bluuebunny/crossref_metadata_2025_split huggingface dataset:
STUDY ON THE POSSIBLE ENTRY OF BACTERIAL ENDOTOXIN AND PROSTAGLANDIN E2 INTO THE CENTRAL NERVOUS SYSTEM FROM THE BLOOD
Authors: DASCOMBE M.J. , MILTON A.S. 
Published: July 2012

A study has been made of the possible entry of 51Cr‐bacterial endotoxin and [5,6,8,11,12,14,15(n)‐3H]‐prostaglandin E2 ([3H]‐PGE2) into the CNS of the anaesthetized cat.
No radioactivity was detected in perfusates of the preoptic‐anterior hypothalamus or in the cerebrospinal fluid (c.s.f.) in vivo, or in brain tissue post mortem following intracarotid infusion of 51Cr‐bacterial endotoxin.
Intracarotid administration of [3H]‐PGE2 resulted in the entry of radioactivity into the CNS of endotoxin pretreated cats. Chromatographic analysis indicated the radioactivity in c.s.f. to be associated with PGE2 and a metabolite similar to 13, 14‐dihydro‐15‐keto PGE2.
Intracarotid administration of 13, 14‐dihydro‐15‐keto [5,6,8,11,12,14(n)‐3H]‐PGE2 resulted in the presence of the compound in the CNS of the anaesthetized cat after pretreatment with bacterial endotoxin.
It is concluded that PGE2 and possibly 13,14‐dihydro‐15‐keto PGE2 but not bacterial endotoxin may enter the CNS from the cerebral circulation to elicit the febrile response to bacterial endotoxin in cats.
AN ANALYSIS OF SOME FACTORS INFLUENCINGα‐ADRENOCEPTOR FEED‐BACK AT THE SYMPATHETIC JUNCTION IN THE RAT HEART
Authors: DOCHERTY J.R. , McGRATH J.C. 
Published: July 2012

The effects of the selective prejunctional α‐adrenoceptor antagonist, yohimbine, on the cardio‐acceleration responses to sympathetic stimulation were examined in the pithed rat.
Yohimbine reversed the inhibitory effects of the α‐adrenoceptor agonist, clonidine. on the stimulation‐induced tachycardia.
Yohimbine failed to potentiate significantly responses to stimulation in the absence of clonidine when stimulation was applied at the optimal level for cardiac responses (C6‐T1).
When the pithing rod electrode was moved to T2‐T6, cardioaccelerator responses were smaller and yohimbine produced potentiation at frequencies of ≥ 1 Hz. This potentiation was prejunctional since responses to exogenous noradrenaline (NA) were not increased by yohimbine.
In the presence of cocaine, potentiation by yohimbine could be shown at the lower frequency of 0.1 Hz.
The possible physiological significance of a negative feed‐back effect of noradrenaline on cardiac sympathetic nerves is discussed.
EFFECTS OF AZAPERONE AND ACETYLPROMAZINE ON SOCIAL AND ENVIRONMENTAL BEHAVIOUR IN SHEEP
Authors: MADSEN B.W. , SYME G.J. , SYME L.A. 
Published: July 2012

Acetylpromazine (Acp, 0.05, 0.1 and 0.5 mg/kg) and azaperone (Azp, 1.0, 1.25 and 1.5 mg/kg) were given by intramuscular injection to separate groups of seven familiar Romney ewes. Thirty minutes after injection the sheep were led into a featureless arena and spatial distribution, activity and shade preference were monitored for 20 min by overhead photography.
Behavioural response was complex with both stimulant and depressant effects being seen. The response trends with increasing time for all three measures were significantly different for the two drugs. In particular, Azp tended to increase animal dispersion and Acp to decrease it, in agreement with earlier predictions.
The dosage range for Azp was adequate for reduction of individual movement and inter‐animal distance but steady state effect was not reached in the time period studied. All doses of Azp initially caused disorientation, as measured by shade preference, but this improved as sedation deepened.
The highest dose of Acp (0.5 mg/kg) achieved steady state effect on individual movement within the study period. The three doses of Acp caused either no change or a slight increase in inter‐animal distance. Disorientation with Acp was less and briefer than that seen with Azp.
CORONARY VASODILATATION: INTERACTIONS BETWEEN PROSTACYCLIN AND ADENOSINE
Authors: BLASS K.‐E. , FÖRSTER W. , ZEHL U. 
Published: July 2012

