bluuebunny/crossref_metadata_2025 huggingface dataset:
CONTRACTILE EFFECT OF MORPHINE AND RELATED OPIOID ALKALOIDS, β‐ENDORPHIN AND METHIONINE ENKEPHALIN ON THE ISOLATED COLON FROM LONG EVANS RATS
Authors: HUIDOBRO‐TORO J. PABLO , WAY E. LEONG
Published: July 2012

Morphine and related synthetic surrogates as well as β‐endorphin and methionine enkephalin caused a contractile response of the longitudinal musculature of the terminal colon of Long Evans rats.

The muscular contraction caused by the narcotic analgesics exhibited stereospecificity, with levorphanol being about 50 times more potent than dextrorphan and (−)‐methadone 4 times more potent than (+)‐methadone. In addition, the rank order in potency of a homologous series of N‐alkyl substituted norketobemidones demonstrated that the activity of these compounds in eliciting contractile responses corresponded to that for analgesic efficacy in the rat and also correlated to the ability of these derivatives to inhibit the muscular twitch evoked by electrical stimulation of the guinea‐pig ileum.

Naloxone blocked the contractile response of the opiates following competitive kinetics; the naloxone pA2 values for morphine, etorphine, levorphanol and methadone were very close, in spite of the marked differences in potency of these agents.

The contractile effect of morphine on the rat colon was abolished by incubation of the tissues with tetrodotoxin 2.0 × 10−7 M or by decreasing the external Ca2+ level 100 fold. Increasing the external Ca2+ concentration caused an apparent non‐competitive antagonism of the response to morphine.

Pretreatment of the tissues with hexamethonium 8.3 × 10−5 M caused a modest antagonism of the morphine effect while atropine 5.8 × 10−7M did not significantly modify the morphine contractile effect. In contrast, methysergide 10−5 M caused a 10 fold increase in the morphine EC50.

Colons from rats rendered tolerant‐dependent on morphine were markedly less sensitive to the contractile effects of morphine than those from placebo‐treated controls. Tolerance to morphine was also accompanied by an increased sensitivity to the contractile effects of 5‐hydroxytryptamine (5‐HT).

A marked increase in the spontaneous muscular activity of segments of the terminal colon of rats chronically treated with morphine was found to occur upon removal of the residual morphine in the tissues by repetitive washings. The spontaneous activity was arrested by applications of morphine, suggesting that physical dependence can be demonstrated in vitro in this particular preparation.

It is concluded that the opiate‐induced contractile response is mediated via stereospecific, naloxone‐sensitive, opiate receptors and that the muscular response involves the activation of a 5‐HT neurone in the nerve terminals of the colon.
ENTERAL ADMINISTRATION OF INSULIN IN THE RAT
Authors: BAR‐ON H. , BERRY E.M. , ELDOR A. , KIDRON M. , LICHTENBERG D. , ZIV E.
Published: July 2012

The effect of the surfactant, Cetomacrogol 1000, on the absorption of insulin across the rectal mucosa has been studied.

Rectal administration of microenemata containing Cetomacrogal 1000 and insulin causes a rise in the plasma concentration of insulin and a consequent fall in the blood glucose concentration in diabetic and non‐diabetic rats.

The hypoglycaemic response is dependent on both the concentration of surfactant and the dose of insulin administered.

The results suggest that the transport of insulin across the rectal mucosa is facilitated by Cetomacrogal 1000.
THE EFFECT OF CIMETIDINE ON BASAL AND STIMULATED PEPSIN SECRETION IN THE ISOLATED WHOLE STOMACH OF THE RAT
Authors: BUNCE K.T. , GREWAL M. , PARSONS M.E.
Published: July 2012

The isolated stomach preparation of the immature rat has been used to study the stimulation and inhibition of pepsin secretion.

The isolated stomach secretes a basal level of pepsin. High concentrations (10−3m) of the H2‐receptor antagonist, cimetidine, and the muscarinic receptor blocking drug, atropine, did not affect this secretion in a manner which was consistently of statistical significance.

Concentrations of histamine of 10−5M, 10−4M and 10−3M stimulated maximum levels of pepsin output of 126%, 155% and 299% respectively of control. There was no evidence that this secretion was secondary to the stimulation of acid secretion.

Cimetidine (10−4m and 10−3m) produced a dose‐related inhibition of the pepsin output to 10−3M histamine, suggesting that histamine H2‐receptors mediate this response.

Atropine (10−3m) had no effect on the pepsin response to 10−3M histamine, suggesting that muscarinic mechanisms play no part, even modulatory, in this secretion.
TYRAMINE ANTAGONISTIC PROPERTIES OF AGN 1135, AN IRREVERSIBLE INHIBITOR OF MONOAMINE OXIDASE TYPE B
Authors: FINBERG J.P.M. , TENNE M. , YOUDIM M.B.H.
Published: July 2012

The effects of the irreversible monoamine oxidase (MAO) inhibitors, AGN 1133, AGN 1135 and (−)‐deprenyl, on tyramine and noradrenaline responses and uptake of [3H]‐metaraminol were investigated in the isolated vas deferens of the rat. Uptake of [3H]‐metaraminol and [3H]‐octopamine was compared in mouse vas deferens. The modification of tyramine and noradrenaline‐induced pressor responses by AGN 1133 and AGN 1135 was examined in anaesthetized rats and cats.

AGN 1133 (7.5 × 10−6m) greatly potentiated responses to tyramine in the rat isolated vas deferens. Both AGN 1135 and (−)‐deprenyl inhibited tyramine responses selectively at concentrations above 10−3m (which caused almost complete inhibition of MAO types A and B) but tyramine responses were potentiated on washing out the inhibitors.

AGN 1135 (10−4m) and (−)‐deprenyl (10−5m) inhibited [−3H]‐metaraminol uptake by about20% in rat and mouse vas deferens; neither inhibitor affected [−3H]‐octopamine uptake in mouse vas deferens. Desmethylimipramine (10−6m) inhibited amine uptake by more than 70%.

AGN 1133 (1.5 mg/kg) potentiated pressor responses to tyramine in rats and cats whereas AGN 1135 (1.5 mg/kg) did not.

