bluuebunny/crossref_metadata_2025 huggingface dataset:
SELECTIVE INHIBITION OF THERMOGENESIS BY TRIBUTYL S,S,S,‐PHOSPHOROTRITHIOATE (DEF)
Authors: RAY D.E.
Published: July 2012

Rats and mice given tributyl S,S,S,‐phosphorotrithioate (DEF) showed large dose‐related falls in body temperature which lasted from several hours to several days at environmental temperatures below thermoneutrality (30 to 31°C).

DEF produced only mild sedation and a remarkable degree of motor control was retained even when body temperatures fell below 30°C. At the dose producing maximal hypothermia only 2% of rats died within the first 24 h, although prolonged hypothermia was usually lethal.

Hypothermia was associated with a complete block of cold‐induced thermogenesis, with relatively little effect on basal metabolism at thermoneutrality.

Heat conservation mechanisms (peripheral vasoconstriction and piloerection) appeared to be unaffected by DEF and retained their usual temperature thresholds.

Adrenal catecholamine secretion in response to handling or acute cold exposure was normal in DEF‐treated rats but the fall in body temperature could be markedly reduced by large intraperitoneal injections of noradrenaline, although not atropine. The increase in oxygen consumption produced by injected catecholamines was also unaffected by DEF treatment.

It is concluded that the block of cold‐induced thermogenesis probably results from a lack of catecholamine release at the tissue level. That this is likely to be mediated at a peripheral site is suggested by the lack of effect of intracerebroventricular DEF.
BIOLOGICAL EFFECTS OF DEGRADATION PRODUCTS OF COLLAGEN BY BACTERIAL COLLAGENASE
Authors: BUCZKO WŁODZIMIERZ , DZIACZKOWSKI JAN , KOPEC MARIA , MONIUSZKO‐JAKONIUK JANINA , SOPATA IRENA , WISNIEWSKI KONSTANTY , WIZE JANINA , WOJTECKA‐ŁUKASIK ELŻBIETA
Published: July 2012

Collagen degradation products (CDP) resulting from bacterial collagenase digestion were fractionated by gel filtration and their biological activities in rats were estimated.

CDP induced the following kinin‐like effects: increase in permeability of skin blood vessels, contraction of the isolated intestine of the rat, depression of locomotor activity and of motor coordination.

The most active CDP fraction was CDP III containing peptides of mol. wt. < 1000 D with a high percentage of hydroxyproline.

As compared with bradykinin, CDP III was less active in the skin permeability test and was 15,000 to 20,000 fold less effective in induction of isolated intestine contraction.

Depression of the CNS induced by 30 μg of CDP III administered into the brain ventricle was similar to that observed after 4 μg of bradykinin given by the same route.

CDP III prolonged the duration of sleep evoked by thiopentone and enhanced the threshold of convulsion induced by pentazol.

The activity of CDP in comparison to other low molecular weight peptides is discussed.
EFFECTS OF HARMINE ON TRANSMEMBRANE POTENTIALS OF GUINEA‐PIG ATRIAL MUSCLE
Authors: CARPENTIER ROBERT G.
Published: July 2012

The effects of harmine 8.3 × 10−5 m on membrane potentials of guinea‐pig atrial muscle were analyzed and compared with those of harmaline. Transmembrane potentials of contractile fibres were measured during exposure to the drug at 30°C.

In preparations superfused with 5.4 mmol K+‐Tyrode, harmine produced a progressive reduction in the amplitude of the action potential (AP), in the absence of any change in resting potential (RP) and a prolongation of the duration of the action potential (APD).

Harmaline produced an enhancement of AP; RP was not affected and APD was prolonged.

The amplitude of slow responses elicited by noradrenaline in 16.2 mmol K+‐Tyrode was enhanced by harmine.

It is proposed that dehydrogenation of harmaline to harmine reverses the initial stimulatory action of harmaline on AP because the depressant action on the fast component of the upstroke prevails over the stimulatory effect on the slow component.
HISTAMINE WEAL FORMATION AND ABSORPTION IN MAN
Authors: COOK JOHN , SHUSTER SAM
Published: July 2012

The weal and flare response to intradermal histamine was measured over a range of doses in forearm skin of man.

The use of calipers to measure weal thickness was validated by measurement of observer and method errors. Repeated measurements at intervals of 5 min or more compressed the weals by 6% per reading.

Flare response reached a maximum at 5 min compared with 20 min for weal thickness and the sensitivity of the flare response was greater than the weal response at lower doses of histamine.

Sensitivity, λ was comparable for the measurement of flare, weal diameter and thickness or volume. The advantage of weal thickness was in the measurement of weal formation and resorption.

The time course of histamine weal formation and disappearance was measured and found to have a T1/2 of 5.4 min and 87 min, respectively.

The T1/2 of disappearance of comparable 0.9% w/v NaCl solution and serum weals were 18 and 28 min respectively.

It is suggested that persistence of histamine weals is due to a vasoactive agent other than histamine.
RATE, FORCE AND CYCLIC ADENOSINE 3′, 5′‐MONOPHOSPHATE RESPONSES TO (—)‐ADRENALINE IN NEONATAL RAT HEART TISSUE
Authors: AU T.L.S. , COLLINS G.A. , WALKER M.J.A.
Published: July 2012

(–)‐Adrenaline sensitivity in 1 to 20 day‐old rat heart tissue was investigated as rate, force and cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) production responses together with sensitivity to (±)‐propranolol blockade.

Resting performances were measured and responsiveness to (–)‐adrenaline then determined as ED50 values and maximal responses together with sensitivity to propranolol (pA2 values).

Resting force, corrected for sample size, did not change with age, whereas resting atrial rate doubled between 1 and 20 days.

ED50 concentrations in atria were constant with age, but decreased in ventricles. Cocaine (10−5 m) and other drugs did not consistently affect ED50 values.

Maximal responses were not age‐dependent in right atria, but increased in left atria. In 2 to 5 day‐old hearts there was no inotropic response to adrenaline and the very small maximal response in ventricles rose 5 to 7 fold by 20 days.

