bluuebunny/crossref_metadata_2025 huggingface dataset:
TRYPTAMINES AND SOME OTHER SUBSTANCES AFFECTING WAKING AND SLEEP IN FOWLS
Authors: MARLEY E. , NISTICO G.
Published: July 2012

Adult fowls (Gallus domesticus) with cannulae chronically implanted in the IIIrd cerebral ventricle and various other sites of the brain, received infusions or injections of tryptamines and catecholamines into the brain; effects of and interactions between these substances on behaviour, electrocortical activity and body temperature were studied. Reserpine‐induced arousal, was investigated in young and adult fowls.

Tryptamine and α‐methyltryptamine, given intraventricularly or into the hypothalamus of intact fowls evoked behavioural and bilateral electrocortical arousal, postural changes, elevation of body temperature and tachypnoea; behavioural and bilateral electrocortical arousal were obtained with infusions into the mesencephalon. Ipsilateral electrocortical arousal only, resulted from infusion of α‐methyltryptamine into the hypothalamus or mesencephalon of fowl encéphale isolé preparations. The above effects in intact fowls were reduced or replaced by sleep following administration of noradrenaline or α‐methylnoradrenaline into the IIIrd ventricle or hypothalamus. Pretreatment of intact fowls with an amine oxidase inhibitor surprisingly attenuated or reversed the excitant effects of intraventricular tryptamine.

5‐Hydroxytryptamine (hydrogen maleinate, creatinine sulphate or oxalate) given intraventricularly or infused into the hypothalamus, elevated body temperature; tachypnoea and postural changes developed at some stage during the elevation of body temperature. Sleep also was induced, although with the oxalate this was succeeded by marked arousal.

Behavioural and electrocortical sleep induced by 5‐hydroxytryptamine infused into the hypothalamus were replaced by arousal on infusing tryptamine into the hypothalamus, and vice versa.

Dexamphetamine infused into the hypothalamus induced drowsiness or sleep which even reversed arousal elicited by systemically administered dexamphetamine.

Reserpine‐induced arousal was achieved in young and adult fowls pretreated with mebanazine; this arousal was attenuated or replaced by sleep following intraventricular noradrenaline or dopamine but not by 5‐hydroxytryptamine nor by noradrenaline or dopamine applied to the hypothalamus. Prenylamine also induced arousal following pretreatment of chicks with mebanazine.
SOME PHARMACOLOGICAL PROPERTIES OF THE CREMASTER MUSCLE OF THE GUINEA‐PIG
Authors: NINOMIYA J.G.
Published: July 2012

The tension developed in the guinea‐pig cremaster was recorded during spontaneous activity and electrical stimulation. Spontaneous rhythmic contraction was observed in many preparations, particularly in the tip of the cremaster. These contractions were very slow, lasting about 20 s and occurring at about 2 min intervals, but different preparations varied greatly. Twitches produced by electrical stimulation were similar to those in other skeletal muscles, being reduced by (+)‐tubocurarine and abolished by tetrodotoxin.

A slow contraction could be initiated by electrical stimulation using a pulse longer than 10 ms in spontaneously active preparations and in some quiescent preparations. Spontaneous and evoked slow contractions were not suppressed by tetrodotoxin, but were selectively abolished by verapamil. Histamine increased the basal tension and generated spontaneous contractions in quiescent preparations. Hypertonic solutions also had excitatory effects.

Contractions produced by acetylcholine and carbachol were blocked by atropine. Those produced by adrenaline and noradrenaline were stronger than those due to histamine, acetylcholine and carbachol and were abolished by an α‐adrenoceptor blocking agent, phentolamine. In the preparations in which the slow contraction was not observed, histamine, acetylcholine or adrenaline had very little effect.

It is suggested that the cremaster muscle consists of striated muscle together with some smooth muscle having properties similar to that in the vas deferens.
THE EFFECTS OF TETRAPHENYLBORON ON NEUROMUSCULAR TRANSMISSION IN THE FROG
Authors: MARSHALL I.G. , PARSONS R.L.
Published: July 2012

The effects of tetraphenylboron (TPB) were studied on the frog sciatic nerve‐sartorius muscle preparation.

TPB (0.01–1 mM) blocked indirectly elicited twitches of the preparation.

TPB (0.01–0.1 mM) produced no depolarization but lowered membrane resistance. TPB increased miniature endplate potential (m.e.p.p.) frequency, the rate of rise of the endplate potential (e.p.p.), and slowed the rate of rise and rate of fall of the muscle action potential.

In Mg2+ solutions the quantal content of e.p.ps was initially increased by TPB (0.01 mM). This was followed by a decrease of e.p.p. and m.e.p.p. amplitudes, accompanied by a lack of e.p.p. failures.

Larger concentrations of TPB (0.1 mM) produced an increase in e.p.p. amplitude followed by the sudden abolition of e.p.ps. This effect was associated with abolition of the nerve terminal spike.

TPB (0.1 mM) exhibited no postjunctional blocking action.

The results indicate that TPB acts prejunctionally, initially causing an increased release of acetylcholine. Subsequently, transmitter output is reduced by a reduction of quantal size.
EFFECTS OF NARCOTIC ANALGESIC DRUGS ON THE CYCLIC ADENOSINE 3′, 5′‐MONOPHOSPHATE‐ADENYLATE CYCLASE SYSTEM IN RAT BRAIN
Authors: CLOUET DORIS H. , GOLD G.J. , IWATSUBO K.
Published: July 2012

The concentrations of cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP), measured in discrete brain areas removed from rats killed by microwave irradiation, rose transiently in most areas after the administration of morphine. The most pronounced changes, however, were found 2 h after doses of either 10 or 60 mg/kg morphine when cyclic AMP levels declined significantly in the hypothalamus, medulla and cerebellum. In morphine‐tolerant rat brains there were no decreases in cyclic AMP levels.

Basal adenylate cyclase activity in crude nerve‐ending fractions from discrete areas of rat brain was unaffected by the addition of active analgesic agonists, antagonists or inactive isomers to the assay medium in vitro, except for a nonspecific inhibition at drug concentrations of 1 mM.

