bluuebunny/crossref_metadata_2025 huggingface dataset:
MODEL OF OPIATE DEPENDENCE IN THE GUINEA‐PIG ISOLATED ILEUM
Authors: COLLIER HARRY O.J. , CUTHBERT NIGEL J. , FRANCIS DAVID L.
Published: July 2012

Segments of ileum, incubated for 2–24 h at 22°C with normorphine (0.01‐1.0 μm), in the presence of hexamethonium, contracted when challenged with naloxone (0.03 μm). No response to this dose of naloxone was induced either by incubation in control solution without opiate for 2–24 h or by exposure of the preparation to opiate for 30 min at 37°C.

When segments were incubated for 24 h, the size of the response to naloxone was directly related both to the normorphine concentration in the incubation fluid (0.01 to 0.1 μm), and to the concentration of naloxone applied (0.03 to 0.1 μm).

A spontaneous withdrawal contracture was elicited in ilea that had been incubated with normorphine (1.0 μm), when the normorphine‐containing bathing fluid was exchanged for one without opiate.

Normorphine restored to resting level the tension of the withdrawal contracture, whether it had been elicited spontaneously or by naloxone challenge.

Addition of naloxone (1.0 μm) to normorphine (1.0 μm) in the incubation fluid abolished the withdrawal contracture to subsequent challenge with naloxone.

Naloxone elicited a contracture from segments incubated for 24 h at 22°C with levorphanol (0.1 μm) but not from those incubated with dextrorphan.

Application of (+)‐naloxone (0.03 μm) to segments previously incubated with normorphine (0.1 μm) did not elicit a contracture.

The contracture elicited by naloxone in preparations incubated with morphine (10 μm) was associated with a reduction in sensitivity to the acute inhibitory effect of morphine on the electrically‐evoked response.

Addition of hyoscine (0.5 μm) immediately after challenge with naloxone restored the tension of the withdrawal contracture to resting level.

Tetrodotoxin (3.0 μm) given before challenge, prevented naloxone from eliciting a withdrawal contracture.

The inclusion of 5‐hydroxytryptamine (10 μm) with morphine (10 μm) inhibited the induction of tolerance to morphine.

These experiments, together with those described earlier, indicate that incubation with opiate induces a dependence in the final cholinergic motor neurones of the myenteric plexus, manifested as a contracture of the longitudinal muscle on removal of opiate or administration of an antagonist. This dependence is associated with tolerance, expressed as a decrease in sensitivity to inhibition by morphine of the electrically‐evoked contracture. Tolerance and dependence are induced and withdrawal precipitated through specific and stereospecific opiate receptors.
CHARACTERIZATION OF THE k‐SUBTYPE OF THE OPIATE RECEPTOR IN THE GUINEA‐PIG BRAIN
Authors: KOSTERLITZ H.W. , PATERSON S.J. , ROBSON L.E.
Published: July 2012

In homogenates of guinea‐pig brain, the characteristics of the binding of [3H]‐ethylketazocine, an agonist for the putative k‐receptor, were determined by estimation of the affinity and capacity of binding, by competitive inhibition for the binding site by unlabelled ligands and by selective protection of the binding site from alkylation by phenoxybenzamine.

At 25°C the maximum number of binding sites for [3H]‐ethylketazocine was about 14pmol/g fresh brain, of which about 50% were high affinity sites.

In competition experiments, the high affinity binding of [3H]‐ethylketazocine to the k‐binding site was readily displaced by several k‐agonists but not by the selective μ‐ligand, D‐Ala2, MePhe4, Glyol5‐enkephalin or the selective δ‐ligand, D‐Ala2, D‐Leu5‐enkephalin. In contrast, the k‐agonists tested so far exhibit a high degree of cross‐reactivity with the μ‐binding site but somewhat less with the δ‐binding site. Similar specificities were observed in protection experiments.

The approximate proportions of the three subtypes of opiate receptor in the guinea‐pig brain are 25% μ‐binding sites, 45% δ‐binding sites and 30% k‐binding sites.

The endogenous opioids, Met‐enkephalin, Leu‐enkephalin and porcine β‐endorphin have only a low affinity for the k‐binding site.
DEVELOPMENT OF A SEVERE MODEL OF EARLY CORONARY ARTERY LIGATION‐INDUCED DYSRHYTHMIAS IN THE ANAESTHETIZED RAT
Authors: MARSHALL R.J. , MUIR A.W. , WINSLOW E.
Published: July 2012

The potential use of catecholamines to increase the severity of dysrhythmias evoked by coronary artery ligation in the anaesthetized rat was investigated. Drugs were given intravenously prior to ligation.

Pressor doses of adrenaline (5 μg/kg) noradrenaline (1 μg/kg) phenylephrine (5–10 μg/kg), and angiotensin (0.25 μg/kg) conferred protection against the development of dysrhythmias.

Atropine (1 mg/kg) increased mortality from ventricular fibrilloflutter (VF) and abolished the protective effects of phenylephrine (10 μg/kg).

Administration of isoprenaline (10 μg/kg) significantly increased the incidence of and the mortality from VF.

The order of antidysrhythmic drug potency of Org 6001 (1–10 mg/kg), disopyramide (2–10 mg/kg) and practolol (2–10 mg/kg) was similar in both the standard (without isoprenaline) and modified (with isoprenaline) models.

Use of the modified method for antidysrhythmic screening purposes allows demonstration of statistically meaningful results with the use of relatively few animals.

Comparison of the pattern of VF in the rat heart induced by various means suggests that the diagnosis of ventricular fibrillation can be made with more confidence in the modified method compared to the standard method.
EFFECT OF IMPROMIDINE (SK&F 92676) ON THE ISOLATED PAPILLARY MUSCLE OF THE GUINEA‐PIG
Authors: BERTACCINI G. , CORUZZI G
Published: July 2012

Impromidine was found to have a positive inotropic effect on the isolated papillary muscle from the guinea‐pig. The dose‐response curve to impromidine was shifted to the right by cimetidine and ranitidine. Impromidine was 35 times more potent than histamine but with a maximal response of only 81% that obtained with histamine. This difference, which was statistically significant (P < 0.005), suggested that impromidine acts as a partial agonist at the histamine H2‐receptors of the papillary muscle as has been observed in other tissues.
DISTRIBUTION AND TYPES OF ADRENOCEPTORS IN THE GUINEA‐PIG ILEUM: THE ACTION OF α‐ AND β‐ADRENOCEPTOR AGONISTS
Authors: BAUER V.
Published: July 2012

Segments of guinea‐pig ileum and the myenteric plexus‐longitudinal smooth muscle preparation were used for a study of the actions of adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine on the responses of coaxially stimulated ileum at different distances from the ileocaecal valve.