Propranolol sensitivity increased slightly (2 to 4 times) with age in all tissue from a pA2 value of 7.5 at 2 days to 8.2 at 20 days.

Control cyclic AMP was higher in 2 day than in 20 day‐old tissue and in atria than ventricular strips or hearts. In 2 and 20 day‐old atria, hearts and ventricles, force increases with different adrenaline concentrations correlated linearly with the log of the increase in cyclic AMP. Such a correlation was not seen in 2 day hearts and ventricles for cyclic AMP rose without corresponding force increases.

Results suggest slight maturational changes in atrial β‐receptors. In 1 to 5 day‐old ventricles, normal ED50 concentrations and good cyclic AMP response in the presence of a much reduced force response may indicate receptor‐response transduction inefficiency, assuming a β1‐receptor occupation and cyclic AMP production response mechanism for inotropism with adrenaline.
EVALUATION OF THE ROLE OF HISTAMINE H1AND H2‐RECEPTORS IN CUTANEOUS INFLAMMATION IN THE GUINEA‐PIG PRODUCED BY HISTAMINE AND MAST CELL DEGRANULATION
Authors: OWEN D.A.A. , POY ELISABETH , WOODWARD D.F. , DANIEL D.
Published: July 2012

The role of histamine H1and H2‐receptors in mediating the cutaneous inflammatory response produced by exogenous histamine and the release of endogenous histamine from mast cells has been investigated by a method which permits simultaneous, quantitative measurement of vasodilatation, vascular permeability and oedema formation.

Histamine and the selective H1‐receptor agonist, 2‐(2‐aminoethyl) pyridine, both produced vasodilatation, increased vascular permeability and oedema formation whereas the selective H2‐receptor agonist, dimaprit, produced only vasodilatation.

Mepyramine and cimetidine both reduced the vasodilatation response to histamine, the combination of antagonists being superior to either antagonist alone. Mepyramine (but not cimetidine) virtually abolished extravascular albumin accumulation and oedema formation.

Mepyramine and cimetidine both reduced the vasodilatation response produced by active cutaneous anaphylaxis and compound 48/80. However, mepyramine was less effective in reducing the vascular permeability response to mast cell degranulation than to histamine.

In conclusion, the vasodilator response to histamine is mediated by both H1‐ and H2‐receptors; the permeability response to histamine is mediated solely by H1‐receptors. A combination of H1‐ and H2‐receptor antagonists appears to be more effective than either antagonist alone in reducing cutaneous inflammatory reactions involving histamine.
THE EFFECT OF BACLOFEN ON THE CARDIOVASCULAR SYSTEM OF THE RAT
Authors: CHAHL LORIS A. , WALKER S. BELINDA
Published: July 2012

The cardiovascular responses to baclofen were investigated in anaesthetized rats.
POTENTIATION OF THE CONTRACTILE RESPONSE TO ACETYLCHOLINE IN AORTIC STRIPS BY LOW CONCENTRATIONS OF VASCULAR CONTRACTILE AGONISTS
Authors: ASANO MASAHISA , HIDAKA HIROYOSHI
Published: July 2012

The potentiating effect of a low concentration of various vascular contractile agonists on the response of rabbit aortic strips to acetylcholine was examined.

A marked parallel displacement to the left (potentiation; not additive effect) of the dose‐response curve for acetylcholine was observed when 5‐hydroxytryptamine (5‐HT), noradrenaline, histamine, angiotensin II or KCl were added at a concentration that caused only slight contraction (0.2 to 0.3 g) in the strips. This leftward displacement (potentiation) of the dose‐response curve by these agonists was reversed to the control response curve by the respective blocking agents for each agonist, although the blocking agents themselves did not shift the acetylcholine dose‐response curve to the right. Atropine produced a rightward displacement of the dose‐response curve for acetylcholine.

The addition of an extremely low concentration of 5‐HT or KC1 which did not cause contraction, also produced a potentiation.

The order of potency of the agonists in potentiating the acetylcholine‐induced contraction was KCl > 5‐HT ≥ histamine ≥ angiotensin II > noradrenaline.

The contractile response of aortic strips to carbamylcholine was also potentiated by these agonists.

The results suggest that the potentiation by these agonists was not mediated through muscarinic receptors but through the respective receptors for each agonist.
INHIBITION OF HISTAMINE RELEASE FROM HUMAN LUNG in vitro BY ANTIHISTAMINES AND RELATED DRUGS
Authors: CHURCH MARTIN K. , GRADIDGE CAROLYN F.
Published: July 2012

A series of cationic, lipophilic histamine H1‐receptor antagonists, neuroleptics, antidepressants and monoamine oxidase inhibitors were tested for their effects on anti‐IgE‐induced histamine release from human lung fragments in vitro.

They had a biphasic effect: at low concentrations a dose‐related inhibition of histamine release was observed whereas, at higher concentrations, the drugs liberated histamine even in the absence of antigen.

Mepyramine, a much less lipophilic drug than the others tested, was only weakly active on mast cells at pharmacological concentrations.

The potency of the drugs as release inhibitors was not related quantitatively to their histamine liberating potency.

There was no correlation between activity on mast cells and histamine H1‐receptor antagonism.

Mast cell stabilization may play a part in the activity of these drugs as Antiallergic agents.
MECHANISM BY WHICH CYPROHEPTADINE INHIBITS INSULIN SECRETION
Authors: DONATSCH P. , LOWE D.A. , RICHARDSON B.P. , TAYLOR PAMELA
Published: July 2012

Isolated islets of Langerhans from the rat have been used in studies designed to elucidate the mechanism by which cyproheptadine inhibits insulin secretion.

d‐Glucose and tolbutamide, both of which require extracellular Ca2+ to produce insulin release, failed to evoke a secretory response from islets pretreated with cyproheptadine. Conversely veratridine, the calcium ionophore A23187 and theophylline, all of which are capable of mobilizing sufficient intracellular Ca2+ to evoke insulin secretion in the absence of extracellular Ca2+, produced similar responses from cyproheptadine pretreated and control islets.