The acute administration of morphine or levorphanol, but not dextrorphan produced transient increases in basal cyclase activity of crude nerve‐ending preparations from midbrain and striatum. In morphine‐tolerant rats, these changes in basal adenylate cyclase activity were no longer seen.
RELATIVE POTENCY OF BOMBESIN‐LIKE PEPTIDES
Authors: BROCCARDO M. , ERSPAMER G. FALCONIERI , MELCHIORRI P. , NEGRI L. , DE CASTIGLIONE R.
Published: July 2012

The pharmacological activity of two natural bombesin‐like peptides, alytesin and litorin, and 25 related synthetic peptides has been compared to that of bombesin.

The minimum length of the amino acid chain required for the first appearance of bombesin‐like effects was represented by the C‐terminal heptapeptide, and the minimum length for maximal effects by the C‐terminal nonapeptide. The latter possessed approximately the same activity as bombesin and may be considered a good substitute.

Both the tryptophan and histidine residues seemed to be essential for bombesin‐like activity.

The C‐terminal octapeptide was less active than either bombesin or the C‐terminal nonapeptide and its action was more rapid in onset and less sustained.

Litorin apparently has an intermediate position between bombesin octapeptide and bombesin nonapeptide in the speed and duration of its effects. The relationship between structure and activity is discussed.
EFFECTS OF ANTICONVULSANT AND CONVULSANT DRUGS ON THE ATPASE ACTIVITIES OF SYNAPTOSOMES AND THEIR COMPONENTS
Authors: GILBERT J.C. , WYLLIE M.G.
Published: July 2012

The effects of anticonvulsants, and other drugs on the Na+, K+‐adenosine triphosphatase (ATPase) (ouabain‐sensitive) and Mg++‐ATPase activities of synaptosomes and their components have been determined.

The Mg++‐ATPase activity of synaptosomes was not affected by the drugs but the Na+, K+‐ATPase activity was inhibited by phenytoin (diphenylhydantoin), ethosuximide and diazepam.

Fractions containing mainly membranes, mitochondria or synaptic vesicles, were prepared from synaptosomes by osmotic shock and subsequent density gradient centrifugation. Inhibition of Na+, K+‐ATPase activity by phenytoin, ethosuximide and diazepam was apparent only in the membrane fraction.

The fraction containing synaptic vesicles exhibited pronounced Mg++‐ATPase but no Na+, K+‐ATPase activity. In contrast to the enzymes of the membranes and mitochondria, the Mg++‐ATPase of the vesicles was inhibited by diazepam and all of the anticonvulsants tested.
IMPAIRMENT IN THE HEPATIC CLEARANCE OF [35S]‐BROMOSULPHO‐PHTHALEIN IN PARACETAMOL‐INTOXICATED RATS
Authors: BUTTAR H.S.
Published: July 2012

The overall functional capacity of the liver was evaluated using [35S]‐bromosulphophthalein (BSP, 100 mg/kg, i.v.) in biliary fistulated adult rats pretreated orally with different doses of paracetamol (APAP) for varying time intervals.

The maximal hepatic damage occurred between 12–18 h after single doses of APAP (0.5 or 1 g/kg); hepatic excretory function returned to control levels by 48–72 hours.

Administration of either 0.5 or 1 g/kg APAP 18 h before BSP caused a dose‐dependent inhibition of the choleretic effect of BSP and of the 60 min cumulative excretion of the dye, but conversely, produced a significant increase in the liver and plasma concentrations of 35S.

Following acute (0.25 g/kg), or subacute (0.5 g/kg, twice daily for 7 days) treatment with APAP, the total excretion of 35S in bile and the retention of 35S in the liver or plasma remained essentially the same as that for the controls.

In rats given single doses of 1 g/kg APAP, the hepatic uptake of the dye was significantly increased during the early stages of intoxication, while the opposite effect was observed at late periods.

The bile flow appeared to be inversely related to the excretion of unchanged BSP, and directly related to the excretion of the major BSP conjugate in bile.

The hepatic clearance of BSP was more rapid in rats treated subacutely with 0.5 or 1 g/kg APAP, than in those treated acutely with equal doses, suggesting that the intensity of APAP‐induced hepatotoxicity became less severe after the repeated administration of this drug.

It is concluded that the hepatic uptake, metabolism and excretion of BSP are reversibly impaired following APAP‐induced liver injury.
BRAIN CONCENTRATIONS OF BIOGENIC AMINE METABOLITES IN ACUTELY TREATED AND ETHANOL‐DEPENDENT RATS
Authors: KAROUM F. , WYATT R.J. , MAJCHROWICZ E.
Published: July 2012

Mass fragmentography was used to measure whole brain concentrations of some of the major metabolites of tyramine, octopamine, dopamine and noradrenaline in acutely treated and in ethanoldependent rats.

Treatments with ethanol, either acutely or chronically, failed to alter significantly brain concentration of p‐hydroxyphenylacetic and p‐hydroxymandelic acid (metabolites derived from tyramine and octopamine respectively). The effect on catecholamine metabolites was marked and therefore suggests that ethanol is selective in its effect on central metabolism of biogenic amines.

Acute ethanol treatment significantly increased brain concentration of homovanillic acid (HVA), 3,4‐dihydroxyphenylacetic acid (DOPAC) and 3‐methoxy‐4‐hydroxyphenylglycol (MHPG). Vanilmandelic acid (VMA) was not affected. All four metabolites (HVA, DOPAC, MHPG and VMA) were increased in the brains of rats rendered dependent on ethanol while still intoxicated (blood ethanol levels above 200 mg/dl). In ethanol‐dependent rats undergoing ethanol withdrawal syndrome (no ethanol present in blood), the brain concentrations of HVA and DOPAC were normal while those of MHPG and VMA continued to be elevated.

From the decline in the concentrations of HVA and DOPAC after 50 mg pargyline/kg in control rats and rats acutely treated with ethanol, it was concluded that ethanol has no effect on the transport of phenolic acids across the blood brain barrier.

No reversal in the metabolism of catecholamines from an oxidative to a reductive pathway, analogous to that produced by ethanol in the periphery, could be established in the brain.

