oxytocin is substantially reduced during opiate‐induced analgesia.
Efflux of 86Rb from rat and mouse pancreatic islets: the role of membrane depolarization
Authors: Matthews E.K. , Shotton P.A.
Published: July 2012

The efflux of 86Rb from rat or mouse perifused islets preloaded with the isotope has been used as an index of the potassium permeability of the islet β‐cell membrane. Cellular transmembrane potentials were altered by changing [K]o or by direct electrical stimulation and the effects on potassium permeability examined.

Omission of KCl from the medium perif using rat islets induced a biphasic change in 86Rb efflux, a brief decline being superseded by a pronounced increase in efflux. Re‐introduction of KCl, 4.7 mm, caused a further increase in 86Rb efflux preceding a return to control values.

Increasing [K]o from 4.7 mm to 10 mm, 20 mm or 47 mm caused a phasic increase in 86Rb efflux with the magnitude of both the peak and average rate of efflux being dependent upon the extent of the change in [K]o.

The increase in 86Rb efflux produced by [K]o, 47 mm, was attenuated by Co2+, 2.56 mm (51% inhibition) or quinine, 10 μm (47% inhibition), but efflux remained significantly (P<0.001) above control values.

Electrical stimulation of single microdissected mouse pancreatic islets by currents of 0.1 to 0.5 mA evoked a rapid, phasic increase in 86Rb efflux. The magnitude of the response was unaffected by EGTA, 2 mm, or nupercaine, 100 μm.

These observations are discussed in relation to the mechanisms controlling the potassium permeability, membrane potential and insulin secretion of the pancreatic islet β‐cell. It is concluded that β‐cell depolarization by a raised [K]o increases potassium permeability and efflux by at least two mechanisms: (i) a calcium‐dependent potassium efflux triggered by an increase in [Ca]i and (ii) an activation of voltage‐sensitive potassium channels which occurs even when the calcium‐dependent potassium permeability is blocked.
Differential effects of D600, nifedipine and dantrolene sodium on excitation‐secretion coupling and presynaptic β‐adrenoceptor responses in rat atria
Authors: Callanan K.M. , Keenan A.K.
Published: July 2012

The stimulation‐evoked release of tritium was measured from rat atria labelled with [3H]‐noradrenaline. The calcium dependence of evoked release and the facilitation of this release via activation of presynaptic β‐adrenoceptors were examined using D600 (methoxyverapamil), nifedipine and dantrolene sodium.

Both D600 and nifedipine at dose levels of 20 and 100 μm inhibited evoked release. Dantrolene (20, 100 μm) reduced release by 25%, the effect being maximal at 20 μLm.

In the presence of 20 nm isoprenaline, a facilitation of evoked release occurred, which was blocked by 0.1 μm (—)‐propranolol.

The facilitatory action of isoprenaline was abolished by omission of calcium from the buffer, or by D600 or nifedipine, (100 μm). In contrast, the response to isoprenaline was not modified by dantrolene (20, 100 μm).

It is concluded that (a) the evoked release of noradrenaline (NA) utilizes Ca from both intra‐ and extracellular sources and that (b) isoprenaline increases NA secretion by promoting the depolarization‐induced influx of Ca.
Hydrodynamic properties of muscarinic acetylcholine receptors solubilized from rat forebrain
Authors: Berrie Christopher P. , Birdsall Nigel J.M. , Haga Kazuko , Haga Tatsuya , Hulme Edward C.
Published: July 2012

Muscarinic receptors from rat forebrain have been solubilized by Lubrol PX, lysophosphatidyl‐choline (LPC), digitonin and cholate/1 M sodium chloride. The overall level of solubilization was characterized using receptors prelabelled with an irreversible antagonist. The recovery of non‐denatured soluble binding activity was estimated using reversible tritiated antagonists.

All these detergents solubilized 60–85% of the total binding sites. In Lubrol PX most of the receptors were recovered in a denatured form. In the other detergents 30–90% of the solubilized receptors were stable and capable of binding reversible [3H]‐antagonists with high affinity.

The hydrodynamic properties of the soluble receptors have been examined by gel filtration and sucrose gradient centrifugation in H2O and D2O.

