bluuebunny/crossref_metadata_2025 huggingface dataset:
FACTORS LIMITING THE RATE OF TERMINATION OF THE NEUROMUSCULAR BLOCKING ACTION OF FAZADINIUM DIBROMIDE
Authors: TYERS M.B.
Published: July 2012

Reasons for the termination of the neuromuscular blocking action of fazadinium dibromide have been investigated.

In the anaesthetized cat, maximum neuromuscular block of tibialis anterior muscle twitches following rapid intravenous injection of fazadinium was obtained as the injection bolus passed through the muscle, indicating that fazadinium very readily crosses capillary membranes.

The half‐life of plasma clearance of fazadinium was about 1 min in both cat and man, despite a 10 fold difference in duration of action in these species. Plasma samples were bioassayed for neuromuscular blocking activity on an isolated, superfused phrenic nerve‐diaphragm preparation of the rat.

In the anaesthetized cat, occlusion of the renal or hepatic circulations did not prolong the neuromuscular blocking action of single doses of fazadinium. Repeated doses accumulated slowly when the hepatic circulation was occluded but not when the renal circulation was occluded.

Fazadinium is eliminated from the body by both the liver and kidneys but the rates of these processes are insufficient to account for the initial rapid plasma clearance.

The rate‐limiting step for the termination of the neuromuscular blocking action of fazadinium is most likely to be the rate of drug‐receptor dissociation.
MECHANISM OF HISTAMINE RELEASE FROM RAT MAST CELLS INDUCED BY THE IONOPHORE A23187: EFFECTS OF CALCIUM AND TEMPERATURE
Authors: JOHANSEN TORBEN
Published: July 2012

The mechanism of histamine release from a pure population of rat mast cells induced by the lipid soluble antibiotic, A23187, has been studied and compared with data for anaphylactic histamine release reported in the literature.

Histamine release induced by A23187 in the presence of calcium 10−3 mol/1 was completed in 10 minutes. By preincubation of the mast cells with A23187 for lOmin in the absence of calcium the histamine release induced by calcium, 10−3 mol/1 or 5 × 10−3 mol/1, was completed in 90s and 45 s, respectively.

A23187‐induced histamine release was maximal with calcium 10−3 mol/1 when the cells were incubated at 33 to 39°C for 10 minutes.

The cellular mechanism, which was stimulated by A23187 and calcium for the release of histamine, was irreversibly inactivated by incubation at 45°C.

An inhibition of energy metabolism was excluded as the cause of the heat inactivation.

The dependence of A23187‐induced histamine release on calcium and temperature, the time course of histamine release and the heat inactivation are consistent with the view that the same mechanism is involved in A23187‐induced and anaphylactic histamine release.
RELEASE OF 3H‐PURINES FROM [3H]‐ADENINE LABELLED RABBIT KIDNEY FOLLOWING SYMPATHETIC NERVE STIMULATION, AND ITS INHIBITION BY α‐ADRENOCEPTOR BLOCKADE
Authors: FREDHOLM BERTIL B. , HEDQVIST PER
Published: July 2012

Rabbit kidneys were isolated and perfused with Tyrode solution. Release of 3H‐purines was studied after labelling of the adenine‐nucleotide stores with [3H]adenine (more than 60% uptake during a single passage).

One hour after labelling the spontaneous 3H‐outflow amounted to 0.1 to 0.2% of the total tissue content per minute. The release rate was enhanced following nerve stimulation (3 to 10 Hz), or brief infusion of noradrenaline (0.1 to 2.4 μg i.a.). Release of radioactivity was also enhanced by angiotensin II, by interruption of perfusion flow for 0.5 to 2 min and by hypoxia (5 to 25% 02).

The release of tracer induced by nerve stimulation or noradrenaline was markedly reduced or abolished by phenoxybenzamine, which also inhibited the vasoconstrictor response. The release following angiotensin II, ischaemia and hypoxia could not be antagonized by this α‐adrenoceptor antagonist.

The radioactivity in the kidney was predominantly in nucleotide form, while that released was N composed mainly of nucleosides, of which adenosine predominated.

The results indicate that in the rabbit kidney vasocontriction, arterial clamping or reduced perfusion oxygen tension, cause release of adenosine and related compounds. In view of the reported actions of adenosine on noradrenaline effects and release in the kidney a possible physiological role is discussed.
RELEASE OF PROSTAGLANDINS DURING CONTRACTION OF THE HUMAN UMBILICAL VEIN ON REDUCTION OF TEMPERATURE
Authors: BOURA A.L.A. , BOYLE LYNDALL , SINNATHURAY T.A. , WALTERS W.A.W.
Published: July 2012

Flow rate was measured through the vein of the human isolated umbilical cord perfused at constant pressure (40 mmHg) at 37.5°C and 20°C. At the latter temperature the flow was decreased by 50.9% when compared with a mean of 201 ml/min at 37.5°C indicating veno‐spasm. Indomethacin (10 ug/g) effected a highly significant reduction in the venous spasm caused by lowering the temperature. After indomethacin pretreatment, changing the cord temperature from 37.5°C to 20°C caused a mean decrease in flow of only 3.1%. When the effluent from the vein was passed over rat isolated stomach fundus and colonic strips, cooling of the cord was accompanied by contractions of the isolated tissues characteristic of prostaglandins. These results suggest that prostaglandins are involved in temperature‐induced closure of the human umbilical vein after birth.
THE EFFECT OF ALKALINE EARTH CATIONS ON THE RELEASE OF HISTAMINE FROM RAT PERITONEAL MAST CELLS TREATED WITH COMPOUND 48/80 AND PEPTIDE 401
Authors: ATKINSON GORDON , ENNIS MADELEINE , PEARCE FREDERICK L.
Published: July 2012

Extracellular calcium ions have a dual effect on the release of histamine from rat peritoneal mast cells treated with compound 48/80 and peptide 401. The release is either potentiated or inhibited according to the relative concentrations of ion and inducer.

Strontium similarly potentiates the release produced by optimal concentrations of inducer but higher concentrations are required than in the case of calcium. Strontium is markedly less inhibitory than calcium.

