bluuebunny/crossref_metadata_2025 huggingface dataset:
AN ANALYSIS OF THE DEPRESSOR RESPONSES TO HISTAMINE IN THE CAT AND DOG: INVOLVEMENT OF BOTH H1‐ AND H2‐RECEPTORS
Authors: BLACK J.W. , OWEN D.A.A. , PARSONS M.E.
Published: July 2012

The depressor responses to histamine, in anaesthetized cats and dogs, have been shown to involve both histamine H1‐ and H2‐ receptors.

In both species, histamine caused dose‐dependent falls in blood pressure. The dose‐response curve could be displaced to the right by administration of mepyramine 2.5 × 10−6 mol/kg i.v. The displacement was maximal with a dose‐ratio of less than ten.

Metiamide alone, up to 2 × 10−6 mol kg−1 min−1, had no significant effect on the histamine dose‐response curve.

When administered in the presence of mepyramine, metiamide, 4 × 10−7 and 2 × 10−6 mol kg−1 min−1, caused dose‐dependent displacements to the right, of the histamine dose‐response curve greater than could be achieved with mepyramine alone.

The results indicate the presence of both histamine H1‐ and H2‐receptors in the cardiovascular system of the cat and dog. Both receptors produce a common response, i.e. a fall in blood pressure.
COMPARATIVE BIOASSAY OF PROSTAGLANDIN E2 AND ITS THREE PULMONARY METABOLITES
Authors: CRUTCHLEY D.J. , PIPER PRISCILLA J.
Published: July 2012

The relative potencies of prostaglandin E2 and its metabolites 15‐keto PGE2, 13,14‐dihydro‐15‐keto‐PGE2 and 13,14, dihydro‐PGE2 were investigated on isolated smooth muscle preparations. These were rat stomach strip, colon and uterus, chick rectum, guinea‐pig ileum, trachea and pulmonary artery and rabbit aorta and pulmonary artery. 15‐keto PGE2 was equiactive or 1–1.8 times more potent than prostaglandin E2 in relaxing guinea‐pig trachea but otherwise the three metabolites were less active than prostaglandin E2 on all preparations.
PRESSOR RESPONSE INDUCED BY LOCAL ANAESTHETICS PERFUSED THROUGH THE CEREBRAL VENTRICLES OF DOGS
Authors: HARANATH P.S.R.K. , INDIRA‐NARAYAN G. , VENKATAKRISHNA‐BHATT H.
Published: July 2012

The antihistamines mepyramine and halopyramine which have local anaesthetic properties, produced a rise in arterial blood pressure followed by a fall, similar to that seen with procaine, when perfused in a 10 mg/ml solution from the lateral ventricle to the cisterna magna in dogs.

The pressor response produced by procaine perfused through the cerebral ventricle is due to an action on structures situated in the caudal half of the floor of the fourth ventricle because a pressor response was obtained when a few microlitres of a 50 mg/ml solution of procaine were applied to a small area of the exposed floor of the fourth ventricle in a region 2 to 4 mm rostral to obex, and after cauterization of this area procaine perfused through the cerebral ventricles no longer raised arterial blood pressure.

Bilateral denervation of the carotid sinus did not affect the pressor response obtained with procaine perfused through the cerebral ventricles.

The pressor response to procaine is mediated through the sympathetic nervous system. It results partly from an increased adrenaline discharge from the adrenal glands and partly from increased sympathetic vasomotor tone, because the response is abolished or attenuated after removal of the adrenal glands and intravenous injections of hexamethonium and phentolamine.
THE ACTION OF 5‐HYDROXYTRYPTAMINE ON CHEMORECEPTOR DISCHARGES OF THE CATS CAROTID BODY
Authors: NISHI K.
Published: July 2012

Chemoreceptor discharges were recorded in vivo from fine filaments of the carotid sinus nerve containing a single or several active units; their frequency was used as an index of receptor activity. The effects of 5‐hydroxytryptamine (5‐HT) on chemoreceptors were studied in 26 adult cats. At times, sinus baroreceptor discharges were recorded from the carotid nerve and the effect of 5‐HT on the discharges was examined.

Intra‐carotid injections of 5‐HT (2–20 μg) induced a sharp and brief increase in chemoreceptor discharges, followed by depression or block which lasted for several seconds. Repeated injections at short intervals, and a small dose after a large dose of 5‐HT resulted in depressed or blocked response to 5‐HT.

5‐HT in high doses (10–20 μg, La.) slightly depressed the chemoreceptor discharges induced by either acetylcholine (ACh) or NaCN, when these substances were applied within 20 s after 5‐HT. 5‐HT (5–20 μg, i.a.) applied during asphyxia induced a further increase in chemoreceptor discharges, soon followed by block of the discharges lasting for several seconds.

Atropine or hexamethonium in high doses did not change the chemoreceptor response to 5‐HT, while that to ACh was markedly depressed.

(+)‐Lysergic diethylamide (LSD), methysergide or gramine did not alter the response to 5‐HT, while LSD in low doses produced a marked increase in chemoreceptor discharges.

Acute and chronic treatment with reserpine (5–10 mg/kg, i.v.) of the animals did not change the sensitivity and the reactivity of the chemoreceptor to ACh and NaCN, while the chemoreceptor response to 5‐HT was augmented, indicating an increase in the sensitivity of chemoreceptors to 5‐HT.

5‐HT in small doses (2–10 μg, i.a.) induced a marked increase in sinus baroreceptor discharges; subsequently discharges were depressed or blocked for several seconds.

The results are discussed in relation to possible mechanism of action of 5‐HT on the chemoreceptors. It is concluded that the exogenous 5‐HT probably acts directly on the chemosensory nerve endings and depolarizes them, but 5‐HT contained in the carotid body does not play a significant role in the generation of chemoreceptor discharges.
REDUCTION IN THE CHOLINESTERASE ACTIVITY OF THE RAT ANOCOCCYGEUS MUSCLE PRODUCED BY CORTICOSTERONE
Authors: GIBSON A. , POLLOCK D.
Published: July 2012

Administration of corticosterone caused a 47% reduction in the cholinesterase (ChE) activity of homogenates of the rat anococcygeus muscle.