AGN 1135 possesses tyramine antagonistic activity which is qualitatively similar to that of (−)‐deprenyl but which cannot satisfactorily be explained by inhibition of neuronal or granular amine uptake.
PROSTAGLANDINS, THROMBOXANES AND THE PREGNANT RAT UTERUS AT TERM
Authors: PHILLIPS1 CHRISTINE A. , POYSER N.L.
Published: July 2012

Prostaglandin and thromboxane release from the term pregnant (Day 22) rat uterus in vitro has been measured by radioimmunoassay and gas chromatography combined with mass spectrometry.

Prostacyclin (prostaglandin I2, PGI2) and thromboxane A2 (TXA2) (measured as their metabolites, 6‐oxo‐PGF1α and TXB2. respectively) were released in large amounts, while PGE2 and PGF2α were released in smaller amounts. PGD2 was released in the largest quantities.

Treatment of the term pregnant rat uterus in vitro with the PGI2 synthesis inhibitors, 15‐hydroperoxy arachidonic acid (15‐OOH AA) and tranylcypromine caused spasm of the tissue.

15‐OOH AA caused dose‐dependent increases in prostaglandin release, while tranylcypromine caused a fall in the release of PGE2 but did not affect the release of other prostaglandins. A possible reason for the effect of 15‐OOH AA on prostaglandin release is discussed.

Indomethacin prevented spontaneous activity of the term pregnant rat uterus in vitro. Contractions were restored by prostaglandins and their order of potency was PGE2>PGF2α>PGI2>PGD2>>6‐oxo‐PGFlα = TXB2
EFFECTS OF HISTAMINE ON THE RESTING AND STIMULATION‐INDUCED RELEASE OF [3H]‐NORADRENALINE IN GUINEA‐PIG ISOLATED ATRIA
Authors: RAND M.J. , STORY D.F. , WONG‐DUSTING H.K.
Published: July 2012

The sympathetic transmitter stores of guinea‐pig isolated atria were labelled with [3H]‐noradrenaline. The effects of histamine (0.3 to 100 μmol/l) on resting and stimulation‐induced (S‐I, 2 Hz for 10 s) release of radioactivity were investigated.

Histamine, in low concentrations (0.3 and 1 μmol/l) had no effect on resting release but inhibited S‐I release of radioactivity. The inhibition was abolished by the H2‐receptor antagonist, cimetidine (10 μmol/l) and also by the H1‐receptor antagonist, mepyramine (1μmol/l).

The inhibitory actions of histamine on S‐I release were not due to indirect effects involving α‐adrenoceptors, β‐adrenoceptors, muscarinic cholinoceptors or prostaglandin synthesis.

Histamine in a high concentration (100 μmol/l) increased the resting and S‐I release of radioactivity. The increase in resting release was abolished by the neuronal uptake blocking drug cocaine (30 μmol/l) but the increase in S‐I release was only partially blocked by cocaine.
EFFECTS OF ASPIRIN, PREDNISOLONE AND INDOMETHACIN ON NEPHROTOXIC SERUM NEPHRITIS IN THE RAT
Authors: KUROKAWA HIROSHI , SAKAMOTO KIMIKO
Published: July 2012

The effects of aspirin, prednisolone, and indomethacin on nephrotoxic serum nephritis in rats was studied. The nephritis was induced by a single intravenous injection of nephrotoxic serum (NTS, rabbit anti‐serum against the water‐soluble renal antigen of the rat). The injection of NTS induced the heterologous phase of proteinuria (within a day after NTS injection) and then the autologous phase (5 to 7 days after NTS injection). The effect of drugs given before the NTS (i.e. prophylactically) or after the NTS (i.e. therapeutically) was investigated.

Aspirin, which was given orally at doses of 150 and 250 mg/kg daily from the day before NTS injection, suppressed the‐development of proteinuria in both the heterologous and the autologous phase, and lowered the serum cholesterol level towards the normal level. Aspirin (250 mg/kg daily, orally) had no significant effect against the established proteinuria in the autologous phase.

Prednisolone, which was given orally at doses of 3 and 5 mg/kg daily from the day before NTS injection, elevated the proteinuria in the heterologous phase, while inhibiting the development of proteinuria in the autologous phase. Prednisolone (5 mg/kg daily, orally) was ineffective against established proteinuria in the autologous phase.

Indomethacin (3 mg/kg daily, orally) did not exert any significant effect on proteinuria in either the heterologous or the autologous phase.
BLOOD ALCOHOL LEVELS IN RATS: NON‐UNIFORM YIELDS FROM INTRAPERITONEAL DOSES BASED ON BODY WEIGHT
Authors: BLOOM FLOYD , LAD PUSHKARAJ , PITTMAN QUENTIN , ROGERS JOSEPH
Published: July 2012

Sprague‐Dawley rats (n = 72) weighing from 125 to 450 g were injected intraperitoneally (i.p.) with 16% (w/v) ethanol to provide 1, 2, or 3 g/kg doses.

Resulting blood alcohol levels (BALs) demonstrated a general inadequacy of dose/body weight (g/kg) formulations of ethanol to provide uniform BALs in animals of different weights.

BAL differences between heavier and lighter rats were not well accounted for by developmental changes in liver weight or alcohol dehydrogenase activity.

From the data, a table was derived of more appropriate ethanol injection volumes to produce 0–300 mg% BALs (20 mg% increments) in rats from 100–500 g (10 g increments).
EFFECTS OF PHENCYCLIDINE AND ITS DERIVATIVES ON ENTERIC NEURONES
Authors: GINTZLER ALAN R. , ZUKIN R. SUZANNE , ZUKIN STEPHEN R.
Published: July 2012

The effects of N‐(1‐phenylcyclohexyl) piperidine (PCP) and related drugs on isolated intact segments of the guinea‐pig ileum were determined.

1–1‐(2‐Thienyl) cyclohexylpiperidine (TCP), PCP and ketamine decreased the height of electrically induced contractions (0.1 Hz) of intact segments of isolated guinea‐pig ileum.

Thirty to forty percent of the inhibition of contraction height (0.1 Hz) was reversed by pretreatment with the pure narcotic antagonist, naloxone. This naloxone‐reversible component showed cross‐tolerance with morphine.

PCP pretreatment caused a shift to the right in the dose‐response curve to acetylcholine (ACh) that was not parallel with the control dose‐response curve. Thus PCP does not interact with the muscarinic cholinoceptor in a strictly atropine‐like competitive fashion.

