bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECTS OF CAFFEINE, THEOPHYLLINE AND THEOBROMINE ON SCHEDULED CONTROLLED RESPONDING IN RATS
Authors: CARNEY JOHN M.
Published: July 2012

Rats were trained to respond under a variable interval 30 s (VI 30) schedule of food reinforcement.

Caffeine (0.32–32 mg/kg), theophylline (1.0–56 mg/kg) and theobromine (10–320 mg/kg) in general produced dose‐related decreases in operant responding. At relatively low doses, caffeine (1.0 mg/kg) and theophylline (3.2 mg/kg) produced slight but nonsignificant increases in VI 30 responding.

The rank order of potency for producing decreases in responding was caffeine > theophylline > theobromine.

Daily caffeine injections (32 mg/kg, i.p.) resulted in the development of caffeine tolerance. This tolerance was characterized by a 6 fold shift to the right in the caffeine dose‐effect curve Saline substitution for the 32.0 mg/kg caffeine maintenance dose resulted in a substantial decrease in responding.
PRODUCTION OF TOLERANCE AND PHYSICAL DEPENDENCE IN THE RAT BY SIMPLE ADMINISTRATION OF MORPHINE IN DRINKING WATER
Authors: BADAWY A.A.‐B. , EVANS C.M. , EVANS M.
Published: July 2012

Rats are capable of consuming solutions of morphine sulphate in drinking water ad libitum in the absence of taste‐masking chemicals and without the need for scheduled provision or prior parenteral administration of the drug.

The success of this method depends on the initial provision of a 0.1 mg/ml solution of morphine sulphate.

When the drug concentration is increased to 0.4 mg/ml, the rats achieve an average daily intake of 50 mg/kg body wt. each.

Daily intake of morphine may be increased by at least about three fold by increasing the drug concentration to 1.2 mg/ml.

Oral morphine administration causes only a moderate loss in body weight.

Rats whose daily intake of the drug is 50 mg/kg exhibit tolerance to the analgesic action of morphine and show a drastic loss in body weight at 24 h after withdrawal and most of the behavioural symptoms of the naloxone‐precipitated withdrawal syndrome.

It is suggested that this simple method of morphine administration is suitable for further biochemical and behavioural studies of the actions of the drug.
THE EFFECTS OF PRAZOSIN, PHENTOLAMINE AND PHENOXYBENZAMINE ON INHIBITORY α‐ADRENOCEPTORS IN THE GUINEA‐PIG ISOLATED ILEUM
Authors: FAGBEMI S.O. , SALAKO L.A.
Published: July 2012

The relaxant effect of noradrenaline on strips of guinea‐pig isolated terminal ileum was blocked by pretreatement with prazosin, phentolamine, yohimbine and phenoxybenzamine.

The presence of a very high concentration of noradrenaline (50 μm) during exposure to the blocking agent protected against the blocking effect of the drugs.

Yohimbine, prazosin and phentolamine partially protected against irreversible blockade by phenoxybenzamine.

Spontaneous release of acetylcholine in the unstimulated ileum was blocked by noradrenaline (0.059–5.9 μm). This effect of noradrenaline was antagonized by phentolamine (0.13–2.6 μm) and yohimbine (0.051–0.51 μm) but not by prazosin (0.53–5.3 μm) or phenoxybenzamine (4.2–42 μm). All four antagonists reversed the noradrenaline‐induced relaxation of the ileum.

Acetylcholine output in the transmurally stimulated ileum was inhibited by noradrenaline. This effect of noradrenaline was antagonized by phentolamine and yohimbine but not by prazosin or phenoxybenzamine. The first two antagonists blocked the noradrenaline‐induced inhibition of evoked twitches of the ileum while the last two had no effect.

The results show (a) that prazosin has no effect on presynaptic α‐adrenoceptors located on cholinergic nerve endings in the guinea‐pig ileum and (b) that prazosin, phentolamine and phenoxybenzamine act on the same subgroup of postsynaptic α‐adrenoceptors on the smooth muscle of the guinea‐pig ileum.
THE EFFECTS OF SUBSTANCE P ON SMOOTH MUSCLE CELLS AND ON NEURO‐EFFECTOR TRANSMISSION IN THE GUINEA‐PIG ILEUM
Authors: FUJISAWA KAZUAKI , ITO YUSHI
Published: July 2012

The effects of substance P (SP) on the membrane and contractile properties of the smooth muscle cell, or on neuro‐effector transmission in the guinea‐pig ileum were observed by means of microelectrodes, double sucrose gap and tension recording.

SP (10−13‐10−10 M) induced a phasic contraction of longitudinal muscle strips, but did not change the muscle tone of circular muscle strips, in concentrations up to 10−8 M.

SP (1010‐10‐8M) evoked three different membrane responses in longitudinal muscle cells: (i) bursts of spike discharges with no significant change in the membrane potential and input membrane resistance; (ii) bursts of spike discharges with a small but clear depolarization of the membrane and increase in the input membrane resistance; (iii) slow waves with no change in the membrane potential.

In the circular muscle cells, low concentrations of SP (< 10−8M) did not affect the membrane potential or the spikes, but SP (10−7M) increased the spike discharges with no significant change in the membrane potential.

SP (10−10M) reduced the threshold depolarization required for the generation of action potentials with no change in membrane potential of the longitudinal muscle cells.

Pretreatment with atropine (5 × 10−6M), tetrodotoxin (TTX 10−6M) or baclofen (4.7 × 10−6M) had no effect on the excitatory actions of SP on the smooth muscle cells of longitudinal and circular muscle strips.

Excitatory actions of SP on the membrane potential or spike activities of longitudinal muscle cells were preserved in NaCl but not in Ca‐deficient solution.

SP (10−10‐10−9M) enhanced the amplitude of the excitatory junction potentials (e.j.ps) evoked by electrical field stimulation in longitudinal muscle cells with no change in the membrane potential and input resistance. SP (10−10‐10−9M), however, did not change the amplitude of inhibitory junction potentials (i.j.ps) recorded from the circular muscle cells.

