bluuebunny/crossref_metadata_2025_split huggingface dataset:
DISTRIBUTION AND FUNCTION OF β‐ADRENOCEPTORS IN DIFFERENT CHAMBERS OF THE CANINE HEART
Authors: BAKER STEPHEN P. , BOYD HELEN M. , POTTER LINCOLN T. 
Published: July 2012

An improved binding assay involving (−)‐[3H]‐dihydroalprenolol (DHA) and KCl‐washed cardiac membranes was developed to study β‐adrenoceptors in the canine heart quantitatively.
Receptor numbers varied from 3.8 to 7.1 pmol/g fresh tissue, showing a steady increase from left atrium → right atrium →right ventricle → interventricular septum → left ventricle. With one minor exception, the same pattern was found for adenylate cyclase activity and Na+, K+ ‐activated ATPase activity.
The binding of DHA was inhibited in the expected manner by β‐adrenoceptor agonists and antagonists, and was stereospecific, in confirmation of previous studies. Dissociation constants determined from Scatchard analyses included DHA: 2.5 nm; (−)adrenaline: 230 nm; (−)noradrenaline: 1167 nm. Kinetic analyses of the binding of DHA yielded a KD of about 4 nm.
The distribution of β‐receptors is closely related to that of blood flow and the arrival plus retention of a circulating catecholamine, but is markedly different from that of endogenous noradrenaline, and thus adrenergic nerve terminals. Most receptors thus appear not at synapses but diffusely localized where they can react with circulating adrenaline.
Evidence is discussed that β‐receptors at synapses respond primarily to neural noradrenaline, less to circulating adrenaline, and hardly at all to circulating noradrenaline; responses mediate increased cardiac output during exercise. In contrast most cardiac β‐receptors appear to respond only to adrenaline, and to be used, except at times of severe circulatory stress, during psychological stress.
PHARMACOLOGICAL ANALYSIS OF SALIVARY AND BLOOD FLOW RESPONSES TO HISTAMINE OF THE SUBMANDIBULAR GLAND OF THE DOG
Authors: SHIMIZU T. , TAIRA N. 
Published: July 2012

The submandibular gland in situ was perfused with blood through the glandular artery at constant pressure in anaesthetized dogs. Drugs were administered intra‐arterially.
Histamine produced both salivation and an increase in blood flow, each response having an early and a late component.
Marked tachyphylaxis to histamine developed in both of the salivary responses but only in the late blood flow response to histamine.
The early and late salivary responses were abolished and the late blood flow response was diminished by infusion of tetrodotoxin in doses that abolished the salivary and blood flow responses to electrical stimulation of the chorda‐lingual nerve.
The whole salivary response to histamine was abolished by infusion of (−)‐hyoscyamine in doses that greatly antagonized the salivary and blood flow responses to acetylcholine, whereas the blood flow responses to histamine were scarcely modified. These doses of (−)‐hyoscyamine abolished the salivary response to chorda‐lingual nerve stimulation but left the blood flow response to it unaffected.
The salivary and blood flow responses to histamine were unaffected by infusion of hexamethonium in doses that almost abolished the salivary and blood flow responses to chorda‐lingual nerve stimulation.
The whole salivary response to histamine was abolished and the late blood response to histamine was partially inhibited by the histamine H1‐receptor antagonist, mepyramine, but not, by the histamine H2‐receptor antagonist, metiamide.
The early blood flow response to histamine was antagonized by both mepyramine and metiamide but mepyramine was far more effective than metiamide.
These results led to the following conclusions: (1) the whole salivary response and a part of the late blood flow response to histamine are due entirely to excitation of parasympathetic postganglionic neurones; (2) neuronal histamine receptors involved are exclusively of the H1‐type; (3) histamine has no direct stimulant action on the glandular cells; (4) the early blood flow response and the remaining part of the late blood flow response to histamine result from the direct action on vascular smooth muscle in the glandular vascular bed; (5) vascular histamine receptors consist of H1‐ and H2‐receptors.
COMPARISON OF THE ANTI‐HYPERTENSIVE RESPONSE TO β‐ADRENOCEPTOR BLOCKING DRUGS IN INTACT AND ADRENAL‐DEMEDULLATED SPONTANEOUSLY HYPERTENSIVE RATS
Authors: BUCKINGHAM R.E. , HAMILTON T.C. 
Published: July 2012