Binding sites for [3H]‐PCP were detected in homogenates of the guinea‐pig longitudinal muscle‐myenteric plexus preparation.

The affinity constants and the rank order of potencies of various PCP derivatives competing with [3H]‐PCP for binding suggest that these binding sites are very similar to those found in the central nervous system.

These data suggest that the guinea‐pig isolated ileum may be used as an in vitro system for studying the mechanism of action of phencyclidines.
CORONARY VASOCONSTRICTOR AND VASODILATOR ACTIONS OF ARACHIDONIC ACID IN THE ISOLATED PERFUSED HEART OF THE RAT
Authors: BELO SUSAN E. , TALESNIK JAIME
Published: July 2012

The administration of arachidonic acid (AA) to the isolated perfused heart of the rat usually produced biphasic coronary responses characterized by initial vasoconstriction followed by prolonged vasodilatation. However, some responses were predominantly vasoconstrictor or vasodilator.

The non‐steroidal anti‐inflammatory agents (NSAA) indomethacin (1–5 mg/l) and naproxen (12.5–25 mg/l) reversibly inhibited both phases of the response induced by AA.

Pretreatment of animals with indomethacin (5 mg/kg) or naproxen (25 mg/kg) daily, resulted in unaltered coronary response to AA. Subsequent addition of NSAA to the perfusate produced inhibition of the AA effect.

Short infusions of acetylsalicylic acid at low concentrations (2.9 μg/ml), dipyridamole (0.6 μg/ml) and sulphinpyrazone (28.7 μg/ml) selectively inhibited the vasoconstrictor phase of the response to AA.

It was confirmed that metabolic coronary dilatation induced by cardiostimulation was inhibited by prolonged A A administration; this effect was prevented by NSAA pretreatment. Reactive hyperaemic responses to short lasting occlusions of coronary inflow were unaffected by NSAA.

Linolenic, linoleic, dihomo‐γ‐linolenic and oleic acid usually produced decreases in coronary flow which were unaffected by NSAA, dipyridamole or sulphinpyrazone.

Intra‐aortic injections of AA, prostacyclin (PGI2) and prostaglandin E2 (PGE2) in the intact rat produced a dose‐dependent decrease in blood pressure with the AA response inhibited by indomethacin. PGI2 and PGE2 produced long lasting coronary vasodilatation in the isolated heart.

The coronary actions of AA appear to be due to its transformation, within the easily accessible vascular wall, into prostaglandin and thromboxane‐like substances. We suggest that a vasoconstrictor thromboxane A2‐like substance may be responsible for coronary vasospasm.

Coronary insufficiency may also result from an inhibition of compensatory metabolic coronary dilatation by increased synthesis of PGE2 within the myocardial cell.
EFFECTS OF 5‐HYDROXYTRYPTAMINE ON CANINE ISOLATED CORONARY ARTERIES
Authors: PORQUET MARIE‐FRANCE , POURRIAS BERNARD , SANTAMARIA RAPHAEL
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) were studied in vitro on proximal and distal portions of canine interventricular and circumflex coronary arterial strips. 5‐HT produced concentration‐related contractions in the proximal portion whether contracted previously with KCl or not. These responses were still present after either chemical sympathetic denervation or release of noradrenaline induced by K+‐free salt solution. In contrast, the distal portions of coronary arteries did not respond to 5‐HT.

Concentration‐response curves to 5‐HT exhibited a classical hyperbolic shape with a calculated Hill‐coefficient of approximately 1.

Methysergide and phentolamine but not morphine shifted to the right and depressed the maximum of the dose‐response curves to 5‐HT.

It is concluded that the contractions produced by 5‐HT in the proximal portion of the interventricular and circumflex coronary arteries are not due to the release of endogenous noradrenaline. The vessels appear to possess separate receptors for 5‐HT and noradrenaline and the 5‐HT responses belong to neither the M nor the D type.
LEUKOTRIENE B4: BIOLOGICAL ACTIVITIES AND THE CYTOSKELETON
Authors: CUNNINGHAM F.M. , SMITH M.J.H.
Published: July 2012

The aggregation and chemokinesis of either rat or human polymorphonuclear leucocytes (PMNs) induced by leukotriene B4 isomer III (LTB4) are inhibited significantly by colchicine (10−6‐10−3m) and vinblastine (10−7‐10−4m). Random migration of the leucocytes is inhibited by colchicine 10−3m and vinblastine 10−4m.

Cytochalasin B (4 × 10−7‐4 × 10−6m) caused the aggregation of rat PMNs but inhibited their random migration. The aggregation of the PMNs induced by LTB4 was enhanced by cytochalasin B but the chemokinesis was inhibited.

It is suggested that both microtubules and microfilaments may be involved in the aggregatory and chemokinetic responses of PMNs to LTB4.
EFFECTS OF PROSTAGLANDINS AND THROMBOXANE ANALOGUES ON BULLOCK AND DOG IRIS SPHINCTER PREPARATIONS
Authors: DONG Y.J. , JONES R.L.
Published: July 2012

The bullock iris sphincter was contracted by low concentrations of prostaglandin E2 (PGE2), 16,16‐dimethyl PGE2 and 17,18,19,20‐tetranor‐16‐p‐chlorophenoxy PGE2. Other compounds with thromboxane‐like actions, for example 11,9‐epoxymethano PGH2, were also potent spas‐mogens. ZK 36374, a stable carbacyclin, was a partial agonist on the PGE‐sensitive system of this tissue.

The thromboxane antagonist, EP 045, had little effect on the action of PGE2 and 16,16‐dimethyl PGE2 on the bullock iris.

The dog iris sphincter was sensitive to PGF2α but not to PGE2 and 11,9‐epoxymethano PGH2.

16,16‐Dimethyl PGE2 had very low activity on the dog iris in contrast to its high activity on the bullock iris. The reverse was found with the 17,18,19,20‐tetranor‐16‐m‐trifluoromethylphenoxy analogue of PGF2α (ICI 81008). This indicates a considerable selectivity of action of the two analogues.