The increase in catecholamine metabolite concentrations after ethanol treatment, either acute or chronic, were interpreted as manifestations of increases catecholamine turnover.
HISTAMINE H2‐RECEPTORS IN THE HUMAN PERIPHERAL CIRCULATION
Authors: CHIPMAN P. , GLOVER W.E.
Published: July 2012

Histamine (10 μg/min for 3 min) infused into the brachial artery caused an increase in forearm blood flow which was reduced by mepyramine (25 mg). This effect was most marked in the first minute of the infusion. Metiamide (25 mg) had no effect on the dilatation during the infusion but caused a quicker return of flow to the resting level. The response was abolished when both drugs were given in combination. It is concluded that the response is initiated mainly by stimulation of H1‐receptors and maintained by H1‐ and H2‐receptors; continued activity of H2‐receptors may account for the slow return of flow to the pre‐infusional level.
NATURE OF HISTAMINE RECEPTORS IN THE EMETIC CHEMORECEPTOR TRIGGER ZONE
Authors: BHARGAVA K.P. , DIXIT K.S. , PALIT G.
Published: July 2012

The protective effects of the intracerebroventricular (i.c.v.) administration of the H1‐receptor antagonist, mepyramine and the H2‐receptor antagonists, burimamide and metiamide on centrally induced histamine‐emesis were studied in unanaesthetized dogs.

The PD50 values of intraventricular mepyramine, burimamide and metiamide against the 100% emetic dose of histamine (3.0 mg i.c.v.) were found to be approximately 200 μg, 20 μg and 20 μg respectively.

Although burimamide (i.c.v. or i.v.) afforded protection against histamine‐induced emesis, there was no protection against intravenous apomorphine‐or oral copper sulphate‐induced emesis.

The results suggest that both H1‐ and H2‐histamine receptors in the emetic chemoreceptor trigger zone of the area postrema are concerned in histamine‐induced emesis.
BLOCKADE BY BURIMAMIDE OF THE RESTORATIVE EFFECT OF HISTAMINE IN TETRODOTOXIN‐TREATED HEART PREPARATIONS
Authors: LEDDA F. , MANTELLI LAURA , MUGELLI A.
Published: July 2012

In isolated heart preparations in which fast sodium channels were blocked by tetrodotoxin (2–4 × 10−5 m), excitability was restored by histamine (6 × 10−6 M to 10−5 m).

This effect was antagonized by EDTA (2 × 10−6 m), D600 compound (0.5 μg/ml) and the H2‐receptor antagonist, burimamide (2 × 10−4 m).
INVESTIGATIONS TO CHARACTERIZE A NEW ANTI‐ARRHYTHMIC DRUG, ORG 6001, INCLUDING A SIMPLE TEST FOR CALCIUM ANTAGONISM
Authors: SALAKO L.A. , WILLIAMS E.M. VAUGHAN , WITTIG J.H.
Published: July 2012

The compound Org 6001 (3α‐amino‐2β‐hydroxy‐5α‐androstan‐17‐one hydrochloride) was found in recent experiments to exhibit anti‐arrhythmic activity. Evidence is presented in this paper concerning its mode of action.

Org 6001 was 1.8 times more potent than procaine as a local anaesthetic on desheathed frog nerve.

Org 6001 had no effect on the resting potential of isolated cardiac muscle of rabbit, but greatly reduced the maximum rate of depolarization (MRD). The action potential duration (APD) was marginally prolonged in atrial and ventricular muscle.

Org 6001 preferentially shortened APD in that part of the Purkinje system in which APD is normally longer than elsewhere, so that APD became more uniform throughout the ventricular conducting system.

Org 6001 did not block chronotropic responses to isoprenaline in atrial muscle.

Org 6001 had only a small negative inotropic effect in atrial muscle, and did not reduce the positive inotropic effect of raised calcium concentrations.

The effect of Org 6001 on MRD was reduced by lowering the external K+ concentration.

It is concluded that Org 6001 is an anti‐arrhythmic drug of the first class (local anaesthetic type), and within this group is of a sub‐class more closely related to lignocaine than to quinidine.
EFFECT OF PROSTAGLANDIN E1 ON NEUROMUSCULAR TRANSMISSION IN THE RAT
Authors: GRIPENBERG J. , JANSSON S.‐E. , HEINÄNEN V. , HEINONEN E. , HYVÄRINEN J. , TOLPPANEN E.‐M.
Published: July 2012

The effect of prostaglandin E1 on neuromuscular transmission in the phrenic nerve‐diaphragm muscle preparation of the rat was studied with intra‐ and extracellular recording techniques.

Prostaglandin E1, in concentrations from 10 nm, induced intermittent failures in the generation of the end‐plate potential in response to repeated indirect stimulation.

Failures appeared abruptly, the end‐plate potential behaving in an all‐or‐nothing fashion. The effect occurred only at 36–38°C when the nerve was stimulated at 30–80 Hz and was reversible upon washing with drug‐free solution.

Since miniature end‐plate potentials were not affected, such failures must be attributed to a presynaptic action of prostaglandin E1.

Extracellular recording suggested that prostaglandin E1 prevented the action potential from reaching the nerve terminal.
MAZINDOL ANOREXIA IS MEDIATED BY ACTIVATION OF DOPAMINERGIC MECHANISMS
Authors: KRUK Z.L. , ZARRINDAST M.R.
Published: July 2012

Anorexia in rats following injections of mazindol (0.1–8 mg/kg i.p.) could be antagonized by pretreatment with a dopamine receptor blocker (pimozide) but not by pretreatment with an α‐adrenoceptor blocker (phenoxybenzamine), a β‐adrenoceptor blocker ((‐)‐propranolol), or a 5‐hydroxytryptamine receptor blocker (methergoline).

In rats with a unilateral lesion in the substantia nigra made by stereotaxic injection of 6‐hydroxydopamine, mazindol caused a dose‐dependent turning towards the lesioned side, indicating an indirect mechanism of action. This effect could be antagonized by pretreatment with a dopamine receptor blocker.

In rats pretreated with reserpine and α‐methyl‐p‐tyrosine, mazindol did not have any motor stimulant action.

In vitro studies with synaptosomes prepared from rat brain, indicated that mazindol blocks uptake and causes release of dopamine.