The β‐adrenoceptor blocking drugs atenolol, metoprolol, practolol, propranolol, timolol and oxprenolol (as racemates) were administered acutely at three dose levels (0.01, 0.03 and 0.1 mmol/kg i.p. or s.c.) to spontaneously hypertensive rats with intact adrenal glands (SH‐rats) and following unilateral adrenalectomy and contralateral adrenal‐demedullation (SHAD‐rats). Changes in mean arterial pressure and heart rate were determined via an indwelling aortic catheter, with the animals placed in a quiet environment.
All drugs significantly lowered the blood pressure of SHAD‐rats, and these responses were not always associated with changes in basal heart rate.
With the exception of metoprolol and atenolol, the β‐adrenoceptor blocking drugs were less effective as anti‐hypertensives in SH‐ than in SHAD‐rats. Notably, timolol and oxprenolol lowered the blood pressure of SH‐rats at low doses only, whereas propranolol evoked a pressor response in this model.
Whilst (+)‐propranolol lowered the blood pressure of SHAD‐rats only at a dose which caused myocardial depression, the anti‐hypertensive response to (−)‐propranolol did not parallel changes in heart rate and was preceded by a pressor response.
The results imply that adrenal catecholamine release contributes towards masking the anti‐hypertensive effects of some β‐adrenoceptor antagonists in SH‐rats.
EFFECTS OF SULPHASALAZINE AND ITS METABOLITES ON PROSTAGLANDIN SYNTHESIS, INACTIVATION AND ACTIONS ON SMOOTH MUSCLE
Authors: HOULT J.R.S. , MOORE P.K. 
Published: July 2012

We have investigated the effects of sulphasalazine and of its principal colonic metabolites (5‐aminosalicylic acid and sulphapyridine) on prostaglandin inactivation, synthesis and actions on gastrointestinal smooth muscle.
Sulphasalazine inhibits prostaglandin F2α breakdown in 100,000 g supernatants in all organs so far tested from 7 species with an ID50 of approx. 50 μm; it has a selective action on prostaglandin 15‐hydroxydehydrogenase and does not inhibit prostaglandin Δ‐13 reductase, prostaglandin 9‐hydroxydehydrogenase or ‘enzyme X’ at millimolar concentrations. Enzyme activities were measured radiochemically or by bioassay.
Sulphapyridine and 5‐aminosalicylic acid do not inhibit prostaglandin inactivation in vitro (4 species tested). A methyl analogue of sulphasalazine is a more potent inhibitor than the parent compound. Rabbit colon prostaglandin F2α metabolism in vitro was inhibited by the following drugs with ID50 values (μm) of: diphloretin phosphate 20, sulphasalazine 50, indomethacin 220, frusemide 1000 and aspirin 10,000. A similar rank order of potencies was obtained with rabbit kidney.
Sulphasalazine at 50 to 100 μm inhibited inactivation of prostaglandin E2 in the perfused rat and guinea‐pig lung by 3 to 40% (rat) and 32 to 100% (guinea‐pig) when measured by superfusion cascade bioassay and of prostaglandin F2α by 43.6 ± 6.5% in rat lung perfused with 50 μm sulphasalazine and assayed radiochemically.
Prostaglandins E1 and E2 were 97.0 ± 8.2% and 92.3 ± 6.8% inactivated in the lungs after intravenous injection in the anaesthetized rat as measured by reference to their vasodepressor potencies when injected intra‐arterially. Prostaglandin A2 was not similarly inactivated. Pulmonary inactivation was prevented in the presence of an intravenous infusion of 16.3 μg kg−1 min−1 sulphasalazine and partially inhibited at a lower infusion rate.
Prostaglandin biosynthesis from arachidonic acid was measured in microsomal preparations from four sources by bioassay and radiochemical methods. Indomethacin was a potent inhibitor (ID50 0.8 to 4.1 μm) but sulphasalazine and its methyl analogue were very weak inhibitors (ID50 1500 to > 5000 μm), 5‐aminosalicylic acid was weaker still and sulphapyridine inactive.
Sulphasalazine at 50 μm did not affect the actions of prostaglandins on five smooth muscle preparations; at 500 μm there was a rapidly reversible and probably non‐specific antagonism of responses to low doses of prostaglandins.
The specificity and selectivity of the interaction of sulphasalazine and its metabolites with the formation, breakdown and actions of prostaglandins are discussed.
THE INTERACTION OF HUMAN HAEMOGLOBIN WITH ALLOSTERIC EFFECTORS AS A MODEL FOR DRUG‐RECEPTOR INTERACTIONS
Authors: GOODFORD P.J. , ST‐LOUIS J. , WOOTTON R. 
Published: July 2012