The results are discussed in relation to the existing knowledge of prostanoid receptors.
GENERATION OF LEUKOTRIENE B4, ITS ALL trans ISOMERS AND 5‐HYDROXYEICOSATETRAENOIC ACID BY RAT BASOPHILIC LEUKAEMIA CELLS
Authors: FORD‐HUTCHINSON A.W. , PIPER PRISCILLA J. , SAMHOUN MARWA N.
Published: July 2012

When rat basophilic leukaemia (RBL‐1) cells were incubated for 4 min, in the presence of arachidonic acid (AA) and calcium ionophore A23187, three isomers of leukotriene (LT) B4 and 5‐hydroxyeicosatetraenoic acid (5‐HETE) were generated.

The isomers of LTB4 separated by reverse phase high pressure liquid chromatography (h.p.l.c.) were found to be 5(S),12(S)‐dihydroxy‐6,14‐trans‐8,10‐trans‐eicosatetraenoic acid; 5(S), 12(R)‐dihydroxy‐6,14‐trans‐8,10‐trans‐eicosatetraenoic acid and 5(S),12(R)‐dihydroxy‐6,14‐cis‐8,10‐trans‐eicosatetraenoic acid or LTB4.

5(S), 12(R)‐cis, trans, trans‐LTB4 produced by RBL‐1 cells caused aggregation of rat polymorphonuclear leucocytes (PMNs). Its other two isomers (5(S), 12(S)‐all trans‐LTB4; 5(S),12(R)‐all trans‐LTB4) were much less active and 5‐HETE was found to be inactive.

5(S),12(R)‐cis, trans, trans‐LTB4 formed from RBL‐1 cells contracted guinea‐pig parenchymal strips (GPPs) and was indistinguishable from synthetic 5(S),12(R)‐cis, trans, trans‐LTB4. The other two isomers of LTB4, i.e. 5(S),12(S)‐all trans‐LTB4 and 5(S),12(R)‐all trans‐LTB4 as well as 5‐HETE were inactive on GPP.

RBL‐1 LTB4 was equipotent with LTD4, in most experiments, in contracting GPP but had no activity on guinea‐pig ileum smooth muscle (GPISM).

RBL‐1 cells contain the enzyme systems necessary for generating LTB4 as well as the leukotriene(s) with amino acid residues at C‐6.
ADENOSINE 5′‐DIPHOSPHATE ANTAGONISTS AND HUMAN PLATELETS: NO EVIDENCE THAT AGGREGATION AND INHIBITION OF STIMULATED ADENYLATE CYCLASE ARE MEDIATED BY DIFFERENT RECEPTORS
Authors: CUSACK N.J. , HOURANI S.M.O.
Published: July 2012

Adenosine 5′‐diphosphate (ADP) induces human platelet aggregation and noncompetitively inhibits stimulated human platelet adenylate cyclase; it has been suggested that these two effects are mediated by separate ADP receptors on the platelet surface.

Adenosine 5′‐triphosphate and seven adenine nucleotide analogues were tested as inhibitors of both effects of ADP on human platelets, and were found to be competitive.

pA2 values were calculated for each antagonist for inhibition of both effects of ADP, and a good correlation (correlation coefficient 0.87; P < 0.01) was found between the pA2 values for inhibition of ADP‐induced aggregation and the pA2 values for inhibition of the effect of ADP on stimulated adenylate cyclase.

Such a correlation does not support the suggestion that ADP‐induced aggregation and the inhibition by ADP of stimulated adenylate cyclase are mediated by two separate receptors.
CATECHOLAMINE TRANSPORT IN ISOLATED LUNG PARENCHYMA OF PIG
Authors: GOLDIE ROY G. , PATERSON JAMES W.
Published: July 2012

Lung parenchyma strips of the pig incubated at 37°C with [3H]‐(−)‐noradrenaline ([3H]‐NA) or [3H]‐(±)‐isoprenaline ([3H]‐Iso), accumulated radioactivity via saturable, high affinity uptake processes. Apparent saturation constants (Km) for [3H]‐NA and [3H]‐Iso were 1.34 × 10−6 m and 1.63 × 10−6 m respectively, while apparent transport maxima (Vmax) were 4.86 and 1.63 × 10−9 mol min−1 g−1 respectively.

Cellular accumulation of radioactivity from radiolabeled catecholamines was greatly reduced by lowering the temperature to 7°C, pre treatment with ouabain (100 μm), phentolamine (15 μm) or phenoxybenzamine (80 μm). However, accumulation of radioactivity derived from (3H]‐NA was inhibited selectively by cocaine (10 μm) and desipramine (1 μm), while normetanephrine (80 μm) and 3‐O‐methylisoprenaline (50 μm) caused much greater reductions in cellular radioactivity from [3H]‐Iso than from (3H]‐NA. Taken together with information from kinetic studies, the results indicate that these amines are transported by separate uptake processes.

Cocaine (50 μm) which selectively reduced [3H]‐NA transport, had no significant effect on the sensitivity (EC50) of isolated parenchyma lung strips of the pig to the contractile effects of cumulative concentrations of NA. The catechol‐O‐methyl transferase (COMT) inhibitor, U‐0521 (60 μm), also failed to alter the potency of NA, while normetanephrine (80 μm) caused a 2 fold decrease in potency.

Phentolamine (15 μm), which reduced the cellular accumulation of radioactivity derived from [3H]‐Iso by 64%, caused a small potentiation of Iso‐induced relaxations of porcine lung strips. Normetanephrine (80 μm) and 3‐O‐methylisoprenaline (50 μm), which also depressed the accumulation of cellular radioactivity from [3H]‐Iso by > 50%, caused rightward shifts in Iso concentration‐effect curves as a result of β‐adrenoceptor blockade. In sharp contrast, cortisol (80 μm) and U‐0521 (60 μm), which caused smaller reductions in the cellular accumulation of radioactivity derived from [3H]‐Iso, both caused an approximately 9 fold potentiation of responses to Iso in isolated lung strips.