These results indicate that SP in relatively low concentrations acts on both smooth muscle cells and on excitatory neuro‐effector transmission in the longitudinal muscle; the main site of the action of SP is probably the muscle membrane.
PROTECTIVE EFFECTS OF GLUCAGON DURING THE ANAPHYLACTIC RESPONSE IN GUINEA‐PIG ISOLATED HEART
Authors: ANDJELKOVIC IVAN , ZLOKOVIC BERISLAV
Published: July 2012

Cardiac anaphylaxis and the effects of glucagon pretreatment were studied in guinea‐pig isolated hearts actively sensitized to ovalbumin.

Antigen challenge of the sensitized hearts markedly increased creatine Phosphokinase (CPK) activity in the coronary venous effluent. Control values of CPK release from the hearts before challenge were 3.56 ± 0.15 mu min−1 mg−1. In the first 10 min following challenge, CPK release remained stable at increased levels which ranged between 4.88 ± 0.20 to 5.39 ± 0.38 mu min−1 mg−1. There was no correlation between immunologically released histamine and CPK release.

Pretreatment of the hearts with glucagon (0.15 μmol l−1) exerted a pronounced anti‐arrhythmic activity, reducing the conduction arrhythmias and completely preventing automaticity arrhythmias which normally occurred following ovalbumin challenge.

Anaphylactic histamine release was reduced significantly in the presence of glucagon. The percentage inhibition of histamine release from glucagon pretreated hearts, during the first 10 min after challenge, ranged between 58% and 94% of that from hearts similarly challenged in the absence of glucagon.

Glucagon significantly elevated sinoatrial nodal automaticity, enhanced atrioventricular conduction, improved coronary flow and reduced contractile force during anaphylaxis. It appears that these effects are caused both by modulating anaphylactic histamine release and by influencing the effects of the released histamine.

CPK release from the anaphylactic hearts was significantly inhibited in the presence of glucagon. The average percentage inhibition of CPK activity during the first 10 min after challenge ranged between 42% and 98%.

The findings from this study provide experimental evidence for protective effects of glucagon pretreatment during cardiac anaphylaxis.
EFFECT OF TMB‐8 ON THE PULMONARY VASOCONSTRICTOR ACTION OF PROSTAGLANDIN F2α AND THE THROMBOXANE MIMIC, U46619
Authors: ANGERIO ALLAN D. , FITZPATRICK THOMAS M. , KOT PETER A. , RAMWELL PETER W. , ROSE JOHN C. , SANTOIAN EDWARD C.
Published: July 2012

TMB‐8 (8–(N,N‐diethylamino)octyl‐3, 4, 5 trimethoxybenzoate HCl), an intracellular calcium antagonist, had no direct action on the pulmonary vasculature of the perfused canine lung lobe preparation.

The pulmonary pressor response to the thromboxane mimic, U46619, was not affected by TMB‐8.

The vasopressor response to prostaglandin F2α (PGF2α>) was significantly attenuated but not completely blocked by TMB‐8.

We conclude that the pulmonary pressor response to PGF2α is dependent on both intracellular and extracellular calcium pools for contraction and that U46619 facilitates either solely extracellular calcium influx or mobilizes an intracellular calcium pool not inhibited by TMB‐8.
ELIMINATION OF GLYCERYL TRINITRATE: EFFECTS OF SEX, AGE, SPECIES AND ROUTE OF ADMINISTRATION
Authors: IOANNIDES C. , PARKE D.V. , TAYLOR I.W.
Published: July 2012

Orally administered glyceryl trinitrate to rats undergoes extensive first pass metabolism leading to low bioavailability.

Sex differences in the plasma elimination of glyceryl trinitrate were seen in the rat, the female exhibiting the longer plasma half‐life. No sex differences in this respect were detected in the rabbit.

The plasma half‐life of glyceryl trinitrate was longer and the volume of distribution larger, in older animals.

The plasma elimination of glyceryl trinitrate was different in various animal species. There was a good correlation between plasma half‐life and animal bodyweight.
DESENSITIZATION OF PROSTACYCLIN RECEPTORS IN A NEURONAL HYBRID CELL LINE
Authors: BLAIR I.A. , LEIGH P.J. , MacDERMOT J.
Published: July 2012

Prostacyclin and its stable analogue, carbacyclin, bind competitively to a single population of receptors, and activate adenylate cyclase of the NCB‐20 neuronal somatic cell hybrid (Kact = 40.1 nM and 96.1 nM respectively).

Culture of NCB‐20 cells in the presence of 1 μm carbacyclin for 4 to 16 h results in a progressive decrease in the prostacyclin‐dependent activation of adenylate cyclase in cell homogenates with an increase at 16 h of the Kact from 64.1 nm to 174.0 nm and decrease in the maximum adenylate cyclase activation from 41.2 to 15.1 pmol cyclic AMP min−1 mg−1 protein.

The prediction that the apparent decrease in affinity in the prostacyclin‐dependent activation of adenylate cyclase was secondary to a reduction in receptor numbers was tested directly by measuring binding of [3H]‐prostacyclin to membranes of cells exposed to carbacyclin for 16 h. This showed an actual decrease in affinity of the prostacyclin‐receptor interaction, as well as a decrease in the total receptor numbers. Thus prolonged exposure of NCB‐20 cells to carbacyclin caused reductions in both receptor numbers and affinity, reflected by measurements both of binding and adenylate cyclase activation.
EVIDENCE FOR CARRIAGE OF SILVER BY SULPHADIMIDINE: HAEMOLYSIS OF HUMAN ERYTHROCYTES
Authors: BALLINGER P.M. , BROWN B.S. , GRIFFIN M.M. , STEVEN F.S.
Published: July 2012

Human erythrocytes suspended in isotonic saline haemolyse in the presence of both Ag+ ions and sulphadimidine.

Neither Ag+ ions nor sulphadimidine on their own will haemolyse erythrocytes suspended in isotonic saline.

At constant Ag+ ion concentration the degree of haemolysis of saline‐suspended erythrocytes depends upon the concentration of sulphadimidine.