It is concluded that the anorectic action of mazindol is mediated by a dopaminergic mechanism.
A COMPARISON OF AFFINITY CONSTANTS FOR MUSCARINE‐SENSITIVE ACETYLCHOLINE RECEPTORS IN GUINEA‐PIG ATRIAL PACEMAKER CELLS AT 29°C AND IN ILEUM AT 29°C AND 37°C
Authors: BARLOW R.B. , BERRY K.J. , GLENTON P.A.M. , NIKOLAOU N.M. , SOH K.S.
Published: July 2012

The affinity of 17 compounds for muscarine‐sensitive acetylcholine receptors in atrial pacemaker cells and ileum of the guinea‐pig has been measured at 29°C in Ringer‐Locke solution. Measurements were also made at 37°C with 7 of them.

Some of the compounds had much higher affinity for the receptors in the ileum than for those in the atria. For the most selective compound, 4‐dipnenylacetoxy‐N‐methylpiperidine methiodide, the difference was approximately 20‐fold. The receptors in the atria are therefore different in structure from those in the ileum.

The effects of temperature on affinity are not the same for all the compounds tested, indicating different enthalpies and entropies of adsorption and accounting for some of the difficulty experienced in predicting the affinity of new compounds.
CALCIUM DEPLETION OF SYNAPTOSOMES AFTER MORPHINE TREATMENT
Authors: CARDENAS H.L. , ROSS D.H.
Published: July 2012

It was confirmed that morphine administration in vivo produced a selective decrease in the calcium content of synaptosomal fractions prepared from rat cerebral cortices. This effect was prevented by naloxone.

After morphine or naloxone, there were no changes in the sodium, potassium and magnesium contents of any of the seven subcellular fractions tested.

Since the selective calcium loss was found to occur from fractions similar to those reported to exhibit opiate receptor binding, it is concluded that calcium may play a role in the action of narcotic agonist drugs.
MYOCARDIAL DIGOXIN UPTAKE: DISSOCIATION BETWEEN DIGITALIS‐INDUCED INOTROPISM AND MYOCARDIAL LOSS OF POTASSIUM
Authors: STEINESS EVA , VALENTIN N.
Published: July 2012

The time course of myocardial uptake of digoxin, of increase in inotropic effect and of changes in myocardial potassium content were studied following a single intravenous dose of digoxin.

Nineteen dogs with intact circulation were investigated by the use of a biopsy technique which allowed samplings before and 10, 30, 60, and 90 min after administration of digoxin.

The myocardial concentration of digoxin was 196 × 10−9 mol/kg 10 min after administration of digoxin. Uptake continued at a slower rate, maximum concentration being 293 × 10−9 mol/kg at 60 minutes.

The inotropic effect increased parallel with the uptake of digoxin; 10 min after digoxin, contractility was 127% of the control value and this increased to 139% at 90 minutes.

Myocardial potassium content was slightly increased 10 min after digoxin, suggesting an initial stimulation of membrane Na+‐K+ ATPase. A subsequent significant fall in the myocardial potassium content probably reflects ATPase inhibition.

The temporal dissociation between the early onset of the positive inotropic effect and the delayed inhibition of membrane Na+‐K+ ATPase indicates that inotropism of digitalis glycosides is not mediated by the same binding site as that responsible for inhibition of Na+‐K+ ATPase.
THE EFFECTS OF RESERPINE AND 6‐HYDROXYDOPAMINE ON THE CONCENTRATIONS OF SOME ARYLALKYLAMINES IN RAT BRAIN
Authors: BOULTON A.A. , JUORIO A.V. , PHILIPS S.R. , WU P.H.
Published: July 2012

The concentrations of p‐ and m‐tyramine were measured in the caudate nucleus of the rat brain following subcutaneous injection of reserpine or intraventricular injection of 6‐hydroxydopamine. β‐Phenylethylamine was analysed in the hypothalamus after reserpine.

Endogenous levels of p‐tyramine and m‐tyramine in the caudate nucleus, and β‐phenylethylamine in the hypothalamus were 8.02, 2.25 and 2.52 ng/g respectively.

Tyramine concentrations were reduced to less than 20% of control values one day after a reserpine injection of 1 or 10 mg/kg. A single dose of reserpine (0.4 mg/kg) significantly decreased the content of both tyramines in the caudate nucleus. The effects became apparent as early as 45 min after drug administration and persisted for at least 6 h in the case of p‐tyramine and for at least 19 days in the case of m‐tyramine.

The hypothalamic content of β‐phenylethylamine was unaffected by reserpine.

Ten days after an intraventricular injection of 6‐hydroxydopamine (250 μg), p‐ and m‐tyramine concentrations in the caudate nucleus were significantly below control levels.

The results suggest that p‐ and m‐tyramine may be stored by an intraneuronal reserpine‐sensitive storage mechanism. Alternatively, the tyramines may replace some of the catecholamines from their storage granules and then be released as false transmitters by the nervous impulse. The observed changes in tyramine levels might also reflect the fact that these amines may be metabolically related to another amine which is stored in reserpine‐sensitive granules.
THE DISTRIBUTION AND METABOLISM OF ARACHIDONIC ACID IN RABBIT PLATELETS DURING AGGREGATION AND ITS MODIFICATION BY DRUGS
Authors: BLACKWELL G.J. , DUNCOMBE W.G. , FLOWER R.J. , PARSONS M.F. , VANE J.R.
Published: July 2012

1Gas chromatographic and radio‐isotope labelling techniques have been used to establish the origin of the arachidonic acid used by the platelet cyclo‐oxygenase for the synthesis of pro‐aggregatory prostaglandin endoperoxide derivatives.

2Measurements of total platelet arachidonate content indicated that more than 95% is esterified in the phosphatide fraction of the cells.

3During aggregation by collagen or thrombin as much as 80% of the total platelet arachidonate may be liberated and transformed by the platelet enzymes into hydroxyacids and other more polar compounds.

4The phosphatidylethanolamine, phosphatidylcholine and phosphatidylinositol fractions are major sources of the arachidonate thus used.

5Indomethacin, which prevents platelet aggregation by inhibiting the cyclo‐oxygenase, did not affect this release of arachidonate from the phosphatides but did prevent the transformation of arachidonate to endoperoxide derivatives.