Mast cells may be depleted of intracellular calcium by incubation for short periods with the chelating agent, ethylenediamine tetraacetic acid (EDTA). They thereby become unresponsive to compound 48/80 and peptide 401 unless calcium is reintroduced into the incubation medium. Strontium and barium, but not magnesium, will substitute for calcium in this system. Barium additionally produces a marked release of histamine even in the absence of inducer. Pretreatment with the ionophore A23187 similarly inhibits the subsequent response to peptide 401 in divalent cation‐free medium. This inhibition is reversed on the reintroduction of calcium.

Compound 48/80 and peptide 401 release histamine from mast cells incubated in isotonic sucrose in the complete absence of added metal ions. However, the corrected release under these conditions is potentiated by both mono and divalent cations.

On the basis of these results, the possible mechanism of action of the basic releasing agents and their usefulness as models for studying histamine secretion is discussed.
NALOXONE REVERSES THE ANTIHYPERTENSIVE EFFECT OF CLONIDINE
Authors: FARSANG CSABA , KUNOS GEORGE
Published: July 2012

In unanaesthetized, spontaneously hypertensive rats the decrease in blood pressure and heart rate produced by intravenous clonidine, 5 to 20 μg/kg, was inhibited or reversed by naloxone, 0.2 to 2 mg/kg. The hypotensive effect of 100 mg/kg α‐methyldopa was also partially reversed by naloxone. Naloxone alone did not affect either blood pressure or heart rate. In brain membranes from spontaneously hypertensive rats clonidine, 10−8 to 10−5 m, did not influence stereoselective binding of [3H]‐naloxone (8 nm), and naloxone, 10−8 to 10−4 m, did not influence clonidine‐suppressible binding of [3H]‐dihydroergocryptine (1 nm). These findings indicate that in spontaneously hypertensive rats the effects of central α‐adrenoceptor stimulation involve activation of opiate receptors. As naloxone and clonidine do not appear to interact with the same receptor site, the observed functional antagonism suggests the release of an endogenous opiate by clonidine or α‐methyldopa and the possible role of the opiate in the central control of sympathetic tone.
THE EFFECTS OF HISTAMINE ON RESPONSES OF THE RABBIT EAR ARTERY TO ELECTRICAL STIMULATION AND TO EXOGENOUS NORADRENALINE
Authors: FOLDES A. , HALL R.C.
Published: July 2012

The effects of a subconstrictor dose of histamine (9 × 10−7 mol/l) on the responses of the isolated perfused ear artery of the rabbit to electrical stimulation (E.S.) and to exogenous noradrenaline (NA) were investigated.

Both intraluminal (I/L) and extraluminal (E/L) histamine potentiated responses to E.S. and to I/L NA to the same extent.

Mepyramine alone (2.5 × 10−6 mol/l) had no effect on the response of the ear artery to either stimulus, but in the presence of this concentration of mepyramine, the potentiation by histamine of the response to I/L NA was significantly decreased and that to E.S. was replaced by inhibition.

The H1‐receptor agonist, 2(2‐pyridyl) ethylamine, applied I/L potentiated responses to I/L NA at both concentrations used (5.1 and 51 × 10−7 mol/l), but only potentiated the effects of E.S. at the higher concentration.

The H2‐receptor antagonist, metiamide (4 × 10−6mol/l), alone did not alter the extent of potentiation of responses to either E.S. or I/L NA by histamine. This suggests relatively weak H2‐receptor activity in the rabbit ear artery. In the presence, but not the absence of metiamide, the potentiation by histamine of the I/L NA response was reversible, an observation suggesting an interaction between metiamide and the non‐reversible component of the potentiating effect of histamine.

These results are interpreted in terms of postsynaptic H1‐receptors which potentiate and presynaptic H2‐receptors which inhibit contractile responses in the ear artery.
THE EFFECTS OF ISOPRENALINE AND BRADYKININ ON CAPILLARY FILTRATION IN THE CAT SMALL INTESTINE
Authors: GRANGER D.N. , RICHARDSON P.D.I. , TAYLOR A.E.
Published: July 2012

Lymph flow, and both lymph and plasma protein concentrations were measured in isolated, blood‐perfused loops of cat ileum.

Permeability‐surface area (PS) products and the osmotic reflection coefficient (σ) of the intestinal capillaries were calculated.

Isoprenaline (one dose) or bradykinin (two different doses) was infused into the superior mesenteric artery.

Isoprenaline (blood concentration about 50 ng/ml) did not affect PS or σ.

Bradykinin (about 36 ng/ml) increased PS but as σ was unaltered, this was primarily due to an increased capillary surface area.

Bradykinin (about 680 ng/ml) increased PS and as σ was reduced, there was an increased capillary permeability.

Reasons for the lack of effect of isoprenaline at concentrations which increase capillary filtration coefficient are discussed.

These data show that this technique separates drug effects on capillary surface area from effects on capillary permeability.
AN EXAMINATION OF THE NEGATIVE FEEDBACK FUNCTION OF PRESYNAPTIC ADRENOCEPTORS IN A VASCULAR TISSUE
Authors: CHAN CHI‐CHUNG , KALSNER STANLEY
Published: July 2012

The hypothesis was examined that presynaptic α‐adrenoceptors exert a negative feedback function regulating noradrenergic transmission.

Renal artery strips from cattle, pre‐incubated with [3H]‐noradrenaline, were stimulated with 300 pulses at 5 different frequencies, spanning the physiological range, and the efflux of tritium assessed both in the absence and presence of functional presynaptic receptors.

Considerable variation in the synaptic level of free and active noradrenaline with increasing frequency was apparent from the rates of development and the magnitudes of the mechanical responses but the overflow of tritium was constant at 1, 2, 10 and 15 Hz and slightly elevated at 5 Hz, providing no evidence for presynaptic modulation of release.

Phenoxybenzamine (3.3 × 10−5 m) enhanced the overflow of tritium most at the lowest frequency tested and to a similar extent at the other test frequencies, except 10 Hz where its effect was slightly reduced.

