bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECT OF AMITRIPTYLINE ON PRESYNAPTIC MECHANISMS IN NORADRENERGIC NERVES
Authors: HUGHES I.E.
Published: July 2012

Electrically evoked and resting overflow of tritium was measured from mouse vas deferens previously incubated with [3H]‐(—)‐noradrenaline.

At low concentrations (1.6 × 10−7 to 4 × 10−6m) amitriptyline increased only the evoked tritium overflow while higher concentrations increased both evoked and resting overflow.

In the presence of atropine (1 × 10−6m) amitriptyline still produced an increase in evoked tritium overflow.

In the presence of a concentration of cocaine (1.1 × 10−5m) which produced a maximal blockade of the uptake of exogenous noradrenaline the application of amitriptyline still produced an increase in evoked tritium overflow.

In the presence of a concentration of phentolamine (1 × 10−5m) that produced complete blockade of the presynaptic α‐adrenoceptors, amitriptyline still produced an increase in evoked tritium overflow.

In the presence of cocaine and phentolamine together the effect of amitriptyline on evoked overflow was abolished.

It is concluded that amitriptyline may raise synaptic levels of noradrenaline by blocking presynaptic α‐adrenoceptors controlling noradrenaline release and by blocking its uptake into sympathetic neurones.
RELATIONSHIP BETWEEN ATRIAL AND VENTRICULAR RATES OF FIBRILLATION AND CARDIAC CONTRACTILE TISSUE EFFECTIVE REFRACTORY PERIODS IN THE DOG
Authors: FARGES J.P. , FAUCON G. , LIEVRE M. , OLLAGNIER M.
Published: July 2012

During total cardiopulmonary bypass, acetylcholine‐, isoprenaline‐, ouabain‐ and quinidine‐induced variations in the atrial and ventricular rates of fibrillation were studied and compared with the variations in effective refractory periods (ERP) of atrial and ventricular contractile tissue obtained under the same experimental conditions.

Acetylcholine significantly shortened the ERP and accelerated the rate of fibrillation in the atrium but did not provoke any change in ventricular tissue. A parallel decrease in atrial and ventricular ERP and a parallel increase in atrial and ventricular rates of fibrillation were observed with isoprenaline.

Ouabain exerted a biphasic effect on the atrium, with an initial decrease in the ERP and an initial acceleration of the rate of fibrillation. It produced only a slight decrease in the ventricular ERP and no significant variation in the ventricular rate of fibrillation.

Quinidine induced a greater increase in the ERP and a greater slowing of the rate of fibrillation in the atrium than in the ventricle.

The variations in percentage change of refractoriness and rate of fibrillation were strictly correlated: r = 0.89 (P > 0.001); the equation of the regression line was y = −0.86 × −2.98.
PROSTAGLANDIN PRODUCTION BY MACROPHAGES AND THE EFFECT OF ANTI‐INFLAMMATORY DRUGS
Authors: BRAY M.A. , GORDON D.
Published: July 2012

Macrophages derived from peritoneal cavity inflammatory exudates of guinea‐pigs produced substantial amounts of prostaglandin E2‐like activity during in vitro culture, so providing the basis for an experimental model of prostaglandin production during inflammatory reactions.

Dose‐related inhibition of prostaglandin biosynthesis was demonstrated by 16 acidic non‐steroidal anti‐inflammatory drugs.

Seven anti‐inflammatory glucocorticosteroid preparations inhibited prostaglandin production in a dose‐related manner. The relative potencies of dexamethasone, prednisolone and hydrocortisone were consistent with clinical anti‐inflammatory ranking. Cortisone, however, failed to inhibit macrophage prostaglandin production.

Three other agents used in the treatment of inflammatory joint diseases were examined. Sodium aurothiomalate inhibited prostaglandin production, although higher concentrations were toxic to macrophages. D‐Penicillamine did not affect macrophage prostaglandin production. Colchicine, in contrast, enhanced prostaglandin production at some concentrations.

The probable significance of macrophages as a source of prostaglandins, during inflammatory responses, is discussed.
FURTHER EVIDENCE FOR THE PREVENTION BY GUANETHIDINE OF NORADRENALINE EFFLUX FROM RABBIT VENTRICULAR SLICES INDUCED BY A LOW EXTERNAL SODIUM CONCENTRATION
Authors: HOSOTANI T. , MISU Y.
Published: July 2012

When guanethidine was applied to rabbit ventricular slices at 37°C for an initial 30 min incubation period, doses of 4 × 10−5 and 8 × 10−5m irreversibly inhibited increases in efflux of noradrenaline induced by the subsequent reduction of external sodium concentrations to 18 dim. This inhibition was prevented if the temperature was reduced to 0°C during the drug application period. Guanethidine transported into adrenergic nerve endings appears to increase permeability to Na+, thereby leading to the reduction in efflux.
DIFFERENCES BETWEEN PRESYNAPTIC AND POSTSYNAPTIC α‐ADRENOCEPTORS IN THE ISOLATED NICTITATING MEMBRANE OF THE CAT: EFFECTS OF METANEPHRINE AND TOLAZOLINE
Authors: ARBILLA SONIA , LANGER S.Z.
Published: July 2012

The α‐adrenoceptor blocking agent, tolazoline, and the O‐methylated metabolite of adrenaline, metanephrine, produced a concentration‐dependent increase of tension in the smooth muscle of the cat isolated nictitating membrane. These effects were considered to be due to the activation of postsynaptic α‐adrenoceptors.

The responses to nerve stimulation of this muscle were neither potentiated nor blocked by tolazoline (0.1 to 10 μm) or metanephrine (1 to 10 μm).

3H‐transmitter overflow evoked by electrical stimulation was not modified by tolazoline or metanephrine in concentrations in which these drugs stimulated the postsynaptic α‐adrenoceptors.