6Mepacrine, a drug which possesses weak anti‐phospholipase activity in platelets, also prevents aggregation by collagen or thrombin, but seems to do so by preventing substrate release from the phosphatide fraction.

7It is suggested that phospholipase A2 plays a key role in the initial events during platelet aggregation induced by collagen.
EFFECT OF ISOPRENALINE AND PHENYLEPHRINE ON THE ADENOSINE 3′,5′‐MONOPHOSPHATE CONTENT AND MECHANICAL ACTIVITY OF COLD‐STORED AND FRESH TAENIA CAECUM FROM THE GUINEA‐PIG
Authors: HONDA F. , KATSUKI S. , MIYAHARA J.T. , SHIBATA S.
Published: July 2012

1 Cold storage treatment of the guinea‐pig taenia caecum had a greater inhibitory effect on the isoprenaline‐induced relaxation than that induced by phenylephrine. Prolonged cold storage (12‐14 days) almost abolished the effect of isoprenaline but only reduced the phenylephrine effect. The ED50 of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) that elicited muscle relaxation was not altered by the prolonged cold storage.

2 After cold storage treatment, tissue cyclic AMP content was decreased; however, isoprenaline still caused a dose‐dependent increase in the cyclic AMP level. The threshold dose of isoprenaline for cyclic AMP accumulation was the same in fresh and cold‐stored preparations.

3 In the fresh preparation, the onset of the isoprenaline (10−6 M)‐induced relaxation preceded the increase in tissue cyclic AMP.

4 Isoprenaline, phenylephrine, adrenaline and noradrenaline at doses (ED50) sufficient to induce muscle relaxation did not always increase the cyclic AMP level.

5 Similarly, the responses to papaverine and nitroglycerine were not accompanied by an increase in cyclic AMP.

6 The adenylate cyclase and phosphodiesterase (low and high Km) activities of taenia caecum were not attenuated by the prolonged cold storage.

7 Propranolol inhibited both the isoprenaline‐induced relaxation and cyclic AMP accumulation; however, the pA2 values were significantly different for the two events.

8 Based on these results, both the relaxation and cyclic AMP accumulation caused by isoprenaline are mediated by activation of β‐adrenoceptors but are independent phenomena.
THE EFFECT OF ANGIOTENSIN I CONVERTING ENZYME INHIBITOR (SQ 20881) ON THE RELEASE OF PROSTAGLANDINS BY RABBIT KIDNEY, in vivo
Authors: JOHNS E. J. , MURDOCK R. , SINGER BERTHA
Published: July 2012

1 Prostaglandin E‐ and F‐like material has been estimated in renal venous blood of the left kidney of anaesthetized rabbits following renal nerve section. Prostaglandins were estimated by bioassay following solvent extraction and column chromatography.

2 Electrical stimulation of the renal nerves of the left kidney to reduce renal blood flow by approximately 15% for 15 min resulted in a significant increase in the concentration of prostaglandin E‐like material in the renal venous blood. The peak values were normally seen either in the last 5 min of the stimulation period or in the first 5 min after the end of the stimulation period. The concentration of prostaglandin F‐like material was not significantly altered.

3 Similar reduction of renal blood flow of the left kidney by renal artery constriction also resulted in a significant increase in the concentration of prostaglandin E‐ but not F‐like material in renal venous blood. The timing and magnitude of the response was comparable with that observed with renal nerve stimulation.

4 The effect of an angiotensin I converting enzyme inhibitor, SQ 20881, on the response to both renal nerve stimulation and renal artery constriction has been studied. The administration of the drug did not significantly reduce the release of prostaglandins from the denervated kidneys, however, the increase in prostaglandin E‐like material, in response to both stimuli, was abolished.

5 The results suggest that the increase in prostaglandin E‐like material released from the kidney in response to low frequency stimulation or to modest reductions in renal blood flow is dependent on the release of renin and that the effect is mediated by the formation of angiotensin II and not angiotensin I.
THE MECHANISM OF ACTION OF NARCOTIC ANALGESICS IN THE GUINEA‐PIG ILEUM
Authors: NORTH R.A. , TONINI M.
Published: July 2012

Intracellular recordings were made from neurones in the myenteric plexus of the guinea‐pig ileum. Single myenteric ganglia were maintained in vitro and drugs were applied by adding them to the perfusing solution.

Narcotic analgesics hyperpolarized the membrane of a proportion of neurones in the myenteric plexus.

The membrane hyperpolarization was sometimes associated with a decrease in input resistance. These effects reduced the excitability of myenteric neurones.

The effects of narcotics occurred at low concentrations (10 nM to 1 μM), were stereospecific and were reversed by naloxone.

It is proposed that the morphine‐sensitive neurones may be the cholinergic efferents to the muscle layers. By hyperpolarizing these neurones, morphine may prevent their excitation by electric field stimulation. This may explain why narcotic analgesics reduce the output of acetylcholine and the contractile response of this preparation when it is excited by field stimulation.
DIURETICS AND THE RENAL ADENYLATE CYCLASE SYSTEM
Authors: DAWBORN J.K. , MACNEIL S. , MARTIN T.J.
Published: July 2012

The relationship between the diuretic effectiveness and the effect on the renal adenylate cyclase of three diuretics, acetazolamide, frusemide and ethacrynic acid, was examined. The hypothesis that acetazolamide and parathyroid hormone (PTH), inhibit renal carbonic anhydrase by a cyclic adenosine 3′,5′‐monophosphate (cyclic AMP)‐dependent mechanism was also tested.

In vitro, acetazolamide, frusemide and ethacrynic acid at high concentrations (10−3M) all produced some inhibition of basal and stimulated rat kidney plasma membrane adenylate cyclase. The effect of acetazolamide was much less than that of frusemide and ethacrynic acid. These plasma membrane effects were reproduced in studies of cyclic AMP formation in isolated kidney tubules of rats.

Intravenous injections of acetazolamide did not change the total cyclic AMP content of the kidneys of rats killed by microwave irradiation.