ChE activity was also reduced by morphine withdrawal and this effect was abolished by the corticosteroid synthesis inhibitor, metyrapone.

A single dose of reserpine reduced ChE activity in normal but not in adrenalectomized rats.

ChE activity was increased by adrenalectomy or by metyrapone treatment.

The mechanism of the corticosteroid‐induced reduction in ChE activity is discussed.

The reduction in ChE activity produced by corticosterone, morphine withdrawal, or a single dose of reserpine might explain the leftward shift of the dose‐% response curve to acetylcholine produced by these procedures in the isolated anococcygeus muscle of the rat.
AN ELECTROPHYSIOLOGICAL ANALYSIS OF THE EFFECTS OF AMINE‐UPTAKE BLOCKERS AND α‐ADRENOCEPTOR BLOCKERS ON ADRENERGIC NEUROMUSCULAR TRANSMISSION
Authors: BENNETT M.R. , MIDDLETON J.
Published: July 2012

An electrophysiological study has been made of the effects of either blocking noradrenaline (NA) uptake or α‐adrenoceptors on conduction in adrenergic preterminal axons and on NA release.

The excitatory junction potential (e.j.p.) evoked by a single stimulus increased slightly in duration (maximum 20%) in the presence of high concentrations of desipramine or cocaine (> 1 μg/ml) but there was no change in the spontaneous miniature excitatory junction potential (m.e.j.p.s); the single compound preterminal action potential was decreased in amplitude by a maximum of 10%. The e.j.p., m.e.j.p. and the terminal action potential were not altered by lower concentrations of these drugs (< 1 μg/ml).

The increased decline of the e.j.p. amplitude observed during the first few hundred impulses at high frequencies (10 Hz) in the presence of desipramine or cocaine was accompanied by a similar decline in the amplitude of the preterminal compound action potential, suggesting that the latter gave rise to the former.

These observations suggest that the action on post‐synaptic α‐adrenoceptors of NA released by single impulses is terminated by diffusion, and that any NA which is subsequently taken up into nerves is metabolized.

All the α‐adrenoceptor blocking drugs tested reversed the normal depression in e.j.p. amplitude observed during the first few hundred impulses at high frequencies to facilitation; this was unaccompanied by any changes in the preterminal compound action potential.

α‐Adrenoceptor blocking drugs did not alter the potentiating effect which a conditioning impulse had on the amplitude of the e.j.p. evoked by a subsequent test impulse. The facilitated release of NA during trains of impulses was quantitatively predicted in terms of the addition of the individual potentiations introduced by each impulse in the train.

It is suggested that if there is an auto‐inhibition of NA release, then it is unlikely that the pre‐ and post‐synaptic α‐adrenoceptors are identical.
THE PENETRATION OF DAPSONE, RIFAMPICIN, ISONIAZID AND PYRAZINAMIDE INTO PERIPHERAL NERVES
Authors: ALLEN B.W. , ELLARD G.A. , GAMMON PATRICIA T. , KING R.C. , McDOUGALL A.C. , REES R.J.W. , WEDDELL A.G.M.
Published: July 2012

Dapsone, rifampicin, isoniazid and pyrazinamide were shown to penetrate readily into the sciatic nerves of the dog and sheep.

These findings suggest that the continued persistence of viable drug‐sensitive leprosy bacilli in the peripheral nerves of patients treated for long periods with either dapsone or rifampicin is not due to inadequate intraneural drug penetration.
VASCULAR DOPAMINE RECEPTORS IN THE CANINE HINDLIMB
Authors: BELL C. , CONWAY E.L. , LANG W.J. , PADANYI R.
Published: July 2012

Increases in femoral blood flow were produced by intra‐arterial injections of dopamine (5–50 μg) in some but not all anaesthetized dogs studied, following treatment with the α‐adrenoceptor antagonist, phentolamine.

The dilator effect of dopamine was not due to inhibition of adrenergic vasomotor tone as it was not affected by pharmacological procedures which completely abolished the activity of vasomotor nerves.

Blockade of vascular β‐adrenoceptors using propranolol reduced the flow increases produced by dopamine much less than it did those produced by isoprenaline.

Responses to dopamine were significantly depressed by intra‐arterial administration of ergometrine (0.5 mg). This dose of ergometrine did not reduce femoral dilator responses to acetylcholine, histamine, isoprenaline, bradykinin or 5‐hydroxytryptamine.

It is concluded that the femoral vascular bed in the dog contains specific vasodilator receptors for dopamine. Ergometrine appears to be a selective antagonist of dopamine at these receptors.
THE EFFECTS OF HISTAMINE AND SOME HISTAMINE‐LIKE AGONISTS ON BLOOD PRESSURE IN THE CAT
Authors: OWEN D.A.A.
Published: July 2012

The effects of histamine on blood pressure have been compared with the effects caused by four histamine‐like agonists in anaesthetized cats.

It has been confirmed that the depressor responses to histamine involve both H1‐ and H2‐receptors: depressor responses also follow the administration of selective H1‐ and H2 ‐receptor agonists.

2‐Methylhistamine, in doses up to 1 × 10−7 mol/kg, lowers blood pressure by interaction with H1‐receptors. Larger doses of 2‐methylhistamine also lower blood pressure but this may involve H2‐receptors.

4‐Methylhistamine, in doses up to 1 × 10−7 mol/kg, lowers blood pressure by interaction with H2‐receptors. Larger doses of 4‐methylhistamine also lower blood pressure but this may involve H1‐receptors.

2‐(2‐Aminoethyl)pyridine and 2‐(2‐aminoethyl)thiazole both lower blood pressure by interaction with H1‐receptors only.

The potential value and limitations of these compounds as tools to investigate the cardiovascular effects of histamine are discussed.
HISTAMINE RECEPTORS IN PERIPHERAL VASCULAR BEDS IN THE CAT
Authors: FLYNN SHEILA B. , OWEN D.A.A.
Published: July 2012

The vasodilator activity of histamine has been studied in anaesthetized cats.

Histamine causes dose‐dependent vasodilatation in the vasculature of the hind‐limb and mesentery, perfused with blood at constant flow.