Since tolazoline and metanephrine failed to activate the presynaptic α‐adrenoceptors of the cat nictitating membrane under experimental conditions in which they stimulated the postsynaptic α‐adrenoceptors, these results further support the view that the presynaptic (a2) adrenoceptors differ from the postsynaptic (a1) adrenoceptors.
CARDIOVASCULAR EFFECTS OF ACEBUTOLOL FOLLOWING CORONARY ARTERY OCCLUSION AND REPERFUSION IN ANAESTHETIZED DOG
Authors: CHERNECKI W. , DAS P.K. , DHALLA N.S. , SHARMA G.P.
Published: July 2012

The effects of 5 mg/kg acebutolol given intravenously were investigated in anaesthetized dogs after (a) ligation of the left anterior descending coronary artery and (b) coronary reperfusion following 60 min of ligation of the left anterior descending coronary artery.

Coronary artery ligation produced, after 4 to 6 h, persistent multiple ventricular ectopic beats and abnormalities of R and T waves and of the S‐T segment. Administration of acebutolol, after the development of persistent ventricular arrhythmias, restored normal sinus rhythm within 5 min of injection. Electrocardiographic abnormalities were also reduced.

Coronary artery reperfusion (following 60 min of ligation) resulted in multiple ventricular ectopic beats, ventricular tachycardia and/or ventricular fibrillation. Pretreatment with acebutolol, 15 min before starting reperfusion, markedly reduced the arrhythmias.

Acebutolol did not affect peak inspiratory airway pressure.

Acebutolol produced significant bradycardia and slight, transient, hypotension. It was without effect on left ventricular systolic pressure, left ventricular end‐diastolic pressure, cardiac output or pulmonary arterial pressure.

These results suggest beneficial effects of acebutolol in myocardial ischaemia and coronary reperfusion, without any significant risk of cardiodepression or bronchospasm.
THE PHARMACOKINETICS OF LITHIUM IN THE BRAIN, CEREBROSPINAL FLUID AND SERUM OF THE RAT
Authors: WRAAE O.
Published: July 2012

Addition of lithium carbonate (55 mmol/kg dry wt.) to the diet of rats for 4 days resulted in ratios between lithium in the brain and serum and between the cerebrospinal fluid (CSF) and serum of approx. 1 and 0.4, respectively. The relationships between the concentrations were linear.

After single intraperitoneal injections of lithium chloride (5 mmol/kg body wt.) the concentration of lithium in the CSF was greater than that of the brain for 2 h.

Repeated subcutaneous injections of lithium chloride (0.9 mmol/kg body wt.) resulted in steady state ratios corresponding to those observed when lithium was given in the diet. The rate of elimination from the CSF was intermediate between that of the serum and cerebral tissue until a new equilibrium was reached after approx. 24 h. At that time the ratios between lithium in the brain and serum, and in the CSF and serum were increased to approx. 5 and 0.8, respectively.

These results are consistent with passive transfer kinetics of lithium in the CSF and elimination of lithium from the cerebral tissue via the CSF.

The results may explain some of the phenomena observed in patients during intoxication with lithium.
DEMONSTRATION OF 5‐HYDROXYTRYPTAMINE RECEPTORS THROUGH INHIBITION BY METHERGOLINE IN CAT PIAL ARTERIES in vitro
Authors: EDVINSSON L. , HARDEBO J.E.
Published: July 2012

In an attempt to characterize further the nature of the 5‐hydroxytryptamine (5‐HT)‐induced contraction of intracranial vessels, cat's middle cerebral artery was exposed to this amine and the specific 5‐HT receptor antagonist, methergoline, under standardized conditions in vitro. Methergoline, in increasing concentrations, produced a parallel shift of the log dose‐response curve for 5‐HT.

The Arunlakshana‐Schild plot gave a straight line with a slope of −0.85. The figure corresponding to the pA2 value was 8.80.

The findings offer further support for the assumption that the 5‐HT‐induced intracranial vasoconstriction is mediated by specific 5‐HT receptors.
PHARMACOLOGICAL CHARACTERIZATION OF THE PRESYNAPTIC α‐ADRENOCEPTORS REGULATING CHOLINERGIC ACTIVITY IN THE GUINEA‐PIG ILEUM
Authors: DREW G.M.
Published: July 2012

The presynaptic α‐adrenoceptors located on the terminals of the cholinergic nerves of the guinea‐pig myenteric plexus have been characterized according to their sensitivities to α‐adrenoceptor agonists and antagonists.

Electrical stimulation of the cholinergic nerves supplying the longitudinal muscle of the guinea‐pig ileum caused a twitch response. Clonidine caused a concentration‐dependent inhibition of the twitch response; the maximum inhibition obtained was 80 to 95% of the twitch response. Oxymetazoline and xylazine were qualitatively similar to clonidine but were about 5 times less potent. Phenylephrine and methoxamine also inhibited the twitch response but were at least 10,000 times less potent than clonidine.

The twitch‐inhibitory effects of clonidine, oxymetazoline and xylazine, but not those of phenylephrine or methoxamine, were reversed by piperoxan (0.3 to 1.0 μg/ml).

Lysergic acid diethylamide (LSD) inhibited the twitch response, but also increased the basal tone of the ileum. Mepyramine prevented the increase in tone but did not affect the inhibitory action of LSD. Piperoxan or phentolamine only partially antagonized the inhibitory effect of LSD.

Phentolamine, yohimbine, piperoxan and tolazoline were potent, competitive antagonists of the inhibitory effect of clonidine with pA2 values of 8.51, 7.78, 7.64 and 6.57 respectively.

Thymoxamine was a weak antagonist of clonidine; it also antagonized the twitch‐inhibitory effect of morphine. Thus, its effect against clonidine is probably not mediated specifically at presynaptic α‐adrenoceptors.

Labetalol, itself, depressed the twitch response but did not antagonize the inhibitory effect of clonidine on the residual twitch.

The results demonstrate that the presynaptic α‐adrenoceptors in the guinea‐pig ileum are of the same type as those located presynaptically in sympathetically innervated tissues. They are a2‐adrenoceptors and are different from those located postsynaptically.
INHIBITION BY N‐ACETYL NEURAMINIC ACID OF PLATELET THROMBOGENESIS INDUCED BY LASER INJURY TO RAT AND HAMSTER VENULES
Authors: BORN GUSTAV V.R. , KOVACS IREN B.
Published: July 2012

In rats and hamsters under barbiturate anaesthesia, laser radiation to venules about 50 μm in diameter in mesoappendix and cheek pouch respectively caused the formation of platelet thrombi which occluded the vessels in about 9 min.