The results indicate that the major sites of uptake and metabolism of NA in porcine parenchyma strip are remote from α‐adrenoceptors mediating NA‐induced contraction. Similarly, some major sites of uptake of Iso are remote from β‐adrenoceptors mediating Iso‐induced relaxation. However, β‐adrenoceptors are apparently in close proximity to a compartment containing COMT activity.
AN ASSESSMENT OF THE EFFECTIVENESS OF NEONATAL TREATMENT WITH GUANETHIDINE AS A MEANS OF PRODUCING SYMPATHECTOMY
Authors: BENNETT T. , GARDINER S.M. , KEMP P.A.
Published: July 2012

Male Wistar rats were treated neonatally with guanethidine (following a protocol reported to produce a permanent peripheral sympathectomy) and the extent of the sympathectomy was assessed when the rats were mature.

The noradrenaline content of right and left atria and the ventricles was markedly reduced in 9‐ and 26‐week old rats which had been treated with guanethidine. The extent of depletion in the ventricles was similar at both times but the atrial content increased between 9 and 26 weeks.

Arterial blood pressures were not significantly different in 24–26‐week old conscious rats which had been treated neonatally with guanethidine compared to controls, but the baroreflex sensitivity, assessed by the lengthening of pulse interval in response to a pressor stimulus, was significantly less in the guanethidine‐treated rats.

The blood pressure response to acute bilateral adrenalectomy was similar in control and guanethidine‐treated rats.

Left atria and hepatic portal veins taken from 20–26‐week old rats which had been treated with guanethidine showed classical signs of a denervation supersensitivity, but the chronotropic responses of right atria to noradrenergic nerve stimulation and to noradrenaline were normal.

Fluorescence histochemical studies on the right atria, irides and hepatic portal veins showed that the neonatal treatment had caused a variable degree of destruction both between and within animals.

The findings are consistent with neonatal guanethidine treatment causing extensive damage to peripheral noradrenergic nerves. However, the sympathectomy is neither complete nor permanent. In the heart, there appears to be a selective re‐innervation of the atria.

Despite the impaired efferent sympathetic nerve activity in rats treated neonatally with guanethidine, compensatory mechanisms permit adequate cardiovascular control in the resting state.
EFFECTS OF KETAMINE AND OF HIGH PRESSURE ON THE RESPONSES TO γ‐AMINOBUTYRIC ACID OF THE RAT SUPERIOR CERVICAL GANGLION in vitro
Authors: LITTLE HILARY J.
Published: July 2012

The method of Brown & Marsh (1974) for recording of surface potentials from the rat superior cervical ganglion has been adapted for use in a high pressure chamber in order to study the effects of high pressure of helium and the possible interactions with the effects of general anaesthetics.

Helium pressure of 130 atm did not alter the amplitude of the responses recorded from the ganglion in response to γ‐aminobutyric acid (GABA) application (9.7 and 19.4 μm) but the amplitude of responses to a nicotinic agonist were depressed.

Ketamine, at concentrations between 18 and 180 μm, considerably potentiated the responses of the ganglion to GABA.

Helium pressure (130 atm) did not reverse the potentiation of GABA by ketamine.

The results are discussed in connection with the ability of ketamine to oppose the behavioural effects of high pressure.
ELECTROPHYSIOLOGICAL EFFECTS OF PIPERAZINE AND DIETHYLCARBAMAZINE ON Ascaris suum SOMATIC MUSCLE
Authors: MARTIN R.J.
Published: July 2012

Electrophysiological recordings were made from the bag region of Ascaris suum muscle. Membrane potential and input conductance or membrane current under voltage clamp were measured.

In high‐Cl‐ Ringer, bath‐applied piperazine, at concentrations greater than 10−4 m, produced a dose‐dependent and reversible increase in input conductance associated with a hyperpolarizing potential. The increase in input conductance was reduced when the preparations were bathed in low‐Cl‐ Ringer. γ‐Aminobutyric acid (GABA) and piperazine reversal potentials were measured with a voltage clamp on the same cells using iontophoretic application of the agonists. The reversal potentials were the same and close to the predicted Nernst Cl‐ potential (—65 mV). When GABA and piperazine were applied simultaneously piperazine reversibly reduced the amplitude of the control outward GABA current response. It was concluded that piperazine acts as a GABA agonist of low potency on the extra‐synaptic GABA receptors of the bag, mediating an increase in Cl‐ conductance.

Acetylcholine was applied iontophoretically within 100 μm of the bag region while the preparation was bathed in a low‐Ca2+, low‐Cl‐ Ringer. The response under voltage clamp was a dose‐dependent inward current associated with an increase in input conductance. This response was reversibly antagonized by 3 × 10−5 m tubocurarine, high concentrations of diethylcarbamazine (10−3 to 10−2 m) but not high concentrations of piperazine (10−3 to 10−2 m). It was concluded that there are extra‐synaptic acetylcholine receptors on the bag region of Ascaris muscle and that diethylcarbamazine but not piperazine acts as an antagonist.

Bath‐applied diethylcarbamazine (10−4 to 2 × 10−3m) produced a reversible dose‐dependent depolarization of the membrane potential which was associated with an increase in the amplitude and frequency of spontaneous depolarizing potentials in active preparations at 32°C to 35°C in high‐Cl‐ Ringer. The excitatory action of diethylcarbamazine was not blocked by 3 × 10−5m tubocurarine. Diethylcarbamazine (10−4 to 10−3 m) had no effect on the outward current response to GABA iontophoresis. Diethylcarbamazine (10−4 to 10−2m) reversibly antagonized in a dose‐dependent manner the delayed rectification of the bag membrane. In a low‐Ca2+, low‐Cl‐ Ringer, diethylcarbamazine (10−4 to 2 × 10−3m) reversibly antagonized the voltage‐sensitive outward current of the bag. This effect was mimicked by high‐K+ Ringer or perfusion with 4‐aminopyridine (10−3 to 2 × 10−3 m). It was concluded that diethylcarbamazine did not react with the GABA receptor but antagonized a voltage‐sensitive K+ conductance.
STIMULATION OF ARACHIDONIC ACID METABOLISM AND GENERATION OF THROMBOXANE A2 BY LEUKOTRIENES B4, C4 AND D4 IN GUINEA‐PIG LUNG in vitro
Authors: PIPER PRISCILLA J. , SAMHOUN MARWA N.
Published: July 2012

Leukotriene C4 (LTC4), LTD4, slow‐reacting substance of anaphylaxis (SRS‐A) (from guinea‐pig lung), bradykinin (Bk) and arachidonic acid (AA) release thromboxane A2 (TxA2) and prostaglandin‐like materials from guinea‐pig isolated perfused lungs.