The influence of prostacyclin (PGI2) on the release of adenosine in rabbit hearts perfused by the Langendorff method was examined under normal conditions of perfusion and during perfusion with the adenosine antagonist, aminophylline.
PGI2 increased both coronary flow and the myocardial release of adenosine in a dose‐dependent manner. Aminophylline at a low concentration (10 μg/ml) suppressed the enhanced flow.
Adenosine increased both coronary flow and the release of PGI2 from the isolated hearts; both these effects were inhibited by the low aminophylline concentration. Inhibition of PGI2‐biosynthesis by 75% caused only a nonsignificant reduction in the adenosine‐induced enhancement of coronary flow.
Aminophylline at a high concentration (50 μg/ml) produced an increase in coronary flow and in release of PGI2 as did adenosine; neither of these effects was observed with the low concentration of aminophylline (10 μg/ml).
It is suggested that the coronary vasodilator effects of PGI2 in the isolated perfused rabbit hearts are due, at least partially, to the release of adenosine.
THE IONIZATION OF 5‐HYDROXYTRYPTAMINE AND RELATED COMPOUNDS AND AN APPRAISAL OF METHODS FOR THE ESTIMATION OF ZWITTERION CONSTANTS
Authors: BARLOW R.B. , BURSTON K.N. 
Published: July 2012

The dissociation constants of 5‐hydroxytryptamine and 5‐hydroxy‐N,N‐dimethyltryptamine have been measured and the zwitterion constants have been estimated from the pKas of analogous methoxyamines and the phenolic quaternary ammonium salt.
Direct measurement of zwitterion constants has been made by a spectroscopic method which has been used also with several phenolic amines previously studied electrometrically. It makes fewer assumptions and so should be more reliable but an appraisal of the methods available indicates that none can be singled out as being best and it is desirable to obtain results with as many as possible.
The results consolidate previous observations on the relations between chemical structure and zwitterion constant; possibly zwitterions are stabilized by any factor which stabilizes water structure. Dimethylamino compounds have lower zwitterion constants than their methylamino or amino‐analogues but there is no reason to doubt the previous finding that diethylamino compounds have higher zwitterion constants than their dimethylamino analogues.
The proportion of 5‐hydroxytryptamine present as the neutral molecule or zwitterion in physiological conditions is small; however, with dopamine, the proportion present as the zwitterion could be as much as 10%.
A COMPARISON OF THE CARDIOVASCULAR EFFECTS OF DOBUTAMINE AND A NEW DOPAMINE DERIVATIVE (D4975) DURING SHOCK INDUCED BY E. Coli ENDOTOXIN
Authors: McCAIG DOROTHY , PARRATT J.R. 
Published: July 2012

The effects of a newly developed dopamine‐xanthine derivative, 7‐propyl‐theophylline‐dopamine (D4975) and of dobutamine have been examined in anaesthetized cats before and after the induction of shock with E. coli endotoxin.
Both D4975 and dobutamine caused dose‐related increases in left ventricular (LV) dP/dtmax (and LVdP/dt at fixed isovolumic pressures). Significantly smaller increases in LVdP/dtmax occurred as early as 0.5 to 1 h after endotoxin, with maximal attenuation at 1 to 2 h and some improvement in sensitivity in cats surviving 2 to 4 h. The maximum response to each drug was markedly reduced in shock.
Neither D4975 nor dobutamine had significant effects on heart rate. D4975 caused dose‐related increases in systemic arterial blood pressure which were smaller during shock, the changes in responsiveness following those in LVdP/dtmax.
Possible mechanisms responsible for changing myocardial sensitivity to these and other agents are discussed. It is concluded that D4975 may be more useful in the treatment of shock than either dopamine or dobutamine because (a) it is more potent during shock than dobutamine (perhaps as a result of phosphodiesterase inhibition by the theophylline component of D4975); (b) its action is longer‐lasting than dobutamine or dopamine and (c) like dobutamine, its effect on heart rate is insignificant.
EVIDENCE AGAINST β‐ADRENOCEPTOR BLOCKING ACTIVITY OF DILTIAZEM, A DRUG WITH CALCIUM ANTAGONIST PROPERTIES
Authors: BRILEY M. , CAVERO I. , LANGER S.Z. , ROACH A.G. 
Published: July 2012