This occlusion time was significantly prolonged by the intravenous injection of N‐acetyl neuraminic acid (NANA) but not by D‐glucuronic acid or β‐methoxyneuraminic acid, in doses which had no effect on blood pH or on the condition of the animals.

The results confirm the antithrombotic effect of NANA previously demonstrated with another technique.
THE ROLE OF THE HYPOGASTRIC NERVE IN BLADDER AND URETHRAL ACTIVITY OF THE DOG
Authors: CREED KATE E.
Published: July 2012

Stimulation of the hypogastric nerves increased the pressure in both the bladder and urethra of anaesthetized female dogs.

The responses were reduced but not abolished by the α‐adrenoceptor antagonist phentolamine, whereas the β‐adrenoceptor antagonist propranolol was either without effect or increased the responses. Atropine, methysergide and hexamethonium were without effect.

Close arterial injection of phenylephrine increased and isoprenaline decreased urethral pressure but both produced only a slight increase in bladder pressure.

Hypogastric nerve stimulation reduced subsequent responses of the bladder and urethra to pelvic nerve stimulation or to close arterial injection of acetylcholine. Isoprenaline, but not phenylephrine, also had an inhibitory action and 5‐hydroxytryptamine enhanced the responses.

In the presence of hexamethonium the inhibitory action of isoprenaline still occurred but 5‐hydroxytryptamine no longer enhanced the responses, suggesting that 5‐hydroxytryptamine acts on the ganglia and isoprenaline acts, at least partially, on smooth muscle.

These results suggest that the role of the hypogastric nerves may be to modify inputs to the bladder and urethra as well as to act directly on the smooth muscle.
EFFECTS OF SUBSTANCE P INJECTED INTO THE SUBSTANTIA NIGRA
Authors: JAMES THOMAS A. , STARR MICHAEL S.
Published: July 2012

Behavioural and biochemical effects of substance P (SP, 1 to 10 μg) administered in a small volume to discrete areas of the rat's brain were studied by means of a refined microinjection technique.

SP injected unilaterally into the zona reticulata of the substantia nigra elicited dose‐dependent contraversive circling and an increase in dopamine turnover in the ipsilateral striatum. SP applied to the zona compacta or zona lateralis, or to the medial lemniscus, evoked ipsiversive turning with a fall in dopamine turnover and a rise in 5‐hydroxytryptamine (5‐HT) turnover in the corresponding striatum.

In both cases the onset of turning was immediate, reached a peak at about 5 min and lasted for 10 min. Both types of behaviour were blocked by haloperidol and exaggerated by nialamide.

Unilateral injections of SP given into the crus cerebri, zona incerta, caudate nucleus, putamen or globus pallidus did not modify the animal's behaviour.

In rats pretreated with apomorphine or amphetamine, SP induced contraversive circling which was followed by locomotion in the opposite direction.

Turning responses to a second dose of SP were diminished at 3 h and reproducible at 24 h after the first injection.

Bacitracin (50 ng) injected into the zona reticulata caused ipsiversive turning. Larger intranigral doses of bacitracin (10 μg), as with intracisternal SP (10 μg), evoked ‘barrel rotation’.

No changes in the free concentrations of aspartate, glutamate, γ‐aminobutyric acid, glycine or alanine were detected in any brain region following an intracisternal injection of 10 μg SP, although glutamine levels were elevated throughout the brain 30 to 60 min later.
EFFECTS OF CONCANAVALIN A ON 5‐HYDROXYTRYPTAMINE UPTAKE BY RABBIT BLOOD PLATELETS AND ON THEIR ULTRASTRUCTURE
Authors: NISHIO H. , SEGAWA T. , TAKAGI H.
Published: July 2012

Effects of concanavalin A (Con A) and other lectins on 5‐hydroxytryptamine (5‐HT) uptake by rabbit blood platelets and on their ultrastructure were studied.

Uptake of [3H]‐5‐HT by platelets was decreased by application of Con A, E‐PHA (lectin from Phaseolus vulgaris) and lentil‐PHA (lectin from Lens culinaris), but not by wheat germ agglutinin (WGA). Con A induced specific changes in the ultrastructure of platelets, causing (i) a change in external appearance from a discoid to an irregularly spherical shape, (ii) re‐arrangement of the canalicular system and formation of a concentric structure. These effects of Con A on platelets were antagonized by pretreatment with α‐methyl‐D‐mannoside (a‐MM), a specific inhibitor of Con A binding to glycoprotein.

The inhibition of 5‐HT uptake by Con A was antagonized by colchicine, vinblastine and sodium nitroprusside (SNP), but not by cytochalasin B.

Theophylline, papaverine and dibutyryl cyclic adenosine 3′,5′‐monophosphate (db cyclic AMP) antagonized the effect of Con A on 5‐HT uptake, but dibutyryl cyclic guanosine 3′,5′‐monophosphate had no effect. Theophylline and db cyclic AMP did not influence the effect of Con A on the ultrastructure of platelets.

It is suggested that binding of Con A to specific receptor glycoproteins can inhibit the 5‐HT uptake system of platelets. Microtubules, contractile protein and the membrane adenylate cyclase system of platelets may also be regulatory factors in this mechanism.
SHORT AND LONG‐TERM EFFECTS OF RESERPINE ON THE CONCENTRATION OF 1‐(4‐HYDROXY‐3‐METHOXYPHENYL)‐ETHANE‐1,2‐DIOL (MOPEG‐S04) IN THE BRAIN OF THE RAT
Authors: BAREGGI S.R. , GENOVESE E. , MARKEY K.
Published: July 2012

Reserpine (1.25 mg/kg i.p.) induced an increase (172% of controls) in the concentration of 1‐(4‐hydroxy‐3‐methoxyphenyl)‐etnane‐1,2‐diol sulphate (MOPEG‐S04) in rat brain and a decrease in the noradrenaline (NA) concentration to 50% of controls 2 h after injection. At this time the MOPEG‐S04/NA ratio was 0.28. Thereafter the MOPEG‐SO4 concentration declined and the NA concentration decreased further to 28% of control.