Acetazolamide produced a diuresis in the rat and a slight inhibition of the antidiuretic effect of Pitressin. Frusemide produced a diuresis and greatly reduced the antidiuretic response to Pitressin. Ethacrynic acid was ineffective as a diuretic in the rat and actually enhanced the antidiuretic response to Pitressin.

In investigating the possible influence of diuretics and PTH on the activity and state of phosphorylation of carbonic anhydrase it was found that: there was no correlation between the ability of diuretics to inhibit carbonic anhydrase activity and to inhibit carbonic anhydrase phosphorylation; neither PTH nor cyclic AMP (in the presence of adenosine triphosphate, Mg2+, K+ and incubation at 37°C) inhibited rat cortex homogenate carbonic anhydrase activity.

It seems unlikely that any of the tested diuretics exerts its pharmacological effect by means of changes in kidney cyclic AMP metabolism.
A COMPARISON IN RABBIT ISOLATED HEARTS OF THE DYSRHYTHMOGENIC POTENTIAL OF AMITRIPTYLINE, MAPROTILINE AND MIANSERIN IN RELATION TO THEIR ABILITY TO BLOCK NORADRENALINE UPTAKE
Authors: HARPER BARBARA , HUGHES I.E.
Published: July 2012

In isolated hearts of rabbits, perfusion with (‐)‐noradrenaline (0.0059 to 5.9 μM) resulted in chronotropic and inotropic responses and a shortening of the interval between peak atrial and peak ventricular tensions (the A‐V contraction interval). No dysrhythmias developed but at higher concentrations (590 μM) 2 out of 7 hearts developed dysrhythmias (extrasystoles).

Perfusion with the antidepressants amitriptyline or maprotiline (4.8 μM) or mianserin (28.8 μM) reduced ventricular force, did not change heart rate and only amitriptyline reduced atrial force and lengthened the A‐V contraction interval. At 4.8 μM mianserin produced only a marginal shortening of the A‐V contraction interval.

At these concentrations no dysrhythmias developed but at higher concentrations (amitriptyline 8 μM. maprotiline 8 μM, mianserin 60 μM) all the agents produced dysrhythmias involving an interference with atrio‐ventricular synchronization.

In the presence of mianserin (4.8 μM) perfusion with noradrenaline (0.0059 to 5.9 μM) shortened the A‐V contraction interval and did not produce dysrhythmias. In the presence of amitriptyline or maprotiline (4.8 μM) or mianserin (28.8 μM) the A‐V contraction interval generally lengthened and most hearts developed dysrhythmias (usually involving interference with atrio‐ventricular synchronization).

[3H]‐(‐)‐Noradrenaline uptake in perfused rabbit hearts and in mouse isolated atria or vasa deferentia was inhibited by the antidepressants to a similar extent, amitriptyline being marginally most potent (molar potency taken as 1.0), maprotiline being less potent (1.5) and mianserin least potent (2.0).

It is concluded that of these three antidepressants, mianserin is least cardiotoxic in this preparation and that the ability of these antidepressants to predispose to noradrenaline‐induced dysrhythmias is not related to blockade of noradrenaline uptake.
THE EFFECTS OF PROSTAGLANDIN E1, BRADYKININ AND HISTAMINE ON CANINE SYNOVIAL VASCULAR PERMEABILITY
Authors: GRENNAN D.M. , MITCHELL W. , MILLER W. , ZEITLIN I.J.
Published: July 2012

The relative effects of prostaglandin E1, bradykinin and histamine on canine synovial vascular permeability were investigated by a method based on the measurement of the amounts of radiolabelled dextran (molecular weight 20,000) leaking from the circulation into the synovial cavity.

Bradykinin, prostaglandin E2 and histamine in that order of potency all increased synovial vascular permeability. Threshold concentrations were 0.3 μM, 3 μM and 30 μM respectively.

The effects of infusion of prostaglandin E1 combined with either bradykinin or histamine were greater than mere summation.
DOPAMINE‐INDUCED DEPRESSION OF ADRENERGIC NERVE‐MEDIATED CONTRACTION OF SMOOTH MUSCLE
Authors: BELL C. , MATALANIS G.
Published: July 2012

Dopamine (0.25‐1.0 μM) applied extraluminally depressed vasoconstrictor responses of the perfused rabbit ear artery to low frequency adrenergic nerve stimulation.

The depressant effect of dopamine was prevented in the presence of haloperidol (0.1 μM) but not in the presence of phentolamine (0.03‐0.14 μM).

Extraluminal dopamine (1 μM) or intraluminal injection of dopamine in amounts up to 0.025 %mumol had no dilator effect on arteries partially constricted by infusion of noradrenaline.

Dopamine also depressed contractile responses of guinea‐pig vas deferens to low frequency adrenergic nerve stimulation. However, in this tissue the effect of dopamine was prevented by phentolamine but not affected by haloperidol.

In neither the rabbit ear artery nor the guinea‐pig vas deferens did haloperidol increase the magnitude of responses to nerve stimulation or affect muscle sensitivity to noradrenaline.

We conclude that the adrenergic axons in the rabbit ear artery, but not the guinea‐pig vas deferens, possess specific receptors for dopamine whose activation depresses axonal conduction or transmitter release. However, our results do not favour the view that these receptors are activated during normal transmission at physiological frequencies.
THE EFFECT OF MAGNESIUM ON THE RESPONSE OF SMOOTH MUSCLE TO 5‐HYDROXYTRYPTAMINE
Authors: GOLDSTEIN S. , ZSOTÉR T.T.
Published: July 2012

The responses to 5‐hydroxytryptamine (5‐HT) of rabbit isolated mesenteric artery and vein and longitudinal smooth muscle of guinea‐pig ileum were examined in Krebs solution containing 0, 1.2 or 2.4 mm Mg2+.

When the concentration of Mg2+ was raised the spontaneous contractile activity of rabbit mesenteric vein was depressed. The responses to 5‐HT in rabbit mesenteric artery and vein and guinea‐pig ileum were greater in the absence of Mg2+. The initial fast component of 5‐HT‐induced contractions in rabbit mesenteric vein was reduced more consistently than the subsequent slow component by increasing the Mg2+ concentration.

