bluuebunny/crossref_metadata_2025 huggingface dataset:
MYOCARDIAL UPTAKE OF DIGOXIN IN CHRONICALLY DIGITALIZED DOGS
Authors: STEINESS EVA , VALENTIN N.
Published: July 2012

The time course of myocardial uptake of digoxin, increase in contractility and changes in myocardial potassium concentration was studied for 90 min following an intravenous digoxin dose to long‐term digitalized dogs.

Nineteen dogs were investigated by the use of a biopsy technique which allowed sampling before and after administration of digoxin.

Ten minutes after administration of digoxin the myocardial concentration increased from 60 to 306 nmol/kg tissue; the myocardial concentration of digoxin was significantly lower (250 nmol/kg tissue) after 30 min and then increased again.

The transmural myocardial distribution of digoxin was uniform before and 90 min after administration of digoxin in long‐term digitalized dogs but at 10 min after administration, both the subepicardial and the subendocardial concentration of digoxin were significantly lower than that of the mesocardial layer.

During the first 10 min the dp/dtmax increased to 135% of the control level. The increase remained unchanged during the rest of the study.

Myocardial potassium decreased throughout the study.

The M‐configuration of the myocardial uptake curve and the non‐uniformity of myocardial distribution of digoxin observed at 10 min after administrating digoxin to long‐term digitalized dogs indicate that the distribution of myocardial blood flow may be changed during chronic digitalization.
ANTAGONISM BY SOME ANTIHISTAMINES OF THE AMINO ACID‐EVOKED RESPONSES RECORDED FROM THE LOBSTER MUSCLE FIBRE AND THE FROG SPINAL CORD
Authors: CONSTANTI A. , NISTRI A.
Published: July 2012

The effects of some antihistamines on the lobster muscle fibre and the frog spinal cord were investigated using intracellular and extracellular recordings, respectively.

On lobster muscle, histamine H1‐blockers reversibly antagonized responses to bath‐applied glutamate, aspartate and quisqualate but not responses to γ‐aminobutyric acid (GABA). Iontophoretic glutamate potentials were also reduced. Histamine (up to 1 mm) had no effect on this preparation.

The H1‐antagonists produced a small increase in muscle membrane conductance and a slight hyperpolarization. These effects were largely unchanged in a low Cl− bathing solution. Procaine (1 mm) decreased membrane conductance and did not affect responses to GABA or glutamate.

The H2‐antagonist burimamide blocked both glutamate and GABA‐evoked responses on the lobster muscle without affecting resting potential or conductance.

In the frog cord, bath‐applied histamine produced ventral root depolarizations and dorsal root hyperpolarizations (sometimes biphasic responses). These effects were reduced by tetrodotoxin (TTX) but not by antazoline (H1‐blocker) or burimamide; the latter reversibly antagonized responses to both glutamate and GABA on TTX‐treated cords while antazoline was ineffective.

It is suggested that antihistamines can act as non‐specific amino acid antagonists by interacting at the level of the receptor‐coupled ionophores.
OESTROGENIC, ANTI‐OESTROGENIC AND FERTILITY EFFECTS OF SOME TRIPHENYLETHANES AND TRIPHENYLETHYLENES RELATED TO ETHAMOXYTRIPHETOL (MER 25)
Authors: CLARK E.R. , JORDAN V.C.
Published: July 2012

Five triphenylethylenes, a triphenylethane and a triphenylethanol, carrying methyl substituents ortho to one or both of the ring oxygen functions, have been examined for oestrogenic, and anti‐oestrogenic activity in mice, and three of the compounds, α‐[4‐(β‐diethylaminoethoxy)‐3, 5‐xylyl]‐α‐phenyl‐β‐4‐methoxyphenyl‐ethanol (IV), α′‐[4‐(β‐diethylaminoethoxy)‐3, 5‐xylyl]‐4‐methoxy‐bibenzyl (V) and α′‐[4‐(β‐diethylaminoethoxy)‐3, 5‐xylyl]‐4‐methoxy‐stilbene (VI), were tested for their effects on fertility in mice.

Orthomethylation reduces oestrogenic and/or anti‐oestrogenic activity compared with the reported activities of non‐methylated analogues.

The anti‐oestrogenic ethamoxytriphetol (MER 25) reduced fertility in mice whereas its inactive dimethylated analogue (IV) was ineffective. The weakly active anti‐oestrogens, V and VI, did not affect fertility in mice.
STEREOSPECIFIC ACTIONS OF 2,5‐DIMETHOXY‐4‐METHYLAMPHETAMINE (DOM) ON COLONIC TEMPERATURE IN THE RAT AT VARIOUS AMBIENT TEMPERATURES
Authors: BEATON J.M. , BENINGTON F. , BRADLEY R.J. , KUHLEMEIER K.V. , MORIN R.D.
Published: July 2012

The R(—) and S(+)‐isomers of 2,5‐dimethoxy‐4‐methylamphetamine (DOM) produce a dose‐dependent hypothermia in rats kept in the cold (6°C).

This hypothermia was linearly dependent upon ambient temperature and the R(—)‐isomer was considerably more potent than the S(+)‐isomer.

A statistically significant tachyphylaxis was observed when R(—)‐DOM was administered on two successive days. The response seven days after the second injection was similar to that on the first day of injection.

The hypothermia induced by R(—) and S(+)‐DOM was antagonized by methysergide but not by p‐chlorophenylalanine (PCPA) or pimozide. Methysergide, PCPA or pimozide alone did not elicit hypothermia at the doses used. The results indicate that R(—) and S(+)‐DOM act at post‐synaptic 5‐hydroxytryptamine receptors.
PREVENTION BY ZINC OF CADMIUM‐INDUCED ALTERATIONS IN PANCREATIC AND HEPATIC FUNCTIONS
Authors: MERALI Z. , SINGHAL R.L.
Published: July 2012

Subacute cadmium treatment (CdCl2, 1 mg/kg twice daily for 7 days) in rats disturbs glucose homeostasis as shown by hyperglycemia and decreased glucose tolerance associated with suppression of insulin release, enhancement of hepatic gluconeogenic enzymes and decrease in hepatic glycogen content.