Higher doses of reserpine (2.5 and 5 mg/kg i.p.) did not induce a larger increase in the concentration of MOPEG‐SO4.

While a second dose of reserpine (1.25 mg/kg i.p.) given 24 h after the first did not increase the MOPEG‐SO4 concentration, amphetamine (5.0 mg/kg i.p.) administration or electrical stimulation significantly increased the concentration of MOPEG‐SO4.

NA and MOPEG‐SO4 concentrations were examined during 5 days after a single dose of reserpine (1.25 mg/kg i.p.). While the concentration of NA started to return towards normal after 24 h, that of MOPEG‐SO4 remained at approximately 70% of controls during the entire period.

The probenecid‐induced accumulation rate of MOPEG‐SO4 was significantly lower 3 and 4 days after reserpine and returned to the control value on the fifth day. At this time the concentration of NA had reached 50% of the control value.

These experiments indicate that MOPEG‐SO4 is not the major metabolite of NA during the initial phase of reserpine‐induced NA release. Reserpine acts on the storage pool while amphetamine (like electrical stimulation) acts on the functional pool. During the first phase of post‐drug recovery, there is a clear decrease in NA output which appears to be regulated by the concentration of NA in the storage pool.
THE PROTECTIVE ACTION OF INOSINE ON ISOLATED ARTERIES IN HYPOXIA
Authors: BLOOM DAVID S. , COLE ARTHUR W.G. , PALMÉER T. NORMAN
Published: July 2012

The pressor responses to injected noradrenaline (NA) of isolated perfused femoral or renal arteries of the rabbit were studied.

Vascular smooth muscle is relatively resistant to hypoxia. A combination of hypoxia and dinitro‐phenol (DNP) respiratory uncoupling was necessary to abolish the pressor response to NA. Loss of the pressor response was assumed to result from decreased capacity of arteries to form adenosine 5′‐triphosphate (ATP). Reperfusion of the hypoxic arteries with oxygenated medium resulted in recovery of the pressor response to NA.

Inclusion of inosine (10 mm) in the hypoxic perfusion medium increased significantly the rate and extent of post‐hypoxic recovery of the pressor response to NA.

Whereas the presence of inosine in the hypoxic perfusion medium aided post‐hypoxic recovery, inosine had no direct action on the pressor dose response to NA. Therefore, the action of inosine was protective as opposed to direct.

The protective action of inosine did not involve potentiation of NA binding to NA‐adrenoceptor sites (the equilibrium coefficient, Keq for NA‐receptor interaction was unaltered by hypoxia and/or inosine).

The results are discussed in terms of a presumptive mechanism whereby inosine is believed to act by maintaining intracellular adenine nucleotide concentrations in hypoxia.
EFFECTS OF PROCAINE AND EXTRACELLULAR CALCIUM CONCENTRATION ON RESPONSE OF RAT STOMACH FUNDUS MUSCLE TO ACETYLCHOLINE AND 5‐HYDROXYTRYPTAMINE
Authors: WEINSTOCK MARTA , WEISS CARMELA
Published: July 2012

When rat stomach fundus muscle was incubated for 30 min in Tyrode solution from which calcium chloride had been omitted, there was an almost complete abolition of the contractile response to 5‐hydroxytryptamine (5‐HT) while that to acetylcholine (ACh) was still present.

The maximum tension obtainable with ACh remained the same in external calcium concentrations ranging from 0.45 to 3.6 mm, but the pD2 value increased.

A concentration of at least 0.9 mm calcium was needed to maintain a maximum contraction with 5‐HT, and the pD2 for this agent also increased significantly with increase in calcium content of the medium.

The effects of procaine on the responses of the muscle to 5‐HT and ACh were similar to the respective changes induced by lowering the calcium concentration, and were reduced by the addition of calcium.

Concentrations of 2.2 × 10−7 to 3.6 × 10−5m procaine reduced the effects of both 5‐HT and KCl and suppressed the maximum responses.

The maximum responses to KC1 and 5‐HT were restored at higher concentrations of procaine (>3.6 × 10−4m), while the effect of ACh was reduced.

It is suggested that 5‐HT, like KC1, is almost entirely dependent on extracellular calcium for inducing muscle contraction, while ACh may utilize calcium from bound stores.
ON THE ROLE OF 5‐HYDROXYTRYPTAMINE IN DRUG‐INDUCED ANTINOCICEPTION
Authors: SUGRUE M.F.
Published: July 2012

The effects of four specific inhibitors of 5‐hydroxytryptamine (5‐HT) uptake on morphine‐, methadone‐ or pethidine‐induced antinociception was studied in rats. Antinociception was assessed by means of hot plate (55°C) reaction times. The effect of the compounds on the uptake of [3H]‐5‐HT into rat whole brain synaptosomes was also investigated.

Pretreatment with Org 6582, citalopram, zimelidine or femoxetine at doses devoid of antinociceptive activity potentiated morphine‐ but not methadone‐ or pethidine‐induced antinociception.

A temporal correlation existed between the ability of Org 6582 to potentiate morphine‐induced antinociception and to block synaptosomal [3H]‐5‐HT uptake.

5‐HT plays a critical role in the antinociceptive effect of morphine but not of methadone or pethidine.
THE EFFECTS OF GLUCOCORTICOIDS ON THE DISTRIBUTION AND MOBILISATION OF ARACHIDONIC ACID IN FAT CELL GHOSTS
Authors: LEWIS G.P. , PIPER PRISCILLA J. , VIGO CARMEN
Published: July 2012

The prostaglandin synthesizing enzymes were found to be present in fat cell ghosts isolated from rabbit adipose tissue.

Prostaglandin E2 (PGE2) and PGF2 were synthesized by ghosts after stimulation with adrenocor‐ticotrophic hormone (ACTH).

Indomethacin was found to inhibit this synthesis but not the synthesis of lipoxygenase products.

When fat cell ghosts were stimulated by ACTH, fatty acid release was observed from both neutral lipids and phospholipids.

The arachidonic acid (AA) pool within the ghosts was identified: approximately 90% was present in the phospholipid fraction, 8.5% in the neutral lipids and 1.5% unbound.

The glucocorticoids were found to stimulate incorporation of [14C]‐AA into neutral lipids and inhibit its incorporation into phospholipids.