Experiments using the selective antagonists mepyramine and metiamide indicate the involvement of both H1‐ and H2‐receptors in the vasodilator responses to histamine. Mepyramine (2.5 × 10−6 mol/kg), causes displacement of the histamine dose‐response curve. This displacement is maximum with a dose‐ratio of about 10. Further dose‐dependent displacement of the dose‐response curve occurred after metiamide (4 × 10−7 mol kg−1 min−1 and 2 × 10−6 mol kg−1 min−1), although these does of metiamide had no effect on histamine responses in the absence of mepyramine.

Vasodilator responses could also be elicited by the selective H1‐receptor agonists, 2‐methylhistamine, 2‐(2‐aminoethyl)pyridine and 2‐(2‐aminoethyl)thiazole and the selective H2‐receptor agonist, 4‐methylhistamine.

The selectivity of mepyramine and metiamide as histamine receptor antagonists was confirmed by their failure to reduce the vasodilator responses to acetylcholine, isoprenaline and bradykinin.
RAPID REDUCTION OF PROSTAGLANDIN 15‐HYDROXY DEHYDROGENASE ACTIVITY IN RAT TISSUES AFTER TREATMENT WITH PROTEIN SYNTHESIS INHIBITORS
Authors: BLACKWELL G.J. , FLOWER R.J. , VANE J.R.
Published: July 2012

The capacity of rat kidneys to metabolize prostaglandins is rapidly lost when de novo protein synthesis is reduced by cycloheximide and puromycin. Enzyme activity declines to about half control values 45–75 min after a single dose of cycloheximide. Prostaglandin metabolism by the lung is also diminished.

These inhibitors apparently act by preventing the synthesis of new prostaglandin 15‐hydroxy dehydrogenase enzyme.

The RNA synthesis inhibitor actinomycin D has no effect on metabolism.

It is concluded that prostaglandin dehydrogenase is a short‐lived enzyme in the cell whose replacement depends upon de novo protein (but not RNA) synthesis. The implications of this finding are discussed.
BIOASSAY OF HISTAMINE IN THE PRESENCE OF PROSTAGLANDINS
Authors: GRYGLEWSKI R.J. , KORBUT R.
Published: July 2012

An Amberlite XAD‐2 column in a heated (37°C) jacket was incorporated in between two banks of bioassay organs superfused with Krebs bicarbonate solution in cascade. The column removed prostaglandins E1, E2 and F2α and also rabbit aorta contracting substance (RCS) and possibly slow reacting substance of anaphylaxis (SRS‐A).

The column gave free passage to histamine in concentrations up to 3000 ng/ml. The method described improves the accuracy of histamine bioassay in the presence of prostaglandins.
PROLONGED EFFECTS OF p‐CHLOROPHENYLALANINE ON THE BLOOD PRESSURE OF CONSCIOUS NORMOTENSIVE AND DOCA/SALINE HYPERTENSIVE RATS
Authors: BUCKINGHAM R.E. , HAMILTON T.C. , MOORE R.A.
Published: July 2012

In deoxycorticosterone acetate (DOCA) saline hypertensive rats a single dose of p‐chlorophenylalanine methylester (PCPAME) (400 mg/kg i.p.) produced a significant fall in blood pressure (20–43 mmHg) which lasted for at least 8 days and was accompanied by a parallel depletion of brain stem 5‐hydroxytryptamine (5‐HT) but not of noradrenaline (NA).

In normotensive rats single doses of PCPAME (200 and 400 mg/kg i.p.) produced a significant hypotension (15–20 mmHg) after a latent period of 5 days. An initial pressor response (12 mmHg) was observed at the higher dose level only on day 3.

The hypotensive response to PCPAME (200 mg/kg i.p.) in normotensive rats was not modified by pretreatment with 5,6‐dihydroxytryptamine (5,6‐DHT; 50 μg i.c.v.) or 6‐hydroxydopamine (6‐OHDA; 3 × 250 μg intracerebroventricularly).

It is concluded that the hypotensive response to PCPAME in normotensive rats is independent of brain stem depletion of 5‐HT and is probably not mediated by the formation of a false transmitter substance acting via central noradrenergic inhibitory pathways. The mechanism involved in the antihypertensive response to PCPAME in DOCA/saline hypertensive rats has yet to be defined.
THE UPTAKE OF TRITIATED Δ1‐TETRAHYDROCANNABINOL BY THE ISOLATED VAS DEFERENS OF THE RAT
Authors: EGAN SANDRA M. , GRAHAM J.D.P. , LEWIS M.J.
Published: July 2012

Weighed stripped vasa deferentia were incubated in Holman's solution containing (a) [14C]‐sorbitol 0.014 mM, (b) [3H]‐noradrenaline ([3H]‐NA) 12.31 nM, (c) [3H]‐tetrahydrocannabinol ([3H]‐Δ1‐THC) 1 μg/ml for 5, 10, 20 and 30 minutes.

Tissues were washed, dissolved in Protosol, counted by standard scintillation counting technique and ‘drug space’ expressed as ct min−1 mg−1 tissue/ct min−1 μl−1 bathing fluid.

Vasa incubated for 30 min with [14C]‐sorbitol were washed for varying lengths of time; 82% clearance had taken place after 2 washes of 5 minutes.

The uptake of [3H]‐NA was inhibited by the presence of desmethylimipramine (DMI) 10 nM in the bath or by pretreatment of rats with 6‐hydroxydopamine (6‐OHDA).

The uptake of [3H]‐Δ1‐THC was not inhibited by the presence of DMI. It was reduced but not abolished by 6‐OHDA pretreatment.
THE EFFECTS OF DIMERCAPTOSUCCINIC ACID ON THE EXCRETION AND DISTRIBUTION OF MERCURY IN RATS AND MICE TREATED WITH MERCURIC CHLORIDE AND METHYLMERCURY CHLORIDE
Authors: MAGOS L.
Published: July 2012

All five rats in a group survived if dimercaptosuccinic acid (DMSA), a water soluble derivative of 2,3‐dimercaptopropanol (BAL), was given in doses of 10–40 mg/kg intraperitoneally 30 min, 4 and 24 h after administration of 2.4 mg/kg Hg as HgCl2, whereas three out of a group of five died if DMSA was not given. DMSA 20 mg/kg increased urinary excretion and decreased the body burden significantly more than 10 mg/kg DMSA, but further doubling of the dose had only marginal effects.