The release of bound oxygen from oxyhaemoglobin by allosteric effectors is considered as a model for those drug‐receptor interactions where the primary response to agonist binding is the release of a second messenger species.
A theory of haemoglobin oxygenation, based on the two‐state model of Monod, Wyman & Changeux (1965) is used to predict the relationship between ‘pharmacological’ response and dose of agonist. This relationship is the same as that derived from classical pharmacological occupancy theory.
The potency of an agonist is a weighted average of its affinities for the two conformational states of the receptor.
The efficacy of an agonist depends not only upon its preferential binding to one of the two conformational states, but also on its ability to alter the functional properties of that state by lowering the affinity of the state for the second messenger.
2,3‐Diphosphoglycerate and adenosine triphosphate are approximately equipotent and of similar efficacy, but inositol hexaphosphate is about 500 times more potent and has a higher efficacy.
STUDY OF CENTRAL NEUROTRANSMITTERS IN STRESS‐INDUCED GASTRIC ULCERATION IN ALBINO RATS
Authors: BHARGAVA K.P. , DAAS M. , GUPTA G.P. , GUPTA M.B. 
Published: July 2012

Restraint when combined with cold (4°C) consistently induces gastric ulceration in rats at 2 h. The cold‐restraint ulcer (CRU) technique provides a suitable model for acute studies.
The peripheral mechanisms in CRU seem to be increased sympathetic and parasympathetic outflow since CRU was significantly reduced by prior spinal transection or vagotomy or by appropriate blocking agents. Since metiamide significantly reduced CRU, H2‐histamine receptors are also involved.
Central catecholaminergic as well as cholinergic mechanisms seem to be responsible for the activation of peripheral sympathetic and parasympathetic outflow in CRU, since central administration of dibenamine, propranolol, 6‐hydroxydopamine and atropine prevented the CRU.
Exogenous administration of putative neurotransmitters (adrenaline, noradrenaline and acetylcholine) into the cerebroventricular system produced gastric ulceration similar to CRU. However, dopamine, histamine and 5‐hydroxytryptamine failed to induce gastric ulceration.
The results with intracerebroventricular adrenaline and acetylcholine indicate a central cholinergic link distal to adrenergic activation in the ulcerogenesis.
Intracerebroventricular adrenaline‐induced gastric ulceration appears to be most akin to CRU. However, other central neurotransmitter mechanisms may also be involved.
INFERIOR CARDIAC NERVE ACTIVITY IN THE CAT DURING SUPER‐FUSION OF THE VASCULARLY ISOLATED CAROTID SINUS WITH PROPRANOLOL
Authors: McCLEARY M. , TUTTLE R.S. 
Published: July 2012