When fatty acid release was stimulated with ACTH, the glucocorticoids were found to inhibit the mobilisation of [14C]‐AA from the phospholipids and enhance its release from the neutral lipids.

The glucocorticoids inhibit prostaglandin formation in fat cell ghosts.
5‐HYDROXYTRYPTAMINE AND MYOCLONUS INDUCED BY 1,2‐DI‐HYDROXYBENZENE (CATECHOL) IN THE GUINEA‐PIG
Authors: CHADWICK D. , JENNER P. , MARSDEN C.D.
Published: July 2012

Myoclonus induced by catechol in the guinea‐pig is not altered by manipulation of cerebral 5‐hydroxytryptamine (5‐HT). The administration of catechol does not alter brain levels of 5‐HT or its metabolite 5‐hydroxyindole acetic acid. This form of myoclonus therefore is not of relevance to the 5‐HT‐sensitive post‐anoxic action myoclonus occurring in man.
FUNCTIONAL ANTAGONISM AS A MEANS OF DETERMINING DISSOCIATION CONSTANTS AND RELATIVE EFFICACIES OF SYMPATHOMIMETIC AMINES IN GUINEA‐PIG ISOLATED ATRIA
Authors: BROADLEY K.J. , NICHOLSON C.D.
Published: July 2012

The positive inotropic and chronotropic responses to sympathomimetic amines were examined in guinea‐pig isolated atria.

The order of potency measured from EC50 values was isoprenaline > orciprenaline > salbutamol ≥ fenoterol > terbutaline. Terbutaline and salbutamol were partial agonists on rate and together with orciprenaline and fenoterol also on tension responses.

Functional antagonism by carbachol caused a rightwards shift of the dose‐response curve and depression of the maximum response. The rate maxima for orciprenaline, fenoterol and terbutaline were above that of isoprenaline. All the tension maxima were below isoprenaline.

Dissociation constants (KA) and relative efficacies (er) were determined by analogy with irreversible antagonism.

The relative orders of affinity (KA) were isoprenaline > orciprenaline > fenoterol > salbutamol > terbutaline. Affinities were identical on rate and tension.

The relative efficacies were all greater than isoprenaline for rate responses. On tension they were the same or less than isoprenaline.

The implications of these results are discussed, in particular the fact that a partial agonist has a greater efficacy than a full agonist.
MECHANISM OF INHIBITION OF PROSTAGLANDIN BIOSYNTHESIS BY HYDROCORTISONE IN RAT LEUCOCYTES
Authors: DI ROSA M. , PERSICO P.
Published: July 2012

Hydrocortisone (10 μg/ml) greatly inhibits the prostaglandin release by rat peritoneal leucocytes phagocytosing killed bacteria. The inhibition, which occurs after an initial latency of 30 min, is completely reversed by either actinomycin D (0.5 μg/ml) or cycloheximide (1 μg/ml). Since these antibiotics are known inhibitors of DNA‐dependent RNA synthesis and protein synthesis respectively, it appears that the mechanism of inhibition of prostaglandin biosynthesis by hydrocortisone in rat leucocytes involves stimulation of transcription and induction of protein synthesis.
PHARMACOLOGICAL EFFECTS OF PHOSPHATIDYLSERINE LIPOSOMES: REGULATION OF GLYCOLYSIS AND ENERGY LEVEL IN BRAIN
Authors: BIGON E. , BOARATO E. , BRUNI A. , LEON A. , TOFFANO G.
Published: July 2012

The accumulation of glucose in the brain produced by the administration of phosphatidylserine liposomes into mice has been studied by measurement of the cerebral contents of glycolytic intermediates and high‐energy compounds.

With a normal supply of oxygen to the brain, inhibition of glycolysis is indicated mainly at the phosphofructokinase step. The ratio of glucose‐6‐phosphate to fructose‐1,6‐diphosphate increased, whereas the levels of pyruvate and especially lactate decreased.

Under conditions of cerebral ischaemia, the administration of phosphatidylserine delays glycogen mobilization and ATP use. As a consequence of decreased energy utilization, the brain adenylate energy charge remains at a high level.

It is concluded that the phosphatidylserine‐induced glucose accumulation in the brain is due to reduced energy expenditure and therefore to a decrease in carbohydrate consumption. The inhibition of glycolysis by the high level of adenylate energy charge is probably the control mechanism explaining the decreased carbohydrate utilization.
EVIDENCE FOR AN INDIRECT CHOLINERGIC REGULATION OF BLOOD FLOW IN THE HYPOTHALAMUS OF CONSCIOUS RABBITS
Authors: KLUGMAN K. , MITCHELL G. , ROSENDORFF G.
Published: July 2012

The effects of methacholine, atropine and adrenoceptor blockade on hypothalamic blood flow (HBF) were measured in conscious rabbits.

A dose of 1 μg methacholine increased HBF while smaller and larger doses had no significant effect.

The vasodilatation induced by methacholine was blocked by atropine and by chemical sympathectomy of the hypothalamus with 6‐hydroxydopamine.

The vasodilatation was reversed by propranolol but was not affected by phenoxybenzamine.

These results suggest that the vasodilator action of muscarinic receptor agonists on hypothalamic resistance vessels depends upon the integrity of a noradrenergic system, and is mediated via β‐adrenoceptors.
RESPONSES TO dl‐IBOTENIC ACID AT LOCUST GLUTAMATERGIC NEUROMUSCULAR JUNCTIONS
Authors: CLARK R.B. , GRATION K.A.F. , USHERWOOD P.N.R.
Published: July 2012

The responses of excitatory junctions on locust skeletal muscle fibres to iontophoretically applied l‐glutamic acid and dl‐ibotenic acid, a rigidly extended analogue of glutamate, were recorded by means of intracellular microelectrodes.

Iontophoresis of l‐glutamate to junctional sites produced transient depolarizations. Ibotenate applied iontophoretically to these sites usually evoked small hyperpolarizations which probably resulted from the activation of glutamate H‐receptors on the extrajunctional membrane surrounding the junctions. However, at a minority (∼20%) of junctions, ibotenate iontophoresis evoked transient depolarizations.