In isolated spontaneously beating atria of the rat, diltiazem (0.01 to 0.1 μm) shifted the atrial rate concentration‐response curves to isoprenaline to the right in a non‐parallel manner and depressed their maxima. Under the same experimental conditions, (±)‐propranolol (0.03 to 0.1 μm) behaved as a competitive β‐adrenoceptor antagonist.
Whereas (±)‐propranolol (IC50 = 12 nm) and isoprenaline (IC50 = 0.9 μm) inhibited (—)‐[3H]‐dihydroalprenolol binding to rat brain membrane preparations, diltiazem failed to do so in concentrations up to 10 μm.
Diltiazem but not (±)‐propranolol, antagonized the positive chronotropic responses to calcium in spontaneously beating rat atria.
It is proposed that diltiazem inhibited the tachycardia induced by isoprenaline through an effect on calcium which may be an essential modulator of the sequence of events linking the β‐adrenoceptor activation and heart rate response.
STRUCTURE‐ACTIVITY STUDIES WITH NEUROTENSIN: ANALYSIS OF POSITIONS 9, 10 and 11
Authors: QUIRION R. , REGOLI D. , RIOUX F. , ST‐PIERRE S. 
Published: July 2012

The stimulant effects of neurotensin (NT) and NT analogues modified in positions 9, 10 or 11 were evaluated and compared in two pharmacological preparations: the rat stomach strip and the isolated spontaneously beating atria of guinea‐pig.
The data derived from our structure‐activity study suggest that Arg9 and Pro10 mainly contribute to the affinity of neurotensin for its cardiac and smooth muscle receptors. Tyr11 seems to be more closely involved in the process of receptor activation by NT.
The order of potency of some NT analogues modified in position 11 (e.g. [d‐Phe11]‐NT, [d‐Tyr11]‐NT) was strikingly different from that described in other systems (e.g. hypothermia test and specific mast cell binding). The importance of this observation is discussed.
ATTENUATION OF PETHIDINE‐INDUCED ANTINOCICEPTION BY ZIMELIDINE, AN INHIBITOR OF 5‐HYDROXYTRYPTAMINE REUPTAKE
Authors: GEBHART G.F. , LORENS STANLEY A. 
Published: July 2012

The effect of selective inhibition of 5‐hydroxytryptamine (5‐HT) re‐uptake by fluoxetine and zimelidine on morphine‐ and pethidine‐induced antinociception was studied in rats. The hot plate (55°C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception.
Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base).
Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine‐induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine‐induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine.
These and other results support (a) a role for 5‐HT in the expression of morphine‐induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5‐HT in pethidine‐induced antinociception remains unclear.
A MODEL OF REFLEX TRACHEAL CONSTRICTION IN THE DOG
Authors: ALLOTT C.P. , EVANS D.P. , LOVEDAY B.E. , MARSHALL P.W. 
Published: July 2012

A tracheal pouch with its nerve and blood supply intact has been prepared in situ in dogs.
Mechanical stimulation of the upper airways in dogs anaesthetized with chloralose induced a consistent increase in pouch pressure which was abolished by bilateral vagal section.
The response of the pouch following mechanical stimulation of the airways was abolished by intravenous pentobarbitone, atropine, administered systemically or when present in the pouch, and tetracaine, applied to the stimulus area or when present in the pouch.
Salbutamol had no inhibitory effects on the response regardless of its route of administration.
These results suggest that the increase in pouch pressure following mechanical stimulation of the upper airways is mediated by a vagal reflex arc.
The technique may distinguish between drugs the site of action of which is at the afferent or efferent end of this reflex arc.
COMPARISON OF THE BINDING CHARACTERISTICS OF TRITIATED OPIATES AND OPIOID PEPTIDES
Authors: GILLAN MAUREEN G.C. , KOSTERLITZ H.W. , PATERSON S.J. 
Published: July 2012