Human erythrocytes suspended in isotonic sucrose (chloride‐free) haemolyse in the presence of Ag+ ions.

Sulphadimidine in chloride‐free sucrose competes with erythrocytes for Ag+ ions resulting in stoichiometric protection of the erythrocytes from the haemolytic action of Ag+ ions.

Haemolysis occurs when each erythrocyte receives approximately 1.2 × 109 Ag+ ions whether suspended in saline or sucrose.

Sulphadimidine acts as a carrier for Ag+ ions and so prevents their precipitation as AgCl when erythrocytes are suspended in saline.
RECEPTOR INTERACTIONS OF IMIDAZOLINES: α‐ADRENOCEPTORS OF RAT AND RABBIT AORTAE DIFFERENTIATED BY RELATIVE POTENCIES, AFFINITIES AND EFFICACIES OF IMIDAZOLINE AGONISTS
Authors: RUFFOLO ROBERT R. , WADDELL JAMES E.
Published: July 2012

Noradrenaline and a series of imidazolines were used to characterize and differentiate the postsynaptic α‐adrenoceptors of rat and rabbit aortae.

Dose‐response curves in each tissue revealed marked differences in the profile of agonist activity among the compounds. Based on the ED50 values for each compound, a rank order of potency of oxymetazoline > noradrenaline > tramazoline > tetrahydrozoline > clonidine was obtained in rabbit aorta and an order of noradrenaline > clonidine > tramazoline > oxymetazoline was obtained in rat aorta. Tetrahydrozoline had no agonist activity in rat aorta.

Dissociation constants were determined for each agonist in rat and rabbit aortae. Again, differences between the tissues were observed to the extent that the rank order of affinities for the imidazolines were exactly opposite for the two tissues. In rabbit aorta the order was, oxymetazoline > tramazoline > tetrahydrozoline > clonidine, whereas in rat aorta it was, clonidine > tetrahydrozoline > tramazoline > oxymetazoline. The extremes in tissue selectivity were observed with clonidine, which had approximately 125 fold higher affinity in rat aorta, and oxymetazoline, which had approximately 4 times higher affinity in rabbit aorta.

The absolute values of relative efficacies of the imidazolines studied, and their rank order, also differed between the two tissues. The relative efficacies of oxymetazoline and tramazoline were more than 15 fold greater in rabbit aorta than in rat aorta. Furthermore, tetrahydrozoline had a greater relative efficacy than clonidine in rabbit aorta while the converse was true in rat aorta.

Differences in the rank order of potency, affinity and relative efficacy of noradrenaline and a series of imidazolines in rat and rabbit aortae indicate that the postsynaptic α‐adrenoceptors in these tissues are different. While the postsynaptic α‐adrenoceptor of rabbit aorta is clearly of the α1‐subtype, the exact nature of the postsynaptic α‐receptor of rat aorta is not clear. The unique α‐receptor of rat aorta has properties of both α1‐ and α2‐adrenoceptors.
The influence of substance P on the response of guinea‐pig isolated ileum to periarterial nerve stimulation
Authors: Grbović Leposava , Radmanoviě B.Ž.
Published: July 2012

The effects of substance P (SP) on the responses of the guinea‐pig isolated ileum to periarterial nerve stimulation were studied. Electrical stimulation (2–50 Hz) of mesenteric periarterial nerves resulted in contraction of preparations pre treated with guanethidine. The responses were abolished by atropine and morphine, but unaffected by hexamethonium.

SP in a high concentration (0.65 μmol) inhibited reversibly, by about 40%, the responses of the guinea‐pig isolated ileum to periarterial nerve stimulation.

SP in a very low concentration (0.18 pmol) potentiated (by about 20%) the responses of the guinea‐pig isolated ileum to periarterial nerve stimulation.

In the presence of low concentrations (0.06–0.32 pmol) of SP, morphine (2.65 μmol) produced less inhibition of the responses to periarterial nerve stimulation, and recovery from morphine inhibition of contraction was accelerated.

These results indicate that SP may act as a modulator on prejunctional acetylcholine release in the guinea‐pig ileum.
Pharmacological characterization of the opioid receptor in the submucous plexus of the guinea‐pig oesophagus
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: July 2012

The cholinergically mediated electrically‐induced contractions of the submucous plexus‐longitudinal muscularis mucosae preparation of the guinea‐pig oesophagus were used to study the actions of opioid peptides and morphine.

The twitch contractions of the tissue (0.1 Hz, 0.5 ms, supramaximal voltage) were inhibited by all the opioid peptides and morphine in a concentration‐dependent manner. The order of potency was dynorphin‐(1–13) > α‐neo‐endorphin > β‐endorphin > [d‐Ala2]‐methionine‐enkephalin ≪≪ α‐endorphin, methionine‐enkephalin, leucine‐enkephalin and morphine.

The inhibitory actions of dynorphin‐(1–13) (20 nm), α‐neo‐endorphin (100 nm) and β‐endorphin (3 μm) were completely reversed either by naloxone (1 μm) or by morphine (100 μm). The Ke values of naloxone against dynorphin‐(1–13) and α‐neo‐endorphin were 30 and 25 nm, respectively.

Increasing the concentration of calcium from 1.8 to 3.6 mm in Tyrode solution decreased the sensitivity of the tissue to dynorphin‐(1–13) 7.4 times and to α‐neo‐endorphin 462 times.

The inhibitory actions of dynorphin‐(1–13) (100 nm) and α‐neo‐endorphin (300 nm) were inversely related to stimulus frequency, being most active at low frequencies (0.1–1 Hz), and least active at high (30 Hz).

Exogenously applied acetylcholine produced concentration‐dependent contractions of the isolated muscularis mucosae, with an EC50 of 72.6 ± 4.5 nm. The contractile response of the oesophagus to acetylcholine was not affected by the pretreatment of the tissue with dynorphin‐(1–13) (100 nm), α‐neo‐endorphin (300 nm) or β‐endorphin (3 μm).