The conditions of the present experiments appeared optimal for the operation of the negative feedback system and the failure to observe an increased effectiveness of the antagonist with increasing frequency indicates that the physiological relevance of such a system is highly questionable and suggests that it may not function at all.
THE ACTIONS OF 5‐HYDROXYTRYPTAMINE AND HISTAMINE ON THE ISOLATED ILEUM OF THE TREE SHREW (Tupaia glis)
Authors: SAKAI K. , SHIRAKI Y. , TATSUMI T. , TSUJI K.
Published: July 2012

Contractions to 5‐hydroxytryptamine (5‐HT) and histamine of longitudinal muscle from the isolated ileum of the tree shrew (Tupaia), guinea‐pig and rat were investigated by constructing dose‐response curves and studying the effects of various antagonists.

In the Tupaia and rat ileum the contraction to 5‐HT was reduced by methysergide but not affected by tetrodotoxin (TTX), morphine, hexamethonium (C6) or atropine. The response of guinea‐pig ileum to 5‐HT was not significantly inhibited by methysergide or C6, but was blocked by TTX, morphine and atropine.

Histamine‐induced contraction of Tupaia and guinea‐pig ileum was antagonized by diphenhydramine but not by TTX, morphine, C6 or atropine. Histamine was almost without effect on the rat ileum.
THE EFFECT OF INTRACEREBROVENTRICULAR ADMINISTRATION OF METHIONINE‐ENKEPHALIN ON THE STRESS‐INDUCED SECRETION OF CORTICOSTERONE IN MICE
Authors: GIBSON A. , GINSBURG M. , HALL M. , HART S.L.
Published: July 2012

Ether stress or intracerebroventricular (i.c.v.) administration of saline, met‐enkephalin, or naltrexone raised plasma corticosterone levels in mice. The response to ether stress was abolished by a preceding ether stress or by pretreatment. with i.c.v. saline or naltrexone. However, following i.c.v. met‐enkephalin, plasma corticosterone was significantly elevated by ether stress, the effect being blocked by simultaneous injection of met‐enkephalin and naltrexone. Met‐enkephalin appears to prevent fast‐feedback inhibition of the hypothalamus‐pituitary‐adrenal system.
RELATIONSHIP BETWEEN INHIBITION OF ACETYLCHOLINESTERASE AND RESPONSE OF THE RAT PHRENIC NERVE‐DIAPHRAGM PREPARATION TO INDIRECT STIMULATION AT HIGHER FREQUENCIES
Authors: HEFFRON P.F. , HOBBIGER F.
Published: July 2012

Rat isolated diaphragm preparations were stimulated indirectly either intermittently at 20, 50 or 100 Hz or continuously at 0.2 Hz.

Addition of 1.8 μm paraoxon (which inhibits acetylcholinesterase by forming a phosphorylated enzyme which undergoes slow spontaneous reactivation) for 5 min to the organ bath produced a failure of the muscle to maintain tetanic tension (tetanic fade, Wedensky inhibition) and potentiated the neuromuscular blocking activity of exogenous acetylcholine. The rates of recovery from both these effects were recorded.

In a series of experiments with dyflos (which inhibits acetylcholinesterase by forming a phosphorylated enzyme which does not undergo spontaneous reactivation) the relationship between functional acetylcholinesterase activity and neuromuscular blocking activity of exogenous acetylcholine was also determined.

From the data obtained, the relationship between functional acetylcholinesterase activity and tetanic fade was calculated. These calculations show that (i) a considerable reduction in functional acetylcholinesterase activity is required before the diaphragm loses its ability to respond with a sustained tetanus to indirect stimulation at higher frequencies, (ii) the minimum (critical) level of functional acetylcholinesterase activity required for a normal tetanic response is directly related to the frequency of stimulation and (iii) once functional acetylcholinesterase activity has been reduced to the critical level, a very small further reduction leads to a complete tetanic fade.

The meaning of functional acetylcholinesterase assays and of conclusions which can be drawn from them, is discussed.
RENIN‐ANGIOTENSIN MEDIATION OF ADRENAL CATECHOLAMINE SECRETION INDUCED BY HYPOGLYCAEMIA IN THE CAT
Authors: BUMPUS MERLIN F. , FEUERSTEIN GIORA , GUTMAN YEHUDA , KHOSLA MAHESH C.
Published: July 2012

The mechanism involved in catecholamine (CA) release from the cat adrenal gland in response to insulin hypoglycaemia was studied. In intact cats, hypoglycaemia induced an 11 fold increase in adrenomedullary CA secretion.

Acute bilateral nephrectomy nearly abolished the increased CA release from the adrenal gland during hypoglycaemia.

Infusion of Sar1‐Ileu8‐Angiotensin II (AII), a competitive AII antagonist, suppressed the adrenomedullary response to the insulin‐induced hypoglycaemia. After termination of the antagonist infusion, CA secretion from the adrenal medulla increased rapidly, reaching the same level as in insulin‐treated cats.

Infusion of rabbit anti‐angiotensin I antibodies suppressed CA release from the adrenal gland of hypoglycaemic cats. This effect was more prolonged than that of Sar1‐Ileu8‐AII.

These results indicate that CA release from the adrenal medulla of the cat in response to insulin‐induced hypoglycaemia, is mediated through the renal reninangiotensin system. Since hypoglycaemia causes sympathetic stimulation through a central mechanism, angiotensin may act through the central nervous system.
DIFFERENTIAL EFFECTS OF THE CALCIUM ANTAGONIST, VERAPAMIL, ON LUMEN SIZES OF TERMINAL ARTERIOLES AND MUSCULAR VENULES IN THE RAT MESENTERIC, PIAL AND SKELETAL MUSCLE MICROVASCULATURES
Authors: ALTURA BURTON M. , ALTURA BELLA T. , GEBREWOLD ASEFA
Published: July 2012

The actions of the local perivascular application of verapamil to rat mesenteric, pial and cremaster muscle arterioles and muscular venules (15 to 35 μm i.d.), was examined in situ, at the microcirculatory level, by use of a high‐resolution closed circuit television microscope recording system. Local application of verapamil (1 to 100 μg) to cremaster muscle arterioles and venules of the rat induces dose‐dependent vasodilatation and increased perfusion of capillaries. However, neither arteriolar nor muscular venular lumen sizes and capillary blood flow of the rat mesenteric or pial vasculatures were altered by even high doses of verapamil. Although these direct in situ microvascular findings do indicate that verapamil can induced dilatation of microscopic resistance and capacitance vessels in skeletal muscle, our data do not support the concept that verapamil induces non‐specific peripheral vasodilatation.
MUSCARINIC RECEPTORS IN RAT SYMPATHETIC GANGLIA
Authors: BROWN D.A. , FATHERAZI S. , GARTHWAITE J. , WHITE R.D.
Published: July 2012

Potential changes in isolated superior cervical ganglia of the rat produced by muscarinic‐receptor agonists were recorded by an extracellular ‘air‐gap’ method.