Binding assays on homogenates of guinea‐pig brain showed that the maximal number of binding sites was different for different tritiated ligands interacting with the opiate receptors.
At 25°C the binding capacity of morphine or dihydromorphine was only about 3 pmol/g fresh brain whereas etorphine and d‐Ala2‐l‐Leu5‐ and d‐Ala2‐l‐Met5‐enkephalin amide had capacities of 13 to 15 pmol/g brain. d‐Ala2‐d‐Leu5‐enkephalin had an intermediate capacity of about 6 pmol/g brain.
The binding capacities of the natural methionine‐ and leucine‐enkephalins measured at 0°C were 5 to 6 pmol/g brain. At this temperature, the binding capacity of dihydromorphine, d‐Ala2‐d‐Leu5‐enkephalin and of the two enkephalin amides was only slightly lower than at 25°C.
In assays in which unlabelled ligand competed with the same labelled ligand, the inhibition constants (K1) were equal to or not more than twice as large as the equilibrium dissociation constant (Kd) determined in saturation assays. In contrast, the K1 of unlabelled dihydromorphine against [3H]‐d‐Ala2‐d‐Leu5‐enkephalin or of unlabelled d‐Ala2‐d‐Leu5‐enkephalin against [3H]‐dihydromorphine were about 20 times higher than the respective Kd values.
When for a given compound the ratio of the K1 value against [3H]‐d‐Ala2‐d‐Leu5‐enkephalin to the K1 value against [3H]‐dihydromorphine (discrimination ratio) is calculated, a high value indicates selectivity in favour of the μ‐receptor and a low value selectivity in favour of the δ‐receptor. The most selective μ‐agonist known so far is normorphine with a discrimination ratio of 70 and the most selective δ‐agonist is d‐Ala2‐d‐Leu5‐enkephalin with a ratio of 0.11. The selectivity of the known antagonists is in favour of the μ‐receptor, since their discrimination ratios are larger than 1, varying between 10 for naloxone and 4 for Mr 2266.
FURTHER STUDIES ON THE INHIBITION OF MONOAMINE SYNTHESIS BY MONOFLUOROMETHYLDOPA
Authors: BEY PHILIPPE , JUNG MICHEL J. , KOCH‐WESER JAN , PALFREYMAN MICHAEL G. , SJOERDSMA ALBERT , WAGNER JOSEPH , ZRAÏKA MONIQUE 
Published: July 2012

α‐Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme‐activated irreversible inhibitor of aromatic l‐amino acid decarboxylase produces a substantial and long‐lasting decrease in the catecholamine content of mouse brain, heart and kidney.
Single doses of MFMD reduce the 5‐hydroxytryptamine concentration of mouse brain without altering the tryptophan concentration.
In animals treated with MFMD, peripheral but not brain noradrenaline is restored within 1 h to control levels by an intraperitoneal injection of dopamine.
EVIDENCE FOR TWO TYPES OF EXCITATORY RECEPTOR FOR 5‐HYDROXYTRYPTAMINE IN DOG ISOLATED VASCULATURE
Authors: APPERLEY EIRA , FENIUK W. , HUMPHREY P.P.A. , LEVY G.P. 
Published: July 2012