It is concluded that the submucous plexus‐longitudinal muscularis mucosae of the guinea‐pig oesophagus is inhibited by opioid peptides acting at prejunctional opioid receptors, probably of the κ‐subtype.
Dendrobine, an antagonist of β‐alanine, taurine and of presynaptic inhibition in the frog spinal cord
Authors: Kudo Yoshihisa , Tanaka Atsuko , Yamada Kiyoyuki
Published: July 2012

The effects of dendrobine and nobiline, alkaloids isolated from Dendrobium nobile, on the electrical activity and on amino acid‐induced depolarizations of primary afferent terminals were tested on the frog isolated spinal cord and were compared with those of picrotoxinin and strychnine.

Dendrobine (3 × 10−5 m) caused a slight hyperpolarization in both dorsal and ventral roots and this hyperpolarization was accompanied by the augmentation of the dorsal root potential (DR‐DRP) and the ventral root potential and reflex (DR‐VRP and DR‐VRR). The amplitude of the dorsal root reflex (DR‐DRR) however, was reduced significantly. Nobiline (3 × 10−5 m) had no significant effect on either the root potentials or the reflexes.

Dendrobine (3 × 10−5 m) reduced the dorsal root potential induced by repetitive antidromic stimulation of ventral root (VR‐DRP) as well as diminishing the maximum rate of rise of the dorsal root potential induced by the stimulation of adjacent dorsal roots (DR‐DRP), during which time the amplitude of the DR‐DRP was seen to be augmented.

Dendrobine (3 × 10−5 m) reduced the β‐alanine‐ and taurine‐induced depolarizations of primary afferent terminals, while having little effect upon GABA‐ and glycine‐induced depolarizations.

Dendrobine (10−5 m) reversibly blocked the presynaptic inhibition caused by antidromic conditioning stimulation of the ventral root.

These effects of dendrobine were qualitatively similar to those of strychnine but were somewhat different from those of picrotoxinin, a molecule having the same picrotoxane skeleton.

The present results are discussed with reference to the likely neurotransmitters involved in presynaptic inhibition in the frog spinal cord, and with respect to the structure‐activity relationship of picrotoxane compounds as amino acid antagonists.
Accelerating effects of pentobarbitone on the inactivation process of the calcium current in Helix neurones
Authors: Nishi K. , Oyama Y.
Published: July 2012

The effect of pentobarbitone on Ca2+ current (ICa), separated from other ionic currents was studied under voltage clamp using a suction pipette technique in Helix neurones.

Pentobarbitone depressed the maximal peak amplitude (MPA) of ICa in a concentration‐dependent manner without shifting the current‐voltage (I‐V) relationships along the voltage axis. Increases in external Ca2+‐concentration ([Ca2+]***o) overcame the inhibitory action of the agent on MPA.

Pentobarbitone markedly accelerated the decay phase of ICa which took a distinctly different time course from that of the control. The accelerating action of the agent on the decay phase of ICa was not overcome by increases in [Ca2+]o. In the presence of internal EGTA (20 mm), pentobarbitone also accelerated the decay of ICa.

Changes in pH of the external perfusing solution altered the potency of pentobarbitone in depressing MPA; in the presence of pentobarbitone (3 × 10−4 m) at pH of 7.0, 8.0 and 9.0, fractional inhibition was approx. 46%, 21% and 4%, respectively.

Internal application of pentobarbitone (10−4‐10−3 m) inhibited MPA, but exerted no effect on the decay phase of ICa.

Pentobarbitone (10−4 m) markedly accelerated the decrease of MPA of ICa induced by repetitive stimuli applied at an interval of 150 ms, indicating a use‐dependent depression of MPA.

Results provide evidence that pentobarbitone has a dual action on ICa, inhibiting MPA and accelerating the decay phase of ICa.
Actions of isosorbide dinitrate on smooth muscle cells of rabbit vascular tissues
Authors: Ishikawa S. , Ito Y. , Itoh T. , Kanmura Y. , Kuriyama H. , Makita Y.
Published: July 2012

To investigate the mechanism of the anti‐anginal actions of isosorbide dinitrate (ISDN), the effects of this agent on smooth muscle cells of intact and skinned preparations of the rabbit mesenteric artery and vein, and of the coronary artery were studied.

ISDN (<10−5 m) had no effect on the membrane potential or resistance of smooth muscle cells of the mesenteric artery and vein under resting conditions, nor when the membrane was depolarized by the presence of various concentrations of [K]o or noradrenaline (NA). The amplitude of spike evoked by outward current pulse after pretreatment with 10 mm tetraethylammonium (TEA) in the mesenteric artery was slightly inhibited by application of 10−5 m ISDN.

The K‐induced and NA‐induced contractions in the mesenteric artery were not affected by 10−5 m ISDN, while those evoked in the mesenteric vein were inhibited in concentrations above 10−6m.

The amplitude and facilitation of excitatory junction potentials evoked by perivascular nerve stimulation in the mesenteric artery were not affected by 10−5 m ISDN.

In skinned muscles, the free calcium concentration (pCa)‐tension relationships observed in the mesenteric artery and vein were not affected by 10−5 m ISDN. This agent had no effect on Ca accumulation into and Ca release from the stores in muscle cells of the mesenteric artery and vein, in skinned preparations.

In the rabbit coronary artery, the membrane potential, resistance and spike evoked in the presence of 10 mm TEA were not affected by application of 10−5 m ISDN. The contraction evoked by excess concentrations of [K]o was not affected. The contraction evoked by a low concentration of acetylcholine (3 × 10−7 m) but by high concentrations (> 10−6m) was slightly inhibited by 10−5 m ISDN. A tonic contraction induced in 39 mm [K]o was reduced by 10−5 m nitroglycerine but not by 10−5m ISDN.