Exposure to cadmium increases hepatic cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) and this is accompanied by stimulation of basal, adrenaline‐as well as glucagon‐stimulated form(s) of adenylate cyclase.

In contrast to cadmium, subacute administration of zinc (ZnCl2, 2 mg/kg twice daily for 7 days) fails to alter the activities of hepatic gluconeogenic enzymes, cyclic AMP synthesis, as well as glucose clearance and insulin release in response to a glucose load.

Zinc, when administered at the same time as cadmium, prevents the cadmium‐induced lesions in both hepatic and pancreatic functions.

The results are discussed in relation to the possible mechanisms of cadmium toxicity and to the role of sulphydryl groups in the protection exercised by zinc.
NORADRENALINE MODULATION OF THE RESPONSES OF THE CEREBELLAR PURKINJE CELL TO AFFERENT SYNAPTIC ACTIVITY
Authors: FREEDMAN R. , HOFFER B.J. , PURO D. , WOODWARD D.J.
Published: July 2012

Noradrenaline, applied by microiontophoresis to rat cerebellar Purkinje neurones, selectively depressed spontaneous neuronal discharge. Simple spike and complex spike excitations, evoked by stimulation of the mossy and climbing fibres, were relatively preserved during the inhibition of spontaneous activity, and the number of full‐sized action potentials in the complex spike increased. Inhibition mediated by the basket and stellate cells was augmented. Thus, relative to the change in spontaneous activity, noradrenaline increased the responsiveness of the Purkinje cell to afferent input.
RECEPTORS FOR 5‐HYDROXYTRYPTAMINE AND NORADRENALINE IN RABBIT ISOLATED EAR ARTERY AND AORTA
Authors: APPERLEY EIRA , HUMPHREY P.P.A. , LEVY G.P.
Published: July 2012

5‐Hydroxytryptamine (5‐HT) is thought to be implicated in the vascular disturbances of the external carotid artery bed associated with migraine. As part of a study of the pharmacology of some 5‐HT antagonists used in the treatment of migraine we have examined the interactions of these drugs with 5‐HT and noradrenaline in rabbit isolated ear artery and aortic strip. The results provide new information on the distribution of 5‐HT‐receptors and α‐receptors in these preparations.

In the aorta, 5‐HT and noradrenaline were of similar potency in producing contractions. Methysergide produced very small contractions and was about 1000 times less potent than the other two agonists.

In the ear artery noradrenaline produced monophasic vasoconstrictor responses, whereas 5‐HT and methysergide produced prolonged biphasic responses. 5‐HT was about 700 times less potent and methysergide about 4500 times less potent than noradrenaline. Methysergide was a better agonist in the ear artery than in the aorta. Biphasic responses to 5‐HT and methysergide were also obtained in ear arteries from reserpine‐treated rabbits indicating that neither agonist was acting by releasing endogenous noradrenaline.

Pizotifen, cyproheptadine and phentolamine had no agonistic actions in either the aorta or ear artery.

In the aorta methysergide, pizotifen and cyproheptadine were potent antagonists of 5‐HT and much weaker antagonists of noradrenaline. Phentolamine possessed the opposite profile of selectivity. These results show that there are distinct receptors for 5‐HT and noradrenaline in rabbit aorta.

In the ear artery the pA2 values for each of the four antagonists were virtually identical against 5‐HT and noradrenaline and similar to those obtained on α‐adrenoceptors in the aorta. We conclude that 5‐HT and noradrenaline act directly at α‐receptors to produce vasoconstriction in the ear artery and that this preparation does not contain specific 5‐HT‐receptors.

This insight into the distribution of 5‐HT‐receptors and α‐receptors allows interpretation of the various actions of methysergide. In the aorta, methysergide was a potent antagonist at 5‐HT‐receptors and a weak partial agonist at α‐receptors. In the ear artery, methysergide was a partial agonist at α‐receptors; it was only a weak antagonist of 5‐HT because this preparation does not contain specific 5‐HT‐receptors.

The cross‐reactivity demonstrated throughout these experiments indicates that 5‐HT‐receptors and α‐receptors, although distinct entities, have features in common.

These results are discussed in relation to the mode of action of methysergide, pizotifen and cyproheptadine in the treatment of migraine.
ATROPINE RESISTANCE AND MUSCARINIC RECEPTORS IN THE RAT URINARY BLADDER
Authors: CARPENTER F.G.
Published: July 2012

The action of an anticholinesterase and an antimuscarinic drug upon nerve‐induced contractions of the rat urinary bladder were examined during transmural stimulation at 20 Hz. Responses were graded in magnitude by limiting the duration of the stimulus trains.

Responses of low magnitude produced by short stimulus trains were unchanged by atropine; however, maximal responses resulting from long stimulus trains were diminished in magnitude and shortened in duration.

Responses of small magnitude elicited by short stimulus trains involve muscarinic receptors in close proximity to the neuroeffector junction and are resistant to atropine.

Maximal responses elicited by long stimulus trains involve ‘junctional’ muscarinic receptors as well as receptors located at the periphery of the junction; the ‘extrajunctional’ receptors are blocked by atropine.

Responses of low magnitude produced by short stimulus trains were unaffected by echothiophate; however, the duration of maximal responses resulting from the long stimulus trains was extended.

The inhibition of cholinesterase did not increase the occupation of muscarinic receptors by the transmitter; however, after large quantities of transmitter were released by the long stimulus trains the association between the receptors and acetylcholine was prolonged.
INTERACTIONS BETWEEN THE EFFECTS OF α‐ AND β‐ADRENOCEPTOR AGONISTS AND ADENINE NUCLEOTIDES ON THE MEMBRANE POTENTIAL OF CELLS IN GUINEA‐PIG LIVER SLICES
Authors: JENKINSON D.H. , KOLLER KARIN
Published: July 2012

The β‐adrenoceptor agonist isoprenaline normally causes only a small and inconsistent increase in the membrane potential of cells in guinea‐pig liver slices, in contrast to the large hyperpolarizations seen with α‐agonists. However, after a selective α‐adrenoceptor agonist has been applied, the response to isoprenaline becomes greatly enhanced.