Inferior cardiac nerve activity in 9 cats was in inverse relationship to the pressure maintained in the systemically isolated and perfused carotid sinus.
Perfusion with propranolol produced no change in this relationship at a concentration of 5.0 μg/ml, but abolished it at 50.0 μg/ml.
The results suggest that concentrations of propranolol which have been reported to enhance the sensitivity of the carotid sinus to pressure do not enhance one neurophysiological component of the reflex depressor response.
INTERACTION BETWEEN SYNTHETIC ANALOGUES OF QUINOXALINE ANTIBIOTICS AND NUCLEIC ACIDS: ROLE OF THE DISULPHIDE CROSS‐BRIDGE AND d‐AMINO ACID CENTRES IN DES‐N‐TETRAMETHYL‐TRIOSTIN A
Authors: FOX K.R. , OLSEN R. K. , WARING M.J. , CHAKRAVARTY P.K. , OLSEN R.K. 
Published: July 2012

[Ala3, Ala7] TANDEM is an analogue of des‐N‐tetramethyl‐triostin A (TANDEM) in which both l‐Cys residues of the octapeptide ring are replaced by l‐Ala; accordingly it lacks the disulphide cross‐bridge which limits the conformational flexibility of TANDEM.
In [l‐Ser1] TANDEM the configuration of one of the serine residues is inverted, altering the disposition of one of the quinoxaline chromophores with respect to the peptide ring.
Both compounds interact weakly but detectably with natural DNAs as judged by spectral shifts and increases in the thermal denaturation (‘melting’) temperature Tm. They also raise the Tm of poly rA.poly rU.
Binding isotherms determined by solvent partition analysis with [Ala3, Ala7] TANDEM yield association constants of about 103 m−1 for its interaction with natural DNAs. A Scatchard plot for binding to poly(dA‐dT) determined by solvent partition and spectrophotometric methods shows marked evidence of cooperativity with an intrinsic association constant 1.9 times 104 m−1, 8.7 nucleotides per binding site, and cooperativity parameter 15.
Binding of [Ala3, Ala7] TANDEM to short rod‐like fragments of poly(dA‐dT) increases their contour length by almost the theoretical amount expected for an ideal process of bifunctional intercalation.
No effect of either compound on the winding of the DNA helix could be detected in sedimentation experiments with closed circular duplex PM2 DNA.
It is concluded that the cross‐bridge of TANDEM greatly stabilizes its binding to DNA, most probably via entropic factors, but is not the only structural feature that influences its AT sequence‐selectivity. The consequences of epimerising one of the d‐Ser residues appear as disastrous as epimerising both.
The experimental details for the synthesis of [Ala3, Ala7] TANDEM and [l‐Ser1] TANDEM are given in an appendix to this paper.
THE ACTION OF POLYMYXIN B AT THE FROG NEUROMUSCULAR JUNCTION
Authors: DURANT NICHOLAS N. , LAMBERT JEREMY J. 
Published: July 2012

The effects of polymyxin B at the neuromuscular junction of the frog were studied by conventional electrophysiological and voltage clamp techniques.
At a concentration of 2.5 μg/ml polymyxin B produced neuromuscular blockade in 10 to 15 min and endplate potentials (e.p.ps) could be recorded. Resting membrane potential was unaffected. The neuromuscular block was characterized by a depressed e.p.p. quantal content (28 ± 7), which was similar to that determined from endplates exposed to 13 mm magnesium (23 ± 3), and a low e.p.p. quantal size, which was similar to that determined from endplates exposed to 3 μm (+)‐tubocurarine.
Polymyxin B (0.25 to 0.75 μg/ml) decreased mean miniature e.p.p. amplitude with little effect on frequency.
At a concentration of 5 μg/ml polymyxin B markedly shortened the duration of endplate currents (e.p.cs) and abolished the relationship between holding potential and the time to half‐decay at negative potentials greater than −;60 mV. This action is consistent with block of open acetylcholine activated ionic channels.
4‐Aminopyridine (20 μm) antagonized the depressed e.p.p. quantal content produced by polymyxin B but did not alter the shortened e.p.c. duration.
It is concluded that polymyxin B decreases quantal release and produces some degree of postjunctional receptor blockade and a marked and persistent blockade of acetylcholine activated channels. The latter action may explain the difficulty of reversal of polymyxin B‐induced neuromuscular blockade and its non‐competitive nature.
INHIBITION OF LYMPHOCYTE CAPPING AND TRANSFORMATION BY PROPRANOLOL AND RELATED COMPOUNDS
Authors: ANDERTON BRIAN H. , AXFORD JOHN S. , COHN PETER , MARSHALL NICHOLAS J. , SHEN LI , SPRAKE SALLY 
Published: July 2012