DMSA was able to reduce body burden and increase urinary excretion of Hg when intraperitoneal treatment started eight days after the subcutaneous administration of HgCl2.

DMSA was effective in decreasing body burden and the brain concentration of Hg in rats dosed orally with methylmercury (MeHgCl) when intraperitoneal treatment started with 40 mg/kg DMSA 24 h after Hg. Increase in the urinary excretion of mercury was responsible for the decrease in body burden.

DMSA was effective when given in the drinking water of rats or mice both against inorganic Hg and MeHgCl. In mice treated intraperitoneally with MeHgCl, DMSA 19.5 μg/ml in the drinking water caused a significant decrease in the body burden and increase in the excretion of Hg.

DMSA was about four times more efficient than d‐penicillamine in decreasing the body burden of Hg. As their toxicity is in the same range, the higher efficiency of DMSA offers a larger margin of safety for the mobilization of Hg.
EFFECT OF EXPERIMENTAL DIABETES, FOOD DEPRIVATION AND GENETIC OBESITY ON THE SENSITIVITY OF PITHED RATS TO AUTONOMIC AGENTS
Authors: FOY J.M. , LUCAS P.D.
Published: July 2012

The sensitivities of alloxan and streptozotocin diabetic and hereditary obese pithed rats to acetylcholine, isoprenaline and noradrenaline were compared to those of controls.

Blood pressure and heart rate recordings made before dosing was started showed the streptozotocin‐treated animals to have a significantly reduced heart rate and increased pulse pressure as compared with controls.

Both diabetic groups were found to have reduced sensitivities to the pressor effect of noradrenaline, the depressor effect of acetylcholine, the positive chronotropic and inotropic effect of isoprenaline and the reduction in diastolic pressure induced by isoprenaline. The reduction in sensitivity was generally much greater in the streptozotocin diabetic animals.

The genetically obese rats were found to have similar sensitivities to all three agents as did their non‐obese litter mates.

When either diabetic group was deprived of food for 24 h preceding the tests the sensitivities were found to be raised significantly towards normal in almost all cases.

The results are contrasted with previous in vitro results and possible causative metabolic factors discussed. It is suggested that sensitivity changes are unevenly distributed within the cardiovascular system.
SELECTIVITY OF β‐ADRENOCEPTOR AGONISTS AND ANTAGONISTS ON BRONCHIAL, SKELETAL, VASCULAR AND CARDIAC MUSCLE IN THE ANAESTHETIZED CAT
Authors: APPERLEY G.H. , DALY M.J. , LEVY G.P.
Published: July 2012

The potencies of fifteen β‐adrenoceptor agonists of widely differing chemical structures were compared with that of (–)‐isoprenaline on bronchial muscle, soleus muscle, blood pressure and heart rate in the anaesthetized cat. The β‐adrenoceptor antagonist potencies of propranolol and practolol were determined against (—)‐isoprenaline in the same model.

(—)‐Isoprenaline was the most potent agonist and its action was essentially unselective. Thus, on all four parameters the minimal effective dose was 0.003‐0.01 μg/kg and maximal or near maximal responses were produced by 0.3‐1 μg/kg. Trimetoquinol was also an essentially unselective agonist.

For thirteen of the remaining fourteen agonists, potency was similar on bronchial muscle, soleus muscle and blood pressure but significantly lower on heart rate.

The remaining agonist — AH 7616 (4‐hydroxy‐α1‐[[(1‐methyl‐3,3‐diphenyl‐propyl)amino]methyl]‐m‐xylene‐α1,α3‐diol, acetate) — was also significantly less potent on heart rate than on the other parameters; in addition, it was clearly less potent on soleus muscle and blood pressure than on bronchial muscle when 5‐hydroxytryptamine (5‐HT) was used to induce bronchospasm. However, when acetylcholine was used instead of 5‐HT the potency of AH 7616 on bronchial muscle, soleus muscle and blood pressure was very similar. AH 7616 may therefore possess a specific 5‐HT antagonist action in addition to its β‐adrenoceptor agonist action.

The fifteen test agonists were longer acting than (—)‐isoprenaline and this was particularly true of trimetoquinol and soterenol.

The β‐adrenoceptor antagonist potency of propranolol was almost identical on bronchial muscle, soleus muscle and blood pressure and very slightly lower on the heart. Practolol was 10–12 times more potent on the heart than on bronchial muscle, soleus muscle and blood pressure.

These findings suggest that it may not be possible to separate the bronchodilating and tremor‐enhancing properties of β‐adrenoceptor agonists. The results with agonists and antagonists are in accord with Lands' dual β‐adrenoceptor sub‐classification.
COMPARATIVE EFFECTS OF PROPRANOLOL AND PRACTOLOL IN THE EARLY STAGES OF EXPERIMENTAL CANINE MYOCARDIAL INFARCTION
Authors: MARSHALL R.J. , PARRATT J.R.
Published: July 2012

The effects of propranolol and practolol, at equivalent myocardial β‐adrenoceptor blocking doses, (as assessed by the degree of shift of isoprenaline dose‐response curves) were investigated in anaesthetized greyhounds before and after acute coronary artery ligation.

When administered intravenously to the intact closed‐chest dog, propranolol (0.1 mg/kg) and practolol (0.5 mg/kg) caused similar decreases in heart rate, left ventricular dP/dt max, myocardial blood flow and cardiac output. Only propranolol increased peripheral vascular resistance.

When administered 2–3 h after acute coronary artery ligation, propranolol (0.1 mg/kg) significantly decreased blood flow in both normally perfused and ischaemic regions of the heart. There was also electrocardiographic evidence of further deterioration after propranolol; two out of seven animals died following this treatment.