Simultaneous application of small doses of an α‐ and a β‐agonist produce hyperpolarizations larger than the sum of the responses to each agent alone.

These interactions occur with a range of sympathomimetic amines, including some which are not substrates for various processes for the uptake and inactivation of catecholamines.

Hyperpolarizations caused by externally applied cyclic adenosine‐3′,5′‐monophosphate (cyclic AMP) also become larger after application of an α‐agonist.

The adenine nucleotides adenosine 5′‐diphosphate (ADP) and adenosine 5′‐triphosphate (ATP) hyperpolarize guinea‐pig liver cells in the dose range 0.1‐1.0 mm. This response is not increased after an α‐agonist. However, ADP and ATP are themselves able to enhance the response to β‐agonists.

These interactions between α‐agonists, β‐agonists and adenine nucleotides seem to involve steps subsequent to receptor activation. Changes in the intracellular actions of cyclic AMP may be concerned.
PRODUCTION OF PROSTAGLANDINS BY THE PSEUDOPREGNANT RAT UTERUS, in vitro, AND THE EFFECT OF TAMOXIFEN WITH THE IDENTIFICATION OF 6‐KETO‐PROSTAGLANDIN F1α AS A MAJOR PRODUCT
Authors: FENWICK LINDA , JONES R.L. , NAYLOR B. , POYSER N.L. , WILSON N.H.
Published: July 2012

Prostaglandin production by rat uterus homogenates has been studied, in vitro, on days 2 to 13 of pseudopregnancy.

The highest production of prostaglandins occurred on day 5.

The amounts of prostaglandins F and D formed were higher than the amounts of prostaglandin E on every day studied.

The ratios of prostaglandins F and D to prostaglandin E produced steadily decreased up to day 6. It then increased with the highest values occurring between days 10 and 13.

Progesterone levels in peripheral plasma increased rapidly from days 2 to 5, remained high up to day 9, then steadily decreased between days 10 and 13.

The anti‐oestrogenic drug, tamoxifen administered on day 2, significantly inhibited the increase of prostaglandin production which occurred on day 5. Prostaglandin E production was inhibited more than the production of prostaglandins F and D.

Analysis of the uterine extracts by gas chromatography and mass spectrometry showed prostaglandin F2α, F1α (in trace amounts), E2 and D2 to be present.

The major product detected was 6‐keto‐prostaglandin F1α. Its identification forms an addendum to the paper.

Also present as a major product was 6(9)‐oxy‐11,15‐dihydroxyprosta‐7,13‐dienoic acid.
EFFECTS OF DIBUTYRYL CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE AND THEOPHYLLINE ON THE BULLFROG SYMPATHETIC GANGLION CELLS
Authors: AKASU T. , KOKETSU K.
Published: July 2012

1 Effects of dibutyryl cyclic adenosine 3′,5′‐monophosphate (dibutyryl cyclic AMP) and theophylline on bullfrog sympathetic ganglion cells were examined in order to test the hypothesis that cyclic AMP is essential for the generation of slow inhibitory postsynaptic potentials (i.p.s.ps) in these cells.

2 In the absence or presence of theophylline, dibutyryl cyclic AMP did not hyperpolarize but rather tended to depolarize ganglia that were hyperpolarized by adrenaline.

3 Theophylline augmented neither the P‐potential (slow i.p.s.p.) nor adrenaline‐induced hyperpolarization.

4 Thus, cyclic AMP does not seem to be essential for the generation of the slow i.p.s.p., at least in amphibian sympathetic ganglion cells.
ANAPHYLACTIC REACTIONS TO ENDOTOXIN IN GUINEA‐PIG TISSUES: RELATIONSHIP TO ENDOTOXIN TOXICITY
Authors: McLEAN A.J.
Published: July 2012

1 A lipopolysaccharide extract of Escherichia coli 026:B6 cells (026:B6(B) endotoxin) was shown to be toxic to normal adult guinea‐pigs.

2 The agent had no action on isolated preparations of ileum and heart taken from normal adult guinea‐pigs.

3 Ileal segments from animals actively immunized against 026:B6(B) endotoxin showed dose‐dependent contractions when exposed to endotoxin. Desensitization phenomena were demonstrated.

4 Reactivity of 026:B6(B) endotoxin was transferred to isolated preparations of ileum and heart from normal animals by passive transfer of immune serum.

5 Tissue responses to 026:B6(B) were associated with release of ileal spasmogen into the bath medium. Mepyramine blocked the effects of this spasmogen at bath concentrations which caused little change in ileal responses to carbachol.

6 It is concluded that E. coli endotoxin can elicit anaphylactic reactions, and that this process may potentiate endotoxin toxicity in sensitized animals. However, endotoxin toxicity in guinea‐pigs does not appear to depend on this kind of allergic process.
COMPARISON OF THE EFFECTS OF CAFFEINE AND A 2‐ALKYL‐1,2,3‐BENZOTRIAZINIUM IODIDE ON FROG RECTUS ABDOMINIS
Authors: MUIR C.K. , SCOTT N.C.
Published: July 2012

1 The mode of action of 2‐n‐propyl‐4‐p‐tolylamino‐1,2,3‐benzotriazinium iodide (TnPBI), which induced contractures of frog rectus abdominis muscle, was investigated.

2 TnPBI caused contractures of frog rectus abdominis when the muscle had been depolarized with potassium chloride.

3 Experiments with TnPBI and caffeine in calcium‐free Ringer suggested that both compounds produce contractures by releasing intracellular bound calcium.