The effects of propranolol on phytohaemagglutinin (PHA)‐induced transformation of murine T lymphocytes and capping of anti‐IgG on the surface of murine B lymphocytes have been examined.
A 50% inhibition of transformation was observed with 10−5m propranolol, whereas a higher concentration, of the order of 10−3m propranolol was required to inhibit capping by 50%. The (+)‐and (−)‐isomers of propranolol proved equipotent in these respects, and the relative potencies of selected analogues of propranolol (alprenolol, oxprenolol, metoprolol, practolol and sotalol) coincided with their potencies as membrane stabilizers; however, lymphocyte transformation was consistently more sensitive than capping.
Similar effects were also seen with quinidine, chlorpromazine and lignocaine, and it was concluded that the inhibition of both lymphocyte functions was due to the membrane stabilizing actions of propranolol.
THE EFFECTS OF TRIMETHADIONE ON PENTETRAZOL‐INDUCED DISCHARGES OF PRIMARY MUSCLE SPINDLE AFFERENTS FROM THE HIND LIMB OF THE RAT
Authors: ANGEL A. , CLARKE K.A. 
Published: July 2012

Recordings have been made from primary muscle spindle afferents in split dorsal root filaments of rats anaesthetized with urethane.
Injection of pentetrazol (PTZ, 10 mg/kg) produced elevated discharge in the afferents with intact efferents without any changes in tension or electrical activity of the muscle of origin.
This elevated discharge was found to contain elements of both γd and γs activation.
Trimethadione (100 mg/kg), itself produced a transient increase in discharge and effectively suppressed PTZ‐induced discharges of the afferents for at least 2 h.
These results are discussed in the context of established effects on sensory and motor systems.
ORAL HYOSCINE BUTYLBROMIDE DOES NOT ALTER THE PATTERN OF SMALL INTESTINAL MOTOR ACTIVITY
Authors: THOMPSON D.G. , WINGATE D.L. 
Published: July 2012

Continuous recording of proximal jejunal motility in conscious healthy subjects was made following ingestion of 200 mg hyoscine butylbromide (ten times the recommended therapeutic dosage).
There was no detectable modification of fasting or postprandial motor activity, although the therapeutic potency of the standard intravenous dose was confirmed.
INHIBITION BY CLINICALLY USED DYES OF PROSTAGLANDIN INACTIVATION IN RAT AND HUMAN LUNG
Authors: BAKHLE Y.S. 
Published: July 2012

The effect of several clinically used dyes on prostaglandin E2 (PGE2) inactivation was studied in rat and human isolated lung.
All the dyes, given as infusions through the pulmonary circulation, inhibited the inactivation of PGE2 as measured by bioassay. The action of the dyes was readily reversible on stopping the infusion.
The concentration producing 30% inhibition varied from 0.6 μm for indocyanine green to over 100 μm for methylene blue.
Inhibition of PGE2 inactivation was also observed when the dyes were given as bolus injections during PGE2 infusions through the lung.
These dyes are therefore not physiologically inert as they had previously been thought to be and their interaction with prostaglandins may affect the variables they are used to measure.
DRUG‐RECEPTOR RECOGNITION: ELECTROSTATIC FIELD LINES AT THE RECEPTOR AND DIELECTRIC EFFECTS
Authors: DEAN P.M. 
Published: July 2012