Muscarinic agonists produced a delayed low‐amplitude ganglion depolarization, frequently preceded by a hyperpolarization. Potentials were enhanced by reducing [K+]o or [Ca2+]o.

Mean ED50 values (μm) for depolarization at 25°C were: oxotremorine 0.004, methylfurmethide 0.11, (±)‐muscarine 0.24, furmethide 1.56, pilocarpine 4.81 and AHR‐602 (N‐benzylpyrrolidylacetate methobromide) 10.8. Responses produced by oxotremorine, pilocarpine and AHR‐602 showed some characteristics of ‘partial agonism’. ED50 values (μm) for choline esters (measured in the presence of 2.5 mm hexamethonium) were: acetylcholine 3.2, methacholine 59 and bethanechol 78.

Responses to muscarine were antagonized by hyoscine (K1 0.49 nm) atropine (K1 0.24 nm) methylscopolamine (K1 0.09 nm) lachesine (K1 0.15 nm) and (weakly) by hexamethonium (K1 0.2 mm). Propylbenzilylcholine mustard produced irreversible antagonism with an apparent onset rate constant of 2 times 105 m−1s−1.

Depolarization was accompanied by facilitation of submaximal ganglionic transmission.

Muscarine (1 to 100 μm) initially reduced, then increased, the rate of 86Rb+‐efflux from isolated ganglia at both 6 and 120 mm [K+]o. These effects were reduced by 1 μm hyoscine.

No consistent change in the amounts of cyclic 3′,5′‐guanosine monophosphate in isolated ganglia accompanying muscarinic depolarization could be detected.

Mean against ED50 values (μm) for contracting the rat isolated ileum were: oxotremorine 0.012, methylfurmethide 0.29, (±)‐muscarine 0.48, pilocarpine 7.8 and AHR‐602 9.9. Mean antagonist K1 values (nm) were: hyoscine 0.17, atropine 0.34 and lachesine 0.27.

It is concluded that ganglionic muscarinic receptors are quite similar to ileal receptors in terms of agonist ED50 and antagonist K1 values, and that the major difference between them lies in the greater ‘efficacy’ of certain agonists (pilocarpine, AHR‐602 and McN‐A‐343) on the ganglion.
THE EFFECT OF VERAPAMIL ON THE Ca2+‐TRANSPORTING AND Ca2+‐ATPase ACTIVITY OF ISOLATED CARDIAC SARCOLEMMAL PREPARATIONS
Authors: MAS‐OLIVA JAIME , NAYLER WINIFRED G.
Published: July 2012

The effect of (±)‐, (+)‐ and (‐)‐verapamil on the Ca2+‐binding, Ca2+‐transporting activity, and Ca2+‐dependent adenosine triphosphatase (ATPase) activity of isolated cardiac sarcolemmal preparations was studied. Enzymatic treatment was used to establish the nature of the sites facilitating [14C]‐(±)‐verapamil binding.

(±)‐Verapamil 1 μm inhibited the passive binding of 45Ca2+. The (+)‐ and (‐)‐isomers were equiactive.

(±)‐Verapamil 1 μm inhibited the ATP‐dependent transport of 45Ca2+ and the associated activation of the Ca2+‐sensitive ATPase. The activity resided in the (‐)‐isomer.

Lineweaver‐Burk plots for the initial rates of ATP‐dependent transport showed that the inhibition induced by the (‐)‐isomer was accompanied by a reduced Km and Vmax.

Enzymatic removal of N‐acetyl neuraminic acid and galactose residues increased [14C]‐(±)‐verapamil binding; removal of N‐acetylglucosamine and treatment with phospholipase C and trypsin decreased the binding.

These results have been interpreted to mean that (‐)‐verapamil interferes with the ATP‐dependent Ca2+‐transporting properties of the sarcolemma, and that this effect is accompanied by an altered activity of the intrinsic Ca2+‐sensitive ATPase. N‐acetylneuraminic acid and galactose residues do not provide binding sites for verapamil at the cell surface.
DIPYRIDAMOLE: A POTENT STIMULATOR OF PROSTACYCLIN (PGI2) BIOSYNTHESIS
Authors: BLASS K.‐E. , BLOCK H.‐U. , FÖRSTER W. , PÖNICKE K.
Published: July 2012

Dipyridamole (0.01 to 0.75 mm) increased prostacyclin (PGI2) biosynthesis from tritiated arachidonic acid in rat stomach fundus homogenates by 21 to 350%. The transformation of prostaglandin H2 (PGH2) to PGI2 by a microsomal fraction of pig aorta was stimulated by dipyridamole at 0.1 m by 63%

In the isolated perfused heart of the rabbit dipyridamole at 1 and 5 μg/ml increased PGI2 release by 70% and 146% respectively.

Our results show a stimulation of the second step in PGI2 biosynthesis (from endoperoxides) by dipyridamole. This effect should be considered in relation to the therapeutic usage of the drug in myocardial infarction.
CURARE‐LIKE EFFECT OF PROPRANOLOL ON RAT EXTRAOCULAR MUSCLES
Authors: CHIARANDINI D.J.
Published: July 2012

The effects were studied of the β‐adrenoceptor blocking drug, (±)‐propranolol and its (+)‐ and (−)‐isomers on contractility of rat isolated diaphragm and inferior rectus muscles.

Propranolol (10−5 m) did not modify the resting tension nor the electrically‐induced twitch contraction in diaphragm and extraocular muscles, nor the tonic tension evoked in the latter by high K concentrations.

In inferior rectus preparations (±)‐propranolol (5 × 10−6 m) reduced significantly tensions evoked by succinylcholine (SCh). Cumulative dose‐response curves to SCh were shifted to the right in a nearly parallel manner by (+)‐ and (−)‐propranolol which were about equiactive.