As part of an investigation into the mode of action of anti‐migraine drugs, a study of the excitatory receptors for 5‐hydroxytryptamine (5‐HT) has been carried out in a range of isolated vascular preparations from the dog.
5‐HT contracted the dog isolated femoral artery and saphenous vein over the concentration‐range 1.0 × 10−8to 5.0 × 10−6mol/l.
In the femoral artery methysergide and cyproheptadine were potent, competitive and specific antagonists of the contractile responses to 5‐HT, with pA2 values of 8.52 and 8.55 respectively.
In the saphenous vein, methysergide was only a weak antagonist of 5‐HT. In addition, it was an agonist over the concentration‐range 5.0 × 10−8to 1.0 × 10−5mol/l. Cyproheptadine was a weak and unsurmountable antagonist of contractile responses to 5‐HT and methysergide.
Contractile responses to 5‐HT and methysergide in the saphenous vein were not antagonized by morphine (3.0 × 10−5mol/l), indomethacin (5.0 × 10−5mol/l), phentolamine (5.0 × 10−7mol/l), propranolol (1.0 × 10−6mol/l), atropine (1.0 × 10−6mol/l), mepyramine (1.0 × 10−6mol/l) or cimetidine (1.0 × 10−5mol/l).
In the external carotid and lingual arteries the pattern of activity obtained with methysergide and cyproheptadine was the same as that in the femoral artery, while in the auricular artery the pattern of activity was the same as that in the saphenous vein.
The results are consistent with the hypothesis that there are two types of receptor mediating 5‐HT‐induced vasoconstriction in dog vasculature. One type, characterized by the pattern of activity obtained in the femoral artery, is like the previously described ‘D‐receptor’. The other type, characterized by the pattern of activity obtained in the saphenous vein, has not been described before. The verification of this hypothesis requires the identification of a specific antagonist of 5‐HT and methysergide in the saphenous vein.
EFFECTS OF CHANGES IN THE STRUCTURE OF ENKEPHALINS AND OF NARCOTIC ANALGESIC DRUGS ON THEIR INTERACTIONS WITH μ‐ AND δ‐RECEPTORS
Authors: KOSTERLITZ H.W. , LORD J.A.H. , PATERSON S.J. , WATERFIELD ANGELA A. 
Published: July 2012

The activity pattern of analogues of the enkephalins was determined in four parallel assays, the inhibition of the electrically evoked contraction of the guinea‐pig ileum and mouse vas deferens at 36°C and the inhibition of [3H]‐naltrexone and [3H]‐leucine‐enkephalin binding at 0 to 4°C in homogenates of guinea‐pig brain.
The activity pattern was best characterized by the ratio of the potency in the guinea‐pig ileum to that in the mouse vas deferens (G.p.i./M.v.d.) and the ratio of the potency in inhibiting [3H]‐naltrexone binding to that in inhibiting [3H]‐leucine‐enkephalin binding (Nal/Leu).
The enkephalins had low G.p.i./M.v.d. (0.02 to 0.09) and low Nal/Leu (0.05 to 0.18) ratios whereas the corresponding values for morphine were 7.0 and 7.5.
Analogues obtained by substituting d‐Ala for Gly2and d‐Met or d‐Leu for l‐Met5or l‐Leu5showed only minor changes in G.p.i./M.v.d. (0.01 to 0.11) and in Nal/Leu (0.06 to 0.13) ratios.
Analogues in which resistance to enzymatic degradation was brought about by amidation of the C‐terminal carboxylic group or methylation of the amino group of tyrosine or both modifications, had G.p.i./M.v.d. ratios of 1.2 to 5.5 and Nal/Leu ratios of 0.5 to 21. High values (2.1 and 3.4) were found for the potent antinociceptive analogue of Sandoz, Tyr‐d‐Ala‐Gly‐NCH3Phe‐Met(O)‐ol.
In the mouse vas deferens, some of the analogues with high G.p.i./M.v.d. and Nal/Leu ratios were tested for antagonism by naloxone and found to require less than the high concentration needed for the natural enkephalins. C57/BL mice, which have a lowered sensitivity to morphine but a normal response to peptides with low G.p.i./M.v.d. and Nal/Leu ratios, had a lowered sensitivity to analogues with high ratios.
In the alkaloid‐like series of narcotic analgesic drugs, ketobemidone, levorphanol, methadone, etorphine and the antagonist Mr 2266 had lower Nal/Leu ratios (1.0 to 2.8) than morphine, normorphine, naloxone and naltrexone (8 to 12).
It would appear that compounds with low G.p.i./M.v.d. and Nal/Leu ratios interact mainly with δ‐receptors in the brain and peripheral nervous system while compounds with high ratios interact mainly with μ‐receptors. For antinociceptive action μ‐receptors may be more important than δ‐receptors.
POTENTIATION BY DILAZEP OF THE NEGATIVE INOTROPIC EFFECT OF ADENOSINE ON GUINEA‐PIG ATRIA
Authors: FUJITA SHINJI , ISHIDA YUKIO , IZUMI KYOKO , MORITOKI HIDEKI , OHARA MASAYUKI , TAKEI MASAO 
Published: July 2012