The responses of the ileum to electrical stimulation were suppressed by adrenaline, noradrenaline and ephedrine, while phenylephrine and isoprenaline inhibited them only partially.

The twitch inhibition elicited by these adrenoceptor agonists was the same at all distances from the ileocaecal valve. There was no significant difference between their cumulative and non‐cumulative concentration‐response curves.

Smooth muscle relaxation was induced only by isoprenaline and contraction only by phenylephrine at all distances from the ileocaecal junction. Adrenaline and noradrenaline evoked smooth muscle contraction in the terminal (0 to 20 cm), a concentration‐dependent, biphasic response in the intermediate part (21 to 50 cm) and a relaxation in the proximal ileum (>50 cm from the ilecocaecal valve). Ephedrine did not change significantly the smooth muscle tension in the terminal and the intermediate segments and induced smooth muscle relaxation in the proximal ones.

Ouabain and a potassium‐free solution did not appear to influence the prejunctional action of noradrenaline nor the amplitude of smooth muscle relaxation in the proximal ileum, whereas the concentration‐contractor response curves were significantly depressed and shifted to the right by ouabain and in a potassium‐free solution.

The brief initial (phasic) contraction induced by acetylcholine was not influenced during the sustained increase or decrease in tension induced by catecholamines. On the contrary, the stimulatory catecholamine actions disappeared or were changed to smooth muscle relaxation by acetylcholine pretreatment. Potassium chloride pretreatment did not change the character of the adrenoceptor agonist action of the agonists studied.

Since there is a similar prejunctional action at all distances from the ileocaecal valve and a different postjunctional effect of the adrenoceptor agonists at different distances from the ileocaecal junction, it could be suggested that in the guinea‐pig ileum there are at least two α‐adrenoceptors (inhibitory prejunctional‐α2, stimulatory postjunctional‐α1), an inhibitory postjunctional β‐adrenoceptor and an as yet uncharacterized inhibitory postjunctional receptor.

Based on the specific postjunctional action of phenylephrine and the prejunctional action of ephedrine in the guinea‐pig ileum, these drugs could be used with success as ‘specific’ α1 and α2‐adrenoceptor stimulants.
MECHANISM OF ACTION OF MUSCARINE ON THE LONGITUDINAL MUSCLE OF THE GUINEA‐PIG ISOLATED ILEUM
Authors: OCHILLO RICHARD F. , TSAI CHENG S. , TSAI MEI H.
Published: July 2012

dl‐Muscarine elicited a contraction of the ileal longitudinal muscle of the guinea‐pig and the contraction was characterized by an after‐response.

Physostigmine (2.0 × 10−8 m) potentiated the contraction of the longitudinal muscle elicited by dl‐muscarine.

Hemicholinium‐3 (HC‐3) caused a rightward shift of the dose‐response curve to dl‐muscarine on the ileal longitudinal muscle of the guinea‐pig ileum.

β‐Bungarotoxin (10 μg/ml) significantly (P < 0.025) reduced the contraction elicited by dl‐muscarine (2.5 × 10−8 m) suggesting presynaptic release of acetylcholine as an indirect mechanism of action of dl‐muscarine.

Morphine (1.0 × 10−8 m) significantly (P < 0.05) reduced the contractions elicited by dl‐muscarine (2.5 × 10−8 m) further suggesting presynaptic release of acetylcholine as an indirect mechanism of action of dl‐muscarine.

A subthreshold dose of dl‐muscarine (2.0 × 10−10 m) potentiated the effect of acetylcholine (2.5 × 10−8 m) and the potentiation was blocked by β‐bungarotoxin.
DIFFERENTIAL EFFECT OF BENSERAZIDE (Ro4‐4602) ON THE CONCENTRATION OF INDOLEAMINES IN RAT PINEAL AND HYPOTHALAMUS
Authors: ARENDT J. , HO A.K. , LAUD C. , MARSTON A. , NOHRIA V. , SMITH J.A. , SYMONS A.M.
Published: July 2012

Low doses (50 and 80 mg/kg) of benserazide (Ro4‐4602), an aromatic amino acid decarboxylase inhibitor, markedly reduced 5‐hydroxytryptamine and melatonin in the rat pineal gland without affecting hypothalamic 5‐hydroxytryptamine.

This differential effect shows that inhibition of the pineal gland decarboxylase activity is possible, and confirms that the rat pineal gland is accessible to peripherally acting agents.
CARDIOTOXIC AND INOTROPIC EFFECTS OF OUABAIN ON ATRIA ISOLATED FROM RABBITS OF DIFFERENT AGES
Authors: TODA NOBORU
Published: July 2012

In sino‐atrial node‐right atrial preparations and left atrial preparations obtained from rabbits of different ages (2 to 360 days old), cardiotoxic and inotropic effects of ouabain were compared. Tachyarrhythmias were produced in immature and mature rabbit right atria exposed for 6 to 8 min to ouabain (5 × 10−6 m). The total number of contractions before the arrhythmias developed varied inversely with age (2 to 90 days old). Percentage reductions in the resting membrane potential, overshoot and maximum rate of rise induced by ouabain were greater in mature rabbit atria than in immature rabbit atria.

Reduction of Ca2+ in the bathing media suppressed the development of tachyarrhythmias.

In electrically‐driven left atria isolated from immature and mature rabbits, similar frequency‐contractile force curves were obtained, maximum contractions being attained at a frequency of 120/min. Ouabain at 2 × 10−7 m shifted the curve upward and at 10−6 m greatly potentiated the contractile force developed at low frequencies (6 to 30/min). Increase in contractions induced by ouabain relative to pre‐drug contractions at a frequency of 60/min were greater in immature rabbit atria (15 days old) but the positive inotropic effect of 2 × 10−7 m ouabain relative to the effect seen at 10−6 m was appreciably less.