Exposure of mesenteric vein to Ca‐free solution containing ethyleneglycoltetra‐acetic acid (EGTA) promptly abolished 5‐HT contraction in normal‐Mg but not in low‐Mg Krebs solution.

In mesenteric veins, no difference was observed in either the ‘lanthanum‐resistant’ uptake of 45Ca or total tissue Ca, measured by atomic absorption spectrophotometry, after 60 min exposure to either low‐Mg or normal‐Mg Krebs solution. On the other hand, after 5 min exposure, the ‘lanthanum‐resistant’ uptake of 45Ca was greater in the absence of Mg2+ than in the presence of higher Mg2+ concentrations.

It is suggested that Mg2+ depressed the 5‐HT response at least partly by reducing the availability of Ca2+ from a rapidly equilibrating intracellular pool.
BIOCHEMICAL EVIDENCE FOR THE DUAL ACTION OF LABETALOL ON α‐ AND β‐ADRENOCEPTORS
Authors: AGGERBECK MARTINE , GUELLAEN GEORGES , HANOUNE JACQUES
Published: July 2012

Labetalol (AH 5158A) inhibited the adrenaline‐stimulated adenylate cyclase activity of rat liver and heart. This drug had no effect on basal or guanosine triphosphate (GTP)‐activated adenylate cyclase activities.

Labetalol displaced the binding of the specific ligands [3H]‐dihydroergocryptine and (—)‐[3H]‐dihydroalprenolol from their respective α and β‐adrenoceptors in rat heart and liver. The affinity of labetalol was 10 fold higher for the β‐ than for the α‐adrenoceptor. It appeared to be 10 to 100 times less potent than phentolamine in blocking α‐adrenoceptors and 5 to 10 times less potent than propranolol in blocking β‐receptors.

It is concluded that labetalol exerts its dual α‐ and β‐antagonism by acting directly on the plasma membranes, where it binds competitively to α‐ and β‐adrenoceptors.
INHIBITION OF [3H]‐DIHYDROALPRENOLOL BINDING TO RAT CARDIAC MEMBRANES BY VARIOUS β‐BLOCKING AGENTS
Authors: CHENIEUX‐GUICHENEY P. , DAUSSE J.P. , MEYER P. , SCHMITT H.
Published: July 2012

Binding of [3H]‐dihydroalprenolol ([3H]‐DHA) to rat cardiac membranes was rapid and reversible (fcj = 0.633‐0.701 × 106M_1 s_1 and fc_x = 0.0017‐0.0043 s_1).

[3H]‐DHA bound to a single class of binding sites with an equilibrium dissociation constant (Kd25°c) Of 5.7 ± 1.1 × 10−9M.

This binding was specific and the order of potency of adrenoceptor agonists in competing for the binding sites was (—)‐isoproterenol < (±)‐isoproterenol < (+)‐isoproterenol < (—)‐adrenaline < (—)‐noradrenaline. This was in agreement with the β1 nature of the cardiac β‐receptors.

Cardioselective β‐blockers (i.e. metoprolol, acebutolol and practolol) were shown to have lower binding site affinities, when compared to other blockers. This may be related to steric hindrance by the side‐chain at the aromatic end of these molecules.
VASODILATATION BY PROSTAGLANDIN F2α IN THE CANINE TONGUE THROUGH A PARASYMPATHETIC MECHANISM
Authors: SHIMIZU T. , TAIRA N.
Published: July 2012

The vascular bed of the tongue in situ was perfused with blood through the lingual arteries at a constant pressure in anaesthetized dogs. All drugs except for SQ 14,225 were administered intra‐arterially.

Prostaglandin F2at (PGF2a) produced a dose‐dependent increase in blood flow through the lingual arteries (vasodilatation).

Marked desensitization was observed on the vasodilator “responses to repeated administration of PGF2a.

The vasodilator response to PGF2a was abolished by tetrodotoxin in doses that abolished the vasodilator response to electrical stimulation of the lingual nerve.

The vasodilator response to PGF2a was not affected by hexamethonium in doses that almost abolished the vasodilator response to lingual nerve stimulation.

The vasodilator responses to PGF2flt and to lingual nerve stimulation were scarcely modified by (‐)‐hyoscyamine in doses that fully antagonized the vasodilator response to acetylcholine.

Electrical stimulation of the vago‐sympathetic trunk and noradrenaline produced a decrease in blood flow through the lingual arteries.

These results indicate that the vasodilator response of the tongue to PGF2ae is due exclusively to excitation of parasympathetic postganglionic neurones and that neuronal receptors involved are quite distinct from nicotinic receptors.

Intravenous administration of SQ 14,225, an inhibitor of angiotensin I converting enzyme or kininase II, augmented the vasodilator responses to bradykinin and kallikrein but not that to lingual nerve stimulation.

The results suggest that neither kallikrein noukinin (including bradykinin) is responsible for the parasympathetically induced vasodilatation in the tongue.
UPTAKE AND INACTIVATION OF PROSTAGLANDIN E2 METHYL ANALOGUES IN THE RAT PULMONARY CIRCULATION
Authors: BAKHLE Y.S. , JANCAR SONIA , WHITTLE B.J.R.
Published: July 2012

The fate of (15S)‐15‐methyl prostaglandin E2 methyl ester and 16,16‐dimethyl prostaglandin E2 in the pulmonary circulation of rat isolated lungs was compared with that of prostaglandin E2 by means of bioassay.

Calculated on the basis of height of response of the assay tissues, the inactivation of prostaglandin E2 was 96 ± 1%, of 15‐methyl prostaglandin E2 methyl ester, 53 ± 6% and of 16,16‐dimethyl prostaglandin E2, 50 ± 4%.

Responses of the hamster stomach strip to the prostaglandin E2 analogues passing through the pulmonary circulation were prolonged and slower in onset than those to the analogue given directly to the tissue. No such difference was observed with prostaglandin E2.

Bromocresol green, bromothymol blue, bromocresol purple and thymol blue (10−5 M) all inhibited the inactivation of the three prostaglandins studied, as did diphloretin phosphate (1.5 × 10−6 M). All five inhibitors also reversed the shape change in response seen after transpulmonary injection of 16‐16‐dimethyl prostaglandin E2.