Dilazep, a coronary dilator, has been reported to potentiate the negative inotropic and negative chronotropic responses of guinea‐pig atria to adenosine. Studies were made on the mechanism of the potentiating action of dilazep with special reference to the degradation and uptake of adenosine.
The negative inotropic actions of adenosine and adenine nucleotides, such as ATP, ADP, AMP and cyclic AMP, on guinea‐pig atria were selectively and dose‐dependently augmented by dilazep at concentrations insufficient to produce any effect alone (0.01 to 1 μm).
Incubation of atrial tissue with 8.8 nm adenosine, containing 0.1 μCi of [3H]‐adenosine, resulted in accumulation of [3H]‐adenosine in the tissue; dilazep (0.01 to 1 μm) inhibited this accumulation.
Adenosine (10 μm to 10 mm) was degraded to inosine and hypoxanthine during incubation with atrial tissue; dilazep (0.1 to 10 μm) retarded the disappearance of adenosine and the formation of inosine and hypoxanthine.
These results suggest that dilazep potentiates the negative inotropic effect of adenosine on guinea‐pig atria by preventing both its accumulation by atrial tissue and degradation by deaminase.
INCREASES IN AGGREGATION BY AND UPTAKE OF 5‐HYDROXYTRYPTAMINE WITH PLATELETS FROM RABBITS TREATED WITH CHLORPROMAZINE
Authors: CI M. BALDAC , BALDACCI MARA , BERGEL T.D. , BORN G.V.R. , HICKMAN MARGARET 
Published: July 2012

Citrated platelet‐rich plasma was prepared from New Zealand white rabbits before, during and after administration of chlorpromazine (2 mg/kg) intramuscularly once daily for 3 to 4 weeks.
In these plasmas, the velocity of platelet aggregation by 5‐hydroxytryptamine (5‐HT) added at 1, 3 and 10 μm increased greatly, beginning 3 to 4 days after the start of chlorpromazine injections and lasting for a similar period after they were terminated The increase had two maxima, the first after 6 to 10 days and the second after 17 to 24 days. Chlorpromazine treatment did not affect aggregation by adenosine diphosphate (ADP).
The uptake of 5‐HT by rabbit platelets was very fast and linear for less than 10 s. In platelets from untreated rabbits the uptake had a Km of 0.35 ± 0.08 μm and a Vmax of 39.8 ± 6.1 pmol 10−8 platelets 10−1 (n = 5).
In platelets from rabbits injected with chlorpromazine (see (2) above) both kinetic constants increased significantly, the Km to 0.88 ± 0.08 μm and the Vmax to 67.8 ± 5.5 pmol. 10−8 platelets. 10−1 s (n = 9).
PRESYNAPTIC AND POSTSYNAPTIC DEPRESSANT EFFECTS OF PHENYTOIN SODIUM AT THE NEUROMUSCULAR JUNCTION
Authors: GAGE P.W. , LONERGAN M. , TORDA T.A. 
Published: July 2012

Phenytoin sodium, 10μg/ml (3.6 × 10−5 m), reduces the amplitude of endplate potentials in mouse sternomastoid neuromuscular junctions.
The reduction in amplitude is due to a reduction both in the quantal content of endplate potentials and in the amplitude of the voltage response to quanta of acetylcholine.
The reduction caused by phenytoin in the amplitude of spontaneous miniature end plate potentials was due to a reduction in the time constant of decay of miniature endplate currents.
It is concluded that phenytoin depresses neuromuscular transmission by reducing both the amount of acetylcholine secreted in response to an action potential and by reducing the lifetime of postsynaptic channels activated by acetylcholine.