It may be concluded that atria isolated from immature rabbits tolerate higher concentrations of ouabain than those isolated from mature rabbits.
THE GASTRIC ANTISECRETORY ACTIONS OF PROSTAGLANDIN E2 AND STABLE PROSTACYCLIN ANALOGUES AGAINST DIFFERENT SECRETAGOGUES IN PERFUSED WHOLE‐STOMACHS OF RAT OR MOUSE in vitro
Authors: BOUGHTON‐SMITH N.K. , WHITTLE B.J.R.
Published: July 2012

The characteristics of the antisecretory actions of prostaglandin E2 (PGE2) and two stable prostacyclin analogues during different rates of acid stimulation have been evaluated in the lumen‐perfused isolated whole stomach of the rat and mouse.

In the rat isolated stomach, histamine induced a dose‐dependent increase in acid output. Preincubation with PGE2 caused a dose‐related and surmountable inhibition.

The stable prostacyclin analogues, 6β‐PGI1 and a 16‐phenoxy derivative likewise caused a surmountable inhibition of histamine‐stimulated acid output from rat stomach.

PGE2 had inconsistent actions on the acid secretion stimulated by pentagastrin, methacholine or dibutyryl cyclic adenosine 3′,5′‐monophosphate.

In the mouse isolated stomach, acid secretion was stimulated by low concentrations of histamine, pentagastrin or methacholine.

PGE2 failed to inhibit histamine‐stimulated acid output from mouse stomach, but high concentrations of the potent 16‐phenoxy analogue did show anti‐secretory activity.

The results indicate the usefulness of the rat isolated stomach for studying the interaction of prostaglandins with the acid secretory process in mammalian gastric mucosa.
EXOCYTOTIC SECRETION OF CATECHOLAMINES FROM THE CAT ADRENAL MEDULLA BY SODIUM DEPRIVATION: INVOLVEMENT OF CALCIUM INFLUX MECHANISM
Authors: NISHIMURA S. , SORIMACHI M. , YAMAGAMI K.
Published: July 2012

Cat adrenal glands were perfused with Ca‐deficient medium and secretion of catecholamines (CA) was induced by perfusion with Na‐free medium in which NaCl was replaced by an osmotically equivalent amount of sucrose.

Release of CA and dopamine‐β‐hydroxylase (DBH), but not that of phenylethanolamine‐N‐methyltransferase, was concomitantly found in the effluents when the adrenals were stimulated, indicating that secretion was due to exocytosis.

Secretion of CA induced by Na‐free (sucrose) medium was dependent on the concentration of Ca and was saturated at 0.5 mm of Ca.

Sr or Ba substituted for Ca in maintaining secretion by Na‐free (sucrose) medium.

The addition of Na, Li or alkali metal ions to Na‐free (sucrose) medium containing Ca reduced the response to a variable extent but this inhibition was reversed by raising the concentration of Ca in the Na‐free medium.

All of the Na substitutes used induced secretion only when this medium contained Ca. However, different Na substitutes released different amounts of CA; sucrose was most effective, K, Tris and choline were moderately and Li least effective.

Secretion of CA by Na‐free (sucrose) medium was strongly inhibited by D‐600, tetracaine or divalent cations such as Co, Ni, Zn and Mg. The inhibition by Co was partially reversed by raising the concentration of Ca in the Na‐free medium.

Secretion of CA from bovine isolated chromaffin cells was induced by Na‐deficient (sucrose) medium and was dependent on the concentrations of ionized Ca involved.

All the Na substitutes tested increased secretion of CA and 45Ca uptake, in a parallel fashion.

A correlation between secretion and 45Ca uptake was found under various experimental manipulations which reduced secretion of CA.

These results demonstrated that unlike the perfused bovine adrenals, the Ca influx mechanism is essential for secretion by Na deprivation in the perfused cat adrenals as it is in bovine isolated chromaffin cells.

It is suggested that Na deprivation increases Ca entry through the Ca channels by eliminating the competition between Na and Ca, and possibly by activating Ca influx linked with Na efflux.
LIBERATION OF CATECHOLAMINES FROM BLOOD PLATELETS
Authors: PLETSCHER ALFRED
Published: July 2012

Platelet‐rich plasma (PRP) of guinea‐pigs with or without reserpine was preincubated either with [14C]‐5‐hydroxytryptamine ([14C]‐5‐HT) plus [3H]‐dopamine or with [14C]‐5‐HT plus [3H]‐noradrenaline ([3H]‐NA). After isolation on two successive dextran gradients the double‐labelled platelets were incubated in Tris‐buffer in the presence or absence of various drugs. The decrease in radioactivity in the platelets was measured in order to determine the amount of the amine that had been liberated.

Spontaneous liberation of the labelled amines was more marked in reserpine‐treated platelets than in normal ones and somewhat more pronounced for the 3H‐catecholamines than for [14C]‐5‐HT.

The reserpine‐like benzoquinolizine, Ro 4–1284, caused liberation of all three labelled amines in normal but not in reserpine‐treated platelets. More [3H]‐dopamine was liberated than [14C]‐5‐HT and less [3H]‐NA.

The arylalkylamines, tyramine and p‐chloromethamphetamine (PCMA), liberated all three labelled amines from normal platelets, and [14C]‐5‐HT and [3H]‐dopamine, but not [3H]‐NA from reserpine‐treated ones. In normal platelets dopamine was reduced to a greater extent than [14C]‐5‐HT and [3H]‐NA to a smaller extent, whereas in reserpine‐treated platelets [14C]‐5‐HT was more markedly diminished than [3H]‐dopamine.

The 5‐HT uptake inhibitor, imipramine, had little influence on the spontaneous and drug‐induced liberation of [14C]‐5‐HT and [3H]‐dopamine.

It is concluded that 3H‐catecholamines like [14C]‐5‐HT are mostly localized in the granular pool of platelets; the three drugs tested liberate [3H]‐dopamine [3H]‐NA and [14C]‐5‐HT from the granular pool. Ro 4–1284 does not liberate 3H‐catecholamines and [14C]‐5‐HT from extragranular sites whereas tyramine and PCMA also act on the extragranular pool of [3H]‐dopamine and [14C]‐5‐HT but not [3H]‐NA.