Cyproheptadine completely inhibited Ca2+ uptake induced by d‐glucose and high K+o, two agents which depolarize the islet β‐cell membrane, whilst Ca2+ uptake elicited by removal of extracellular Na+ (i.e. Na+‐Ca2+ counter transport) was only slightly reduced.

A significant increase in Na+ uptake produced by veratridine was sensitive to tetrodoxin but only partially reduced by cyproheptadine.

These results suggest that cyproheptadine inhibits depolarization‐dependent calcium entry into pancreatic β‐cells.
THE INTEGRITY OF THE SOCIAL HIERARCHY IN MICE FOLLOWING ADMINISTRATION OF PSYCHOTROPIC DRUGS
Authors: POSHIVALOV VLADIMIR P.
Published: July 2012

Mice in small groups develop a despotic type of social hierarchy, a feature of which is to resist alteration through the medium of psychotropic drugs. This makes a rapid pharmacologically induced change in the social hierarchy impossible.

Patrolling the territory and a certain level of social interaction are both critical factors in maintaining the phenomenon of inertia in the social hierarchy. Psychotropic drugs (diazepam, droperidol and mescaline) altered both these factors to a varying degree and also displayed a differing ability to maintain the inertia of the social hierarchy.

A drug‐induced alteration in the level of aggression in a subordinate mouse in a group of three does not cause an alteration in its social position.

Chronic administration of diazepam, droperidol or mescaline, all of which alter the level of aggression in different ways, can result in an inversion of the social hierarchy where a competitive rival is present in the group of mice. The rate of inversion of the social hierarachy depends on the type of pre‐existing social hierarchy.

It is suggested that the ability of psychotropic drugs to maintain the inertia of the hierarchy be used as an index of their effect upon certain types of species‐specific behaviour; in particular aggression.
THE EFFECTS OF THE CALCIUM IONOPHORE, A23187, ON THE AXOPLASMIC TRANSPORT OF DOPAMINE β‐HYDROXYLASE
Authors: ESQUERRO E. , GARCIA A.G. , SANCHEZ‐GARCIA P.
Published: July 2012

The effects of the ionophore, A23187, on the intra‐axonal transport of dopamine β‐hydroxylase (DBH) were investigated in the cat hypogastric nerve‐inferior mesenteric ganglion preparation by monitoring, in vitro, the enzyme accumulation above a ligature, 2 to 2.5 cm distal to the ganglion.

DBH accumulation in the proximal segment immediately above the ligature (P1) increased linearly up to 6 h, during incubation in normal Krebs solution at 37°C. The ionophore, A23187, interfered with the enzyme accumulation, but did not modify the previously accumulated DBH activity present in P1.

The blocking effects of A23187 on DBH transport were greatly impaired in the absence of extracellular calcium ions; an excess of calcium in the bathing solution (7.5 mM) itself blocked the enzyme transport by 50%.

A23187 did not significantly modify the levels of adenosine triphosphate (ATP) in the segments P1 and P2 of the nerve proximal to the ligature.

Nerves incubated in an A23187‐containing medium showed many mitochondria of normal shape and fine structure; however, typical microtubules or filaments were not seen in these preparations.

The results suggest that the ionophore A23187, by considerably raising the axoplasmic ionized calcium levels, interferes with the assembling of microtubules. In this manner, the ionophore would inhibit the transport of adrenergic vesicles and therefore of DBH along the axon. The results also provide additional evidence in favour of the view that for the transport system to work adequately, it is necessary to maintain the intra‐axoplasmic ionized calcium concentration between certain critical levels.
PHARMACOLOGICAL DIFFERENTIATION OF PRESYNAPTIC INHIBITORY α‐ADRENOCEPTORS AND OPIATE RECEPTORS IN THE CAT NICTITATING MEMBRANE
Authors: DUBOCOVICH MARGARITA L. , LANGER S.Z.
Published: July 2012

The action of morphine, naturally occurring and synthetic opiate peptides on [3H]‐noradrenaline release induced by nerve stimulation was studied in the isolated nerve muscle preparation of the cat nictitating membrane under experimental conditions in which the α‐presynaptic receptors were blocked by phentolamine 1 μm.

Morphine and the naturally occurring peptides: [Met5]‐enkephalin, [Leu5]‐enkephalin and β‐endorphin reduced 3H‐transmitter overflow and responses to nerve stimulation from the cat nictitating membrane, effects which were completely antagonized by naloxone 0.3 μm. The relative order of potency for the inhibition of the stimulation‐induced 3H‐transmitter overflow at the level of the IC50 (μm) was as follows: [Met5]‐enkephalin (0.020 μm) ≥ [Leu5]‐enkephalin (0.036 μm) > morphine (0.3 μm) > β‐endorphin (1 μm).

The synthetic opiate pentapeptides: BW 180 C (Tyr‐d‐Ala‐Gly‐Phe‐d‐Leu), and BW834 C (Tyr‐d‐Ala‐Gly‐pC1Phe‐dLeu), which are resistant to enzymatic degradation were more potent than the enkephalins in reducing the stimulation‐evoked transmitter overflow from the cat nictitating membrane. On the other hand, the tetrapeptide BW832 C, which lacks the d‐leucine terminal of BW180 C was less potent than the enkephalins in inhibiting neurotransmission.

In the presence of phenoxybenzamine 1 μm, 3H‐transmitter overflow was increased 8 fold and the inhibition of neurotransmission by methionine‐enkephalin was not affected. Exposure to phenoxybenzamine 10 μm increased [3H]‐noradrenaline overflow 15 fold and antagonized the effects of methionine enkephalin on transmitter release.

In the cat nictitating membrane the inhibitory presynaptic opiate receptors are different from the presynaptic α‐autoreceptors which regulate the release of noradrenaline elicited by nerve depolarization through a negative feed‐back mechanism.
THE EFFECT OF PRAZOSIN ON THE GUINEA‐PIG ILEUM
Authors: FAGBEMI S.O. , SALAKO L.A.
Published: July 2012

The α‐adrenoceptor blocking activity of prazosin was compared with that of phentolamine, yohimbine and phenoxybenzamine in the guinea‐pig isolated ileum.