Practolol (0.5 mg/kg) when administered after coronary artery ligation also decreased normal myocardial blood flow but flow in the ischaemic area remained unchanged. Evidence was obtained from electrocardiographic, myocardial temperature, myocardial O2 consumption and lactate measurements that the administration of practolol, in contrast to propranolol, benefited the ischaemic myocardium.

Analysis of the results suggests that this beneficial action of practolol may be related to at least two mechanisms. Firstly the ability of practolol to increase the period during diastole when perfusion of the subendocardium is possible, without decreasing the transventricular pressure during this period. Secondly that practolol does not unmask α‐adrenoceptor vasoconstriction in the ischaemic region.
THE EFFECTS OF PENTOBARBITONE AND PETHIDINE ON FOETAL BREATHING MOVEMENTS IN SHEEP
Authors: BODDY K. , DAWES G.S. , FISCHER R.L. , PINTER S. , ROBINSON J.S.
Published: July 2012

Small doses of pentobarbitone (4 mg/kg i.v.) administered to sheep in the last third of pregnancy had little overt effect on the mothers. In the foetus they caused arrest of breathing movements, an alteration in the character of the electrocorticogram and cardiovascular changes which varied with gestational age.

In contrast, relatively large doses of pethidine (100–200 mg) administered to the mother had no consistent effect on normal foetal breathing movements, though they abolished the foetal response to hypercapnia.

The results are discussed in relation to foetal sleep state.
THE ROLE OF BOUND CALCIUM IN SUPER‐SENSITIVITYINDUCED BY COCAINE
Authors: GREENBERG R. , INNES I.R.
Published: July 2012

Noradrenaline caused a small contraction of the cat isolated spleen strip bathed in a calcium‐free solution; this contraction was greatly potentiated by cocaine. This potentiation was also present in isolated spleen strips where noradrenaline stores were depleted by reserpine. The maximum response of the spleen strip to noradrenaline in the absence of extracellular calcium was also increased by cocaine.

The disodium salt of ethylenediaminetetraacetic acid (Na‐EDTA) but not Ca‐EDTA antagonized the potentiation of the response to noradrenaline by cocaine in a calcium‐free solution, and greatly reduced the magnitude of subsequent responses to noradrenaline and cocaine.

Strontium caused equivalent contractions of normal and reserpine‐treated spleen strips bathed in a calcium‐free solution. These responses were potentiated by cocaine.

Histamine caused a small contraction of the isolated spleen strip bathed in a Ca‐free solution. Cocaine failed to potentiate these very small histamine contractions, but did potentiate the contraction of these same strips in response to noradrenaline.

It is concluded that the potentiation of the response of the isolated spleen strip to noradrenaline by cocaine in the absence of extracellular calcium is due to a mechanism other than decreased neuronal uptake of noradrenaline. It is suggested that cocaine makes a bound store of calcium more available to promote contraction of the spleen strip by noradrenaline.
ADENOSINE ON MYOCARDIAL OXYGEN CONSUMPTION
Authors: GROSS G.J. , HARDMAN H.F. , WARLTIER D.C.
Published: July 2012

A 3 min intracoronary infusion of adenosine (50 μg/min) produced a significant decrease in coronary artery perfusion pressure, left ventricular systolic pressure and myocardial O2 consumption in the isolated supported heart preparation of the dog perfused at a constant coronary blood flow. Heart rate was controlled at 150, 190 or 230 beats/minute.

Myocardial contractile force and maximal left ventricular dp/dt were not changed by adenosine infusion.

The absolute decrease in myocardial O2 consumption was greater at increasing heart rates whereas the decrease in coronary artery perfusion pressure and peak left ventricular systolic pressure were similar.

The results suggest that the reduction in myocardial O2 consumption produced by adenosine is not related to coronary vasodilatation or to a negative chronotropic or inotropic action, but may be due to a functional shunting of blood flow from high O2 extracting regions of the myocardium to low O2 extracting ones and/or to important effects on myocardial substrate utilization.
THE EFFECT OF CATECHOLAMINES ON THE INFLUX OF CALCIUM AND THE DEVELOPMENT OF TENSION IN DENERVATED MOUSE DIAPHRAGM MUSCLE
Authors: EVANS R.H. , SMITH J.W.
Published: July 2012

The nature of the catecholamine‐induced contracture of chronically denervated mouse diaphragm muscle has been investigated and compared with the contractural response evoked by acetylcholine.

The time course of onset of catecholamine‐sensitivity in denervated diaphragm muscles was similar to the development of acetylcholine sensitivity. However, catecholamine contractures were absent in tissues denervated for periods longer than 90 days whereas acetylcholine‐sensitivity was still evident several months after denervation.

The catecholamine‐induced contracture of the denervated muscle was inhibited specifically by β‐receptor blocking drugs and was unaffected by α‐receptor blocking drugs and cholinoceptor antagonists.

Catecholamine‐induced contractures of denervated muscles, unlike contractures to acetylcholine, were dependent upon the presence of spontaneous fibrillation and the amplitude of spontaneous fibrillation was increased by catecholamines. Fibrillation was absent in the presence of tetrodotoxin (1 μm), 2,4‐dinitrophenol (10 μm), potassium cyanide (10 μm), ouabain (100 μm), in lithium chloride Ringer solution and at low temperature. Under these conditions catecholamine‐induced contractures, but not those to acetylcholine, were abolished.

Labelled calcium was found progressively to enter denervated muscle fibres and this entry of calcium was increased by catecholamines. It is suggested that this calcium entry may represent either an increased calcium permeability of denervated muscle fibres which is increased further by catecholamines or the presence of a calcium current that occurs during the fibrillatory potentials of denervated muscle.
EXTRA‐VESICULAR BINDING OF NORADRENALINE AND GUANETHIDINE IN THE ADRENERGIC NEURONES OF THE RAT HEART: A PROPOSED SITE OF ACTION OF ADRENERGIC NEURONE BLOCKING AGENTS
Authors: GIACHETTI A. , HOLLENBECK R.A.
Published: July 2012

The binding and efflux characteristics of [14C]‐guanethidine and [3H]‐noradrenaline were studied in heart slices from rats which were pretreated with reserpine and nialamide.