In this paper the directional component of the vector electrostatic field emanating from a drug receptor is analysed in the three orthogonal planes
B‐DNA with an alternating guanine‐cytosine sequence was chosen for a receptor model and the lines of force constructed for two dielectric conditions, namely the cases where firstly the dielectric is homogeneous and a constant throughout the space surrounding the receptor, and secondly where the dielectric is inhomogeneous and is treated as a vector quantity
Electric field line maps indicate marked differences in the local fields situated in the helical wide and narrow grooves for the different sequences of cytosine and guanine; these variations are enhanced when the dielectric is handled as a vector
The significance of electric field lines in interpreting receptor‐induced ligand orientation effects is discussed since the direction of the lines is related to the torque that a receptor would impose on an attacking drug molecule.
ACTIONS OF VERAPAMIL, DILTIAZEM AND OTHER DIVALENT CATIONS ON THE CALCIUM‐CURRENT OF Helix NEURONES
Authors: AKAIKE N. , BROWN A.M. , NISHI K. , TSUDA Y. 
Published: July 2012

Effects of organic Ca2+‐antagonists, verapamil and diltiazem, and cations, Ni2+, Mn2+, Co2+ and La3+ on Ca2+ current (ICa) separated from other ionic currents in a Helix neurone were studied. A suction pipette technique which allows internal perfusion of the cell body and voltage clamp was used
Verapamil and diltiazem (10−6‐10−4m) increased the threshold, and decreased both the amplitude and rate of rise of the soma Ca2+‐spike. Both agents inhibited ICa over the entire range of the current‐voltage (I‐V) relationship dose‐dependently, without shifting the threshold of the I‐V relationship. Increases in external Ca2+ overcame the inhibitory action of the agents
Divalent cations, Ni2+, Mn2+, Co2+ and the trivalent cation, La3+ inhibited ICa dose‐dependently, but induced shifts of the I‐V relationship to more positive voltages. The order of potency of inhibition of ICa among these cations was as follows; Ni2+ > La3+ > Mn2+ > Co2+
Double reciprocal plots for peak ICa versus external Ca2+ concentrations in the presence or absence of both organic and inorganic Ca2+‐antagonists intersect at the ordinate. Results indicate that both organic and inorganic Ca2+‐antagonists compete for Ca2+ at the common binding site for Ca2+
Internal application of the organic Ca2+‐antagonists (10−4m) inhibited ICa in a time‐dependent manner to about 40–60% of the control. Ni2+, when applied internally, also depressed ICa
The results provide evidence that organic Ca2+‐antagonists occupy the binding site for Ca2+ in a competitive manner at the surface of the soma membrane of the Helix neurone, while divalent and trivalent cations, in addition to inhibiting ICa in a similar manner to the organic Ca2+‐antagonists, change the surface charge of the soma membrane.
DIFFERENT MECHANISMS OF ACTION OF HISTAMINE IN ISOLATED ARTERIES OF THE DOG
Authors: KONISHI MAKOTO , TODA NOBORU , YAMAMOTO MASAKATSU 
Published: July 2012

In helically‐cut strips of dog coronary, superior mesenteric, right gastro‐epiploic and renal arteries contracted with prostaglandin F2β (PGF2β), histamine produced a dose‐related relaxation, while, in contrast, the amine caused only a contraction of cerebral arterial strips
The contractile response of cerebral arteries to histamine was attenuated by chlorpheniramine (10−6M)but was unaffected by cimetidine (10−5m). Relaxant responses to histamine of coronary and renal arteries were significantly attenuated by treatment with cimetidine and to a similar extent by combined treatment with cimetidine and chlorpheniramine. Chlorpheniramine alone was ineffective
In mesenteric and gastro‐epiploic arteries, relaxant responses to histamine were attenuated only slightly by cimetidine. Chlorpheniramine slowed the development of histamine‐induced relaxations but did not alter the magnitude of the relaxations. Combined treatment with these H1‐ and H2‐ antagonists attenuated the histamine‐induced relaxations to an appreciably greater extent than treatment with cimetidine alone
It may be concluded that the cerebroarterial contraction induced by histamine is mediated through H1‐receptors and the relaxations of coronary and renal arteries induced by histamine are mediated through H2‐receptors. It appears that H1‐ and H2‐receptors interact with each other to produce potentiation of histamine‐induced relaxations of mesenteric and gastro‐epiploic arteries.