Release of TxA2 induced by LTC4 and LTD4 is inhibited by a thromboxane synthetase inhibitor, imidazole (2.9 mm).

Mepacrine (200 μm), a phospholipase inhibitor, inhibits release of TxA2 and prostaglandin‐like materials caused by SRS‐A and Bk but not that due to exogenous AA

Leukotrienes B4, C4 and D4 are approximately equipotent in inducing dose‐related contractions of guinea‐pig parenchymal strips (GPPs).

Leukotriene‐induced contractions of GPPs are greatly inhibited by imidazole (2.9 mm), carbox‐yheptylimidazole (24 μm) and mepacrine (400 μm).

FPL 55712 (1.9 μm), the SRS‐A antagonist, blocks contractions of GPPs induced by LTC4 and LTD4 but not those due to LTB4 or Bk.

Tachyphylaxis to LTB4 occurs in GPPs but not to LTC4 or LTD4.

These results suggest that in guinea‐pig lung in vitro, LTB4, LTC4 and LTD4 activate a phospholipase with subsequent generation of cyclo‐oxygenase products of which TxA2 plays an important role.
FAST DESENSITIZATION OF THE NICOTINIC RECEPTOR AT THE MOUSE NEUROMUSCULAR JUNCTION
Authors: PENNEFATHER P. , QUASTEL D.M.J.
Published: July 2012

When low concentrations of carbachol (2–20 μm) were applied by local superfusion to mouse diaphragm endplates, there occurred a rapid decrease (within seconds) in the height of miniature endplate currents (m.e.p.cs) in addition to the increase of muscle membrane conductance.

With 2, 5, 10 and 20 μm carbachol, m.e.p.c. heights were diminished by 5, 10, 30 and 50% respectively. A subsequent slow decrease in height took place at a rate corresponding to that reported for the slow desensitization produced by bath‐applied carbachol (see Adams, 1975).

The effect of carbachol on m.e.p.c. height was not affected by poisoning of acetylcholinesterase (AChE). After poisoning of AChE, 4 μm acetylcholine (ACh) depressed m.e.p.c. height by 23%.

At 20 μm carbachol, both the onset and offset of the effect on m.e.p.c. height lagged behind the subsynaptic conductance change, and the calculated change of subsynaptic agonist concentration, by about 3 s; the onset rate was at least ten times faster than expected for slow desensitization.

When the conductance responses produced by carbachol were corrected for fast desensitization, the slope of the log‐response log‐dose line (Hill coefficient) was increased from 1.7 to 2.0.

The Hill coefficient for fast desensitization was 1.4. The data were compatible with a cyclic model for fast desensitization, with receptor activation not a prerequisite for desensitization of receptors.

The failure of AChE poisoning to affect m.e.p.c. height during desensitization suggests that desensitized receptor associated with exogenous agonist can continue to bind quantal ACh.
THE EFFECT OF CHLORPROMAZINE, METYRAPONE, IMIPRAMINE AND SKF 525‐A ON THE HEPATIC FIRST PASS ELIMINATION OF PROPRANOLOL IN THE PITHED RAT
Authors: BARBER H.E. , KITTERINGHAM N.R. , PETRIE J.C.
Published: July 2012

The effect of chlorpromazine, metyrapone, imipramine and SKF 525‐A on the hepatic first pass elimination of propranolol has been studied in the pithed rat.

The effect of chlorpromazine, metyrapone, imipramine and SKF 525‐A on the inhibition caused by propranolol of an elicited electrically induced tachycardia has also been studied.

The hepatic first pass elimination of propranolol was reduced following pretreatment with chlorpromazine, imipramine and SKF 525‐A but was not affected by pretreatment with metyrapone.

Chlorpromazine, imipramine and SKF 525‐A all resulted in an increased propranolol blood concentration after hepatic portal vein administration which was associated with decreased formation of metabolites and an enhanced inhibition of an electrically induced tachycardia.
EFFECTS OF 3, 4‐DIHYDRO‐8‐(2‐HYDROXY‐3‐ISOPROPYLAMINOPROPOXY)‐3‐NITROXY‐2H‐1‐BENZOPYRAN (K‐351) ON SMOOTH MUSCLE CELLS AND NEUROMUSCULAR TRANSMISSION IN THE CANINE MESENTERIC ARTERY
Authors: KOU KATSUHIRO , KURIYAMA HIROSI , SUZUKI HIKARU
Published: July 2012

The effects of K‐351 on the electrical and mechanical responses were investigated in the canine mesenteric artery by isometric tension recording and the use of intracellular microelectrodes. The results were compared to the responses observed with other α‐adrenoceptor blocking agents.

K‐351 (> 3 × 10−7m) consistently inhibited the contraction evoked by perivascular nerve stimulation; however, K‐351 had no effect on the contraction evoked by direct muscle stimulation, after pretreatment with 3 × 10−7m tetrodotoxin.

Phentolamine enhanced and prazosin had no effect on the amplitude of contraction evoked by perivascular nerve stimulation at a high frequency (over 1.0 Hz). Pretreatment with phentolamine inhibited the contraction evoked by lower frequencies of perivascular nerve stimulation (below 0.5 Hz).

The potency for the inhibition of the response to perivascular nerve stimulation was in the order of K‐351 > phentolamine > prazosin, while the contractions induced by exogenously applied noradrenaline (5 × 10−7m) were inhibited in the order: prazosin > phentolamine > K‐351.

K‐351 (< 3 × 10−5m) did not modify the resting membrane potential or the membrane resistance, as estimated from the change in the amplitude of electrotonic potentials in the smooth muscle cell membranes.

K‐351 (> 3 × 10−7m) inhibited the amplitude of the first e.j.p. and e.j.ps after completion of the facilitation process following stimulation at frequencies over 0.25 Hz.

K‐351 (< 3 × 10−5m) did not modify the compound action potentials recorded from peripheral nerve bundles distributed on the mesenteric artery.

Phentolamine (> 1 × 10−8 m) inhibited the first e.j.p. but this agent either inhibited or enhanced the amplitude of e.j.p. after completion of the facilitation process produced by repetitive stimulation below or over 1.0 Hz stimulus frequencies, respectively. Prazosin (1 × 10−6m) had no effect on e.j.ps evoked by perivascular nerve stimulation, at any stimulus frequency applied.