It is concluded that the depressant action of propranolol is independent of its adrenoceptor blocking potency and it is not due to an alteration of the contraction mechanism. Propranolol appears to depress SCh‐evoked tensions through a curare‐like effect on cholinoceptors.
THE RESPONSE OF THE ISOLATED DUCTUS ARTERIOSUS TO TRANSMURAL STIMULATION AND DRUGS
Authors: BODACH E. , COCEANI F. , DUMBRILLE A. , OKPAKO D.T. , OLLEY P.M.
Published: July 2012

Responses of isolated ductus arteriosus preparations from near term guinea‐pigs and lambs to transmural electrical stimulation and drugs were studied in a low oxygen medium (Po2 19 to 28 mmHg).

Acetylcholine and noradrenaline contracted both vessels in a dose‐dependent manner, their threshold being between 10−8 and 10−7 m. Transmural stimulation (pulse width 0.2 to 0.6 ms, typically 20 Hz) also contracted the vessels.

Atropine and phentolamine or dibenzyline selectively blocked responses to acetylcholine and noradrenaline, respectively.

In the guinea‐pig ductus, part of the response to transmural stimulation was due to activation of intrinsic adrenergic nerves since the responses were reduced by α‐adrenoceptor antagonists, bretylium or prior reserpine treatment, but not by atropine. The response of the lamb ductus to transmural stimulation varied greatly in magnitude and was inconsistently affected by α‐adrenoceptor blocking drugs.

There was no evidence that transmural stimulation activated cholinergic nerves in either species.

After inactivation of α‐adrenoceptors with dibenzyline, noradrenaline caused a β‐adrenoceptor‐mediated relaxation. Both this effect and isoprenaline‐mediated relaxation were blocked by propranolol. β‐Adrenoceptor activity was more prominent in the ductus of the guinea‐pig than of the lamb.

Raising the Po2 from 19–28 to 92–98 mmHg increased the response of the guinea‐pig ductus to transmural stimulation suggesting that, in this species, physiological elevation of oxygen tension at birth may increase transmitter release from intrinsic adrenergic nerves. Whether this mechanism would contribute to ductus closure remains an open question.

We postulate that β‐adrenoceptor‐mediated relaxation has a role in maintaining ductus patency in the guinea‐pig foetus.
A MAXIMUM CONTRACTION AND SUBSTANTIAL QUANTITIES OF TRITIUM CAN BE OBTAINED FROM TETRAETHYLAMMONIUMTREATED [3H]‐NORADRENALINE PRELOADED, RAT VAS DEFERENS IN RESPONSE TO A SINGLE ELECTRICAL SHOCK
Authors: WAKADE ARUN R.
Published: July 2012

In the normal and phenoxybenzamine‐treated vasa deferentia of the rat the overflow of tritium after preloading with [3H]‐noradrenaline increased with the increase in frequency of transmural stimulation. Phenozybenzamine enhanced overflow by 5 to 7 fold.

After tetraethylammonium (TEA, 10 mm), fractional tritium overflow at 5 Hz increased from a control value of 2.8 to 53 × 10−4, and at 0.5 Hz it reached 154 × 10−4. Enhancement of overflow was inversely related to the frequency of stimulation.

Contractor responses of the vas deferens induced by transmural stimulation were markedly potentiated, both in amplitude and duration, by 10 mm TEA. The contraction developed in the presence of 10 mm TEA at 0.5 Hz was comparable to that obtained at 10 Hz in normal Krebs solution.

In the presence of 5 mm TEA, contractions of the vas deferens caused by exogenous noradrenaline were potentiated about 5 fold.

The overflow and contractor response induced by 45 mm K were enhanced about 5 fold in 10 mm TEA‐Krebs solution. Facilitation of K‐induced overflow by TEA was reduced over 50% by tetrodotoxin (TTX, 1 μm).

Delivery of a single shock (1.0 ms duration) to 10 mm TEA‐treated vas deferens resulted in a 63% increase in tritium overflow over background overflow. The fractional overflow amounted to almost 720 × 10−4 after a single shock, as compared to 154 × 10−4 obtained at 0.5 Hz.

The vas deferens treated with 10 mm TEA and stimulated by a single shock developed a contraction which was greater in amplitude and duration than that seen in normal tissue at 10 Hz.

Five second serial samples collected from superfused 10 mm TEA‐treated vas deferens contained maximum quantities of radioactivity in the first 5 s after a single shock. In subsequent samples, radioactivity gradually declined, and reached prestimulation level after about 25 s.

The fractional overflow caused by stimulation at 0.1 Hz in 10 mm TEA‐treated tissue progressively increased as external Ca was gradually raised from 0.83 to 10 mm.

The mechanism of action of TEA in enhancing the overflow of sympathetic transmitter, particularly in response to a single shock, is discussed in relation to Ca.
ANTAGONISM OF 5‐HYDROXYTRYPTAMINE RECEPTORS BY QUIPAZINE
Authors: LANSDOWN M.J.R. , NASH H.L. , PRESTON P.R. , WALLIS D.I. , WILLIAMS R.G.
Published: July 2012

The antagonist actions of quipazine on 5‐hydroxytryptamine (5‐HT) receptors have been investigated in the rabbit isolated superior cervical ganglion and on the rat isolated spinal cord and stomach strip.

Changes in membrane potential induced by 5‐HT or by the nicotinic agonist, 1,1‐dimethyl‐4‐phenyl piperazinium (DMPP), were measured in the ganglion by the sucrose‐gap technique. At ganglionic receptors, quipazine had little or no agonist activity, but greatly depressed depolarizations evoked by 5‐HT but not depolarizations evoked by DMPP or trimethylammonium (TMA). Injections into the superfusion stream to the ganglion of 2 to 5 μmol quipazine in a small volume of Krebs solution prevented all subsequent responses to 5‐HT. Superfusion of the ganglion with quipazine at a concentration of 1 μm produced complete blockade of responses to 5‐HT in 3 of 6 ganglia and reduced responses by over 90% in 2 others; responses to DMPP were potentiated in amplitude and duration. Superfusion at a concentration of 0.1 μm depressed responses to 5‐HT by 75% on average. The threshold concentration for the blocking action was around 0.01 μm, which depressed responses by 42% on average in 6 experiments (range 0 to 75%).