The liberation of catecholamines from platelets differs from that of 5‐HT in several respects and platelets are only partly comparable to neurones as far as drug‐induced liberation of biogenic amines is concerned.
NUCLEOTIDE PYROPHOSPHATASE ANTAGONIZES RESPONSES TO ADENOSINE 5′ ‐TRIPHOSPHATE AND NON‐ADRENERGIC, NON‐CHOLINERGIC INHIBITORY NERVE STIMULATION IN THE GUINEA‐PIG ISOLATED TAENIA COLI
Authors: SATCHELL D.G.
Published: July 2012

The enzyme, nucleotide pyrophosphatase converted adenosine 5′ ‐triphosphate (ATP) to adenosine 5′ ‐monophosphate (AMP). In the isolated taenia coli of the guinea‐pig it reduced the inhibitory responses to exogenously applied ATP. This could be explained on the basis that the ATP was rapidly converted to AMP which is less potent. The enzyme also reduced inhibitory responses to stimulation of non‐adrenergic, non‐cholinergic nerves but failed to reduce inhibitory responses to either perivascular sympathetic nerve stimulation or to noradrenaline. The results support the hypothesis that ATP is the transmitter released by non‐adrenergic, non‐cholinergic (‘purinergic’) inhibitory nerves.
THE INHIBITION BY HYDROCORTISONE OF PROSTAGLANDIN BIOSYNTHESIS IN RAT PERITONEAL LEUCOCYTES IS CORRELATED WITH INTRACELLULAR MACROCORTIN LEVELS
Authors: CARNUCCIO ROSA , DI ROSA M. , FLOWER R.J. , PINTO A.
Published: July 2012

Hydrocortisone inhibits prostaglandin generation by rat peritoneal leucocytes by releasing the polypeptide phospholipase inhibitor, macrocortin. The susceptibility of these cells to hydrocortisone is directly correlated with their intracellular macrocortin content. Cells depleted of the peptide by prior incubation with steroid cannot respond to the steroid, until a fresh intracellular store has been synthesized. In vitro, this process requires 4–5 h. Cells remain sensitive to the inhibitory action of the peptide at all times.
ELECTRICAL AND MECHANICAL ACTIVITY OF THE ISOLATED LOWER URINARY TRACT OF THE GUINEA‐PIG
Authors: CALLAHAN STEPHEN M. , CREED KATE E.
Published: July 2012

Strips of urethra taken from guinea‐pigs contracted in response to acetylcholine, noradrenaline (via α‐adrenoceptors) and 5‐hydroxytryptamine, and were relaxed by adenosine triphosphate (ATP) if the tone was raised. Isoprenaline produced relaxation of bladder strips (via β‐adrenoceptors) whereas ATP caused contraction

Atropine completely blocked all responses to acetylcholine; quinidine failed to block ATP responses selectively; methysergide blocked responses of the urethra but not the bladder to 5‐hydroxy tryptamine

Spontaneous electrical activity was recorded with intracellular microelectrodes from all regions: in the urethra infrequent bursts of spikes occurred at 1–7 min intervals; regular spikes at 6–30/min were recorded from the detrusor muscle. In the bladder base, bursts of spikes were superimposed on the regular pattern

Bursts of spikes in the urethra were initiated by noradrenaline, phenylephrine or acetylcholine and inhibited by ATP; regular spikes in the bladder were accelerated by acetylcholine or ATP and slowed by noradrenaline or isoprenaline

The intrinsic electrical activity and pharmacological properties of the urethra therefore differ from those of the bladder. This may account for the different responses of the two regions in normal function.
COMPARATIVE STUDIES OF (−)‐, (±), (+)‐PROPRANOLOL, ATENOLOL, GUANETHIDINE, BRETYLIUM AND TETRACAINE ON ADRENERGIC TRANSMISSION
Authors: KAIHO M. , KUBO T. , MISU Y.
Published: July 2012

Effects of (−)‐, (±)‐, and (+)‐propranolol, atenolol, guanethidine, bretylium and tetracaine were studied on relaxation responses of rabbit ileum and contractile responses of rabbit pulmonary artery and guinea‐pig vas deferens to electrical nerve stimulation (2 to 50 Hz)

In the ileum, inhibition by tetracaine 3.3 × 10−6M occurred at high frequencies of stimulation, while bretylium 1.2 × 10−4 M and guanethidine 2 × 10−5 M inhibited responses at all frequencies, the latter producing greater inhibition at low frequencies

(±)‐Propranolol 10−5 M produced a tetracaine‐type inhibition after 1 h and a bretylium‐pattern after 2 h in the ilea and pulmonary arteries and a transition from bretylium‐ to guanethidine‐pattern in the vas deferens, while atenolol 2 × 10−5 to 10−4M produced guanethidine‐type inhibition in all preparations

(−)‐, (±)‐, and (+)‐Propranolol 3 × 10−6 to 3.3 × 10−5M were equipotent in the vas deferens and ileum. However, inhibition by (−)‐propranolol 3.3 × 10−5 M persisted in the ileum, while that by the (+)‐isomer was partially restored by washing

(−)‐ or (+)‐Propranolol 3.3 × 10−5M or atenolol 2 × 10−5M did not inhibit relaxation of the ileum after the bath temperature was maintained at 4deg;C for 2 h during drug application

In conclusion, propranolol and atenolol both have gradually developing guanethidine‐like adrenergic neurone blocking actions.
EFFECTS OF CALCIUM ANTAGONISTS ON THE ALTERNATION OF THE ST‐T COMPLEX AND ASSOCIATED CONDUCTION ABNORMALITIES DURING CORONARY OCCLUSION IN DOGS
Authors: HASHIMOTO HISAKUNI , NAKASHIMA MITSUYOSHI
Published: July 2012

The effects of Ca2+‐antagonists on the relationships between alternate changes in the ST‐T complex in the epicardial electrogram, ST‐T alternans, and associated excitation‐conduction abnormalities during coronary occlusion were examined in anaesthetized dogs