These results indicate that K‐351 inhibits the extra‐junctional adrenoceptor with a slightly weaker potency than prazosin or phentolamine, but that this agent has a potent action as an intra‐junctional adrenoceptor blocking agent. Phentolamine acts mainly on the extra‐junctional adrenoceptors and also has weak actions on intra‐junctional adrenoceptors, as a blocking agent. This agent also inhibits the presynaptic α2‐adrenoceptor. Prazosin inhibits only the extra‐junctional α1‐adrenoceptor.
α2‐Adrenoceptor agonists induce mydriasis in the rat by an action within the central nervous system
Authors: Berridge T.L. , Gadie B. , Roach A.G. , Tulloch I.F.
Published: July 2012

The effects of intravenous administration of the selective α2‐adrenoceptor agonists clonidine, UK 14,304 and guanoxabenz on rat pupil diameter were investigated.

In rats anaesthetized with pentobarbitone, each agonist produced a marked dose‐related increase in pupil diameter; the rank order of potency was: clonidine > UK 14,304 > guanoxabenz.

Pretreatment with the selective α2‐adrenoceptor antagonist, RX 781094 (0.5 mg/kg, i.v.), produced a parallel 30–40 fold shift to the right of the dose‐pupil dilator response curves for the three agonists. Yohimbine (1.5 mg/kg, i.v.) produced about a 10 fold rightward shift of the dose‐response curve for guanoxabenz. In contrast, the α1‐selective antagonist, prazosin (0.5 mg/kg, i.v.), failed to affect the dose‐response relation for guanoxabenz.

Several antagonists of varying selectivities towards α1‐ and α2‐adrenoceptors were tested for their ability to reverse the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.). The rank order of potency of the antagonists producing a 50% reversal of this effect was: RX 781094 > yohimbine > piperoxan = rauwolscine > mianserin > RS 21361. Neither corynanthine nor prazosin reversed the guanoxabenz‐induced mydriasis.

Topical application of RX 781094 (0.1 to 3% w/v solutions) onto one eye produced a slow reversal of guanoxabenz‐induced mydriasis; the time course and degree of reversal were virtually the same in both eyes.

Intracerebroventricular administration of RX 781094 (1.25–15 μg total dose) caused a rapid dose‐related reversal of the maximal mydriasis induced by guanoxabenz (0.3 mg/kg, i.v.).

Guanoxabenz (0.3 and 1.0 mg/kg, i.v.) did not produce any dilation of the physostigmine‐constricted undamaged pupil of the pithed rat. Intravenous adrenaline was found to produce a small mydriatic effect, while atropine completely antagonized the effects of physostigmine in this preparation.

These results indicate that α2‐adrenoceptor agonists induce mydriasis in the rat through a central α2‐adrenoceptor mechanism. However, the site of action within the central nervous system remains to be determined.
Experimental conditions required for the enhancement by α‐adrenoceptor antagonists of noradrenaline release in the rabbit ear artery
Authors: Auch‐Schwelk Wolfgang , Starke Klaus , Steppeler Anton
Published: July 2012

Segments of the rabbit ear artery were preincubated with (—)‐[3H]‐noradrenaline and then perfused/superfused and stimulated by transmural electrical pulses. The outflow of [3H]‐noradrenaline, separated from its metabolites by column chromatography, was determined.

Tetrodotoxin abolished, cocaine increased, and clonidine reduced the overflow of [3H]‐noradrenaline elicited by 10 shocks at 0.2 Hz, 10 shocks at 2 Hz or 100 shocks at 2 Hz.

The effects of yohimbine (0.1 or μm), phentolamine (1 μm) and piperoxan (1 or 10 μm) depended on the stimulation conditions. No antagonist increased the overflow of [3H]‐noradrenaline evoked by 10 pulses at 0.2 Hz, but all markedly increased the overflow evoked by 100 pulses at 2 Hz. Only piperoxan (10 μm) slightly enhanced the overflow at 10 pulses, 2 Hz. The effects of yohimbine and piperoxan were similar in arteries not exposed to cocaine and in those that were perfused/superfused with medium containing cocaine (10 μm) after preincubation.

It is concluded that yohimbine, phentolamine and piperoxan increase the release of noradrenaline only when the concentration of noradrenaline in the biophase of the ear artery is sufficiently high. The effect is, hence, an anti‐noradrenaline effect and due to the blockade of presynaptic α‐adrenoceptors. A second prerequisite for the release‐enhancing effect appears to be a sufficient length of the pulse train, indicating that the α‐adrenergic auto‐inhibition develops relatively slowly.
Increased surface glycoconjugates of synaptic membranes in mice during chronic ethanol treatment
Authors: Goldstein Dora B. , Hungund Basalingappa L. , Lyon Robbe C.
Published: July 2012

Synaptosomal plasma membranes from mice treated chronically with ethanol were incubated with galactose oxidase and [3H]‐sodium borohydride, in order to label the exposed galactose and N‐acetylgalactosamine groups of glycoconjugates. The ethanol treatment approximately doubled the amount of exposed sugars. This change may be related to previously observed alterations in the physical properties of neuronal membranes in ethanol‐treated mice.
Effects of aspirin and prostacyclin on arrhythmias resulting from coronary artery ligation and on infarct size
Authors: Johnston Kathleen M. , MacLeod B.A. , Walker M.J.A.
Published: July 2012

The effects of pretreatment with aspirin, and of prostacyclin (PGI2) infusions, on responses to myocardial ischaemia and infarction produced by ligation of a coronary artery were investigated in conscious rats.

Surgical preparation, under halothane anaesthesia, consisted of implanting exteriorized aortic and jugular cannulae, ECG leads and a polypropylene/polyethylene occluder for the left anterior descending coronary artery. Ligation of the coronary artery was performed six to nine days after surgery.

Aspirin pretreatment consisted of 100 mg/kg given intravenously 1 or 36 h before ligation. PGI2 infusions (10–400 ng kg−1 min−1, i.v.) were begun 2 min before ligation and continued for 4 h afterwards.

ECG, blood pressure, heart rate and arrhythmias were recorded starting 30 min before, and continuing for 4 h after, ligation. Twenty‐four hours after ligation, in surviving animals, the heart was removed for estimation of occluded and infarcted zones.