5‐HT (1 μm or 100 μm) depressed the amplitude of the dorsal root potentials recorded from the isolated, hemisected cord of the neonate rat by 27 ± 5% (mean ± s.e. mean, n = 14) and by 45 ± 6% (n = 14), respectively. In the presence of quipazine (0.01 μm), 5‐HT (1 μm or 100 μm) depressed the amplitude by 6 ± 2% (n = 15) and by 3 ± 1% (n = 7), respectively.

Concentration‐response curves of the contractions induced by 5‐HT in the fundus of the rat stomach were obtained in the absence and presence of quipazine. Quipazine (1 μm) shifted the concentration‐response curve to the right and depressed the maximum, suggesting a non‐competitive mode of antagonism. pI50 values were calculated in order to assess the antagonist activity of quipazine at rat fundus 5‐HT receptors; the mean pI50 was 6.91 ± 0.2 (n = 6).

It is concluded that quipazine may be an effective antagonist at 5‐HT receptors in various tissues.
A DEMONSTRATION OF NALOXONE‐PRECIPITATED OPIATE WITHDRAWAL ON SINGLE NEURONES IN THE MORPHINE‐TOLERANT/DEPENDENT RAT BRAIN
Authors: FRY J.P. , HERZ A. , ZIEGLGÄNSBERGER W.
Published: July 2012

A comparison has been made between the effects of microelectrophoretically applied naloxone on single neurones in the frontal cerebral cortex and the striatum of naive and of morphine‐tolerant/dependent rats, anaesthetized with a mixture of α‐chloralose and urethane.

Specificity of the results obtained was evaluated by contrasting the effects of alternate applications of the (+)‐ and (−)‐isomers of naloxone to the same neurones.

In naive rats naloxone had predominantly no effect, only a few cells revealing non‐specific depressant responses to the drug.

In morphine‐tolerant/dependent rats a higher proportion of neurones responded to naloxone; either with stereospecific excitatory responses, in which the activity evoked by l‐glutamate or acetylcholine was increased, or with a non‐specific inhibition, similar to that observed in naive animals.

It is suggested that these excitatory responses to microelectrophoretically applied (−)‐naloxone represent opiate withdrawal responses at the single neurone level and that they reflect a latent hyperexcitability of the postsynaptic membrane in the morphine‐tolerant/dependent state.
THE SYNOVIAL PROSTAGLANDIN SYSTEM IN CHRONIC INFLAMMATORY ARTHRITIS: DIFFERENTIAL EFFECTS OF STEROIDAL AND NONSTEROIDAL ANTI‐INFLAMMATORY DRUGS
Authors: BOMBARDIERI S. , CATTANI P. , CIABATTONI1 G. , DI MUNNO O. , PASERO G. , PATRONO C. , PINCA E. , PUGLIESE F.
Published: July 2012

The present study was undertaken to characterize the spectrum of arachidonic acid metabolites present in synovial effusions of patients with rheumatoid or psoriatic arthritis, and to compare changes in their concentration following a short‐term treatment with 6α‐methyl‐prednisolone (6‐MeP: 4–8mg/day) or indoprofen (1.2g/day), a nonsteroidal anti‐inflammatory agent with proven synovial prostaglandin inhibitory effect.

Measurements of prostaglandin E2 (PGE2), thromboxane (TX) B2, 6‐keto‐PGF1α and PGF2α were performed by radioimmunoassay techniques in synovial effusions obtained from 23 patients, and validated by thin‐layer chromatographic analysis of the extracted immunoreactivity.

PGE2 and TXB2 accounted for more than 60% of the total immunoreactivity in untreated patients. The absence of any constant ratio between the different arachidonic acid metabolites detected in synovial fluid is consistent with a heterogeneous cellular origin of these compounds.

Indoprofen treatment was associated with a consistent reduction of synovial prostaglandin and thromboxane concentrations, ranging from 36% in the case of 6‐keto‐PGF1α to 90% in the case of PGE2.

In contrast, 6‐MeP caused opposite changes on different metabolites originating via the cyclo‐oxygenase pathway. Thus, 6‐keto‐PGF1α concentrations were reduced by 35%, PGF2α concentrations were increased by 30%, while PGE2 and TXB2 were unchanged following 6‐MeP.

Although the mechanism(s) underlying the failure of 6‐MeP to reduce synovial PGE2 and TXB2 levels are uncertain, the results of the present study clearly indicate that therapeutic doses of steroidal and nonsteroidal anti‐inflammatory drugs cause quite distinct changes in arachidonic acid metabolism, which might be relevant to their specific therapeutic actions and side‐effects.
CHARACTERIZATION OF THE RAT PAROTID β‐ADRENOCEPTOR
Authors: CARLSÖÖ BENGT , DANIELSSON ÅKE , HENRIKSSON ROGER , IDAHL LARS‐ÅKE
Published: July 2012

The effects of various β‐adrenoceptor agonists on amylase secretion from the rat parotid gland were studied by means of two different in vitro techniques.

The dose‐response relation for each agonist was established, as also were the ED50 values.

All drugs appeared to act directly on the acinar cells, as reserpine‐treatment did not abolish their secretagogic effects.

Two groups of agonists could be distinguished: one group consisting of adrenaline, noradrenaline and the β1‐selective agonist prenalterol (H133/22) with a high enzyme discharge potency and a second group consisting of the β2‐agonists, terbutaline and salbutamol, with a markedly lower effect.

The present data further support the theory that rat parotid acinar cells are supplied mainly with β‐adrenoceptors of the β1‐subtype, similar to those present in heart and adipose tissue.
THE EFFECT OF MELANOTROPHIN RELEASE INHIBITING FACTOR (MIF) AND CYCLO (LEU‐GLY) ON THE TOLERANCE TO MORPHINE‐INDUCED ANTINOCICEPTION IN THE RAT: A DOSE‐RESPONSE STUDY
Authors: BHARGAVA HEMENDRA N.
Published: July 2012

The effects of melanotrophin release inhibiting factor (MIF) and its cyclic analogue cyclo (Leu‐Gly) on tolerance to the analgesic effect of morphine were studied in male Sprague‐Dawley rats.

Tolerance to morphine was induced by implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3 day period.