Iontophoretically applied glutamate desensitized the ibotenate receptors, and vice versa. In experiments performed at junctional sites at which ibotenate depolarizations were absent, ibotenate had no effect on the responses to glutamate.

Glutamate and ibotenate junctional currents had similar reversal potentials, measured under voltage‐clamp, suggesting that the ionic bases for these currents are identical.

It is proposed that the excitation caused by ibotenate results from the activation of receptors for extended l‐glutamate and that these receptors co‐exist on the post‐junctional membranes of locust excitatory nerve‐muscle synapses with ibotenate‐insensitive glutamate receptors activated by glutamate in partially folded conformation.
IMPROVED INSULIN RECEPTOR ASSAY: EFFECTS OF AN ANTIDIABETIC SULPHONYLUREA ON LIVER MEMBRANE INSULIN RECEPTORS FROM OBESE HYPERGLYCAEMIC MICE
Authors: GREENSTEIN B.D.
Published: July 2012

A simple assay of liver membrane insulin receptors is described, under conditions which apparently stabilized the insulin‐receptor complex. The receptor population was measured in the presence of physiological doses of radioactive hormone under conditions which minimized negative co‐operativity effects.

Equilibrium between receptor and hormone was attained in vitro within 60 min of incubation time at 13°C with no apparent loss of binding sites after 3 h of incubation.

Liver membranes from lean mice possessed 8.8 times the receptor number per mg membrane protein measured in membranes from obese hyperglycaemic (ob/ob) littermates. After treatment of ob/ob mice with ARDF‐26 (Gliquidon; Boehringer Ingelheim Ltd) the concentration of liver membrane insulin receptors was increased 5 fold.
PHARMACOLOGY OF SCHULTZ‐DALE REACTION IN CANINE LUNG STRIP in vitro: POSSIBLE MODEL FOR ALLERGIC ASTHMA
Authors: CHAND N. , DEROTH L. , EYRE P.
Published: July 2012

Isolated lung parenchymal strips of the dog contracted in response to histamine > carbachol > prostaglandin F2α (PGF2α) > bradykinin (Bk) > 5‐hydroxytryptamine (5‐HT). The order of the relative activity of these agents on the tracheobronchial smooth muscles (TBSM) was carbachol > 5‐HT > histamine; PGF2α and Bk were inactive. Thus there are marked differences in the responsiveness of the smooth muscle of central (trachea and bronchus) and peripheral (lung strip) airways to autonomic and autacoid agents.

Lung strips and TBSM partially contracted by carbachol, histamine or horse plasma, were relaxed by isoprenaline, PGE1 and PGE2.

Lung strips from dogs sensitized to horse‐plasma contracted in response to antigen (Schultz‐Dale anaphylactic reaction). Tachyphylaxis or desensitization to subsequent antigen challenge was invariably observed; it was followed after 1 to 2 h of rest by partial recovery of the anaphylactic response.

Mepyramine selectively antagonized responses to histamine without altering responses to carbachol and antigen.

Metiamide, an H2‐receptor antagonist, did not influence responses to histamine, carbachol or horse plasma.

Indomethacin was found to be ineffective as an inhibitor of the Schultz‐Dale anaphylactic reaction.

The results showed the presence of H1‐histamine receptors mediating constriction in the peripheral airways of the dog. Histamine and PGF2α appear to have no important role in the anaphylactic reaction in this tissue. The involvement of slow reacting substance of anaphylaxis (SRS‐A) and endoperoxides (thromboxanes) in allergic reactions of canine lung is strongly suggested.
NORADRENALINE RELEASE IN RATS DURING PROLONGED COLD‐STRESS AND REPEATED SWIM‐STRESS
Authors: BENEDICT C.R. , FILLENZ MARIANNE , STANFORD CLARE
Published: July 2012

Plasma noradrenaline concentration in rats was measured during prolonged cold‐stress and repeated swim‐stress.

Cold exposure for 6 h caused a rise in plasma noradrenaline which reached a peak at 4 h.

Administration of desmethylimipramine and normetanephrine to block neuronal and extraneuronal uptake of noradrenaline raised plasma noradrenaline concentration without changing the pattern of the response to cold exposure.

Repeated cold exposure on subsequent days produced no change in the pattern of plasma noradrenaline concentration.

Five successive 1‐min swims at 30‐min intervals caused a rise in plasma noradrenaline concentration which was maximal after the third swim.

It is suggested that prolonged and repeated activation of sympathetic nerve terminals leads to a decline in noradrenaline release.
STUDY ON THE POSSIBLE ENTRY OF BACTERIAL ENDOTOXIN AND PROSTAGLANDIN E2 INTO THE CENTRAL NERVOUS SYSTEM FROM THE BLOOD
Authors: DASCOMBE M.J. , MILTON A.S.
Published: July 2012

A study has been made of the possible entry of 51Cr‐bacterial endotoxin and [5,6,8,11,12,14,15(n)‐3H]‐prostaglandin E2 ([3H]‐PGE2) into the CNS of the anaesthetized cat.

No radioactivity was detected in perfusates of the preoptic‐anterior hypothalamus or in the cerebrospinal fluid (c.s.f.) in vivo, or in brain tissue post mortem following intracarotid infusion of 51Cr‐bacterial endotoxin.

Intracarotid administration of [3H]‐PGE2 resulted in the entry of radioactivity into the CNS of endotoxin pretreated cats. Chromatographic analysis indicated the radioactivity in c.s.f. to be associated with PGE2 and a metabolite similar to 13, 14‐dihydro‐15‐keto PGE2.

Intracarotid administration of 13, 14‐dihydro‐15‐keto [5,6,8,11,12,14(n)‐3H]‐PGE2 resulted in the presence of the compound in the CNS of the anaesthetized cat after pretreatment with bacterial endotoxin.

