bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of mechanisms controlling the release and inactivation of the adrenergic transmitter in the rabbit portal vein and vas deferens
Authors: HUGHES J.
Published: July 2012

A method is described for the detection and assay of picogramme quantities of noradrenaline. This involves transferring Krebs solution containing noradrenaline to a cascade system where the catecholamine may be bioassayed on superfused preparations of the rabbit aorta and iliac artery.

Electrical field stimulation of the rabbit vas deferens and portal vein caused the release, into the bathing medium, of a material which was identified by pharmacological and chemical tests as noradrenaline.

Cocaine (0·3–5 μg/ml) caused a marked increase in noradrenaline output after electrical stimulation of the portal vein and vas deferens. This effect appeared to be maximal at a concentration of 2·4 μg/ml; when the cocaine concentration was increased above 10 μg/ml the noradrenaline output was greatly reduced.

Phenoxybenzamine (5 μg/ml) caused a 4–8 times greater increase in noradrenaline output than cocaine; however, the increase in output due to phenoxybenzamine was much smaller in tissues pretreated with cocaine.

Corticosterone (20 μg/ml) increased noradrenaline output by 30–40% in untreated vas deferentia, but caused a 300% increase in output in tissues pretreated with cocaine. Cocaine also caused a much greater increase in output in tissues pretreated with corticosterone than in untreated tissues.

Treatment with pargyline plus tropolone caused a 100–200% increase in noradrenaline output; this effect was not modified by cocaine, but was abolished when the tissues were pretreated with either phenoxybenzamine or corticosterone.

When tissues were stimulated for 240 pulses at 1–16 Hz, the output per pulse of noradrenaline increased linearly with the logarithm of the frequency of stimulation. This relationship between frequency and output was seen in both untreated tissues, and in tissues treated with cocaine, phenoxybenzamine, corticosterone or pargyline plus tropolone.

It is concluded that cocaine enhances output by blocking the neuronal reuptake of noradrenaline, and corticosterone by blocking the extraneuronal uptake and subsequent metabolism of noradrenaline. Phenoxybenzamine acts by blocking both neuronal and extraneuronal uptake mechanisms. There appears to be a dynamic balance in the distribution of noradrenaline between the two uptake mechanisms after the release of the transmitter from the nerve endings.

It is calculated that more than 90% of the noradrenaline released by nerve stimulation (240 pulses at 2–16 Hz) is inactivated by neuronal and extraneuronal uptake mechanisms.

It is calculated that the fraction of the total noradrenaline store that is released by one pulse at 2 Hz is 6·6 × 10−5 in the portal vein and 5·6 × 10−5 in the vas deferens; the corresponding values at 16 Hz were 15·9 × 10−5 and 16·2 × 10−5.
Evaluation of cryogenine on rat paw thermal oedema and rat isolated uterus
Authors: MALONE M. H. , TROTTIER R. W.
Published: July 2012

. Significant inhibition of oedema formation caused by thermal injury was observed for calcium carbaspirin, phenylbutazone, hydrocortisone, cryogenine and indomethacin when given daily beginning 2 days prior to thermal exposure and afterwards. Several anti‐inflammatory drugs, including cryogenine, failed to reduce thermal oedema significantly when given as single doses 1 h prior to the thermal injury.

. Kinetic experiments on the rat isolated uterus demonstrated that cryogenine, chlorpromazine, and flufenamic acid were, in part, competitive inhibitors of synthetic bradykinin, while indomethacin and tetrabenazine showed only non‐competitive antagonism.
The bradykininase activities of extracts of dog lung
Authors: ALABASTER VALERIE A. , BAKHLE Y. S.
Published: July 2012

Homogenates of dog lungs freed from blood inactivate bradykinin. The bradykininase activity is present in soluble and particulate subcellular fractions.

The fraction with the highest relative specific activity is that sedimenting between 8,700 g and 78,000 g. This fraction has been studied in more detail.

There is evidence for two bradykinin inactivating enzymes in this fraction with apparent Km values of 7·5 μm and 120 μm.