Epicardial unipolar electrograms, bipolar electrograms (BPEG) and monophasic action potentials (MAP) were recorded with unipolar, composite and suction electrodes, respectively

ST‐T alternans was associated with serious conduction delay. During the period of ST‐T alternans, the amplitude of MAP changed alternately and the negative deflection of the ST‐T complex was associated with a larger MAP. A depression of the TQ level and decrease in the resting potential of MAP were marked

Verapamil (0.2 mg/kg) and diltiazem (0.5 mg/kg) inhibited ST‐T alternans, conduction abnormalities, TQ depression and changes in MAP. However, after these drugs, the TQ depression and the decrease in the resting potential were evident after a longer period of occlusion at a time when ST‐T alternans, conduction abnormalities and alternate changes in MAP were still inhibited. Dipyridamole (0.5 mg/kg) had no effect on either ST‐T alternans or the conduction abnormalities

Verapamil and diltiazem inhibited ST‐T alternans and the associated excitation and conduction abnormalities. The effects of these two drugs cannot be explained on the basis of attenuation of the decrease in the resting potential.
EFFECTS OF VASODILATOR AGENTS ON SMOOTH MUSCLE CELLS OF THE CORONARY ARTERY OF THE PIG
Authors: ITOH T. , KAJIWARA M. , KITAMURA K. , KURIYAMA H.
Published: July 2012

Effects of the vasodilator agents, papaverine, diltiazem, and sodium nitroprusside (SNP) on the electrical and mechanical activities of the smooth muscles of the coronary artery of the pig were compared

At a concentration of 10−5 M, papaverine hyperpolarized and increased the ionic conductance of the membrane, SNP slightly hyperpolarized but diltiazem had no effect on the membrane potential and membrane ionic conductance

At a concentration of 10−5 M, diltiazem abolished the spike evoked by outward current pulses in the presence of tetraethylammonium (TEA) 10 mM, while papaverine and SNP slightly reduced spike amplitude

The K‐induced contraction produced by any given concentration of [K]o over 20.2 mM was suppressed by diltiazem and SNP dose‐dependently in concentrations greater than 10−6m; higher concentrations of papaverine were required to suppress contraction

The acetylcholine (ACh)‐induced contraction was suppressed by diltiazem and SNP at concentrations greater than 10−6 M and by papaverine in concentrations over 10−5 M

In saponin‐treated skinned muscles, papaverine, diltiazem and SNP had no effect on the pCa‐tension relationship, i.e. these agents had no effect on the Ca receptor of contractile proteins. Furthermore, the caffeine‐induced contraction in skinned muscles (after Ca loading) was not affected by these agents, i.e. the mechanism of Ca release by caffeine in skinned muscles was not affected

Chlorpromazine, an agent interacting with calmodulin, antagonized the contractile effect of calcium on skinned muscle fibres

The results obtained are discussed in relation to spike and contraction generating mechanisms, i.e. the effects of these agents on Ca influx and Ca release from stored sites. The results indicated that at equimolar concentrations diltiazem suppressed the mechanical response in the coronary artery of the pig more than SNP or papaverine.
REVERSAL BY NALOXONE OF THE EFFECTS OF CHRONIC ADMINISTRATION OF DRUGS OF DEPENDENCE ON RAT LIVER AND BRAIN TRYPTOPHAN METABOLISM
Authors: BADAWY A. A.‐B. , EVANS M. , PUNJANI NAZEERA F.
Published: July 2012

Chronic administration of ethanol, morphine, nicotine or phenobarbitone has previously been shown to enhance rat brain 5‐hydroxytryptamine (5‐HT) synthesis by increasing the availability of circulating tryptophan to the brain secondarily to the NADPH‐mediated inhibition of liver tryptophan pyrrolase activity

Naloxone reverses the above enhancement of 5‐HT synthesis and the accompanying increase in tryptophan availability to the brain and the inhibition of liver tryptophan pyrrolase activity

It is suggested that naloxone exerts these effects by antagonizing the chronic drug‐induced increase in liver [NADPH]

Naloxone increases serum corticosterone concentration in rats chronically treated with the above four drugs of dependence. Possible explanations of this effect are discussed.
THE MECHANISM OF THE ANTAGONISM BY NALOXONE OF ACUTE ALCOHOL INTOXICATION
Authors: BADAWY A.A.‐B. , EVANS M.
Published: July 2012

Naloxone lowers blood‐ethanol concentration and causes a simultaneous reversal of the disturbances in the redox states of the hepatic nicotinamide‐adenine dinucleotide (phosphate) couples in acutely‐ethanol‐intoxicated rats. It is suggested that these effects of naloxone form the basis of its antagonism of acute alcohol intoxication.
A COMPARISON OF CARDIAC REACTIVITY AND β‐ADRENOCEPTOR NUMBER AND AFFINITY BETWEEN AORTA‐COARCTED HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: CERVONI PETER , HERZLINGER HELEN , LAI FONG M. , TANIKELLA TARAK
Published: July 2012

The effects of noradrenaline (NA) and isoprenaline on isolated atria from aorta‐coarcted hypertensive rats (AHR) at early (6 day) and chronic (28 day) stages of hypertension were studied and compared with time‐matched, sham‐operated, normotensive rats (SNR). The number and affinity of β‐adrenoceptors ((−)‐[3H]‐dihydroalprenolol binding sites) were also studied in cardiac membranes prepared from these animals.

Six and 28 days after complete ligation of the abdominal aorta between the two renal arteries, rats became hypertensive with significantly greater arterial blood pressures than time‐matched SNR.

At both stages of hypertension, the atrial inotropic or chronotropic effects of NA and isoprenaline from hypertensive rats were similar to time‐matched SNR. Moreover, no differences in atrial reactivity were observed between the early and chronic stages of hypertension.

Irrespective of the stage of hypertension, cardiac membranes from the AHR contained the same number of β‐adrenoceptors as time‐matched SNR. In addition, the receptor affinity for the radioligand within each group was equivalent. However, the chronic stage hypertensive rats and their time‐matched controls contained fewer β‐adrenoceptors and these receptors had greater affinity for the radioligand when compared with cardiac membranes from rats at the early stage of hypertension and their controls.