4 It is suggested that at least two calcium stores are involved, one of which is sensitive to caffeine while both are sensitive to TnPBI.
OLFACTORY BULB ABLATION IN THE RAT: BEHAVIOURAL CHANGES AND THEIR REVERSAL BY ANTIDEPRESSANT DRUGS
Authors: van RIEZEN H. , SCHMIEDEN H. , WREN ALLISON F.
Published: July 2012

1 The effects of bilateral olfactory bulbectomy, sham‐operation and inducement of peripheral anosmia were studied on locomotor activity, passive avoidance acquisition and irritability.

2 Bulbectomized rats were hyperactive, deficient at learning a step‐down passive avoidance response and hyperirritable. Peripheral anosmia, induced by intranasal infusion of ZnSO4 solution resulted in no behavioural changes.

3 Chronic pretreatment with amitriptyline (3 and 10mg/kg) and a tetracyclic antidepressant mianserin (Org GB 94, 5 and 15 mg/kg) reversed the hyperactivity and reduced the learning deficit of bulbectomized rats. These drugs had no significant effects on sham‐operated animals.

4 Neither amitriptyline nor mianserin reduced the exaggerated responses of bulbectomized rats to external stimuli.

5 (+)‐Amphetamine (1 and 3 mg/kg) accelerated the acquisition of the passive avoidance response, greatly enhanced the locomotor activity and slightly increased the irritability score of both sham‐operated and bulbectomized rats.

6 Chlorpromazine (1 and 3 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the acquisition, locomotor activity and irritability of experimental and control rats.

7 Lithium sulphate (1 and 3 mg/kg) had no effect on activity or irritability but produced a small impairment in acquisition of bulbectomized rats.

8 It is concluded that the reversal by antidepressant drugs of the behavioural syndrome seen after olfactory bulb ablation could constitute a new model for the detection of this group of centrally acting compounds.
AGONIST AND ANTAGONIST PROPERTIES OF BUPRENORPHINE, A NEW ANTINOCICEPTIVE AGENT
Authors: COWAN A. , LEWIS J.W. , MACFARLANE I.R.
Published: July 2012

1 Buprenorphine is a highly lipophilic derivative of oripavine. In rodent antinociceptive assays (writhing, tail pressure), buprenorphine had an action which was rapid in onset and of long duration; it was 25‐40 times more potent than morphine after parenteral injection and 7‐10 times more potent after oral administration.

2 The log dose‐response relationship for buprenorphine was curvilinear in mouse and rat tail flick tests with the antinociceptive effect decreasing at higher, non‐toxic doses.

3 Tolerance developed to the antinociceptive activity of buprenorphine in mice.

4 No signs of abstinence were observed on naloxone challenge or after abrupt withdrawal in monkeys receiving buprenorphine chronically for one month.

5 Buprenorphine antagonized the antinociceptive actions of morphine in mouse and rat tail flick tests but was an ineffective antagonist in the rat tail pressure test.

6 Buprenorphine precipitated signs of abstinence in morphine‐dependent mice and monkeys but not in morphine‐dependent rats.

7 Buprenorphine produced Straub tails in mice. This effect was not antagonized when the animals were pretreated with naloxone. However, in the rat tail pressure test high doses of diprenorphine antagonized established antinociceptive effects of buprenorphine.

8 It is concluded that buprenorphine represents a definite advance in the search for a narcotic antagonist analgesic of low physical dependence potential.
THE UPTAKE AND OVERFLOW OF RADIOLABELLED β‐ADRENOCEPTOR BLOCKING AGENTS BY THE ISOLATED VAS DEFERENS OF THE RAT
Authors: LEWIS M.J.
Published: July 2012

1 A comparison of uptake into and overflow from the isolated vas deferens of the rat has been made between [3H]‐noradrenaline ([3H]‐NA), [14C]‐D‐sorbitol and three radio‐labelled β‐adrenoceptor blocking agents, [14C]‐practolol, [14C]‐(+)‐propranolol and [3H]‐penbutolol.

2 The accumulation of [3H]‐NA after 30 min incubation was reduced by desmethylimipramine (DMI) 1 × 10−8M and was also reduced in vasa from rats pretreated with 6‐hydroxydopamine (6‐OHDA). This was not so with [14C]‐D‐sorbitol.

3 6‐OHDA pretreatment of the rats reduced the uptake of f [3H]‐penbutolol after 30 min incubation but not that of [14C]‐propranolol or [14C]‐practolol. DMI 1 × 10−8M did not alter the tissue uptake of [14C]‐propranolol, [14C]‐practolol or [3H]‐penbutolol.

4 Electrical stimulation of vasa preloaded with [3H]‐NA caused a significantly greater increase in [3H]‐NA overflow than during the resting, unstimulated periods. No such increase in overflow was observed with [14C]‐sorbitol or any of the three β‐adrenoceptor blocking agents used.

5 The β‐adrenoceptor blocking agent penbutolol was shown to possess adrenergic neurone blocking activity in the isolated vas deferens of the rat.

6 It is concluded that any effect that practolol or (+)‐propranolol have on noradrenergic neurones is brought about without the need for these drugs to gain access to the interior of the neurone.
THE EFFECT OF SYSTEMICALLY AND TOPICALLY APPLIED DRUGS ON ULTRAVIOLET‐INDUCED ERYTHEMA IN THE RAT
Authors: LAW E. , LEWIS A.J.
Published: July 2012

Exposure of the skin of rats to u.v. light (>295 nm) for 30 s or longer elicited a delayed erythema response, the rate of onset increasing with the period of irradiation. The erythema was still present at 24 h and was replaced by scab formation in 48 hours.

Both topically applied steroidal and non‐steroidal anti‐inflammatory drugs reduced the erythema formation when administered immediately after u.v. exposure. Propyl gallate, an antioxidant with sun screening properties in man, also possessed topical anti‐erythemic activity.

Both steroidal and non‐steroidal anti‐inflammatory drugs, systemically administered 1 h before u.v. exposure, reduced the erythema. However, the steroidal compounds were less effective than the nonsteroids and reduced the intensity of erythema by less than 50%. Antagonists of 5‐hydroxytryptamine (5‐HT) reduced the erythema but several other drugs with different pharmacological activities were ineffective.