Thus in rabbit vascular tissues, ISDN mainly acts on the venous system in vitro. The induced vasodilatation may lead to a reduction in the venous return and hence, reduce oxygen consumption in the cardiac muscles. This effect of ISDN may relate to the anti‐anginal actions.
Electrophysiological studies of some semisynthetic cardiac glycoside derivatives in isolated papillary muscle of the guinea‐pig
Authors: Lüllmann H. , Niehus U. , Pulss W. , Ravens Ursula
Published: July 2012

The effects of digitoxin, 3α‐methyl‐digitoxigenin‐3β‐monoglucoside (3α‐MDM), 3α‐methyl‐digitoxigenin (3α‐MD), proscillaridin, 4, 5‐methylene‐procillaridin (4, 5‐MP), and 3β‐hydroxy‐4, 5‐methylene‐A, B‐trans‐scillarenin (3β‐HMTS) on force of contraction and on the transmembrane action potentials were examined in isolated papillary muscles of guinea‐pigs.

All derivatives exhibited the typical cardiac glycoside effects: i.e. they increased the force of contraction and shortened the action potential duration at 20% (plateau phase) and 90% of repolarization. With digitoxin, 3β‐HMTS and 4, 5‐MP a transient prolongation in action potential duration was observed at the lower concentrations. The action potential amplitude and the resting membrane potential were reduced consistently only with the higher concentrations used.

The onset of the positive inotropic effects of 3α‐MDM, 3α‐MD and 3β‐HMTS was more rapid than that of digitoxin and proscillaridin. The increment in contractile force reached a maximum well before the full shortening effect on the action potential duration had developed. The shortening of the action potential is thought to be responsible for the biphasic nature of the positive inotropic effect.

With 3α‐MD and 3α‐MDM even toxic effects, e.g. increase in baseline tension, were completely reversible after washing in drug‐free solution.

The dose‐response curves for the positive inotropism can only be compared reliably once the equilibrium of drug action has been established. This steady state is probably reflected by the development of the full shortening in action potential duration.
Depolarizing responses to glycine, β‐alanine and muscimol in isolated optic nerve and cuneate nucleus
Authors: Simmonds M.A.
Published: July 2012

Concentration‐dependent depolarizations were evoked by glycine and β‐alanine 5 × 10−4‐10−2m and by the γ‐aminobutyric acid (GABA) analogue, muscimol 10−6‐10−4m.

The maximal response to glycine was several‐fold higher than that to muscimol on optic nerve but the reverse was found on the dorsal funiculus fibres in the cuneate nucleus, β‐Alanine evoked a similar maximal response to glycine on optic nerve but a considerably higher maximum than glycine in the cuneate nucleus.

Strychnine was 19.5 times more potent as a glycine antagonist (pA2 = 6.58) than as a muscimol antagonist. Bicuculline was 156 times more potent as a muscimol antagonist than as a glycine antagonist. Other antagonists of muscimol, i.e. tubocurarine, Picrotoxin and leptazol, and potentiators of muscimol, i.e. pentobarbitone and flurazepam, had little or no effect on responses to glycine.

Responses to β‐alanine had pharmacological properties compatible with a mixed action on both GABA and glycine receptors.

The rat isolated optic nerve appears to be a useful preparation for studying the pharmacology of the neuronal glycine receptor plus chloride ionophore complex.
The relative significance of spinal and supraspinal actions in the antinociceptive effect of morphine in the dorsal horn: an evaluation of the microinjection technique
Authors: Clark S.L. , Edeson R.O. , Ryall R.W.
Published: July 2012

Large quantities of morphine injected directly into the brainstem of spinal anaesthetized cats inhibited the noxious heat‐evoked excitation of dorsal horn neurones. The amounts required were similar to those that were required intravenously in cats with the spinal cord intact or transected.

When the spinal cord was intact the amount of morphine microinjected into the brainstem required to inhibit the excitation of dorsal horn neurones was about ten fold less than it was in spinal animals.

It is concluded that large, but not small doses of morphine microinjected into the brainstem can exert effects on the spinal cord after first entering the circulation. The effects of small doses are attributed to a local action in the brainstem which causes inhibition of spinal neurones either by activating descending inhibitory neuronal systems or by liberating endogenous substances which reach the spinal cord via the cerebro‐spinal fluid.

The concentrations of morphine achieved at various distances from the site of injection by the microinjection of μg quantities and the time courses of the concentration changes were calculated from diffusion equations, assuming diffusion coefficients of 3 or 5 × 106 cm2 s−1. The curves obtained closely approximated those obtained experimentally.

The concentrations achieved at distances up to 2 mm from the site of injection of 10 μg of morphine were calculated to exceed 10−4m and the time‐courses of these concentration changes were compatible with the time course of inhibition of spinal neurones, or the production of analgesia after microinjection. Such concentrations are vastly in excess of those achieved in the brain after the systemic administration of morphine in analgesic doses.

It is concluded that the local effects in the brainstem produced by the microinjection of pig quantities of morphine have no relevance to the mechanism of analgesia produced by systemic administration.
Spinal interneurone depression by DS103–282
Authors: Curtis D.R. , Leah J.D. , Peet M.J.
Published: July 2012

The depressant effect of 5‐chloro‐4‐(2‐imidazolin‐2‐yl‐amino)‐2,1,3‐benzothiodiazole (DS 103–282) on the polysynaptic excitation of interneurones in the cat spinal cord appears to be related to a postsynaptic reduction in the effectiveness of excitatory transmitters rather than to interference with their presynaptic release.
Effects of ovarian steroids upon responses mediated by adrenoceptors in separated layers of the myometrium and in the costo‐uterine muscle of the guinea‐pig
Authors: Hartley Margaret L. , Pennefather Jocelyn N. , Story Margot E.
Published: July 2012

This study describes the effects of ovarian steroid hormones upon the responses to adrenoceptor agonists of isolated myometrium, separated into its longitudinal and circular layers, and of costo‐uterine muscle from guinea‐pigs. The preparations were field‐stimulated at 100 s intervals, and the adrenoceptor agonists phenylephrine and isoprenaline produced enhancement or inhibition of the evoked contractions.