It is concluded that PGE2 and possibly 13,14‐dihydro‐15‐keto PGE2 but not bacterial endotoxin may enter the CNS from the cerebral circulation to elicit the febrile response to bacterial endotoxin in cats.
AN EFFECT OF HALOPERIDOL ON THE INCREASED FOOD AND WATER INTAKE INDUCED IN RABBITS BY 2‐DEOXY‐d‐GLUCOSE
Authors: ANDERSON J. , SHARMAN D.F. , STEPHENS D.B.
Published: July 2012

Rabbits treated with 2‐deoxy‐D‐glucose (2DG) (300 mg/kg) show an increased intake of food and water. Pretreatment with haloperidol (1 mg/kg) abolishes the increase in water intake but does not prevent the increase in food intake.
UPTAKE AND RELEASE OF 5‐HYDROXYTRYPTAMINE BY ENTERIC 5‐HYDROXYTRYPTAMINERGIC NEURONES: EFFECTS OF FLUOXETINE (LILLY 110140) AND CHLORIMIPRAMINE
Authors: GERSHON M.D. , JONAKAIT G. MILLER
Published: July 2012

The effect of fluoxetine on uptake of 5‐hydroxytrypt‐amine(5‐HT) by enteric 5‐hydroxytryptaminergic neurones has been analyzed in order to compare further these neurones with 5‐HT neurones of the CNS. In addition, the effects of fluoxetine and chlorimipramine on efflux of [3H]‐5‐HT from the myenteric plexus were also evaluated. Fluoxetine was found to be a competitive inhibitor of 5‐HT uptake by the myenteric plexus and was a more potent inhibitor of 5‐HT uptake than was chlorimipramine. However, chlorimipramine enhanced the efflux of [3H]‐5‐HT more than could be explained by inhibition of 5‐HT uptake and, therefore. appears to have the additional action of releasing the amine. These observations, similar to those of others studying central neurones, support the view that enteric 5‐HT neurones resemble those of the CNS and are a useful model for the evaluation of drugs.
AN ANALYSIS OF SOME FACTORS INFLUENCINGα‐ADRENOCEPTOR FEED‐BACK AT THE SYMPATHETIC JUNCTION IN THE RAT HEART
Authors: DOCHERTY J.R. , McGRATH J.C.
Published: July 2012

The effects of the selective prejunctional α‐adrenoceptor antagonist, yohimbine, on the cardio‐acceleration responses to sympathetic stimulation were examined in the pithed rat.

Yohimbine reversed the inhibitory effects of the α‐adrenoceptor agonist, clonidine. on the stimulation‐induced tachycardia.

Yohimbine failed to potentiate significantly responses to stimulation in the absence of clonidine when stimulation was applied at the optimal level for cardiac responses (C6‐T1).

When the pithing rod electrode was moved to T2‐T6, cardioaccelerator responses were smaller and yohimbine produced potentiation at frequencies of ≥ 1 Hz. This potentiation was prejunctional since responses to exogenous noradrenaline (NA) were not increased by yohimbine.

In the presence of cocaine, potentiation by yohimbine could be shown at the lower frequency of 0.1 Hz.

The possible physiological significance of a negative feed‐back effect of noradrenaline on cardiac sympathetic nerves is discussed.
INVOLVEMENT OF A CENTRAL α‐ADRENOCEPTOR SYSTEM IN ANTIDEPRESSANT POTENTIATION OF HYPERTHERMIA INDUCED BY THYROTROPIN RELEASING HORMONE
Authors: DESILES MARGUERITE , PUECH ALAIN J. , RIPS RICHARD
Published: July 2012

Thyrotropin releasing hormone (TRH) causes hyperthermia in mice which is potentiated by tricyclic antidepressants (nortriptyline, imipramine, clomipramine, amitriptyline), the monoamine oxidase inhibitor, tranylcypromine, and various other antidepressants (maprotiline, nomifensin, viloxazine). Only iprindole is ineffective. The effect of mianserin, itself hypothermic, could not be interpreted. A property shared by the potentiating substances seems to be activation of a central adrenoceptor system. The potentiation of TRH‐induced hyperthermia which seems to be specific to antidepressants might be used in the selection of antidepressants.
EFFECTS OF AZAPERONE AND ACETYLPROMAZINE ON SOCIAL AND ENVIRONMENTAL BEHAVIOUR IN SHEEP
Authors: MADSEN B.W. , SYME G.J. , SYME L.A.
Published: July 2012

Acetylpromazine (Acp, 0.05, 0.1 and 0.5 mg/kg) and azaperone (Azp, 1.0, 1.25 and 1.5 mg/kg) were given by intramuscular injection to separate groups of seven familiar Romney ewes. Thirty minutes after injection the sheep were led into a featureless arena and spatial distribution, activity and shade preference were monitored for 20 min by overhead photography.

Behavioural response was complex with both stimulant and depressant effects being seen. The response trends with increasing time for all three measures were significantly different for the two drugs. In particular, Azp tended to increase animal dispersion and Acp to decrease it, in agreement with earlier predictions.

The dosage range for Azp was adequate for reduction of individual movement and inter‐animal distance but steady state effect was not reached in the time period studied. All doses of Azp initially caused disorientation, as measured by shade preference, but this improved as sedation deepened.

The highest dose of Acp (0.5 mg/kg) achieved steady state effect on individual movement within the study period. The three doses of Acp caused either no change or a slight increase in inter‐animal distance. Disorientation with Acp was less and briefer than that seen with Azp.
BIPHASIC RESPONSIVENESS OF RAT PIAL ARTERIOLES TO DOPAMINE: DIRECT OBSERVATIONS ON THE MICROCIRCULATION
Authors: ALTURA BURTON M. , GEBREWOLD ASEFA , LASSOFF SAMUEL
Published: July 2012

The effects of local perivascular application of dopamine to rat pial arterioles, (20–40 μm i.d.) were examined in situ, at the microcirculatory level, by use of a high‐resolution closed circuit television microscope recording system. Local application of very low, physiological doses (1 to 10 pg) of dopamine to pial arterioles of the anaesthetized rat induces vasodilatation, whereas higher doses induce vasoconstriction. The magnitudes of these biphasic responses obtained in male rats were not significantly different from those obtained in female animals. Our findings support the theory that local release of this neurotransmitter amine from perivascular cells in the brain may promote local increases in cerebral blood flow.
CORONARY VASODILATATION: INTERACTIONS BETWEEN PROSTACYCLIN AND ADENOSINE
Authors: BLASS K.‐E. , FÖRSTER W. , ZEHL U.
Published: July 2012

The influence of prostacyclin (PGI2) on the release of adenosine in rabbit hearts perfused by the Langendorff method was examined under normal conditions of perfusion and during perfusion with the adenosine antagonist, aminophylline.