Neither topical nor systemic treatments of any of the drugs examined suppressed the scab formation at 48 hours.

These results and those using other selective blocking agents indicate that in the mediation of the erythema reaction prostaglandins may play a major role and 5‐HT perhaps a minor one but that H1 histamine receptors and α‐ and β‐adrenoceptors have no significant role.
THE SYMPATHOMIMETIC ACTIVITY OF FENFLURAMINE HYDROCHLORIDE ON RAT VAS DEFERENS
Authors: MOTTRAM D.R. , WADHWANI D.
Published: July 2012

The peripheral, pharmacological effects of the anorexigenic agent, fenfluramine hydrochloride, have been investigated on rat isolated vas deferens.

Characteristic spiked contractions were observed within 2 to 3 min after exposure to fenfluramine; these contractions reached a rate of around 13 per min and were of variable height.

Pre‐treatment of vasa with the indirectly acting sympathomimetic amine, tyramine, greatly reduced both the height and rate of contraction induced by fenfluramine.

The uptake inhibitor, desipramine, required a concentration in excess of 10 μM to affect fenfluramine‐induced contractions. Effects of desipramine on fenfluramine contractions were of equal magnitude whether desipramine was administered before fenfluramine or at the height of the fenfluramine‐induced contractions.

Pre‐treatment with debrisoquine (0.5 mM), reduced the contractions in response to fenfluramine over a period of time.

Fenfluramine, added to vasa from rats which had been injected intraperitoneally with 5 mg/kg reserpine 24 h and 48 h previously, failed to induce its characteristic contractions.

It is concluded that fenfluramine can be classed as an indirectly acting sympathomimetic amine on peripheral adrenergic nerve terminals.
EVIDENCE FOR A VISCERAL SMOOTH MUSCLE ABNORMALITY IN OKAMOTO SPONTANEOUS HYPERTENSION
Authors: ALTMAN J. , DA PONTE F. , WORCEL M.
Published: July 2012

In order to discover whether the changes in reactivity are related to the primary cause of hypertension in spontaneously hypertensive rats (SHR) or are just an adaptation induced by the high arterial blood pressure we tested the contractile response of a visceral smooth muscle from such rats.

Longitudinal strips of the fundus from 20 week old male and female SHR and Wistar normotensive (NW) rats were used. Dose‐response curves to Ba2+ in SHR strips were displaced to the right as compared to NW rats. Maximal responses were identical. Male SHR fundus strips contracted much more with Sr2+ (SHR: 42 ± 3% of maximum response to Ba2+, n= 10; NW: 19 ± 4%, n= 10, P<0.01) than NW strips. There was no difference in the response to both BaCl2 and SrCl2 between female SHR and NW fundus strips, and MnCl2 and LaCl3 were relaxant in all cases.

Dose‐response curves to Ca2+ of depolarized SHR and NW fundus strips were obtained and the effect of diazoxide on Ca2+ contractions was observed. The contractile action of Ca2+ in depolarized preparations was enhanced in both male and female SHR strips. The effect of diazoxide was more marked in SHR strips than in NW fundus strips.

SHR fundus smooth muscle shows the same modification of reactivity to Ba2+, Sr2+, Ca2+ and diazoxide that was previously described in arterial smooth muscle. This indicates that the cellular modification responsible for the increase of vascular tonus in SHR is not an adaptive reaction to high blood pressure. The differences between female SHR and male SHR responses are not unexpected, considering the natural evolution of hypertension in Okamoto rats which is milder in the female.
EFFECT OF INTRAHYPOTHALAMIC PHENTOLAMINE ON HYPOTHERMIA PRODUCED BY PERIPHERAL NORADRENALINE IN THE PIGEON
Authors: HISSA R. , PYÖRNILÄ A.
Published: July 2012

The effect of intrahypothalamic phentolamine (1 and 2 μl of a 10 μg/μl solution) on hypothermia induced by intramuscular injection of noradrenaline (NA, 2 mg/kg) at different times (2, 10, 20 min) after phentolamine was investigated in pigeons.

Administration of phentolamine shortly before NA was shown to attenuate hypothermic responses to NA.

It is suggested that the attenuation is due to blockade of central hypothermic effects of intramuscular NA.

The mapping of injection sites in the brains was carried out.
LIGAND BINDING TO MUSCARINIC RECEPTORS IN INTACT LONGITUDINAL MUSCLE STRIPS FROM GUINEA‐PIG INTESTINE
Authors: WARD DAWN , YOUNG J.M.
Published: July 2012

The binding of ligands to muscarinic receptors in intact longitudinal muscle strips from guinea‐pig small intestine has been determined by measuring the inhibition of the irreversible binding of [3H]‐propylbenzilylcholine mustard ([3H]‐PrBCM).

The IC50 values for inhibition of [3H]‐PrBCM binding by a given ligand were generally higher in intact strips than those reported for broken‐cell preparations. This effect is probably due, at least in part, to the presence of an access‐limitation factor in the kinetics of the irreversible binding of [3H]‐PrBCM to the intact tissue.

The mean Hill coefficients for antagonist binding approached unity, but those for strong agonists were significantly less than unity. There was, with the possible exceptions of hexyltrimethylammonium and oxotremorine, reasonably good agreement with the Hill coefficients reported for brain homogenates.
THE EFFECTS OF PENTOBARBITONE AND CHLORALOSE ANAESTHESIA ON THE VAGAL COMPONENT OF BRONCHOCONSTRICTION PRODUCED BY HISTAMINE AEROSOL IN THE ANAESTHETIZED DOG
Authors: JACKSON D.M. , RICHARDS I.M.
Published: July 2012

Total lung resistance (RL) and dynamic lung compliance (Cdyn) were measured in dogs anaesthetized with pentobarbitone or chloralose and subjected to aerosols of histamine during 4 successive inspirations.