Phentolamine (2.56 × 10−8 to 2.56 × 10−6 m) and yohimbine (5.12 × 10−8 to 5.12 × 10−6 m) antagonized the sympathetic inhibition of twitches induced by transmural stimulation, whereas prazosin (5.28 × 10−8 to 5.28 × 10−6 m) and phenoxybenzamine (4.2 × 10−9 to 4.2 × 10−7 m) had no effect.

Phentolamine, yohimbine, prazosin and phenoxybenzamine antagonized the relaxant response of the ileum to periarterial nerve stimulation and to exogenous noradrenaline in the absence of transmural stimulation.

The pA2 value for phentolamine against noradrenaline in the transmurally‐stimulated gut (presynaptic α‐adrenoceptor site; 8.17 ± 0.04) was significantly different from that in the non‐stimulated gut (postsynaptic α‐adrenoceptor site; 6.88 ± 0.12).

Phentolamine and prazosin probably block noradrenaline responses at the same α‐adrenoceptor site on the postsynaptic membrane.
EFFECTS OF RMI 12330A, A NEW INHIBITOR OF ADENYLATE CYCLASE ON MYOCARDIAL FUNCTION AND SUBCELLULAR ACTIVITY
Authors: GRUPP G. , GRUPP I.L. , JOHNSON C.L. , MATLIB M.A. , ROUSLIN W. , SCHWARTZ A. , WALLICK E.T. , WANG T. , WISLER P.
Published: July 2012

RMI 12330A, a lactam‐imine, at concentrations of 10−4 m and higher, inhibited basal as well as isoprenaline and NaF‐stimulated adenylate cyclase activity of guinea‐pig heart homogenates. However, RMI 12330A was a more potent inhibitor of histamine‐stimulated adenylate cyclase (IC50 of 1.5 × 10−5 m).

In the isolated work‐performing heart of the guinea‐pig, RMI 12330A (IC50 of 1.1 × 10−6 m) depressed all cardiac functions: pressures developed, dP/dt, contractile force, dF/dt, work performance and stroke work. Left atrial pressure rose and the positive inotropic response to increasing heart rate (staircase) became negative. Histamine, isoprenaline and ouabain no longer caused positive inotropic effects.

Increasing the perfusate calcium concentration from 2.5 mm to 4.5 and 6.5 mm completely restored cardiac function after its depression by RMI 12330A.

RMI 12330A uncoupled mitochondrial oxidative phosphorylation; the classical uncoupler, dinitrophenol, had the same effects on cardiac dynamics as RMI 12330A.

RMI in high doses inhibited hydrolytic activity of Na+, K+‐ATPase of crude and purified heart preparations (IC50 of 1.7 × 10−4 m) and inhibited ouabain binding to the same enzymes (IC50 of 1.5 × 10−4 m).

A lactam‐imine analogue of RMI 12330A that had no effect on adenylate cyclase, was also without effect on any of the systems examined.
CONTRIBUTION OF PROSTAGLANDINS TO THE ADENOSINE TRIPHOSPHATE‐INDUCED CONTRACTION OF RABBIT URINARY BLADDER
Authors: ANDERSSON K.‐E. , HUSTED S. , SJÖGREN C.
Published: July 2012

Adenosine 5′‐triphosphate (ATP) produced an inital rapid, phasic contraction and a later, slowly developing tonic contraction in the isolated detrusor of the rabbit but mainly a rapid, phasic response in the guinea‐pig bladder.

Electrical field stimulation elicited only a rapid, phasic contraction in both rabbit and guinea‐pig bladders.

Prostaglandin synthesis inhibition by means of indomethacin and suprofen abolished the tonic response to ATP in the rabbit detrusor, leaving the phasic part of the contraction almost unaffected. The ATP‐induced contraction in guinea‐pig bladder was not influenced by indomethacin.

The contractile response of rabbit urinary bladder to prostaglandins F2α and E2 and to carbachol were not significantly influenced by indomethacin. The contractions induced by the prostaglandins were similar to the tonic response to ATP.

Tetrodotoxin, atropine, phentolamine, and theophylline did not alter the ATP‐induced contraction. However, the calcium antagonists, nifedipine and nimodipine, abolished the phasic ATP response and greatly reduced the tonic part of the contraction.

Tachyphylaxis occurred on repeated addition of ATP; the response to field stimulation was progressively reduced only after indomethacin pretreatment.

ATP and prostaglandins may contribute to the non‐adrenergic, non‐cholinergic component of the excitation of rabbit and guinea‐pig bladder.
THERMOREGULATORY EFFECTS OF N6‐2′‐O‐DIBUTYRYL ADENOSINE 3′,5′‐MONOPHOSPHATE IN THE RESTRAINED MOUSE
Authors: DASCOMBE M.J. , MILTON A.S. , NYEMITEI‐ADDO I. , PERTWEE R.G.
Published: July 2012

The N6‐2′‐O‐dibutyryl derivative of adenosine 3′,5′‐monophosphate (db cyclic AMP) has been micro‐injected into the third cerebral ventricle of the unanaesthetized, restrained mouse and the effects on body temperature and thermoregulatory activities observed.

Db cyclic AMP (4, 16 and 32 μg) injected intracerebroventricularly produced hypothermia when compared with temperature responses to sodium n‐butyrate (6.8 μg).

Hypothermia induced by db cyclic AMP in mice was associated with a fall in oxygen consumption together with behavioural and autonomic heat loss activities but not cutaneous vasodilatation. The effects on rectal temperature and oxygen consumption were dose‐dependent.

The falls in rectal temperature and oxygen consumption induced by db cyclic AMP (4 μg) were decreased by elevation of the environmental temperature from 22 to 32°C and abolished at 36°C.