Some treatments provided antiarrhythmic and other protection in the first 30 min post‐ligation. By 4 and 24 h post‐ligation, protective effects were lost.

Both aspirin pretreatment and low doses of prostacyclin reduced arrhythmias occurring within 30 min of ligation. The highest dose of prostacylin (400 ng kg−1 min−1) was arrhythmogenic.

None of the treatments influenced the amount of cardiac tissue occluded or infarcted by ligation.

The conclusions from this study in conscious rats were that acute aspirin pretreatment and low doses of infused prostacyclin have limited beneficial actions which are mainly confined to the earliest post‐ligation period.
Non‐competitive antagonism of the α‐adrenoceptor‐mediated fast component of contraction of rat aorta, by doxazosin and prazosin
Authors: Downing O.A. , Wilson K.A. , Wilson V.G.
Published: July 2012

α‐Adrenoceptor antagonists have been compared for their effects on dose‐response curves of fast and slow components of contraction of the rat aorta to noradrenaline (NA).

All agents caused a competitive antagonism of the slow component of contraction to NA. The order of potency was: prazosin > WB4101 = doxazosin > tiodazosin > phentolamine > corynanthine > trimazosin > rauwolscine.

For the fast component, doxazosin, prazosin, tiodazosin and WB4101 caused some depression of the maximum response. Doxazosin (25 nm) and prazosin (25 nm) produced a complete and unsurmountable antagonism of the maximum fast component. Phentolamine, corynanthine, trimazosin and rauwolscine all competitively antagonized the fast component.

The degree of antagonism of the fast component by prazosin and its analogues appeared to be directly related to the potency of individual agents for the slow component. WB4101, which was equipotent with doxazosin and more potent than tiodazosin was less effective than either in reducing the fast component.

The antagonism of the fast component by prazosin or doxazosin was easily reversed by washing and prevented by phentolamine (2.5 μm).

Neither prazosin nor doxazosin in concentrations of up to 2.5 μm had any effect on contractions of the aorta to 5‐hydroxytryptamine (5‐HT, 0.25–250 μm) or caffeine (20 mm).

It is concluded that the ability of some α‐adrenoceptor antagonists to produce a non‐competitive antagonism of the fast component of contraction is (a) dependent upon blockade of α‐adrenoceptors; (b) unrelated to selectivity for α1‐adrenoceptors; (c) related to potency and structure.

EGTA (3.0 mm) caused a selective suppression of the slow component of contraction to NA. Both doxazosin and prazosin caused a non‐competitive antagonism of EGTA‐resistant contractions to NA whereas corynanthine showed competitive antagonism. These observations, together with those above imply that prazosin and doxazosin non‐competitively antagonize α‐adrenoceptor‐induced release of calcium in the rat aorta, but competitively antagonize α‐adrenoceptor‐induced calcium entry.
Antidepressant treatments: effects in rodents on dose‐response curves of 5‐hydroxytryptamine‐ and dopamine‐mediated behaviours and 5‐HT2 receptor number in frontal cortex
Authors: Green A.R. , Heal D.J. , Johnson Pauline , Laurence B.E. , Nimgaonkar V.L.
Published: July 2012

The effects of repeated electroconvulsive shock (ECS) administration, repeated desmethylimipramine injection (5 mg kg−1, twice daily for 14 days) and acute administration of the β‐adrenoceptor, clenbuterol, on 5‐hydroxytryptamine (5‐HT)‐ and dopamine‐mediated behaviours in mice have been examined.

All three treatments enhanced the carbidopa/5‐hydroxytryptophan (5‐HTP)‐induced head‐twitch response at all doses of 5‐HTP examined, producing a parallel shift in the dose‐response curve. A single ECS administration or single dose of desmethylimipramine had no effect.

Only repeated ECS enhanced the locomotor response to injection of apomorphine. The dose‐response curve shift was not parallel. A single ECS had no effect.

A 6‐hydroxydopamine lesion of brain dopamine terminals also enhanced the apomorphine response, but again did not produce a parallel shift in the dose‐response curve.

Both repeated ECS and repeated desmethylimipramine administration to rats increased the number of 5‐HT2 receptor sites in rat brain. Clenbuterol had no effect.

The enhancing effects of repeated ECS and clenbuterol administration on the 5‐HTP‐induced head‐twitch response were additive.

Enhanced 5‐HT‐mediated behavioural responses are seen in both mice and rats after these treatments. If it is assumed, therefore, that similar receptor changes occur in both species it appears that there is no relationship in either behavioural system between the ability of the treatment to alter receptor number and the change in the dose‐response curve (parallel or non‐parallel).

All three antidepressant treatments (ECS, a tricyclic and a β‐adrenoceptor agonist) increase 5‐HT‐mediated behavioural responses although clenbuterol did not increase 5‐HT2 receptor number. Only ECS increased dopamine‐mediated responses.
Convulsant‐induced depression of amino acid responses in cultured mouse spinal neurones studied under voltage clamp
Authors: Barker J. L. , McBurney R.N. , Mathers D. A.
Published: July 2012

A two‐microelectrode voltage‐clamp technique was used to record membrane current responses induced by the application of the neutral amino acids, γ‐aminobutyric acid (GABA) and glycine, to mouse spinal neurones maintained in cell culture.

Membrane current responses to GABA were depressed by the convulsant agents, bicuculline, Picrotoxin and pentylenetetrazole. Membrane current responses to glycine were depressed by the convulsant compound, strychnine.

Analysis of the fluctuations in membrane current about the mean response during prolonged applications of GABA revealed that neither the conductance nor the average open‐time of GABA‐activated ion‐channels was altered in the presence of Picrotoxin or bicuculline. Pentylenetetrazole caused a reduction in the open‐time of GABA‐activated ion‐channels but this effect alone was too small to account for the depression of the current response.

A similar analysis of glycine‐induced responses in the presence of strychnine revealed that the depression of glycine responses by strychnine was not associated with any changes in the conductance or average open‐time of glycine‐activated ion‐channels.

We therefore conclude that the convulsant compounds act by reducing the rate of activation of ion‐channels by the neutral amino acids either through a reduction in the number of free receptors or by a change in the kinetics of channel activation.