Daily subcutaneous administration of MIF and cyclo (Leu‐Gly) before and during the morphine pellet implantation inhibited the development of tolerance to morphine analgesia. The minimum daily dose of the peptides required to produce a significant effect was 0.5 mg/kg.

The effects of single injections of MIF and cyclo (Leu‐Gly) on morphine tolerance revealed that the minimum doses of cyclo (Leu‐Gly) and MIF to inhibit morphine tolerance were 4 and 8 mg/kg, respectively.

Chronic treatment with morphine resulted in an enhanced hypothermic response to a dopamine agonist, apomorphine. The enhancement of this response was blocked by both MIF and cyclo (Leu‐Gly) in doses that inhibited morphine tolerance.

It is concluded that MIF and cyclo (Leu‐Gly) block the development of analgesic tolerance as well as dopamine receptor hypersensitivity induced by chronic morphine treatment and the two phenomena may be interrelated.
THE EFFECT OF A XANTHINE DERIVATIVE, 1‐(5′OXOHEXYL)‐3‐METHYL‐7‐PROPYLXANTHINE (HWA 285), ON HEART PERFORMANCE AND REGIONAL BLOOD FLOW IN DOGS AND RABBITS
Authors: HUDLICKA O. , KOMAREK J. , WRIGHT A.J.A.
Published: July 2012

The effect of a new xanthine derivate 1–5′ oxohexyl‐3‐methyl‐7‐proplyxanthine (HWA 285) was studied on heart performance in dogs and rabbits and on regional blood flow in rabbits.

Heart performance (cardiac output and dP/dt max) in dogs was increased. Cardiac work (calculated as CO x mean BP) was not changed in dogs and did not change or was slightly decreased in rabbits. Heart rate was increased in dogs and unchanged in rabbits.

Blood pressure decreased slightly in dogs, and more markedly in rabbits. Total peripheral resistance was decreased in both species.

Regional blood flow (studied by use of 15 μm labelled microspheres) was increased in the heart, brain and skeletal muscle; the increase was dose‐dependent in the range 0.3, 1.0 and 3.0 mg HWA 285 per kg intravenously. The highest dose produced a 2 fold decrease in the peripheral resistance in the brain, a 2.5 fold decrease in the heart and 4 fold decrease in skeletal muscle.

The drugs preferentially dilated small (7 to 10 μm) rather than larger (12 to 17 μm) arterioles; 9 μm microspheres were found in the outflowing blood after application of the drug, and the calculated blood flow increases were smaller, or absent, as compared with values obtained with 15 μm microspheres.
BRADYKININ‐INDUCED RELAXATION OF RENAL AND PULMONARY ARTERIES IS DEPENDENT UPON INTACT ENDOTHELIAL CELLS
Authors: ALTURA BURTON M. , CHAND NARESH
Published: July 2012

When most arteries are removed from mammals and man, the in vitro response to kinins, particularly of helically‐cut vascular strips, is usually one of contraction; and often no response is observed. This is in sharp contrast to the in situ arterial vasodilator action of kinins. The reason(s) for this transformation is not known. The present in vitro experiments demonstrate that bradykinin can produce potent relaxation of canine isolated intrapulmonary arteries (threshold concentration = 7.5±2.7×10−10m) and renal arteries (threshold concentration = 3.2 ± 1.6 × 10−10m) contracted by phenylephrine, provided the endothelium is left intact. Selective, mechanical destruction of the endothelium transforms the vasodilator activity of bradykinin to either contraction or to no response at all. Our results probably explain why previous investigators have found that bradykinin usually induced contraction, rather than relaxation, of excised peripheral arteries.
EVIDENCE AGAINST THE INVOLVEMENT OF PROSTAGLANDINS IN THE VASOCONSTRICTOR ACTION OF CALCIUM ION IN RAT MESENTERIC BLOOD VESSELS
Authors: COUPAR I.M.
Published: July 2012

Prostaglandin E2 (PGE2) has been claimed to be essential to the vasoconstrictor action of noradrenaline in rat mesenteric blood vessels. Since noradrenaline acts by releasing intracellular calcium, experiments have been performed using the perfused rat superior mesenteric artery preparation to determine whether prostaglandin synthesis is necessary for the direct vasoconstrictor action of calcium

The cyclo‐oxygenase inhibitors, indomethacin and 5, 8, 11, 14‐eicosatetraynoic acid (ETA), inhibited responses to noradrenaline and calcium but both were less effective in inhibiting the response to calcium than to noradrenaline

PGE2 (6 ng‐20 μg/ml) failed to overcome the inhibitory effect of indomethacin (62 μg/ml) and ETA (10 μg/ml) on the response to the EC50 of Ca2+ (100 μg/ml). The EC50 of Ca2+ did not significantly increase PGE2‐like release by the blood vessels from the resting value of 19 ± 8pg of PGE2 equivalents/min

PGA1 (6 μg/ml) and the thromboxane A2 agonist, U‐46619 (200ng/ml), both caused full restoration of indomethacin‐depressed responses to calcium, but did not restore responses depressed by ETA. U‐46619 (200ng/ml) also reversed the inhibitory effect of papaverine (4 μg/ml) and caused a 1.6 fold potentiation of Ca2+ responses

The results do not support the hypothesis that prostaglandin synthesis is essential to the vasoconstrictor action of Ca2+ in rat mesenteric blood vessels.
SELECTIVE ACETYLENIC ‘SUICIDE’ AND REVERSIBLE INHIBITORS OF MONOAMINE OXIDASE TYPES A AND B
Authors: KALIR A. , SABBAGH A. , YOUDIM M.B.H.
Published: July 2012

A number of aromatic‐N‐propargyl (acetylenic) compounds and indoleamines were tested for their inhibitory action on monoamine oxidase (MAO) type A and type B using the substrates 5‐hydroxytryptamine (5‐HT), β‐phenylethylamine (PEA) and dopamine.

Structure activity studies with aromatic‐N‐propragyl (acetylenic) derivatives have shown that MAO inhibitory potency is least dependent on the aromatic portion of the compounds. N‐methylated propargyl derivatives are the most active and replacement of the methyl group with a higher alkyl or aromatic group results in significant reduction of activity. The triple bond in the N‐propargyl portion is absolutely essential for activity and must be β‐to the nitrogen. It is the acetylenic group that gives these compounds their irreversible MAO inhibitory property.