Binding of both compounds occurred at extra‐vesicular sites within the adrenergic neurone. After a brief period of rapid washout, the efflux of [14C]‐guanethidine and [3H]‐noradrenaline proceeded at a steady rate. The efflux of both compounds appeared to occur from a single intraneuronal compartment.

(+)‐Amphetamine accelerated the efflux of [14C]‐guanethidine and [3H]‐noradrenaline; this effect was inhibited by desipramine.

Unlabelled guanethidine and amantadine also increased the efflux of labelled compounds. Cocaine in high concentrations increased slightly the efflux of [14C]‐guanethidine but not that of [3H]‐noradrenaline.

Heart slices labelled with [3H]‐noradrenaline became refractory to successive exposures to releasing agents although an appreciable amount of labelled compound was still present in the slices.

It is suggested that [14C]‐guanethidine and [3H]‐noradrenaline are bound at a common extra‐vesicular site within the adrenergic neurone. Binding of guanethidine to the extra‐vesicular site may be relevant to its pharmacological action, i.e., the blockade of adrenergic transmission.
THE LOCAL ANTINOCICEPTIVE AND TOPICAL ANTI‐INFLAMMATORY EFFECTS OF PROPYL GALLATE IN RODENTS
Authors: McDONALD‐GIBSON WENDY J. , SAEED S.A. , SCHNEIDER C.
Published: July 2012

In common with several anti‐inflammatory, analgesic, local anaesthetic and antioxidant drugs, propyl gallate in vitro inhibited the biosynthesis of prostaglandin E2 and F2α from arachidonic acid by a prostaglandin synthetase from bull seminal vesicles.

In common with analgesic drugs, propyl gallate reduced the ability of arachidonic acid, acetylcholine or acetic acid to cause abdominal constrictions in mice.

Using a new method of evaluating anti‐inflammatory activity, we demonstrated the effectiveness of aspirin or indomethacin given subcutaneously before u.v. irradiation of guinea‐pig ears, the prophylactic action of topically applied sunscreen agents and the therapeutic value of bufexamac and propyl gallate applied after irradiation.
CENTRALLY INDUCED HYPOTENSION AND BRADYCARDIA AFTER ADMINISTRATION OF α‐METHYLNORADRENALINE INTO THE AREA OF THE NUCLEUS TRACTUS SOLITARII OF THE RAT
Authors: DE JONG W. , NIJKAMP F.P.
Published: July 2012

In anaesthetized rats, bilateral injections of α‐methylnoradrenaline, noradrenaline or adrenaline into the area of the nucleus tractus solitarii (NTS) of the brain stem caused dose‐dependent decreases of systemic arterial blood pressure and heart rate. The effects of α‐methylnoradrenaline were most pronounced and lasted longest.

The cardiovascular effects of α‐methylnoradrenaline appeared to be restricted to the medio‐caudal part of the NTS.

Prior administration of the α‐adrenoceptor blocking agent, phentolamine, reversed the fall in blood pressure and heart rate induced by α‐methylnoradrenaline into an increase.

Systemic administration of atropine combined with vagotomy potentiated the inhibitory effects of α‐methylnoradrenaline on the cardiovascular system.
FURTHER EVIDENCE THAT PROSTAGLANDINS INHIBIT THE RELEASE OF NORADRENALINE FROM ADRENERGIC NERVE TERMINALS BY RESTRICTION OF AVAILABILITY OF CALCIUM
Authors: HEDQVIST P.
Published: July 2012

Guinea‐pig vasa deferentia were continuously superfused after labelling the transmitter stores with [3H]‐(—)‐noradrenaline. Release of [3H]‐(—)‐noradrenaline was induced by transmural nerve stimulation.

Prostaglandin E2 (14 nm) drastically reduced the release of [3H]‐(—)‐noradrenaline, while tetraethylammonium (2 mm), rubidium (6 mm), phenoxybenzamine (3 μm) each in the presence or absence of Uptake 1 or 2 blockade, and prolonged pulse duration (from 0.5 to 2.0 ms) all significantly increased the release of [3H]‐(—)‐noradrenaline per nerve impulse.

The inhibitory effect of prostaglandin E2 on evoked release of [3H]‐(—)‐noradrenaline was significantly reduced by tetraethylammonium, rubidium and prolonged pulse duration, whilst it was actually enhanced by phenoxybenzamine. This indicates that increased release of noradrenaline per nerve impulse does not per se counteract the inhibitory effect of prostaglandin E2.

It is concluded that tetraethylammonium, rubidium and prolonged pulse duration counteracted the inhibitory effect of prostaglandin E2 on [3H]‐(—)‐noradrenaline release by promoting calcium influx during the nerve action potential. The results are consistent with, and add more weight to the view that prostaglandins inhibit the release of noradrenaline by restriction of calcium availability.
THE IONIZATION OF PHENOLIC AMINES, INCLUDING APOMORPHINE, DOPAMINE AND CATECHOLAMINES AND AN ASSESSMENT OF ZWITTERION CONSTANTS
Authors: ARMSTRONG J. , BARLOW R.B.
Published: July 2012

The dissociation constants of many phenolic amines, including benzylamines, phenethylamines, phenylethanolamines, phenylpropylamines, catecholamines, and apomorphine have been measured by potentiometric titration at 25°C. Measurements have also been made with many of their methoxy derivatives and with series of phenolic quaternary ammonium salts. Some compounds were also studied at 37°C.

Usually at least five titrations were made with each compound and Debye—Hückel theory was applied to convert concentrations to activities but the estimates of pKa were not constant and found to increase with increasing concentration. The range studied was usually 5–15 mm and a least‐squares line‐fit, based on the empirical assumption that pKa varies with (concentration)1/2, has been used to calculate values for 10 mm solutions and to extrapolate to infinite dilution and to 100 mm. The dependence of pKa on concentration was much less at 37°C than at 25°C.

At 37°C the pKa values of many biologically interesting compounds in the group, dopamine, noradrenaline, adrenaline and isoprenaline, coryneine (the trimethylammonium derivative of dopamine) and apomorphine are within 1 log unit of physiological pH, indicating the presence of a significant proportion of either the zwitterion or of the uncharged phenolic amine.