We conclude that the inactivation of the methyl analogues is due to uptake, as they are not substrates for prostaglandin dehydrogenase.

The lung may act as a depot for some compounds taking them up from the pulmonary vessels and later releasing them slowly into the systemic circulation.
SULPHASALAZINE IS A POTENT INHIBITOR OF PROSTAGLANDIN 15‐HYDROXYDEHYDROGENASE: POSSIBLE BASIS FOR THERAPEUTIC ACTION IN ULCERATIVE COLITIS
Authors: HOULT J.R.S. , MOORE P.K.
Published: July 2012

Sulphasalazine is a potent and selective inhibitor in vitro of prostaglandin 15‐hydroxydehydrogenase in rabbit colon (ID5() = 50 μm) and in several other organs of different species, but does not inhibit prostaglandin A‐13 reductase or microsomal prostaglandin synthesis from arachidonic acid. It is suggested that this action may underly the therapeutic usefulness of sulphasalazine in ulcerative colitis for the prevention of relapse.
EVIDENCE FOR PURINERGIC INNERVATION OF THE ANOCOCCYGEUS MUSCLE
Authors: BURNSTOCK G. , COCKS T. , CROWE RAHIMA
Published: July 2012

Fluorescence histochemical localization of quinacrine (which binds to adenosine 5′‐triphosphate (ATP)) revealed nerve fibres running singly and in bundles in both rat and rabbit anococcygeus muscle. Single neurone cell bodies and ganglia containing between 2 and 50 cells were also observed.

Catecholamine fluorescence studies revealed a dense adrenergic ground plexus, but no adrenergic ganglion cells were detected. No acetylcholinesterase‐positive nerve fibres or ganglion cells were seen in the rat.

When the tone was raised with guanethidine, a relaxation in response to field stimulation was revealed, which was unaffected by atropine but blocked by tetrodotoxin.

Release of ATP increased 3 to 6 times above background during stimulation of these non‐adrenergic, non‐cholinergic, inhibitory nerves.

Neither quinacrine staining nor the release of ATP during inhibitory nerve stimulation was affected by 6‐hydroxydopamine treatment, which abolished catecholamine fluorescence.

Exogenous ATP produced relaxation in high tone preparations of the rabbit anococcygeus muscle. ATP produced either contraction or a small relaxation followed by a contraction of the rat anococcygeus muscle, but treatment with low concentrations of the prostaglandin synthesis inhibitor indomethacin, converted the contraction to a relaxation.

These data are consistent with the view that the anococcygeus muscle is innervated by purinergic inhibitory nerves.
PHARMACOLOGY OF THE ADRENOCEPTORS AND CHOLINOCEPTORS OF THE BC3HI NONFUSING MUSCLE CELL LINE
Authors: MAUGER JEAN‐PIERRE , MOURA ANNE‐MARIE , WORCEL MANUEL
Published: July 2012

We have studied the action of different transmitters on the transmembrane 42K or 86Rb efflux from tissue cultures of the BC3H1 muscle cell line.

The effect of catecholamines and carbachol (CCh) on the isotope efflux rate was measured by addition of the drugs at different times during the washout.

Noradrenaline (NA), phenylephrine (Phe), isoprenaline (Iso) and CCh increased 42K and 86Rb efflux rate in a dose‐dependent manner.

The action of NA seems to be due exclusively to the stimulation of α‐receptors, since its effect was blocked by phentolamine but not by propranolol. The effects of Iso on the 86Rb efflux were inhibited by propranolol. The β‐receptors in the BC3H1 cells seem to be of the β2‐type since they are stimulated by Iso and insensitive to NA.

The effect of CCh was blocked by (‐h)‐tubocurarine but not by atropine. This result confirms the presence of nicotinic receptors in BC3H1 cells.
CHANGES IN BLOOD FLOW AND MEDIATOR CONTENT OF RABBIT SKIN GRAFTS
Authors: LEWIS G.P. , MANGHAM BEVERLEY A.
Published: July 2012

Blood flow changes have been measured in rabbit skin homografts and autografts and an attempt has been made to correlate these changes with the presence of vasoactive agents in homogenates of the grafts.

During the healing‐in of both types of grafts the blood flow and histamine content increased.

If this histamine was responsible for the vasodilatation via an H2‐receptor it must have been released in the form of ‘nascent’ or intrinsic histamine since the vasodilatation was not antagonized by antihistamine.

A peak of histamine concentration occurred in homografts, more than three times that in autografts at the onset of rejection. At the same time the blood flow stopped completely.

This vasoconstriction might be mediated by histamine since treatment with mepyramine delayed the cessation of blood flow from 5 days up to 7 to 10 days.

Prostaglandins appeared to be involved only in the period of peak blood flow in homografts because indomethacin did not delay the onset of rejection, but reduced the peak blood flow in the homografts at a time when there was an increased content of prostaglandin E2 in the homograft tissue.
ON THE CONDUCTANCE PATHWAY TRAVERSED BY STRONTIUM IN MEDIATING THE ASYNCHRONOUS RELEASE OF ACETYLCHOLINE BY MOTOR NERVE IMPULSES
Authors: MELLOW A.M. , PHILLIPS T.E. , SILINSKY E.M.
Published: July 2012

A study was made to determine whether the Sr2+‐dependent asynchronous release of acetylcholine by nerve impulses is mediated by the conventional Ca2+ conductance channel or, as has been suggested recently, through an alternative ion pathway. Experiments were performed on the frog neuromuscular junction by the use of standard electrophysiological techniques. Repetitive nerve stimulation in Sr2+‐Ringer solutions caused a marked increase in miniature end‐plate potential (m.e.p.p.) frequency which was dependent on Sr2+ concentration and inhibited in a competitive fashion by the known Ca2+ antagonists, Co2 + and Mg2 +. The equilibrium dissociation constants (Kds) determined for both Co2+ (0.09 + 0.01 mm, mean ± s.e. mean, n = 5) and Mg2+ (3.7 ± 0.3 mm, mean ± s.e. mean, n = 4) were essentially the same as the reported values for these antagonists in blocking Ca2+‐mediated transmitter release by nerve impulses. These results suggest that Sr2+ mediates asynchronous evoked transmitter release through the conventional calcium conductance channel.