The soluble receptors in Lubrol PX, lysophosphatidylcholine and cholate were, in general, heterogeneous as regards their molecular size. Estimates of the molecular weight after correction for bound detergent, varied from 82,000 to 134, 000. Conditions were identified under which the receptor was largely monodisperse, and the estimates of molecular weight agreed with values (ca. 83, 000) from sodium dodecylsulphate (SDS) Polyacrylamide gel electrophoresis. The amount of bound detergent could not be calculated for the digitonin‐muscarinic receptor complex which had an estimated overall median molecular weight of about 290,000.

It is concluded that a subpopulation of muscarinic receptors from the rat forebrain is capable of existing in a monomelic soluble form and binding ligands. There is also evidence that complexes with other proteins can exist, but their specificity and functional relevance are not known.
Effects of p‐chlorophenylalanine on the sensitivity of rat intestine to agonists and on intestinal 5‐hydroxytryptamine levels during Nippostrongylus brasiliensis infection
Authors: Farmer Stephen G. , Laniyonu Adebayo A.
Published: July 2012

Infection of rats with the nematode N. brasiliensis caused non‐specific increases in maximum response of isolated intestine to acetylcholine and 5‐hydroxytryptamine (5‐HT), and a specific subsensitivity to 5‐HT.

Intestinal levels of 5‐HT, measured fluorimetrically, increased approximately 2 fold during infection.

Treatment of infected rats with parachlorophenylalanine (PCPA) depleted the gut of 5‐HT, and prevented the specific subsensitivity to the amine but not the increases in maximum response.

Depletion of intestinal 5‐HT did not prevent the immune expulsion of the parasites.

It is concluded that the specific subsensitivity of the gut is due to the elevated levels of 5‐HT during infection, but that the increased maximum responses are due to some other factor. Further, the lack of effect of PCPA on parasite rejection casts doubt on the proposed role of 5‐HT in this process.
Location of [125I]‐angiotensin II receptors on rat kidney cortex epithelial cells
Authors: Cox Helen M. , Munday Kenneth A. , Poat Judith A.
Published: July 2012

Angiotensin II (AII) stimulates active Na+ extrusion from Na+ loaded renal cortex slices.

Specific high affinity [125I]‐AII binding sites in partially purified basolateral and brush‐border epithelial membranes exhibit a KD of 0.88 nM and Bmax of 321.13 fmol mg−1 protein.

Separation and purification of brush‐border membranes yielded high affinity [125I]‐AII binding sites with KD of 1.02 nM and Bmax of 56.6 fmol mg−1 protein.

Angiotensin II receptors of the same affinity are present on renal cortex brush‐border and basolateral membranes but a greater proportion are located on the latter. These receptors may be involved in the direct control of Na+ and water transport by AII.
Effect of pertussis toxin on normorphine‐dependence and on acute inhibitory effects of normorphine and clonidine in guinea‐pig isolated ileum
Authors: Tucker J.F.
Published: July 2012

In guinea‐pig isolated ileum from animals pretreated with Pertussis toxin, the acute inhibitory effects of normorphine and clonidine on electrically induced contractions were markedly attenuated whilst responses to acetylcholine and electrical stimulation were unaltered. Pertussis toxin treatment also reduced naloxone‐precipitated withdrawal contractures in normorphine‐dependent tissues. These results suggest that the acute and chronic effects of normorphine are mediated by the same mechanism, namely that of adenylate cyclase inhibition.
Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat
Authors: Curtis M.J. , MacLeod B.A. , Walker M.J.A.
Published: July 2012

The actions of intravenous verapamil against arrhythmias induced by occlusion of a coronary artery were investigated in conscious rats.

Verapamil (2–20 mg kg−1, i.v. given pre‐occlusion) dose‐dependently reduced arrhythmias in rats with either large or small occluded zones at an ED50 of 6 mg kg−1. This dose was effective when given immediately post‐occlusion.

Severe arrhythmias, as opposed to PVC, were preferentially reduced.

In conscious, and pentobarbitone‐anaesthetized rats, verapamil (6 mg kg−1) had different effects on electrically‐induced arrhythmias, and the ECG, from an equi‐effective anti‐arrhythmic dose of quinidine (20 mg kg−1, i.v.). Quinidine decreased following frequency, but increased threshold current and pulse width, whereas verapamil did not. Both drugs increased P‐R interval, but only quinidine increased QRS and Q‐T intervals.