PGI2 increased both coronary flow and the myocardial release of adenosine in a dose‐dependent manner. Aminophylline at a low concentration (10 μg/ml) suppressed the enhanced flow.

Adenosine increased both coronary flow and the release of PGI2 from the isolated hearts; both these effects were inhibited by the low aminophylline concentration. Inhibition of PGI2‐biosynthesis by 75% caused only a nonsignificant reduction in the adenosine‐induced enhancement of coronary flow.

Aminophylline at a high concentration (50 μg/ml) produced an increase in coronary flow and in release of PGI2 as did adenosine; neither of these effects was observed with the low concentration of aminophylline (10 μg/ml).

It is suggested that the coronary vasodilator effects of PGI2 in the isolated perfused rabbit hearts are due, at least partially, to the release of adenosine.
THE IONIZATION OF 5‐HYDROXYTRYPTAMINE AND RELATED COMPOUNDS AND AN APPRAISAL OF METHODS FOR THE ESTIMATION OF ZWITTERION CONSTANTS
Authors: BARLOW R.B. , BURSTON K.N.
Published: July 2012

The dissociation constants of 5‐hydroxytryptamine and 5‐hydroxy‐N,N‐dimethyltryptamine have been measured and the zwitterion constants have been estimated from the pKas of analogous methoxyamines and the phenolic quaternary ammonium salt.

Direct measurement of zwitterion constants has been made by a spectroscopic method which has been used also with several phenolic amines previously studied electrometrically. It makes fewer assumptions and so should be more reliable but an appraisal of the methods available indicates that none can be singled out as being best and it is desirable to obtain results with as many as possible.

The results consolidate previous observations on the relations between chemical structure and zwitterion constant; possibly zwitterions are stabilized by any factor which stabilizes water structure. Dimethylamino compounds have lower zwitterion constants than their methylamino or amino‐analogues but there is no reason to doubt the previous finding that diethylamino compounds have higher zwitterion constants than their dimethylamino analogues.

The proportion of 5‐hydroxytryptamine present as the neutral molecule or zwitterion in physiological conditions is small; however, with dopamine, the proportion present as the zwitterion could be as much as 10%.
A COMPARISON OF THE CARDIOVASCULAR EFFECTS OF DOBUTAMINE AND A NEW DOPAMINE DERIVATIVE (D4975) DURING SHOCK INDUCED BY E. Coli ENDOTOXIN
Authors: McCAIG DOROTHY , PARRATT J.R.
Published: July 2012

The effects of a newly developed dopamine‐xanthine derivative, 7‐propyl‐theophylline‐dopamine (D4975) and of dobutamine have been examined in anaesthetized cats before and after the induction of shock with E. coli endotoxin.

Both D4975 and dobutamine caused dose‐related increases in left ventricular (LV) dP/dtmax (and LVdP/dt at fixed isovolumic pressures). Significantly smaller increases in LVdP/dtmax occurred as early as 0.5 to 1 h after endotoxin, with maximal attenuation at 1 to 2 h and some improvement in sensitivity in cats surviving 2 to 4 h. The maximum response to each drug was markedly reduced in shock.

Neither D4975 nor dobutamine had significant effects on heart rate. D4975 caused dose‐related increases in systemic arterial blood pressure which were smaller during shock, the changes in responsiveness following those in LVdP/dtmax.

Possible mechanisms responsible for changing myocardial sensitivity to these and other agents are discussed. It is concluded that D4975 may be more useful in the treatment of shock than either dopamine or dobutamine because (a) it is more potent during shock than dobutamine (perhaps as a result of phosphodiesterase inhibition by the theophylline component of D4975); (b) its action is longer‐lasting than dobutamine or dopamine and (c) like dobutamine, its effect on heart rate is insignificant.
EVIDENCE AGAINST β‐ADRENOCEPTOR BLOCKING ACTIVITY OF DILTIAZEM, A DRUG WITH CALCIUM ANTAGONIST PROPERTIES
Authors: BRILEY M. , CAVERO I. , LANGER S.Z. , ROACH A.G.
Published: July 2012

In isolated spontaneously beating atria of the rat, diltiazem (0.01 to 0.1 μm) shifted the atrial rate concentration‐response curves to isoprenaline to the right in a non‐parallel manner and depressed their maxima. Under the same experimental conditions, (±)‐propranolol (0.03 to 0.1 μm) behaved as a competitive β‐adrenoceptor antagonist.

Whereas (±)‐propranolol (IC50 = 12 nm) and isoprenaline (IC50 = 0.9 μm) inhibited (—)‐[3H]‐dihydroalprenolol binding to rat brain membrane preparations, diltiazem failed to do so in concentrations up to 10 μm.

Diltiazem but not (±)‐propranolol, antagonized the positive chronotropic responses to calcium in spontaneously beating rat atria.

It is proposed that diltiazem inhibited the tachycardia induced by isoprenaline through an effect on calcium which may be an essential modulator of the sequence of events linking the β‐adrenoceptor activation and heart rate response.
STRUCTURE‐ACTIVITY STUDIES WITH NEUROTENSIN: ANALYSIS OF POSITIONS 9, 10 and 11
Authors: QUIRION R. , REGOLI D. , RIOUX F. , ST‐PIERRE S.
Published: July 2012

The stimulant effects of neurotensin (NT) and NT analogues modified in positions 9, 10 or 11 were evaluated and compared in two pharmacological preparations: the rat stomach strip and the isolated spontaneously beating atria of guinea‐pig.

The data derived from our structure‐activity study suggest that Arg9 and Pro10 mainly contribute to the affinity of neurotensin for its cardiac and smooth muscle receptors. Tyr11 seems to be more closely involved in the process of receptor activation by NT.

The order of potency of some NT analogues modified in position 11 (e.g. [d‐Phe11]‐NT, [d‐Tyr11]‐NT) was strikingly different from that described in other systems (e.g. hypothermia test and specific mast cell binding). The importance of this observation is discussed.