It is concluded db cyclic AMP may inhibit central events mediating the rise in metabolic heat production in mice upon exposure to cold environments.
THE EFFECTS OF (+)‐ AND (–)‐PROPRANOLOL ON 3H‐TRANSMITTER EFFLUX IN GUINEA‐PIG ATRIA AND THE PRESYNAPTIC β‐ADRENOCEPTOR HYPOTHESIS
Authors: KALSNER STANLEY
Published: July 2012

The effects of isoprenaline and of the (+)‐ and (–)‐isomers of propranolol on the stimulation‐induced overflow of 3H‐transmitter was assessed in guinea‐pig atria to evaluate the hypothesis of presynaptic β‐adrenoceptors.

Isoprenaline (1.2 × 10−8 m) enhanced the efflux of tritium at 2 and 5 Hz with 100 pulses and did so to a similar extent at both frequencies.

The (–)‐isomer of propranolol (1.0 × 10−7 m) blocked the enhancing effect of isoprenaline but did not by itself modify transmitter efflux.

The (+)‐isomer of propranolol, almost devoid of β‐adrenoceptor blocking properties, was also effective at 1.0 × 10−7 m in blocking the enhancement of tritium efflux by isoprenaline.

The (–)‐isomer of propranolol (1.0 × 10−7 m) blocked almost entirely the inotropic response to isoprenaline (3 × 10−7 m) but even 3.0 × 10−6 m (+)‐propranolol was inneffective in antagonizing the β‐adrenoceptor‐mediated contractile responses to the catecholamine.

It is concluded that the presynaptic site of isoprenaline action does not show the requisite stereospecifity of β‐adrenoceptors and that a ‘non‐specific’ action of the antagonist probably accounts for its reduction of the effect of isoprenaline.
LEUCINE‐ENKEPHALIN AND METHIONINE‐ENKEPHALIN PRODUCE OPPOSING EFFECTS ON PLASMA CORTICOSTERONE LEVELS IN ETHER‐STRESSED MICE
Authors: GIBSON ALAN , HART STEPHEN L. , SHABIB AMEL
Published: July 2012

The inhibitory effects of intracerebroventricular administration of saline on the plasma corticosterone response to ether stress in mice was reduced by Met‐enkephalin and enhanced by Leu‐enkephalin. When administered simultaneously the effects of the two peptides opposed each other. Met and Leu‐enkephalin may subserve different physiological functions in the response of the hypothalamus‐pituitary‐adrenal system to stress.
MORPHINE DEPENDENCE AND DOPAMINERGIC ACTIVITY: TESTS OF CIRCLING RESPONSES IN RATS WITH UNILATERAL NIGRAL LESIONS
Authors: HALLIWELL J.V. , KUMAR R.
Published: July 2012

Rats with unilateral electrolytic lesions involving both parts of the substantia nigra show dose‐related, ipsilateral circling responses to apomorphine which are stable over time.

In non‐tolerant rats, morphine (up to 10 mg/kg) does not elicit any circling behaviour but as tolerance develops to morphine, initially 10 mg/kg daily and then 100 mg/kg daily for about 4 months, the rats show a progressive tendency to walk more towards the side of the lesion. This behaviour is qualitatively different from apomorphine‐induced circling.

When apomorphine (0 to 1.0 mg/kg) and morphine (10 or 100 mg/kg) are tested together, the total amounts of ‘circling’ are increased in an additive manner. However, after 22 h withdrawal from morphine there is a more marked increase in apomorphine‐induced circling which is related to the level of dependence.

It is suggested that the sensitivity of striatal dopamine receptors is not altered by morphine dependence and that the increased response to apomorphine in abstinence probably reflects changes in the modulating actions of other neurotransmitter systems in the striatum.
ENKEPHALIN RECEPTOR IN THE RABBIT ILEUM
Authors: OKA TETSUO
Published: July 2012

The effects of the classical morphine‐like compounds and opioid peptides on the electrically‐induced contractions of the myenteric plexus‐longitudinal muscle strip of the rabbit ileum were studied. The results indicate that the rabbit ileum contains the new type of opiate receptor, which is not sensitive to morphine but is sensitive to enkephalins, and provides evidence that the enkephalins may function as neurotransmitters in the intestine. The action of the enkephalins was antagonized by relatively high dose of naloxone.
DECREASE OF SUBSTANCE P IN PRIMARY AFFERENT NEURONES AND IMPAIRMENT OF NEUROGENIC PLASMA EXTRAVASATION BY CAPSAICIN
Authors: GAMSE R. , HOLZER P. , LEMBECK F.
Published: July 2012

Rats were pretreated with capsaicin (50 mg/kg, s.c.) on the 2nd, 10th, or 20th day of life. Three months later immunoreactive substance P (I‐SP) was determined in skin, sensory nerves and the central nervous system. Neurogenic plasma extravasation was also examined.

Pretreatment at the age of 2 or 10 days resulted in a decrease (26 to 69%) of I‐SP in skin, saphenous and vagus nerve, dorsal roots, dorsal half of the spinal cord, and medulla oblongata. The I‐SP content of the ventral half of the spinal cord, of midbrain, hypothalamus, striatum, cortex, and cerebellum remained unchanged. Neurogenic plasma extravasation was inhibited by more than 80%.

In contrast to this irreversible effect of capsaicin on newborn rats, pretreatment of 20 day old rats led to reversible depletion of I‐SP and to reversible impairment of neurogenic plasma extravasation.

Capsaicin pretreatment of adult rats caused a marked depletion of I‐SP in the skin of the hind paw and an impairment of neurogenic plasma extravasation. A similar decrease of I‐SP was seen after chronic denervation of the skin.

Intra‐arterial infusion of substance P (threshold dose 5 × 10−13mol/min) or physalaemin induced dose‐dependent plasma extravasation. Somatostatin, vasoactive intestinal polypeptide, caerulein and the enkephalin‐analogue FK 33–824 were ineffective in doses 100 fold higher.