Thirty minutes post‐occlusion, the verapamil content of tissue and blood was determined after a 6 mg kg−1 dose given pre‐ or post‐occlusion. Measurable levels of verapamil were found in both normal and ischaemic myocardium. Plasma and plasma water concentrations were 3.6 ± 0.8 μmol l−1 and 0.6 ± 0.1 μmol l−1 (x̄ ± s.e.mean), respectively following post‐occlusion administration vs. 2.7 ± 1.2 and 0.24 ± 0.04 for pre‐occlusion administration.

Plasma water concentrations were close to IC50 values for inhibition of contractility in rat atria and ventricles. Similar concentrations depressed slow action potentials induced in rat ventricles by raised K+

We suggest that the ability of verapamil to prevent severe ventricular arrhythmias following myocardial ischaemia in the conscious rat is largely due to the calcium antagonist effects of the drug.
Aliphatic alcohols increase the decay rate of glutamate‐activated currents at the crayfish neuromuscular junction
Authors: Wachtel Ruth E.
Published: July 2012

Excitatory junction currents produced by glutamate were recorded with an extracellular electrode at the excitatory neuromuscular junction of the crayfish.

The currents decayed more quickly as the membrane was hyperpolarized. The direction of the voltage sensitivity of the decay phase is thus opposite to that found for acetylcholine‐activated currents at the amphibian endplate.

The aliphatic alcohols ethanol to octanol all increased the rate of decay of the currents. The effects of the short chain alcohols were opposite to their actions at the toad endplate, where ethanol to pentanol prolong the currents. This observation was explained in terms of the opposite direction of the voltage sensitivity in the two preparations.

For each alcohol, the relationship between the half‐decay time of the currents (t1/2) and alcohol concentration was exponential.

The potency of each alcohol in decreasing t1/2 was exponentially related to carbon chain length, which would be predicted if the effects of the alcohols were directly related to their concentration in the lipid phase of the membrane.

These findings are consistent with the ideas that the alcohols may alter membrane polarizability or change membrane fluidity in the vicinity of the channels.
Further evidence for the existence of two receptor sites for bradykinin responsible for the diphasic effect in the rat isolated duodenum
Authors: Boschcov Paulo , Paiva Antonio C.M. , Paiva Therezinha B. , Shimuta Suma I.
Published: July 2012

Low doses of bradykinin (below 10 nM), as well as of K+ (below 10 mM) induced relaxation, whereas higher doses caused contraction of the rat duodenum.

The relaxant responses induced by bradykinin and K+ were not affected by ouabain (1 μM), but pre‐incubation with 5.9 mM K+ abolished the responses to that ion but not those to bradykinin.

The contractile and relaxant components of the response to bradykinin (but not those to K+) increased with the time elapsed after mounting of the preparation, and this was due to stretching by the load of the recording system.

Specific and reversible desensitization (tachyphylaxis) was observed with the contractile response (but not the relaxation) induced by bradykinin.

Des‐Arg9‐bradykinin, an analogue specific for B1‐receptors, was much less active than bradykinin, and elicited only a contractile response.

Among four bradykinin potentiating peptides that were tested, potentiator C enhanced the relaxation only, whereas BPP5a and captopril potentiated only the contraction and BPP9a potentiated both types of response to bradykinin.

Our results support the hypothesis that the relaxant and contractile components of the rat duodenum's response to bradykinin are due to actions at different receptor sites, which can be distinguished by their properties (desensitization) and their different apparent affinities for agonists and for potentiating peptides.
The effects of ablations in the central nervous system on arrhythmias induced by coronary occlusion in the rat
Authors: Curtis M.J. , Macleod B.A. , Walker M.J.A.
Published: July 2012

The role of the central nervous system (CNS) in arrhythmogenesis in the 4 h period following occlusion of a coronary artery was investigated in rats by use of CNS ablations and other procedures.

Ablations in the CNS included pithing, spinalization and decerebration combined with acute and chronic surgical preparation and noradrenaline/adrenaline infusions.

All procedures involving acute surgery reduced the incidence and severity of the arrhythmias induced by occlusion. Such reductions were most marked in the second (0.5‐4 h post‐occlusion) arrhythmic period.

The observed reductions in arrhythmias could not be explained in terms of involvement of the CNS or adrenoceptor activation.

When circulating leucocytes, platelets and serum potassium were measured in a group of pithed rats before and after occlusion, reduced levels (20–50%) of both leucocytes and platelets occurred while serum potassium levels rose by 50–100%.

Arrhythmias following coronary occlusion may depend in part on factors in the blood such as leucocytes, platelets and serum potassium and these factors may be altered by acute surgery.