The observed equivalent chronotropic and inotropic responses to NA and isoprenaline between the hypertensive and normotensive rats in both stages of hypertension may be explained in terms of similar receptor number and receptor binding affinity.

The reduced number of β‐adrenoceptors with greater binding affinity in day 28 normotensive or hypertensive rats may be a compensatory mechanism for these animals to maintain normal cardiac function with increasing age.
CHANGES IN SYNAPTOSOMAL HIGH AFFINITY CHOLINE UPTAKE FOLLOWING ELECTRICAL STIMULATION OF GUINEA‐PIG CORTICAL SLICES: EFFECT OF ATROPINE AND PHYSOSTIGMINE
Authors: ANTONELLI T. , BEANI L. , BIANCHI C. , PEDATA F. , PEPEU G.
Published: July 2012

Superfused guinea‐pig cortical slices were electrically stimulated at different frequencies and the changes in acetylcholine (ACh) content measured. Synaptosomes were prepared at the end of the stimulation period and high affinity choline uptake (HACU) rate was measured.

The effect of increasing KC1 concentrations was compared on ACh content of the slices and on synaptosomal HACU.

Electrical stimulation (2, 5, 10, 20 Hz) elicited a frequency‐dependent linear increase in synaptosomal HACU rate and a decrease in ACh content of the slices.

The addition of atropine (1.5 × 10−8m) to the slices enhanced and that of physostigmine (3 × 10−5 m) reduced the frequency‐dependent increase in HACU rate. Atropine (1.5 × 10−6 m) not only antagonized the effect of physostigmine, but the HACU rate measured after treatment with both drugs was larger than that found after atropine alone.

These results indicate that in the cortical cholinergic nerve endings, depolarization caused by electrical stimulation is coupled with an increase in choline transport which can be modulated by the addition of atropine or physostigmine. Furthermore, within given experimental conditions a linear relationship exists between the reciprocal of ACh content in the slices and synaptosomal HACU.
SHAPE CHANGES INDUCED BY BIOLOGICALLY ACTIVE PEPTIDES AND NERVE GROWTH FACTOR IN BLOOD PLATELETS OF RABBITS
Authors: GUDAT FRED , LAUBSCHER ANDREAS , OTTEN UWE , PLETSCHER ALFRED
Published: July 2012

Nerve growth factor (NGF), substance P (SP) and thymopoietin all caused shape change reactions of rapid onset in rabbit platelets. NGF had the highest maximal effect, and SP the lowest EC50 (concentration causing half maximal shape change). The action of SP was reversible within 5 min, whereas that of NGF lasted for at least 1 h. A series of other peptides were inactive.

After preincubation of platelets with SP, a second application of SP no longer caused a shape change reaction, whereas the effect of NGF was not influenced.

An oxidized NGF‐derivative without biological activity did not cause a shape change reaction, neither did epidermal growth factor.

Prostaglandin E1 (PGE1) and pretreatment of the platelets with 3% butanol, which counteract the shape changes caused by 5‐hydroxytryptamine (5‐HT) and adenosine 3′, 5′‐diphosphate, also antagonized those induced by NGF and SP. Neither heparin nor methysergide, an antagonist of 5‐HT‐receptors, influenced the shape change induced by NGF or SP. The action of NGF was also antagonized by a specific antibody to NGF.

Thymopoietin, like the basic polypeptide polyornithine (mol. wt. 40,000), was not antagonized by PGE1 and butanol. Heparin, which counteracted the effect of polyornithine, did not influence that of thymopoietin.

In conclusion, different modes of action are involved in the shape change of blood platelets induced by polypeptides and proteins. SP and NGF may act by stimulating specific membrane receptors.
SYMPATHETIC MECHANISMS IN DIET‐INDUCED THERMOGENESIS: MODIFICATION BY CICLAZINDOL AND ANORECTIC DRUGS
Authors: ROTHWELL NANCYJ. , STOCK M.J. , WYLLIE M.G.
Published: July 2012

The sympathetic noradrenergic activation of brown adipose tissue and the biochemical mechanisms involved in diet‐induced thermogenesis were studied in rats.

A close correlation was found between brown adipose tissue Na+, K+‐adenosinetriphosphatase (Na+, K+‐ATPase) activity in vitro and in vivo measurements of resting oxygen consumption (VO2). The effects of noradrenaline on in vitro Na+, K+‐ATPase activity in brown adipose tissue and in vivo VO2 could be mimicked by a variety of agents. These included β‐adrenoceptor agonists and agents known to induce the release of noradrenaline or inhibit the noradrenaline uptake process. The pharmacological evidence suggests that dopaminergic mechanisms may also be involved in the control of thermogenesis.

3 Amphetamine did not increase VO2 in rats without causing associated increases in locomotor activity. Ciclazindol at doses of 3–30 mg/kg intraperitoneally increased VO2 but did not appear to increase locomotor activity or evoke any other signs of CNS stimulation including lengthening of time to sleep onset or stereotypy. Separation of metabolic and CNS effects occurred only at the lowest dose of mazindol used (0.3 mg/kg i.p.)‐ These results are probably a reflection of (a) the relative abilities of these drugs to inhibit brain and brown adipose noradrenaline uptake processes and (b) the relatively high accumulation of ciclazindol in brown adipose.

Of the drugs tested, only ciclazindol was a more potent inhibitor of the noradrenaline uptake system in brown adipose tissue (BAT) than in brain. Kinetic analysis also revealed that the actions of ciclazindol on the NA uptake system and Na+, K+‐ATPase in BAT differed from those of mazindol.

These findings suggest that ciclazindol may produce an energy wasting effect in rodents without causing overt CNS stimulation; the implications of these findings in terms of human obesity are discussed.
STIMULATION OF PROSTACYCLIN RELEASE FROM THE EPICARDIUM OF ANAESTHETIZED DOGS
Authors: DUSTING G.J. , NOLAN R.D.
Published: July 2012

The generation of prostanoids in the hearts of anaesthetized dogs was studied by irrigating in situ the epicardial surface with Krebs solution. Prostanoids were measured by direct bioassay on smooth muscles and by radioimmunoassay of 6‐oxo‐prostaglandin F1α (6‐oxo‐PGF1 α) and prostaglandin E2 (PGE2) in the epicardial irrigation fluid.