The results indicate that the action of capsaicin on substance P neurones is restricted to primary sensory neurones. Since in every case a decreased substance P content of the skin was associated with impaired neurogenic plasma extravasation, it is suggested that release of substance P is involved in neurogenic plasma extravasation.
A CALCIUM‐DEPENDENT ACETYLCHOLINE DEPOLARIZATION BLOCKED BY METHOXYVERAPAMIL (D600) AND PROCAINE IN SNAIL NEURONES
Authors: ISRAEL JEAN‐MARC , MEUNIER JEAN‐MARIE
Published: July 2012

Repetitive application of acetylcholine (ACh) revealed two types of ACh depolarization in two types of snail neurone, depending on their desensitization properties.

Further experiments were carried out on neurones which displayed a rapidly desensitizing response.

The amplitude of the response depended on the external sodium and calcium levels.

Procaine antagonized ACh effects with the same efficiency as atropine or hexamethonium, half maximal depression being obtained at a concentration of 10−4m. The blocking effect was independent of the dose of ACh.

The depression of the ACh‐induced depolarization by cobalt ions and D600 suggests that calcium may participate in this response.
EFFECTS OF HYDRALAZINE AND VERAPAMIL ON PHOSPHORYLASE ACTIVITY AND GUANOSINE CYCLIC 3′,5′‐MONOPHOSPHATE LEVELS IN GUINEA‐PIG TAENIA COLI
Authors: DIAMOND JACK , JANIS RONALD A.
Published: July 2012

The roles of guanosine cyclic 3′,5′‐monophosphate (cyclic GMP) and calcium in the relaxation produced by hydralazine and verapamil in potassium‐depolarized guinea‐pig taenia coli have been investigated.

Depolarization of isolated strips of guinea‐pig taenia coli by 124 mm KCl caused sustained contractures and increases in tissue levels of cyclic GMP.

The KCl‐induced increases in cyclic GMP levels appeared to be calcium dependent. No increases in cyclic GMP levels were seen in strips of taenia coli depolarized in the absence of calcium. Re‐addition of calcium to the depolarizing solution contracted the muscles and increased cyclic GMP levels. When calcium was removed from the depolarizing solution during the sustained, tonic phase of a KCl‐induced contracture, both tension and cyclic GMP levels returned to control values.

Administration of 50 um verapamil to KCl‐contracted muscles completely relaxed the muscles and caused cyclic GMP levels to return to control values within 14 min. Hydralazine, 2 mm, on the other hand, relaxed the depolarized muscles without lowering cyclic GMP levels. No significant changes in cyclic AMP levels were seen in any of these experiments.

Similar results were obtained in an analogous series of experiments in which glycogen phosphorylase activity was measured instead of cyclic GMP levels. Activation of phosphorylase during contractions of guinea‐pig taenia coli had previously been reported to be a calcium‐dependent phenomenon.

It was concluded that increases in tissue levels of cyclic GMP (or of cyclic AMP) were not responsible for the relaxant effects of hydralazine or verapamil in these experiments. It was also suggested, based on our results, that verapamil exerted its relaxant effects in the depolarized taenia coli by lowering cytoplasmic calcium levels, whereas hydralazine relaxed the depolarized muscles without lowering intracellular calcium activity.
PRELIMINARY PHARMACOLOGICAL CHARACTERIZATION OF THE BOVINE ISOLATED BRONCHIAL ARTERY STRIP: A NEW PREPARATION
Authors: AROWOLO R.O.A. , EYRE P.
Published: July 2012

This paper describes a preliminary pharmacological study of the isolated helical strip of bovine bronchial artery under isotonic conditions in Krebs‐Henseleit solution.

The tissue contracted to histamine and 5‐hydroxytryptamine (5‐HT), actions which were selectively antagonized by mepyramine and methysergide respectively. Histamine was not inhibited by metiamide and 5‐HT was not affected by morphine.

Slow reacting substance of anaphylaxis (SRS‐A), prostaglandin F2α (PGF2α) and PGE2 were spasmogenic, whereas PGE1 caused relaxation. No potential antagonists of these agents were tested.

Carbachol, at all concentrations, caused contractions of the bronchial artery which were completely, irreversibly blocked by atropine.

The spasmogenic action of phenylephrine was selectively blocked by dibenamine. Vessel strips which were partially contracted to histamine, relaxed to isoprenaline and salbutamol. The action of isoprenaline was inhibited similarly by either propranolol or practolol. The evidence therefore suggests the presence of functional α, β1 and β2‐adrenoceptors.
RELEASE‐MODULATING ACETYLCHOLINE RECEPTORS ON CHOLINERGIC NEURONES OF THE GUINEA‐PIG ILEUM
Authors: FOSBRAEY P. , JOHNSON E.S.
Published: July 2012

Twitch responses of the guinea‐pig ileum to electrical transmural stimulation (0.2 Hz) were smaller after a dose of acetylcholine (ACh) than before it. The magnitude of the post‐ACh inhibition of twitch was dose‐dependent.

The post‐ACh inhibition of twitch could not be explained in terms of post‐junctional desensitization and was not modified by guanethidine, thymoxamine, propranolol or naloxone. Inhibition of twitch also followed high frequency stimulation (10 Hz) but this inhibition, unlike that following ACh, was partially antagonized by naloxone.

Hexamethonium (C6) in concentrations known to block contractions to nicotine, potentiated the post‐ACh inhibition of twitch and modified the pattern of recovery. An initial rapid phase followed by a slower phase was converted by C6 to an initial slow phase followed by a more rapid rate of recovery.

The C6‐sensitive (nicotinic) component of twitch recovery after ACh was also dose‐dependent and contributed greatly to the rapid recovery during the first minute after ACh washout, whereas during the same period the C6‐resistant inhibition remained relatively constant; thereafter both components declined. The C6‐resistant inhibition was considered to be due to the activation of prejunctional muscarinic receptors.

5‐Hydroxytryptamine (5‐HT) and nicotine also caused inhibition of twitch but the pattern of response differed from those due to ACh, the maximum inhibition usually being produced 1 min after recommencing stimulation. High doses of 5‐HT produced inhibitory responses similar to those following ACh, whereas nicotine produced a characteristic triphasic pattern of response.