Histamine caused concentration‐dependent increases in RL and decreases in Cdyn. A significant vagal component was involved, but only when chloralose was employed and then only in the RL response.

The resting values of RL and Cdyn were similar regardless of which anaesthetic was used and remained essentially the same if the vagi were cooled.

Electrical stimulation of the efferent vagi caused large increases in RL of dogs given chloralose and these effects were attenuated by the administration of pentobarbitone. Such stimulation was relatively ineffective in dogs given pentobarbitone alone.

In vitro, electrical field stimulation caused contractions of dog trachealis muscle. The responses were reduced by pentobarbitone in concentrations approximating to plasma levels in the anaesthetized dogs (1 to 5 × 10−4 M), but the effects of exogenous acetylcholine were unaltered. The inhibition was dose‐dependent, reversed by washing and unaltered by hexamethonium.

The results suggest that pentobarbitone inhibits the vagal component of histamine‐induced bronchoconstriction in the dog by an action on the efferent pathway. Furthermore, pentobarbitone acts either by blocking transmission along postganglionic parasympathetic nerves or by preventing the release of acetylcholine from the nerve endings in the lung.
THE EFFECT OF ATROPINE ON ACID SECRETION STIMULATED BY ACETYLCHOLINE, HISTAMINE AND GASTRIN IN THE ISOLATED WHOLE STOMACH OF THE RAT
Authors: BUNCE K.T. , MARSH GILLIAN F. , PARSONS M.E.
Published: July 2012

An isolated stomach preparation from immature rats has been used to study the effect of atropine on gastric acid secretion.

The acid secretory response to acetylcholine was not inhibited by atropine at a concentration of 0.3 μM. Concentrations of atropine of 1 to 3 μM produced a measurable inhibition of acid secretion, and a concentration of atropine of 10 μM caused a complete block of acid secretion which could not be surmounted by high concentrations of acetylcholine.

The acid secretory response to histamine was not inhibited by concentrations of atropine of up to 1 mM.

Concentrations of atropine of 1 μM and 10 μM did not inhibit gastrin‐stimulated acid secretion, although a significant inhibition of acid output was observed with atropine at concentrations of 0.1 mM and 1 mM.

These findings are discussed in relation to the role of cholinergic mechanisms in the control of gastric acid secretion.
ELECTROCORTICAL CHANGES INDUCED BY THE PERFUSION OF NORADRENALINE, ACETYLCHOLINE AND THEIR ANTAGONISTS DIRECTLY INTO THE DORSAL RAPHÉ NUCLEUS OF THE CAT
Authors: KEY B.J. , KRZYWOSKINSKI L.
Published: July 2012

The electrocortical changes induced by the perfusion of drugs directly into the dorsal raphé nucleus of the cat encéphale isolé preparation have been studied.

(−)‐Noradrenaline (NA), (−)‐adrenaline, or (−)‐isoprenaline (Isop) produced intermittent or sustained electrocortical desynchronization during the perfusion period.

These changes were markedly attenuated or completely abolished by the prior perfusion of (±)‐sotalol or (−)‐propranolol, but not by equimolecular concentrations of (+)‐propranolol.

The effects of NA or Isop were also blocked by phentolamine, whereas phenoxybenzamine either potentiated the responses to NA and Isop or mimicked the effects of these catecholamines.

The effect of dopamine was similar to that induced by NA, but could not be elicited at all of the perfusion sites where NA was effective. It could be blocked by (±)‐sotalol or (−)‐propranolol and also by the prior perfusion of fusaric acid.

Acetylcholine (ACh) increased, or initiated, electrocortical synchronization. These effects could be antagonized by sensory stimulation, the prior perfusion of atropine, or the simultaneous perfusion of NA at the same site.

Lignocaine, induced prolonged electrocortical desynchronization, behavioural alerting and an increased responsiveness to sensory stimulation.

The results have been discussed in relation to the possible involvement of inhibitory β‐adrenoceptors and facilitatory cholinoceptors (muscarinic) in the functioning of the dorsal raphé nucleus.
PLASMA CONCENTRATIONS AND CARDIOTOXIC EFFECTS OF DESIPRAMINE AND PROTRIPTYLINE IN THE RAT
Authors: BIANCHETTI G. , BONACCORSI AURORA , CHIODAROLI A. , FRANCO R. , GARATTINI S. , GOMENI R. , MORSELLI P.L
Published: July 2012

Desipramine and protriptyline were administered to anaesthetized rats by two consecutive intravenous infusions in order to obtain a peak level (first infusion) followed by lower steady state concentrations (second infusion) (Wagner, 1974). Theoretical plasma level time courses were confirmed experimentally.

Desipramine and protriptyline were measured in atria and ventricles. Increasing infusion rates led to proportional increases in plasma and atrial concentrations. The tissue/medium ratio ranged from 57 to 21 for desipramine and from 43 to 11 for protriptyline according to the time of determination during infusions.

Heart rate changes, deviation of the electrical axis of the heart and prolongation of atrioventricular conduction were recorded at fixed times during infusion.

Positive chronotropic effects were noted at plasma concentrations ranging from 0.035 to 0.1 μg/ml for desipramine and from 0.04 to 1.2 μg/ml for protriptyline. At higher plasma concentrations the positive chronotropic effect decreased and bradycardia developed. Both drugs induced right rotation of the electrical axis of the heart. Threshold plasma levels giving 40° rotation were 1.35 μg/ml (desipramine) and 1.75 μg/ml (protriptyline). Atrioventricular conduction was prolonged at threshold plasma concentrations of 2.2 μg/ml for desipramine and 3.6 μg/ml for protriptyline.

Desipramine is more cardiotoxic than protriptyline. This difference is discussed in relation to the plasma and heart concentration of the two drugs.
DEVELOPMENT OF NICOTINIC RESPONSES IN THE RAT ADRENAL MEDULLA AND LONG‐TERM EFFECTS OF NEONATAL NICOTINE ADMINISTRATION
Authors: ROSENTHAL R.N. , SLOTKIN T.A.
Published: July 2012

The development of nicotinic responses in the rat adrenal medulla was examined at various ages from 1 to 50 days of age by testing the ability of nicotine (10 mg/kg, s.c.) to deplete catecholamines and induce tyrosine hydroxylase.