The epicardial irrigation fluid contained a prostacyclin‐like substance, as indicated by the bioassay tissues, and immunoreactive 6‐oxo‐PGF1α; PGE2‐like materials were also detected. By both methods the output of the prostacyclin‐like substance, which decreased with time of epicardial irrigation, was increased by manipulating the heart and by adding arachidonic acid (3 μg/ml), and decreased by adding indomethacin (1 μg/ml) to the irrigating fluid.

Bioassayed prostacyclin and immunoreactive 6‐oxo‐PGF1α in the epicardial irrigation fluid increased by about 3‐5ng/ml during and after infusion of isoprenaline (0.1 μg kg−1 min−1). The substance was not released by isoprenaline when indomethacin was added to the irrigating fluid, or when propranolol (0.5 mg/kg) was given intravenously.

Aortic constriction, bilateral carotid artery occlusion and intravenous angiotensin infusion all increased output of the prostacyclin‐like substance into the epicardial irrigation fluid. The output was abolished by treating the heart with indomethacin (10 mg/kg intravenously or 1 μg/ml epicardially).

The prostacyclin‐like substance was also released by all of the above stimuli after the parietal pericardium had been removed and replaced by a plastic sheet.

It is concluded that prostacyclin is continually released from tissues close to the epicardial surface and from the pericardium, and that prostacyclin generation increases when cardiac workload increases. Prostacyclin of epicardial or pericardial origin might therefore contribute to metabolic regulation of coronary blood flow.
A STUDY ON THE ACUTE EFFECT OF AMPHETAMINE ON THE URINARY EXCRETION OF BIOGENIC AMINES AND METABOLITES IN MONKEYS
Authors: CHUANG LIN‐WHEI , KAROUM FAROUK , PERLOW MARK J.
Published: July 2012

The effects of an acute dose (3mg/kg) of amphetamine on the urinary excretion of phenylethylamine (PEA), p‐tyramine, their metabolites, catecholamine metabolites and p‐hydroxymandelic acid, a major metabolite of p‐octopamine were evaluated in the monkey. Amphetamine excretion was also measured.

Amphetamine was slowly eliminated from the body, being found in the urine at least six days after administration.

Amphetamine increased the excretion of PEA and decreased that of its major metabolite, phenylacetic acid (PAA). This pattern of changes is similar to that previously found in the urine of chronic schizophrenics.

The excretion of the dopamine metabolite, 3,4‐dihydroxphenylacetic acid (DOPAC) was markedly reduced, that of vanilmandelic acid (VMA) remained unchanged while 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) was increased on the day of drug administration and persisted for at least a further six days. A similar extended effect on the excretion of p‐hydroxymandelic acid (it was reduced) was also observed.

The excretion of p‐tyramine but not its metabolite, p‐hydroxyphenylacetic acid, was decreased by amphetamine during treatment and returned to normal levels six days later.

From the results obtained, it was concluded that amphetamine effects on behaviour cannot exclusively be attributed to its influence on catecholamines and that other biogenic amines may be involved. 7 Since PEA elicits many behavioural changes similar to those seen with amphetamine, and since amphetamine increases PEA excretion, we suggest that amphetamine may exert some of its behavioural responses through the release of PEA.
ACTIVATION OF CENTRAL MUSCARINIC RECEPTORS CAUSES RESPIRATORY STIMULATION IN CONSCIOUS ANIMALS
Authors: WEINSTOCK MARTA
Published: July 2012

Oxotremorine (10 μg/kg) injected intravenously into conscious rabbits pretreated with atropine‐methyl‐nitrate (ATMN, 0.5 mg/kg) caused significant increases in respiration rate from 94 to 131 per min, and in Pao2 from 13.8 to 15.4 kPa, and a decrease in Paco2 from 3.30 to 2.09 kPa within 15 min. Blood pH fell from 7.44 to 7.16.

Blood pressure increased by 11.6%, 5 min after oxotremorine injection.

The acidosis was shown to be due to an increase in blood lactic acid from 41 to 132 mg/100 ml.

Pretreatment with propranolol (5 mg/kg, s.c.) prevented the lactic acidosis and fall in pH but did not alter the respiratory stimulation induced by oxotremorine.

It is suggested that the lactic acidosis induced by oxotremorine results from stimulation of β‐adrenoceptors in skeletal muscle by catecholamines released from the adrenal medulla and sympathetic nerves.

Since all the above effects of oxotremorine are antagonized by hyoscine (5 mg/kg) but not by ATMN (0.5 mg/kg), it is concluded that oxotremorine can stimulate respiration by a direct action on muscarinic receptors in the central nervous system.
BENZODIAZEPINES REDUCE GASTRIC ULCERS INDUCED IN RATS BY STRESS
Authors: FILE SANDRA E. , PEARCE JACALYN B.
Published: July 2012

The sedative and antiulcer effects of chlordiazepoxide (5 to 50 mg/kg) and lorazepam (0.25 to 2.5 mg/kg) were investigated in the rat.

Sedation was measured by recording locomotor activity in a holeboard. Ulceration of the glandular stomach was induced by a 2 h period of restraint at 4°C.

Acutely, both drugs produced significant sedation at all doses; high doses only (chlordiazepoxide 10 and 50 mg/kg; lorazepam 2.5 mg/kg) produced a significant reduction in ulcer formation.

With chronic treatment, after 5 and 10 days administration of chlordiazepoxide (50 mg/kg), tolerance to sedation was observed without a similar change in antiulcer action.

Cimetidine (20 mg/kg) and atropine (0.2 mg/kg) decreased ulcer formation without causing sedation.

The antisecretory profile of chlordiazepoxide (2 × 10−4m), in the rat isolated gastric mucosa, resembled that of atropine (10−7 m) rather than cimetidine (10−5 m).