Isoprenaline produced propranolol‐sensitive inhibitory effects in longitudinal and circular myometrium and costo‐uterine muscle preparations from animals from all experimental groups: i.e. from nonsteroid‐treated animals (ovariectomized and intact); intact animals treated with either oestrogen or progesterone alone; ovariectomized animals treated with oestrogen; ovariectomized and intact animals treated with progesterone following oestrogen priming; and from animals 1–4 days post‐partum. Longitudinal myometrial preparations from progesterone‐treated oestrogen‐primed and from post‐partum animals were most sensitive to this agonist.

Phenylephrine produced phentolamine‐sensitive excitatory effects in circular myometrial and costo‐uterine muscle preparations from animals from all the experimental groups. In contrast, propranolol‐sensitive inhibitory responses to phenylephrine occurred in longitudinal myometrial preparations taken from animals treated with progesterone following oestrogen priming, and from post‐partum animals. Longitudinal myometrium from animals from the remaining experimental groups exhibited phentolamine‐sensitive excitatory responses to phenylephrine.

The basis for the selective effect upon the longitudinal myometrium of exposure to progesterone following a period of oestrogen priming, is discussed. The results described are consistent with the possibility that in the longitudinal layer of guinea‐pig uterus exposed to progesterone following oestrogen priming there is an increase in the proportion of β‐adrenoceptors in this layer. This increase may reduce the likelihood of contractions arising via direct stimulation of α‐adrenoceptors in this layer in response to sympathetic activation during pregnancy.
Prostaglandin synthesis inhibitors: effect on angiotensin II‐ and oxytocin‐induced contractions in rat uterine smooth muscle
Authors: Hall M.M.
Published: July 2012

Eicosatetraynoic acid, the acetylene analogue of arachidonic acid, which inhibits both the cyclo‐oxygenase and lipoxygenase pathways, reduced the contractile response of rat uterine smooth muscle to either angiotensin II or oxytocin.

Indomethacin, an inhibitor of cyclo‐oxygenase, did not reduce the response to angiotensin II but did abolish the contractile response to low doses of oxytocin.

Nordihydroguaiaretic acid, a lipoxygenase inhibitor, totally abolished the uterine response to either oxytocin or angiotensin II.

The contractile response to carbachol, a cholinoceptor agonist, was unaffected by pretreatment with any of the cyclo‐oxygenase or lipoxygenase inhibitors.

From these findings, it can be implied that some product of the arachidonate lipoxygenase pathway augments peptide‐induced contractions of the rat uterus.
Calcium antagonists: effects on cerebral blood flow and blood‐brain barrier permeability in the rat
Authors: Edvinsson L. , Johansson B.B. , Larsson B. , MacKenzie E.T. , Skärby T. , Young A.R.
Published: July 2012

Because they affect isolated cerebral arteries, some calcium antagonists have been studied on the intact cerebral circulation of the rat.

Global cerebral blood flow (133Xe clearance technique) was measured in anaesthetized rats. Neither perhexiline (0.1 μg/kg to 1.0 mg/kg, i.v.) nor diltiazem (0.06–0.6 mg/kg, i.v.) had any significant effect on resting cerebral blood flow when measured 5 min after each dose. A high dose of nifedipine (1.0 mg/kg, i.v.) was administered during induced hypocapnia. Nifedipine failed to modify the hypocapnic vasoconstriction of the cerebral vasculature when compared to vehicle‐treated rats.

The possibility of discrete changes in regional cerebral blood flow was investigated. Local cerebral blood flow was measured in a number of brain regions by the [14C]‐ethanol technique 15 min after the administration of nifedipine (20 or 100 μg/kg, i.v.). Nifedipine had no apparent effect on regional blood flow in the rat brain.

Acute arterial hypertension increases protein leakage into the brain, a phenomenon susceptible to drugs that act on endothelial pinocytosis which is known to be calcium‐dependent. The increase in protein extravasation, induced by the intravenous administration of either angiotensin II or adrenaline, was unchanged in rats previously treated with either nimodipine (20 μg/kg, i.v.) or nifedipine (50 μg/kg, i.v.) when dissolved in ethanol alone. However, nifedipine (20 μg/kg, i.v.) when dissolved in a solution of polyethylene glycol and ethanol further enhanced the hypertension‐induced increase in brain albumin permeability.

In conclusion, we have been unable to demonstrate any apparent effects of various calcium antagonists on the intact cerebral circulation of the rat, despite the number of different experimental models used.
Formation of 6‐keto prostaglandin E1 in mammalian kidneys
Authors: Griffiths R.J. , Moore P.K.
Published: July 2012

The metabolism of prostacyclin (PGI2) and 6‐keto prostaglandin F1α (6‐keto PGF1α) was studied in cell‐free homogenates of rat, rabbit and guinea‐pig kidney.

Rabbit kidney converted both PGI2 and 6‐keto PGF1α to a stable metabolite with chromatographic and biological activity identical to that of authentic 6‐keto PGE1. Activity was found in the kidney cortex but not medulla, was inhibited by NAD+ or NADP+ (5 mM) and showed an optimum temperature requirement of 37°C.

Guinea‐pig kidney converted PGI2 but not 6‐keto PGF1α to a labile, biologically active metabolite which was not 6‐keto PGE1.

No conversion of prostacyclin or 6‐keto PGF1α to biologically active metabolites occurred in cell‐free homogenates of rat kidney, liver and colon or guinea‐pig liver and colon.

6‐keto PGE1 rapidly lost spasmogenic activity on the rat stomach strip following incubation with rabbit or guinea‐pig kidney supernatant in the absence of added cofactors. No loss of activity occurred on incubation with rat kidney.

Rutin (50 μM) potently inhibited synthesis of 6‐keto PGE1 from added PGI2 by rabbit kidney cortex. This reaction was potentiated by a similar concentration of sulphasalazine, carbenoxolone, imidazole, papaverine or indomethacin.

The relevance of these findings for the possible physiological and pathological roles of 6‐keto PGE1 in the kidney is discussed.
Direct inhibitory effects of some ‘calcium‐antagonists’ and trifluoperazine on the contractile proteins in smooth muscle
Authors: Spedding M.
Published: July 2012

Taenia preparations from the guinea‐pig caecum were treated with Triton X‐100 and glycerol to disrupt the plasma membrane. Disruption of the sarcolemma was confirmed by electronmicroscopy. The preparations contracted in response to low concentration of Ca2+ (10–40 μM) and the contractions were dependent upon exogenous adenosine triphosphate (ATP).