The present study has indicated that since the acetylenic compounds resemble the enzyme substrates the distance between the aromatic ring and the N‐propargyl terminal is crucial in designating the type A or type B MAO inhibitory property. For MAO type A inhibition, a distance equivalent to at least three carbon units is required, while for the inhibition of the B type enzyme this distance can be 1 or 2 carbon units.

The compounds AGN‐1133 and AGN‐1135 show most promise in Parkinson's disease or as anti‐depressants because of their irreversible selective type B MAO inhibition in vitro and in vivo.

A number of indoleamine derivatives were found to be reversible selective type A inhibitors.
THE EFFECT OF HEAVY METAL CHELATORS ON THE RENAL ACCUMULATION OF PLATINUM AFTER cis‐DICHLORO‐DIAMMINEPLATINUM II ADMINISTRATION TO THE RAT
Authors: GRAZIANO JOSEPH , JONES BRIAN , PISCIOTTO PATRICIA
Published: July 2012

Rats received a total of 18 mg/kg cis‐dichlorodiammineplatinum (II) (CDDP) intravenously and were treated concomitantly with calcium ‐disodium ethylenediaminetetraacetic acid (CaNa2EDTA), 2,3‐climercaptopropanol (BAL), deferoxamine, 2,3‐dimercaptosuccinic acid (DMS) or vehicle. In comparison to controls, renal platinum concentration was significantly reduced in the DMS and deferoxamine‐treated groups. However, significant deterioration occurred in the deferoxamine‐treated group. The hepatic platinum concentration was unaffected by the chelating agents.

Following a dose of 6 mg/kg CDDP intravenously, eight days of treatment with DMS, 50 mg/kg daily, had no effect on renal platinum excretion, while treatment with 100 or 200 mg/kg daily reduced renal platinum concentration by 50%.

In order to determine whether DMS could prevent the nephrotoxicity of CDDP, rats were given 6 mg/kg CDDP intravenously, followed by a four day course of DMS treatment at doses of 0,50,100 or 200 mg/kg daily begun 3 h after the CDDP dose. DMS failed to prevent renal toxicity as indicated by weight loss, serum creatinine concentration, renal histology, and the urinary excretion of N‐acetyl‐β‐glucosaminidase, a renal tubular enzyme.
RENAL VASODILATOR ACTIVITY OF PROSTAGLANDIN E2 IN THE RAT ANAESTHETIZED WITH PENTOBARBITONE
Authors: HAYLOR J. , TOWERS J.
Published: July 2012

The effect of intra‐aortic administration (i.a.) of prostaglandin E2 (PGE2) on renal blood flow was studied in the rat anaesthetized with pentobarbitone. Renal blood flow was assessed in two ways, either by use of an electromagnetic flow probe or by measurement of the renal clearance of p‐aminohippurate (PAH).

PGE2 (0.1 μg/min, i.a.) increased renal blood flow measured by either method. However, PAH clearance overestimated the degree of vasodilatation compared to that obtained using the flow meter. The possibility that PGE2 or a metabolite may increase PAH extraction by the kidney was considered.

The sensitivity of the rat to the renal vasodilator actions of PGE2 was enhanced by using a flank retro‐peritoneal approach from which to insert the flow probe, rather than a mid‐line abdominal incision.

Dose‐response curves demonstrate that under the conditions used, PGE2 produced a biphasic change in renal vascular resistance, vasodilatation started at 0.01 μg/min and was maximal at about 3 μg/min, while at the highest dose used (20μg/min) PGE2 induced renal vasoconstriction.

The results indicate that contrary to previous reports, the rat does not exhibit an important species difference in the response of its renal vasculature to PGE2. Therefore, physiological and pathophysiological roles which have previously been attributed to vasoconstriction produced by PGE2 synthesized in the kidney may now have to be considered.
MECHANISMS OF ELEVATION OF RAT BRAIN TRYPTOPHAN CONCENTRATION BY VARIOUS DOSES OF SALICYLATE
Authors: BADAWY A. A.‐B.
Published: July 2012

The roles of inhibition of liver tryptophan pyrrolase activity and of displacement of tryptophan from its binding sites on serum proteins have been investigated in relation to the increase in rat brain tryptophan concentration after administration of various doses of sodium salicylate.

The elevation of brain tryptophan concentration by sodium salicylate (0.5 mg/kg) was caused by inhibition of liver pyrrolase activity, whereas that by doses of the drug of 50 mg/kg and above was achieved mainly by tryptophan displacement. Both tryptophan displacement and pyrrolase inhibition caused the increase in brain tryptophan concentration by sodium salicylate at 10 mg/kg.

The smallest dose of salicylate capable of displacing serum‐protein‐bound tryptophan was 2.5 mg/kg.
REGIONAL RAT BRAIN BENZODIAZEPINE RECEPTOR NUMBER AND γ‐AMINOBUTYRIC ACID CONCENTRATION FOLLOWING A CONVULSION
Authors: BOWDLER JULIE M. , GREEN A. RICHARD
Published: July 2012

Following administration to rats of an electroconvulsive shock (ECS) which resulted in a major tonic‐clonic seizure, no changes in [3H]‐diazepam binding characteristics were observed in cortex or hippocampus with either a well washed membrane preparation or a crude synaptosomal preparation.

No changes were observed in [3H]‐diazepam binding in any other brain region examined 30 min after an ECS.

Thirty min following an ECS, regional brain γ‐aminobutyric acid (GABA) concentrations increased in hippocampus, cortex and hypothalamus. Only in the hippocampus did the increase occur within 5 min of the seizure.

Similar increases in GAB A concentration were seen after a bicuculline‐induced seizure but not after a seizure induced by flurothyl; both treatments produced a tonic‐clonic seizure.

Pretreatment of the rats with (+)‐propranolol 5 min before the ECS abolished the tonic extension and prevented the brain GAB A concentration changes that occur 30 min after the seizure.

No increase in GABA concentration was seen in hippocampus, cortex or hypothalamus 30 min after the final ECS of a course of 10 ECS given once daily for 10 days. In contrast a marked increase in striatal GABA concentration was observed.

These changes in GABA biochemistry following a seizure are discussed in relation to the post‐ictal rise in seizure threshold that is occurring at the same time.