These observations suggest that the antiulcer effect of benzodiazepines probably results from a combination of sedative, anxiolytic and antisecretory actions.
ANTIGEN‐INDUCED BRONCHIAL ANAPHYLAXIS IN ACTIVELY SENSITIZED GUINEA‐PIGS: EFFECT OF LONG‐TERM TREATMENT WITH SODIUM CROMOGLYCATE AND AMINOPHYLLINE
Authors: ANDERSSON PER , BERGSTRAND HÅKAN
Published: July 2012

The effects of long‐term treatment with sodium cromoglycate (SCG) and aminophylline on antigen‐induced bronchoconstriction have been studied in guinea‐pigs actively sensitized according to two different regimens (one producing IgE‐ and IgG‐like antibodies and the other producing exclusively IgG‐like antibodies).

Treatment for three weeks with SCG (10 mg/kg) and aminophylline (10,30 or 60 mg/kg) led to a decreased bronchial response capacity which persisted even three days after treatment ceased. In this respect SCG was effective only in guinea‐pigs sensitized to produce at least partly IgE‐like antibodies; aminophylline was effective in guinea‐pigs sensitized to produce both IgE and/or IgG antibodies.

The results in vivo with SCG were reflected in vitro by a reduced capacity of chopped lung tissue to release histamine at antigen challenge; lungs from animals treated with aminophylline did not show reduced histamine releasing capacity.

Acute treatment with atropine was shown to reduce significantly the antigen‐induced bronchial contraction in guinea‐pigs sensitized to produce both IgE‐ and IgG‐antibodies. No effect of atropine was seen on an IgG‐mediated anaphylaxis.

Increased reactivity to methacholine but not to histamine was seen in guinea‐pigs sensitized to produce both IgG‐ and IgE‐antibodies. Long‐term treatment with SCG did not affect this hyperreactivity to methacholine.

Decreased reactivity to isoprenaline was found in isolated tracheae taken from guinea‐pigs sensitized to produce both IgE‐ and IgG‐like antibodies compared to unsensitized guinea‐pigs. Long‐term treatment with SCG, but not with aminophylline, reversed this decreased reactivity.
In vivo RECEPTOR BINDING OF THE OPIATE PARTIAL AGONIST, BUPRENORPHINE, CORRELATED WITH ITS AGONISTIC AND ANTAGONISTIC ACTIONS
Authors: DUM JANE E. , HERZ ALBERT
Published: July 2012

In order to gain more insight into the mechanisms behind the actions of opiate partial agonists, an analysis of the dual agonist/antagonist properties of the partial agonist, buprenorphine, was made in conjunction with in vivo binding studies of the drug in the rat.

Buprenorphine revealed a bell‐shaped dose‐response curve for antinociception peaking at approx. 0.5 mg/kg subcutaneously. It antagonized morphine antinociception at doses which normally have agonistic effects and produced maximum antagonistic effects at doses above those having prominent agonistic activity. The withdrawal precipitating potency of buprenorphine as measured in highly morphine‐dependent rats was present at doses above those having agonistic activity. The entire dose‐response curve for buprenorphine was shifted symmetrically to the right by the opiate antagonist, naltrexone.

The dose‐dependent occupation of receptors in vivo by buprenorphine seemed to be almost complete over the agonist dosage range; almost no further receptor occupation over the antagonist range was seen.

The possibility is discussed that site‐to‐site receptor interactions leading to cooperativity of effect may be the best explanation of these results.
FACILITATION BY CLONIDINE OF PURINE RELEASE INDUCED BY HIGH KC1 FROM THE RABBIT PULMONARY ARTERY
Authors: KATSURAGI TAKESHI , SU CHE
Published: July 2012

The effect of clonidine on the 3H‐purine release evoked by KC1 or (−)‐adrenaline was assessed in the superfused helical strip of the rabbit pulmonary artery pretreated with [3H]‐adenosine.

Clonidine (3 × 10−5 M to 10−4 m) significantly enhanced the 3H‐purine efflux evoked by 50 mM KC1 but not by 3 × 10−6M (−)‐adrenaline.

This facilitatory effect of clonidine on the KCl‐induced purine release was unaltered by phentolamine 3 × 10−6M. It was absent in arterial segments denervated with 6‐hydroxydopamine 30 jig/ml.

A sustained contractile response was evoked by clonidine 3 × 10−5 M without an increase in the 3H‐purine efflux. This was significantly reduced by phentolamine 3 × 10−6 M, but not by yohimbine 10−5M or by denervation with 6‐hydroxydopamine. 5 The uptake of [3H]‐adenosine into the segments was not inhibited by clonidine 3 × 10−5 M.

It is suggested that the facilitation by clonidine of the KCl‐induced purine release is due to prevention of presynaptic autoinhibition of purine release from adrenergic nerves, by an anti‐adenosine action of the drug.
CIGARETTE SMOKE INHALATION SPECIFICALLY INHIBITS DEPRESSOR RESPONSES TO PROSTACYCLIN IN THE RAT
Authors: BOURA A.L.A. , HUI S‐C.G. , WALTERS W.A.W.
Published: July 2012

Studies have been made of the effects of prior exposure to cigarette smoke on cardiovascular responses of the anaesthetized rat to arachidonic acid, prostaglandin E2 (PGE2), PGF2α and PGI2. When compared with a control group, falls in systolic and diastolic blood pressure and tachycardia following intravenous PGI2 were significantly reduced in those animals exposed to smoke 1 and 24 h previously. Responses 48 h after exposure were not significantly different. Pressor effects of PGF2α and depressor responses to arachidonic acid and PGE2 were not significantly affected at these times. It is suggested that the specific and long lasting attenuation of the effects of PGI2 which occurs following cigarette smoke inhalation could contribute to both acute cardiovascular changes and the circulatory diseases associated with smoking.
AN ANALYSIS OF FUNCTIONAL ANTAGONISM AND SYNERGISM
Authors: MACKAY DENNIS
Published: July 2012

A method is described for deriving null equations for functional antagonism and synergism. These null equations relate together the concentrations of agonist required to produce equivalent states of a cell or tissue in the presence and in the absence of a functional interactant

In one particular case the null equation leads to conclusions which are very similar to those reached by an earlier author who did not use the null method. However, the null equations give a clearer insight into the quantitative aspects of functional interaction.

It is concluded that the use of functional antagonism to estimate affinity constants and relative intrinsic efficacies of agonists has serious limitations. On the other hand, it may be possible to use the null equations, or similar principles, to test the validity of postulated mechanisms and sites of action of functional interactants.