Nifedipine (100 μM), verapamil (100 μM) and diltiazem (100 μM) did not inhibit Ca2+‐induced activation of the contractile proteins.

In contrast, fendiline (100 μM), cinnarizine (100 μM), flunarizine (100 μM), pimozide (100 μM) and trifluoperazine (100 μM) significantly inhibited Ca2+‐induced contractions. The effects of cinnarizine (100 μM) were reversible.

These findings disclose further differences between calcium‐antagonists and suggest that certain of these agents have an intracellular site of action.
Evidence that the spasmogenic action of tetraethylammonium in guinea‐pig trachealis is both direct and dependent on the cellular influx of calcium ion
Authors: Foster R.W. , Small R.C. , Weston A.H.
Published: July 2012

Tetraethylammonium (TEA, 1–8 mmol/l) evoked spasm of guinea‐pig trachealis which was unaffected by atropine (1 μmol/l), mepyramine (1 μmol/l) or tetrodotoxin (3 μmol/l).

The spasm evoked by TEA was markedly suppressed in Ca2+‐free Krebs solution while that evoked by acetylcholine was much less affected.

Extracellular electrical recording showed that exposure to Ca2+‐free Krebs solution suppressed both spontaneous electrical slow wave activity of the trachea and the spasm and slow waves induced by TEA. These effects were reversible.

TEA (2 and 8 mmol/1) increased the lanthanum‐resistant calcium fraction of trachea.

It is concluded that TEA acts directly on the smooth muscle of guinea‐pig trachea, that the spasm and electrical slow waves evoked are Ca2+‐dependent and that the cellular influx of Ca2+ is increased.
Increased inhibitory action against adenosine 5′‐triphosphate in the isolated taenia of the guinea‐pig caecum by substitution in the A‐ring of 2‐phenylisatogen
Authors: Foster H. , Hooper M. , Imam S.H. , Lovett G.S. , Nicholson J. , Swain C.J. , Sweetman A.J. , Weetman D.F.
Published: July 2012

The ability of a series of 17 isatogen derivatives to relax smooth muscle, inhibit adenosine 5′‐diphosphate (ADP)‐stimulated respiration in isolated mitochondria and to antagonize the inhibitory effects of adenosine 5′‐triphosphate (ATP) on smooth muscle was measured.

Substitution in the 4‐ and 7‐positions of the A‐ring gave compounds that were strong inhibitors of mitochondrial ATP synthesis and potent, non‐specific smooth muscle relaxants. The compounds also possessed ATP‐receptor blocking activity.

Substitution in the 5‐ and 6‐positions of the A‐ring decreased both the relaxant effect on smooth muscle and inhibition of ATP synthesis, whilst enhancing ATP‐receptor antagonism.

In a series of 6‐substituted 2‐phenylisatogens, 6‐methoxy‐2‐phenylisatogen was the most effective ATP‐receptor antagonist. This compound also showed the greatest separation of the desired pharmacological activity (ATP‐receptor blockade) from the other two activities (smooth muscle relaxation and inhibition of mitochondrial ATP synthesis).
The effects of 3,4‐dihydro‐8‐(2‐hydroxy‐3‐isopropylaminopropoxy)‐3‐nitroxy‐2H‐1‐benzopyr an (K‐351) and its denitrated derivative on smooth muscle cells of the dog coronary artery
Authors: Kou K. , Suzuki H.
Published: July 2012

Effects of 3,4‐dihydro‐8‐(2‐hydroxy‐3‐isopropylaminopropoxy)‐3‐nitroxy‐2H‐1‐benzopyran (K‐351) and its derivative, 3,4‐dihydro‐8‐(2‐hydroxy‐3‐isopropylaminopropoxy)‐3‐hydroxy‐2H‐1‐benzopyran (K‐351 (N‐)) on the electrical and mechanical properties of smooth muscles of the dog coronary and mesenteric arteries were investigated, and the findings were compared with data obtained with nitroglycerine.

In both proximal and distal regions of the coronary arteries, K‐351 and nitroglycerine reduced the resting tone and suppressed the contractions produced by high‐potassium solution or by current passage to the same extent, with no remarkable change in the electrical properties of the smooth muscle membrane.

In the proximal regions of the descending coronary artery, low and high concentrations of noradrenaline (NA) produced relaxation and contraction of the muscle, respectively. In the distal region, NA consistently relaxed the muscle with concentrations up to 10−5M. In both regions, the contraction or relaxation was suppressed by phentolamine or propranolol, respectively.

K‐351 suppressed the NA‐induced contraction. K‐351(N‐) potentiated the NA‐induced contraction and suppressed the relaxation, but these actions were weaker than those of propranolol. Nitroglycerine suppressed the NA‐induced contraction and the potency was weaker than that of K‐351.

In the mesenteric artery, K‐351 depressed excitatory junction potentials, spikes and contractions evoked by perivascular nerve stimulation, while K‐351(N—) potentiated or depressed mechanical responses, with no change in the electrical responses. Nitroglycerine also depressed the mechanical responses evoked by perivascular nerve stimulation with no change in the electrical responses.

These results suggest that K‐351 has a blocking action on postjunctional adrenoceptors, and also dilator actions similar to the actions of nitroglycerine on the dog coronary artery, while K‐351 (N—) possesses a weak β‐adrenoceptor blocking action.
Captopril potentiates the vasodepressor action of Met‐enkephalin in the anaesthetized rat
Authors: Di Nicolantonio R. , Hutchinson J.S. , Takata Y. , Veroni M.
Published: July 2012

The transient vasodepressor action of Met‐enkephalin (10–80 μg kg−1, i.v.) in anaesthetized rats was significantly potentiated by the angiotensin‐converting enzyme inhibitor, captopril (2 mg kg−1, i.v.); at this dose, it failed to modify the transient vasodepressor action of the non‐specific vasodilator, nitroprusside (2.5, 5.0, 10 μg kg−1, i.v.).