It is concluded that ACh acts on at least two prejunctional receptors subserving a modulatory role on transmitter release, a nicotinic receptor whose activation enhances ACh output and a muscarinic receptor whose activation leads to an inhibition of transmitter secretion.
IMPROMIDINE (SK&F 92676) ACTS AS A PARTIAL AGONIST ON THE ISOLATED WHOLE STOMACH OF THE RAT
Authors: PARSONS M. , SYKES C.
Published: July 2012

The present secretory studies on the isolated stomach of the rat provide evidence that impromidine acts as a partial agonist at the histamine H2‐receptors. It was found to be 100 times more potent than histamine but with a maximal response only 50% that obtained with histamine.
THE EFFECTS OF AROMATIC AMINO ACID DERIVATIVES ON THE EXCITABILITY OF AN IDENTIFIABLE GIANT NEURONE OF THE AFRICAN GIANT SNAIL (Achatina fulica Férussac)
Authors: TAKEUCHI HIROSHI , TAMURA HIROKO
Published: July 2012

The effects of derivatives of aromatic amino acids on the excitability of an identifiable giant neurone (TAN, tonically autoactive neurone) of the African giant snail (Achatina fulica Férussac) were examined.

The following substances had marked inhibitory effects on TAN using bath application: N‐β‐phenylpropionyl‐l‐Tyr and N‐β‐phenylpropionyl‐l‐Trp (critical concentration, 3 × 10−7 m), N‐β‐phenylpropionyl‐l‐Phe, N‐cinnamoyl‐dl‐Trp and N‐phenoxyacetyl‐l‐Trp (critical concentration, 10−5 to 3 × 10−5 m). However, N‐β‐phenylpropionyl‐d‐Tyr and N‐β‐phenylpropionyl tyramine had no effect.

Microdrop (150 μm in diameter) application of a solution of N‐β‐phenylpropionyl‐l‐Tyr or N‐β‐phenylpropionyl‐l‐Trp containing about 100 pg resulted in marked inhibitory effects on TAN. The effect was observed in Ca2+‐free, Mg2+‐rich (24 mm) solution. Substitution of Cl− by acetate did not alter the response. This indicates that the two substances act directly on the TAN membrane and not via synaptic influences, and that the inhibition produced by the two substances is not due to the permeability increase of the TAN membrane to Cl−.
THE EFFECTS OF CASTRATION ON NEUROTRANSMISSION IN THE RAT VAS DEFERENS
Authors: MACDONALD A. , MCGRATH J.C.
Published: July 2012

Responses to adrenoceptor agonist drugs and to field stimulation were examined in vasa deferentia from adult castrated or intact rats. Isometric tension was recorded in vitro from whole or transversely bisected vasa.

After castration vasa exhibited spontaneous contraction, noradrenaline no longer produced a ‘tonic’ contraction but increased the ‘phasic’ spontaneous activity and salbutamol inhibited spontaneous activity by a β‐adrenoceptor‐mediated mechanism.

After castration the ‘adrenergic’ components of the contractile responses to field stimulation were lost whereas ‘noradrenergic’ responses remained, pre‐junctional inhibition of field stimulation‐induced contractions by either endogenous or exogenous activation was lost but adrenergic terminals could still be demonstrated microscopically.

Testosterone treatment partially reversed these effects of castration.

The relevance of these results to the nature of neurotransmission and to the genesis of spontaneous contraction in the vas deferens is discussed.
BEHAVIOURAL CHANGES INDUCED BY N,N‐DIMETHYLTRYPTAMINE IN RODENTS
Authors: JENNER P. , MARSDEN C.D. , THANKI C.M.
Published: July 2012

N,N‐Dimethyltryptamine (DMT) in pargyline pretreated rodents induced a dose‐dependent behavioural syndrome consisting of hyperactivity, prostration and hindlimb abduction, mild tremor, Straub tail, retropulsion and jerking.

In rats pretreated with pargyline, the behavioural syndrome induced by DMT differed from that induced by l‐tryptophan or quipazine, in the lack of forepaw treading and head‐weaving and in the presence of only mild tremor.

The hyperactivity component of the DMT‐induced behavioural syndrome in pargyline‐pretreated mice was potentiated by cyproheptadine, methergoline, and mianserin, inhibited by cinanserin, haloperidol, pimozide, methiothepin and propranolol, and not affected by 501C67‐sulphate and methysergide.

The maximal behavioural changes induced by DMT in rats, other than hyperactivity, were unaffected by pretreatment with cyproheptadine, methysergide, and cinanserin. However, propranolol reduced the intensity of all behavioural effects apart from body jerking, and methergoline decreased the duration of prostration. Phenoxybenzamine and haloperidol, in contrast, enhanced prostration.

DMT plus pargyline did not induce circling behaviour in mice with a unilateral 6‐hydroxydopamine lesion of the nigro‐striatal pathway.

The DMT‐induced behavioural syndrome appears to consist of two components, (a) hyperactivity and (b) other behavioural changes. They differ in their response to drugs affecting brain monoamines. The hyperactivity component may be expressed via dopamine mechanisms, but the other behavioural changes are not. The two behaviours do not respond consistently to drugs believed to alter brain 5‐hydroxytryptamine function.
LACK OF CORRELATION BETWEEN PRESYNAPTIC INHIBITION OF NORADRENALINE RELEASE AND END ORGAN RESPONSES DURING NERVE STIMULATION
Authors: DUBOCOVICH MARGARITA L. , LANGER S.Z. , MASSINGHAM R.
Published: July 2012

LD 3098 (cirazoline) is an imidazoline derivative, possessing agonist properties at α‐adrenoceptor sites.

When transmitter release was measured directly as tritium overflow from perfused cat spleen preparations, prelabelled with [3H]‐noradrenaline, LD 3098 was found to be 10 times more selective for presynaptic than for postsynaptic α‐adrenoceptors.

In addition, in this preparation, LD 3098 appears to induce a postsynaptic sensitization to the transmitter released by nerve depolarization because under conditions in which [3H]‐noradrenaline overflow decreased, there was a paradoxical potentiation in the response to nerve stimulation. This potentiation also occurred with a concentration of LD 3098 that did not per se affect stimulation‐evoked [3H]‐noradrenaline release or the basal perfusion pressure of the spleen.