Catecholamines were depleted 25% 3 h after injection of nicotine at all ages tested, but the degree of tyrosine hydroxylase induction 24 h after nicotine increased with age.

These data indicate that functional nicotinic receptors are present in the neonatal adrenal medulla before the development of functional splanchnic innervation, but that the development of the ability to induce tyrosine hydroxylase is not coupled directly to the development of secretory mechanisms.

The long‐term effects of a single dose of nicotine (10 mg/kg, s.c.) administered to one day old rats were also examined.

After the short‐term catecholamine depletion caused by nicotine, there were persistent elevations of catecholamines and tyrosine hydroxylase until 23 days of age; however, dopamine β‐hydroxylase remained elevated into young adulthood.

These data indicate that neonatal nicotine administration can produce long‐term changes in adrenal catecholamine biosynthetic enzymes.
A COMPARISON OF THE EFFECTS OF BRADYKININ, 5‐HYDROXYTRYPTAMINE AND HISTAMINE ON THE HEPATIC ARTERIAL AND PORTAL VENOUS VASCULAR BEDS OF THE DOG: HISTAMINE H1 AND H2‐RECEPTOR POPULATIONS
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

The hepatic arterial and hepatic portal venous vascular beds of anaesthetized dogs were separately perfused in different experiments.

From measurements of perfusion pressures and blood flows in the two series of experiments, hepatic arterial vascular resistance (HAVR) and hepatic portal venous vascular resistance (HPVR) respectively were calculated.

Bradykinin, 5‐hydroxytryptamine (5‐HT) and histamine were injected intra‐arterially and intraportally and dose‐response curves constructed from these data.

Bradykinin injected intra‐arterially caused dose‐dependent hepatic arterial vasodilatation, and with an ED50 of 2.66 × 10−13 mol was more potent than any other vasodilator agent yet examined on this vascular bed.

Bradykinin injected intraportally at doses up to 10 times those which were maximal on the arterial circuit did not alter the calculated HPVR.

5‐HT injected intra‐arterially caused weak and variable rises in HAVR, indicating vasoconstriction. The maximum rise in HAVR was much less than that attained with noradrenaline in the same preparations.

5‐HT injected intraportally caused dose‐dependent rises in HPVR indicating portal constriction at doses above 15–100 μg: in some experiments small doses of 5‐HT resulted in reductions in calculated HPVR.

Histamine has previously been shown to cause hepatic arterial vasodilatation: by intraportal injection, it caused dose‐dependent rises in HPVR.

In order to examine the receptors responsible for the effects of histamine, dose‐response curves were constructed before and after mepyramine and metiamide.

On the hepatic arterial vascular bed, metiamide did not antagonize the vasodilator effects of intra‐arterial histamine, but these effects were antagonized by mepyramine.

Similarly on the hepatic portal bed, the rises in HPVR due to histamine were antagonized by mepyramine but not by metiamide.

The effects of histamine on both the hepatic arterial and portal venous vascular beds of the dog are therefore mediated predominantly by histamine H1‐receptors.
[3H]‐OUABAIN BINDING TO PERIPHERAL ORGANS OF CATS: EFFECT OF ETHANOL
Authors: BANERJEE SHAILESH P. , SHARMA VIRENDRA K.
Published: July 2012

The specific [3H]‐ouabain binding to microsomal fractions derived from cat heart, liver, spleen, and kidney increased significantly following chronic administration of ethanol.

Since ouabain binds exclusively to cell membrane (Na+ + K+)‐adenosine triphosphatase ((Na+ + K+)‐ATPase), these results provide evidence for an increase in number of (Na+ + K +)‐ATPase macromolecules during chronic alcoholism.

The importance of the increase in number of (Na+ + K+)‐ATPase molecules in the adaptive increase in ethanol metabolism and cardiac myopathy in chronic alcoholism is discussed.
EFFECTS OF OXYPERTINE ON THE ISOLATED VAS DEFERENS OF THE RAT
Authors: MIRANDA H.
Published: July 2012

The isolated vas deferens of the rat was used to examine the peripheral action of oxypertine, a psychotropic‐anxiolytic drug.

Oxypertine (4.4 × 10−10m to 2.6 × 10−5m) antagonized competitively the effects of noradrenaline (pA2 = 7.2), 5‐hydroxytryptamine (pA2 = 8.6) and dopamine (pA2 = 9.8).

Oxypertine (8.8 × 10 −9m to 2.6 × 10−5m) antagonized the effects of low concentrations of acetylcholine and enhanced the contractions elicited by high concentrations of acetylcholine.

The contractions evoked by transmural stimulation of the vas deferens were reduced by oxypertine.

Oxypertine failed to antagonize the responses to potassium chloride.

These findings are compared with the effects of other antidepressant drugs.
HEPATIC DRUG METABOLISM AND HAEM BIOSYNTHESIS IN LEAD‐POISONED RATS
Authors: GOLDBERG A. , MEREDITH P.A. , MILLER S. , MOORE M.R. , THOMPSON G.G.
Published: July 2012

Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P‐450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P‐450 than b5.

The activity of the rate‐limiting enzyme of haem biosynthesis, δ‐aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P‐450 content.

The activity of the haem biosynthetic enzymes δ‐aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment.

The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.
BLOCKADE OF DESENSITIZATION OF NICOTINIC RECEPTORS OF THE CAT ADRENAL MEDULLA BY CONCANAVALIN A
Authors: KIRPEKAR S.M. , PRAT J.C.
Published: July 2012

The possibility of concanavalin A (Con A) blocking the development of desensitization of nicotinic receptors of the cat adrenal gland has been investigated.