Captopril (2 mg kg−1, i.v.) caused a slow, progressive fall in the blood pressure of anaesthetized spontaneously hypertensive (SH) rats when compared to vehicle‐treated controls. Pretreatment with naloxone (1.5 mg kg−1, i.v.) 30 min earlier failed to alter significantly the hypotensive action of captopril in anaesthetized SH rats.

It was concluded that although captopril potentiated the vasodepressor action of Met‐enkephalin in anaesthetized normotensive rats, potentiation of endogenous opioids does not appear to be involved in the hypotensive action of captopril in anaesthetized SH rats.
Effects of amrinone on the transmembrane action potential of rabbit sinus node pacemaker cells
Authors: Kodama Itsuo , Kondo Noriaki , Shibata Shoji
Published: July 2012

Effects of amrinone on the membrane action potential and spontaneous activity were investigated in sinus node pacemaker cells of rabbit heart by use of microelectrode techniques.

Amrinone (1 × 10−4m to 6 × 106m) caused a shortening of cycle length of spontaneous firing (SPCL) accompanied by an increase in the maximum upstroke velocity at phase 0 () and amplitude of action potential (AAP), while it did not affect the maximum diastolic potential (MDP).

All the effects of amrinone on sinus node pacemaker cells were markedly attenuated or abolished in a low calcium medium (Ca+0.1 mm or 0.3 mm) or in the presence of the slow channel blocking agent, verapamil (5 × 10−7m, 2 × 106m).

The effects of amrinone were not antagonized by the β‐adrenoceptor blocking agent, pindolol (2 × 10−7m).

These results indicate that amrinone has an intrinsic effect on sinus node pacemaker cells, increasing their spontaneous firing activity.

It is also assumed that the effects of amrinone on sinus node cells are probably mediated by an augmentation of the slow calcium and/or sodium inward current through the cell membrane.
The potentiation of taurocholate‐induced rat gastric erosions following parenteral administration of cyclo‐oxygenase inhibitors
Authors: Whittle B.J.R.
Published: July 2012

Subcutaneous administration of anti‐inflammatory doses of aspirin, indomethacin, naproxen and flurbiprofen inhibited prostacyclin formation ex vivo in the luminally‐perfused gastric mucosa of anaesthetized rats.

These doses of anti‐inflammatory compounds potentiated the formation of gastric mucosal erosions following 3 h luminal perfusion of the topical irritant, acidified sodium taurocholate (2 mm in 100 mm HCl).

The increase in luminal acid‐loss during gastric perfusion of acidified taurocholate was not significantly enhanced by these anti‐inflammatory agents.

A correlation was found between the increase in gastric erosion formation and the inhibition of mucosal prostacyclin formation ex vivo by intravenous injection of aspirin or ketoprofen during acid‐taurocholate perfusion.

BW755C, which failed to inhibit mucosal prostacyclin formation ex vivo, did not significantly augment acid‐taurocholate induced gastric damage.

The present findings support the potentiating interactions between topical irritation and inhibition of gastric cyclo‐oxygenase in the genesis of the gastric lesions.
Nicotinamide adenine dinucleotide depresses synaptic transmission in the hippocampus and has specific binding sites on the synaptic membranes
Authors: Richards C.D. , Snell C.R. , Snell P.H.
Published: July 2012

The electrical activity of transverse slices of hippocampus was used as a bioassay in which extracts of fresh brain tissue were screened for biological activity. A factor that depressed synaptic transmission was identified as nicotinamide adenine dinucleotide (NAD). This depressant action of NAD could be observed at concentrations in the range 1–10μm and the degree of depression was monotonically related to the concentration of NAD in the bathing medium.

NAD did not affect the antidromic invasion of the granule cells nor did it alter the relationship between the electrically evoked excitatory postsynaptic field potential (e.p.s.p.) and the population discharge of the granule cells (population spike). These results suggest that NAD did not affect the electrical excitability of the neuronal membranes.

NAD had little effect on the sensitivity of granule cells to iontophoretically applied L‐glutamate, the putative excitatory transmitter for the perforant path‐granule cell pathway.

Pure synaptosomal membranes, free of mitochondria, had two binding sites for NAD: a high affinity site with a Kd of 1 μm and a low affinity site with a Kd of 17 μm. These sites were similar in affinity to those of mitochondria, although the density of the high affinity sites was 5 × greater in the synaptosomal membranes. Adenosine had a relatively weak affinity for the NAD binding sites.

It was concluded that NAD probably depressed synaptic transmission in the dentate gyrus by binding to sites on the presynaptic nerve terminal and reducing the amount of transmitter released by a nerve impulse. The physiological significance of this view is discussed.
Biphasic non‐adrenergic, non‐cholinergic relaxations of the mouse anococcygeus muscle
Authors: Gibson A. , Yu O.
Published: July 2012

Trains of field stimulation of 60 s duration caused a biphasic relaxation of carbachol (50 μm)‐induced tone in the mouse anococcygeus. The optimal pulse frequency and width were 10 Hz and 1 ms respectively.

Tetrodotoxin (31, 124, and 310 nm) caused a dose‐dependent reduction in the magnitude of both phases. Neither phase was affected by (±)‐propranolol (1 μm), neostigmine (1 μm), (+)‐tubocurarine (100 μm), or apamin (500 nm). Biphasic relaxations were observed in muscles from 6‐hydroxydopamine pretreated mice.

Haemolysed blood (10, 40, and 100 μm) reduced the magnitude of the first phase of nerve‐induced relaxation to a greater extent than the second. This effect was reversible.

Following a prolonged train of inhibitory nerve stimulation (10 Hz; 10 min) the magnitude of the first phase was reduced only slightly, but the second markedly.

The possible relationships between the biphasic relaxation to field stimulation and putative non‐adrenergic, non‐cholinergic transmitters in the mouse anococcygeus are discussed.