Zwitterion constants have been estimated from the pKa values of the phenolic amines and those of their methoxy and quaternary trimethylammonium analogues. Zwitterion formation does not appear to be associated with activity at α‐adrenoceptors and probably not with activity at β‐receptors. The active species seems likely to contain the unionised phenolic group but at dopamine receptors this may be in the uncharged phenolic amine rather than in the phenolic ammonium salt.
THE EFFECTS OF MORPHINE ON THE RELEASE OF NORADRENALINE FROM THE MOUSE VAS DEFERENS
Authors: HENDERSON G. , HUGHES J.
Published: July 2012

Electrical field stimulation of the mouse vas deferens (TO and C57/BL strains) caused the release of noradrenaline into the bathing medium.

Phenoxybenzamine (30 μm) or phentolamine (36 μm) plus cocaine (13 μm) caused a considerable increase in the noradrenaline output.

In the vasa deferentia from TO mice the output per pulse of noradrenaline was constant at frequencies of stimulation from 0.5 to 15 Hz whereas in the vasa deferentia from C57/BL mice the output per pulse of noradrenaline increased two‐fold from 1.5 to 15 Hz.

Morphine (2 μm) inhibited the contractions of the vasa deferentia from TO mice. This effect was greater at low (0.1‐1 Hz) than at high (10 Hz) frequencies of stimulation. Morphine (2 μm) did not inhibit the response of the tissue to exogenous noradrenaline.

Morphine (1 μm) reduced the noradrenaline output from the vasa deferentia of TO mice stimulated at 1.5 Hz but did not reduce the noradrenaline output at 15 Hz. At 1.5 Hz the reduction of noradrenaline output was reversed by naloxone (0.05 μm).

Morphine (5 μm) did not inhibit the uptake of [3H]‐noradrenaline into the vasa deferentia from TO mice.

Only in high concentrations (ID50 30.88 μm) did morphine inhibit the contractions of the vasa deferentia from C57/BL mice.

Normorphine (100 μm) did not reduce the noradrenaline output from vasa deferentia of C57/BL mice.
THE POSSIBLE INVOLVEMENT OF Na+ IONS IN CORTICOSTERONE‐INDUCED HYPERCONTRACTILITY IN THE RAT ANOCOCCYGEUS MUSCLE
Authors: GIBSON A. , POLLOCK D.
Published: July 2012

The possibility that corticosterone‐induced hypercontractility in the rat anococcygeus muscle might be due to an intramuscular redistribution of Na+ was investigated.

The contractility of the isolated muscle to noradrenaline (NA) was directly dependent on the Na+ concentration of the Krebs solution.

There was a linear relationship between the maximum contractile response of the muscle to NA and the Na+ concentration of the Krebs solution.

Muscle contractility was also increased by the presence of ouabain (10−4m) in the bathing medium.

Muscles from rats treated with corticosterone exhibited increases in both total and ouabain‐sensitive ATPase activity.

The relationship between corticosterone, Na+ distribution, and muscle contractility is discussed.
THE VASODILATOR ACTIONS OF ISOPRENALINE, HISTAMINE, PROSTAGLANDIN E2, GLUCAGON AND SECRETIN ON THE HEPATIC ARTERIAL VASCULAR BED OF THE DOG
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

The sympathetically‐innervated arterial vascular bed of the dog's liver was perfused from a femoral artery. Arterial blood flow and perfusion pressure were measured continuously, and the hepatic arterial vascular resistance calculated. The preparation provided a means of assessing hepatic arterial vasodilatation quantitatively.

Isoprenaline, histamine, prostaglandin E2, glucagon and secretin were injected intra‐arterially and all evoked dose‐dependent vasodilatation of the hepatic arterial vascular bed.

The maximum reduction in the calculated hepatic arterial vascular resistance of 37–38% was the same for each of the five substances.

Comparisons on a weight basis revealed that prostaglandin E2 was the most potent, followed in potency order by secretin, isoprenaline, histamine and glucagon.

Comparisons on a molar basis showed that secretin and prostaglandin E2 were intrinsically considerably more potent than isoprenaline, histamine or glucagon.

The onset of the vasodilatator responses to secretin, isoprenaline, histamine and prostaglandin E2 was rapid, and the duration of their actions was brief.

The onset of the vasodilator effects of glucagon was slow and its duration of action very prolonged.

The implications of these observations with respect to the physiological control of the hepatic arterial vascular bed of the dog are discussed.
A RAPID METHOD FOR THE ESTIMATION OF PROSTAGLANDIN 15‐HYDROXYDEHYDROGENASE ACTIVITY AND ITS APPLICATION TO PHARMACOLOGY
Authors: BLACKWELL G.J. , FLOWER R.J.
Published: July 2012

A novel double‐isotope assay for prostaglandin 15‐hydroxydehydrogenase (PGDH) is described.

The assay is simple, rapid, precise, completely specific for PGDH, and free from artefacts. The results obtained correlate well with a conventional assay.

The method is versatile, being applicable to estimations of enzyme activity in cell‐free systems as well as perfused organs, and is well suited to the assay of PGDH inhibitors.
POSSIBLE INFLUENCE OF INTRARENAL GENERATION OF KININS ON PROSTAGLANDIN RELEASE FROM THE RABBIT PERFUSED KIDNEY
Authors: COLINA‐CHOURIO J. , McGIFF J.C. , MILLER M.P. , NASJLETTI A.
Published: July 2012

The effects of bradykinin and kininogen on renal prostaglandin release were studied in rabbit isolated kidneys perfused with oxygenated Krebs solution.

The concentration of prostaglandin‐like material in kidney effluent was determined by bioassay after extraction of the samples with organic solvents. In 7 experiments the samples were assayed after separation of prostaglandins E and F by thin layer chromatography.

Addition of bradykinin to the perfusing fluid increased the venous and urinary effluxes of prostaglandin E‐like substance by sixfold and fivefold, respectively, but efflux of prostaglandin F‐like material was unaffected.