During perfusion of the adrenal gland with Krebs‐bicarbonate solution containing acetylcholine (ACh), the rate of catecholamine (CA) secretion was very high in the first 2 min; thereafter, as perfusion with ACh was continued the output fell, to reach about 20% of the initial value in 10 minutes. When the adrenal gland was pretreated with Con A, the subsequent desensitization of release during continued infusion of ACh was prevented.

When the adrenal gland was perfused with high K+ solution, there was always a large initial secretion of CA, and as perfusion with high K+ continued the output fell, to reach about 15% of the initial rate in 10 minutes. Con A did not affect the rate of CA secretion induced by high K+.

It is tentatively suggested that Con A blocks the desensitization of CA secretion evoked by ACh by interaction with the glycoprotein moiety of the nicotinic receptor of adrenal chromaffin cells.
TIME COURSE OF DEGENERATION OF SHORT AND LONG POSTGANGLIONIC SYMPATHETIC NERVE FIBRES AND EFFECT OF PENTOBARBITONE AND COLCHICINE ON DEGENERATION
Authors: WAKADE ARUN R.
Published: July 2012

The time‐course of degeneration of sympathetic nerves was investigated by measurement of the endogenous noradrenaline content of the rat vas deferens, submandibular gland and spleen following sympathectomy.

Extirpation of the hypogastric plexus, superior cervical ganglion and coeliac plexus under pentobarbitone anaesthesia caused 50% depletion of the noradrenaline content of the vas deferens, submandibular gland and spleen in approximately 16, 19 and 21 h, respectively.

Under pentobarbitone anaesthesia, proximal sympathectomy (i.e., close to the end organ) produced depletion of the noradrenaline content of the submandibular gland 8 h earlier than that caused by distal sympathectomy. Under ether anaesthesia, the time difference in obtaining the same degree of depletion after the two procedures of sympathectomy was only 2 hours.

Removal of the superior cervical ganglion under ether anaesthesia resulted in almost complete depletion of noradrenaline content of the submandibular gland in 17 h, whereas when a similar operation was performed under pentobarbitone anaesthesia, nearly 24 h were required for the same degree of depletion. Similarly, the noradrenaline content of the spleen was depleted 4 h earlier if the coeliac plexus was ablated under ether as compared to pentobarbitone anaesthesia.

Local application of colchicine (10 mg/ml, 30 min) to postganglionic sympathetic nerve axons had no effect on the noradrenaline content of the submandibular gland up to 24 hours. However, removal of the superior ganglion following colchicine application considerably slowed the depletion of the noradrenaline content of the submandibular gland (at 17 and 20 h after ganglionectomy, 10 and 20% depletion, respectively, in the experimental gland, as compared to 70 and 80%, respectively, in the control gland).

To explain the results, it is proposed that injury to the sympathetic nerves at the site of sectioning triggers a signal (messenger substance) which travels down to the nerve endings to produce degeneration. Thus, the length of the extrinsic nerve fibre influences the time course of degeneration by changing the rate of transport of the messenger substance, whereas pentobarbitone and colchicine alter the synthesis and/or transport of the messenger substance to modify the time‐course of degeneration.
EFFECTS OF MAGNESIUM ON CONTRACTILE RESPONSES INDUCED BY ELECTRICAL TRANSMURAL STIMULATION AND NORADRENALINE IN RABBIT THORACIC AORTA
Authors: FUJIWARA MOTOHATSU , KITAGAWA HISATO , KURAHASHI KAZUYOSHI
Published: July 2012

In rabbit isolated thoracic aortae, effects of magnesium ions on the contraction and 3H‐efflux in response to electrical transmural stimulation and on the contractile responses induced by noradrenaline and KCl were investigated.

Addition of magnesium (1.2, 3.6, 12.0 and 24.0 mm) to the bathing solution inhibited the electrically induced contractions in a dose‐related manner; the inhibition was complete with a concentration of 24.0 mm.

The increase in 3H‐efflux induced by electrical transmural stimulation was inhibited by the addition of magnesium to the superfusing fluid, but a complete block was not obtained even in high concentrations of magnesium.

Magnesium ions (1.2, 3.6, 12.0 and 24.0 mm) inhibited the contractile responses induced by low concentrations of noradrenaline (2 × 108m) and KCl (2 × 10 −2m). However, the responses induced by higher concentrations of noradrenaline (5 × 10−7 and 10−5m) and KCl (3 and 4 × 10−2m) were enhanced by low concentrations of magnesium.

Magnesium ions affect both presynaptic and effector sites in rabbit thoracic aortae but in a different manner; magnesium manifests only an inhibitory effect on noradrenaline release from the adrenergic nerves, but dual effects on reactivity of vascular smooth muscle, depending on concentrations of magnesium and stimulants; it is suggested that the change in vascular reactivity is more important than the reduction in transmitter release when magnesium inhibits the response to nerve stimulation.
EFFECTS OF SOME PYRAZINECARBOXAMIDES ON SODIUM TRANSPORT IN FROG SKIN
Authors: CUTHBERT A. W. , FANELL G. M.
Published: July 2012

The inhibitory effect of amiloride (N‐amidino‐3,5‐diammo‐6‐chloropyrazinecarboxamide) on sodium transport in isolated skin of frog has been compared with 17 of its analogues. The dissociation constant of amiloride for passive sodium channels was 181.9 ± 8.9 nm, and the maximal percentage inhibition of sodium transport was 101.3 ± 0.4% (means of 123 measurements) when measured at a sodium concentration of 111 mm.

The N‐benzylamidino and N‐o‐chlorobenzylamidino compounds had affinities approximately 20 times larger than those for amiloride, and produced maximal inhibition of transport.

Substitution of chlorine in the 6‐position by other halogens showed that the bromo‐compound was equally active to amiloride, whereas the iodo derivative had an affnity equal to 15% of that for amiloride.

Substitution in the 5‐amino group in 10 compounds reduced the affinities to less than 1% of that of amiloride, without affecting their ability to produce complete inhibition of transport.

N‐Amidino‐3,5‐diaminopyrazinecarboxamide was unique in that it produced an unusual concentration‐response relationship.