Both the reduction in 3H‐transmitter release induced through activation of α‐presynaptic adrenoceptors and the potentiation of the responses to nerve stimulation were concentration‐dependent phenomena.

In pentobarbitone anaesthetized dogs, the heart rate response to low frequency ansa‐subclavia stimulation was not affected by LD 3098. Whilst the α1 mediated increase in blood pressure responses to injected noradrenaline and tyramine was significantly potentiated by LD 3098, the β1‐mediated heart rate responses to these injected amines were not modified in the presence of LD 3098.

Thus it is possible that the failure to detect any presynaptic effects with LD 3098 when transmitter release is measured indirectly at the level of the postsynaptic responses is due to end organ sensitivity changes.

These findings emphasize that caution is necessary when assessing presynaptic α‐adrenoceptor effects through end organ responses to nerve stimulation both in vitro and in vivo and the need for measurements of transmitter overflow as well as adequate postsynaptic controls in such experiments.
COMPARISON OF DESENSITIZATION AND TIME‐DEPENDENT BLOCK OF THE ACETYLCHOLINE RECEPTOR RESPONSES BY CHLORPROMAZINE, CYTOCHALASIN B, TRITON X‐100 AND OTHER AGENTS
Authors: ANWYL ROGER , NARAHASHI TOSHIO
Published: July 2012

Chlorpromazine, cytocholasin B, Triton X‐100, lidocaine, QX‐314, pentobarbitone, heptanol and ethanol, but not benzocaine or methylguanidine, caused a time‐dependent inhibition of acetylcholine (ACh) potentials. Increasing the concentration of the agents increased the rate of inhibition.

The recovery rate from the time‐dependent inhibition was the same as from desensitization except in Triton X‐100 which slowed the recovery.

Hyperpolarizing the membrane potential caused an increase in the rate of the time‐dependent inhibition.

It is suggested that the time‐dependent inhibition and desensitization are very similar phenomena, with either ACh (in desensitization) or an agent (in time‐dependent inhibition) causing a block of the activated ACh receptor, and with dissociation from the binding site being very slow.

Many of the agents also cause a steady state inhibition of the ACh receptor which appears to be caused by a separate blocking action of the agents.
BLOCKADE OF STRIATAL NEURONE RESPONSES TO MORPHINE BY AMINOPHYLLINE: EVIDENCE FOR ADENOSINE MEDIATION OF OPIATE ACTION
Authors: PERKINS MARTIN N. , STONE TREVOR W.
Published: July 2012

The responses of cortical and striatal neurones to morphine and adenosine applied iontophbretically have been studied in the male rat.

The majority of cells (57%) within the corpus striatum were profoundly inhibited, and a smaller proportion (18%) excited by morphine. Adenosine depressed the firing rate of 30/44 cells in the striatum, excitation never being observed. In contrast, the responses of cortical cells to morphine were typically weak and required longer ejection pulses to effect comparable changes in firing rate.

Aminophylline applied iontophoretically, as an anion, proved able to antagonize reversibly both morphine and adenosine in parallel.

On a number of cells, γ‐aminobutyric acid (GABA) was used as a control depressant but aminophylline did not appear to reduce these responses.

The responses to morphine (both inhibitory and excitatory) were not easily antagonized by naloxone. Typically, excitatory responses were easier to antagonize than the inhibitory ones.

It is concluded that a consequence of the interaction of morphine with its receptors may be the release of adenosine which subsequently produces the inhibition observed with morphine.
DIABETOGENIC EFFECTS OF CHRONIC ORAL CADMIUM ADMINISTRATION TO NEONATAL RATS
Authors: MERALI Z. , SINGHAL R.L.
Published: July 2012

Chronic exposure of neonatal rats to oral cadmium (Cd) (0.1 and 1.0 μg/g daily for 45 days) disturbed glucose homeostasis, as reflected by hyperglycaemia, reduced liver glycogen and enhanced gluconeogenic potential of hepatic tissue.

This Cd‐exposure regimen also increased hepatic cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) which was accompanied by enhancement of basal, adrenaline and glucagon‐stimulated form(s) of adenylate cyclase.

In order to assess the responsiveness of pancreatic beta cells to glucose, islets isolated from control as well as Cd‐exposed animals were incubated in vitro and their rate of insulin secretion determined. In the presence of glucose 0.5 mg/ml, there was no significant difference in the rate of insulin release. However, at higher glucose concentrations (1.5 and 3.0 mg/ml), the islets from Cd‐exposed rats released significantly less insulin than those of control animals.

The results are discussed in relation to the possible mechanism of the diabetogenic effect of Cd.
CENTRAL CARDIOVASCULAR EFFECTS OF NARCOTIC ANALGESICS AND ENKEPHALINS IN RATS
Authors: BELLET M. , ELGHOZI J.L. , MEYER P. , PERNOLLET M.G. , SCHMITT H.
Published: July 2012

The cardiovascular effects of morphine, fentanyl, [d‐Ala2]‐met‐enkephalinamide were analyzed after intracisternal injection in anaesthetized rats. Pao2 was measured as an index of respiratory function.

At low doses in spontaneously breathing rats, morphine, fentanyl and [d‐Ala2]‐met‐enkephalinamide induced a pressor response with slight tachycardia and no significant change in Pao2.

The pressor response appeared to be due to activation of opiate receptors and mediated through the sympathetic nervous system.

High doses of morphine and [d‐Ala2]‐met‐enkephalinamide induced a biphasic effect with a secondary hypotension associated with bradycardia in spontaneously breathing rats. A marked reduction in Pao2 was found during the depressor phase.

High doses of [d‐Ala2]‐met‐enkephalinamide produced only a pressor response in artificially‐ventilated rats with no signs of secondary hypotension.

Our data support the idea that morphinomimetic agents are centrally pressor at low doses in the rat. The respiratory depression observed with high doses may be the cause of hypotension.