Addition of kininogen to the perfusing fluid augmented the venous and urinary release of prostaglandin E‐like substances by fifteenfold and ninefold respectively and caused a twofold increase in the efflux of prostaglandin F‐like material into the venous effluent.

Aprotinin, a kallikrein inhibitor, reduced the prostaglandin releasing action of kininogen but not of bradykinin. In contrast, inhibition of prostaglandin synthesis by indomethacin suppressed the release of prostaglandin evoked by either bradykinin or kininogen.

This study suggests that augmented release of prostaglandins in response to kininogen is a consequence of renal generation of kinins. Thus, changes in the intrarenal activity of the kallikreinkinin system may modulate renal prostaglandin release.
THE β‐ADRENOCEPTOR OF THE HUMAN LYMPHOCYTE AND HUMAN LUNG PARENCHYMA
Authors: CONOLLY M.E. , GREENACRE J.K.
Published: July 2012

The response of the β‐adrenoceptors of human lymphocytes to selective agonists and antagonists has been studied quantitatively by measuring changes in cyclic adenosine‐3′,5′‐monophosphate (cyclic AMP) levels.

The receptor was activated by isoprenaline and by salbutamol, and blocked by propranolol but not by practolol. A similar pattern of response was obtained with fragments of human lung tissue.

The mean value for pA2 for propranolol was 8.34 and for practolol was 3.95.

These findings indicate that the lymphocyte β‐adrenoceptor is a β2‐receptor and support the validity of using lymphocytes to study β‐adrenoceptor function in bronchial asthma. It may also be of use in the evaluation of selective β2‐blocking drugs in man.
THEOPHYLLINE AND PHENYLEPHRINE EFFECTS ON CARDIAC RELAXATION
Authors: BENFEY B.G.
Published: July 2012

In the driven isolated left atrium of the rabbit theophylline shortened relaxation time in a similar manner to isoprenaline and histamine.

Phenylephrine lengthened relaxation time in a similar manner to calcium.

Theophylline caused phenylephrine to shorten relaxation time, which was inhibited by a β‐adrenoceptor blocking drug, but theophylline did not potentiate the effect of phenylephrine on peak tension.

Theophylline separated drug effects on cardiac relaxation and contraction: in the presence of theophylline at a low calcium concentration, phenylephrine shortened relaxation time by β‐adrenoceptor stimulation and increased peak tension by α‐adrenoceptor stimulation. At a high calcium concentration, theophylline potentiated the effect of isoprenaline, histamine and phenylephrine on relaxation time but inhibited the effect on peak tension.
PULMONARY METABOLISM OF BRADYKININ ANALOGUES AND THE CONTRIBUTION OF ANGIOTENSIN CONVERTING ENZYME TO BRADYKININ INACTIVATION IN ISOLATED LUNGS
Authors: BAKHLE Y.S.
Published: July 2012

The activity and pulmonary metabolism of two peptides, 7‐homo Pro‐bradykinin and 8‐homo Phe‐bradykinin were studied in isolated systems.

Both analogues were about 50–70 times less active than bradykinin on the guinea‐pig ileum and 70–160 times less active on isolated strips of cat terminal ileum.

The action of both analogues on guinea‐pig ileum was potentiated (2.5‐3.0 fold) by a bradykinin potentiating peptide (BPP9a) but less so than the action of bradykinin (4–5 fold).

Like bradykinin, the 8‐homo Phe analogue was extensively inactivated (>90%) in a single passage through the pulmonary circulation of guinea‐pig or rat isolated lungs and this inactivation was prevented by pre‐treatment of the lungs with BPP9a.

The 7‐homo Pro analogue was inactivated to a lesser degree in guinea‐pig lungs (58%) and in rat lungs (89%) and its inactivation was not affected by BPP9a.

It is concluded that the 8‐homo Phe analogue is a substrate for the dipeptidylcarboxypeptidase (angiotensin I converting enzyme) of lung, whereas the 7‐homo Pro analogue is not a substrate.

There is about four times as much dipeptidylcarboxypeptidase activity in guinea‐pig isolated lungs as there is in rat isolated lungs.
THYROID HORMONE‐DEPENDENT INTERCONVERSION OF MYOCARDIAL α‐ AND β‐ADRENOCEPTORS IN THE RAT
Authors: KUNOS G.
Published: July 2012

The effects of thyroid state on the properties of adrenoceptors mediating inotropic and chronotropic responses of the rat heart were assessed on the basis of the relative potencies of α‐ and β‐adrenoceptor agonists, the effects of α‐ and β‐adrenoceptor antagonists and the tissue uptake of [3H]‐phenoxybenzamine ([3H]‐PB).

In isolated, electrically driven left atria the ratio of the inotropic potencies of isoprenaline and phenylephrine and the inhibitory potency of propranolol (40nM‐4 μm) were significantly reduced after thyroidectomy and were moderately increased after thyroxine treatment of control rats.

Block of inotropic responses to noradrenaline and to phenylephrine by PB (7.3nM‐7.3 μm) and the tissue uptake of [3H]‐PB were significantly greater in preparations from thyroidectomized than in those from control or from thyroxine treated rats. α‐Adrenoceptor inhibition by phentolamine (0.26‐2.6 μm) also increased after thyroidectomy, and phentolamine effectively protected α‐adrenoceptors from block by and binding of [3H]‐PB.

The β1‐receptor antagonist H 93/26 (0.1 μm) significantly potentiated α‐adrenoceptor blockade by PB in hypothyroid but not in control preparations.

In spontaneously beating right atria the chronotropic potency of agonists and the effects of antagonists were altered in the same way as were inotropic responses and the slope of the agonist concentration‐response curves were significantly reduced after thyroidectomy. Effects of agonists and antagonists were not significantly influenced by thyroxine treatment.

Changes in the effects and tissue uptake of sympathomimetic drugs observed after thyroidectomy were reversed to or beyond control levels by thyroid hormone treatment of thyroidectomized animals.

The results presented are interpreted as indicating a thyroid hormone‐dependent interconversion of myocardial α‐ and β‐adrenoceptors. It is suggested that this interconversion is similar to that observed earlier in frog hearts at different temperatures, and that both effects may reflect an allosteric transition between two forms of a single basic structure.