The bradykininase activity is not dependent on the concentration of chloride ion.

The bradykininase activity is inhibited by EDTA, 2:3‐dimercaptopropanol, nickel ions and some of the peptides from the venom of Bothrops jararaca and of Agkistrodon halys blomhoffii but not by 2‐mercaptoethanol or N‐ethylmaleimide.

Angiotensin II in either 15 or 170 mm chloride ion is not an inhibitor of bradykininase activity but angiotensin I at either chloride concentration is an inhibitor. It is proposed that chloride is not necessary for binding of angiotensin I to converting enzyme but is necessary to ensure the correct orientation of substrate for hydrolysis to proceed.
EFFECT OF SELECTIVE DESTRUCTION OF CENTRAL AND PERIPHERAL CATECHOLAMINE‐CONTAINING NEURONES WITH 6‐HYDROXYDOPAMINE ON CATECHOLAMINE EXCRETION IN THE RAT
Authors: HOELDTKE R. , ROGAWSKI M. , WURTMAN R.J.
Published: July 2012

The contribution of various tissues to some of the pools of catecholamine metabolites in urine has been estimated by measuring the excretion of these compounds by rats given DOPA‐free diets and intravenous, intraventricular, or intracisternal 6‐hydroxydopamine.

Destruction of peripheral sympathetic neurones by repeated intravenous doses of 6‐hydroxy dopamine led to a 34% decrease in noradrenaline excretion, and a 38% decrease in 4‐hydroxy‐3‐methoxyphenylglycol sulphate excretion. Depletion of brain noradrenaline (by 67%), after intracisternal 6‐hydroxydopamine, was unassociated with changes in the excretion of noradrenaline or of 4‐hydroxy‐3‐methoxyphenylglycol sulphate. This suggests that these compounds in rat urine are derived mainly from peripheral tissues.

Depletion of brain dopamine (by 80%) by intraventricular 6‐hydroxydopamine was associated with a 27% decrease in the excretion of homovanillic acid. Destruction of peripheral sympathetic neurones with intravenous 6‐hydroxydopamine led to a 25% decrease in homovanillic acid excretion. The data suggest that the homovanillic acid in rat urine derives partially from brain dopamine and partially from dopamine released from or metabolized within sympathetic neurones.

Neither depletion of brain dopamine, nor destruction of sympathetic neurones, caused alterations in the excretion of dopamine or dihydroxyphenylacetic acid.
THE EFFECT OF TRANQUILLIZING DRUGS ON THE CONCENTRATION OF THE SULPHATE ESTER OF 4‐HYDROXY‐3‐METHOXYPHENYLETHANE‐1,2‐DIOL IN RAT BRAIN
Authors: BERRIDGE T.L. , SHARMAN D.F.
Published: July 2012

A total of 17 butyrophenone, phenothiazine, benzodiazepine and imidazoline tranquillizing drugs were examined for their ability to increase the cerebral concentration of the sulphate ester of 1(4‐hydroxy‐3‐methoxyphenyl)ethane‐1,2‐diol (MHPG‐SO3H), a metabolite of noradrenaline in the rat brain. Of these drugs, when given in a dose of 10 mg/kg i.p., only trifluperidol, haloanisone, azaperone, clozapine and haloperidol were found to increase the cerebral concentration of MHPG‐SO3 H. This effect is unrelated to the ability of such drugs to antagonize the lethal effects of an intravenous injection of noradrenaline and suggests that the properties of the central noradrenaline receptors differ from those of the peripheral noradrenaline receptors.
RELATIONSHIP BETWEEN THEOPHYLLINE UPTAKE AND INOTROPIC EFFECT IN THE GUINEA‐PIG HEART
Authors: BELLEMANN P. , SCHOLZ H.
Published: July 2012

The time course of the positive inotropic effect of theophylline was compared with the time course of the uptake and release of [3H]‐theophylline in guinea‐pig isolated, electrically driven hearts perfused by the Langendorff method.

Formation of theophylline metabolites could not be detected under the experimental conditions used.

Theophylline entered myocardial tissue very rapidly in two different phases. The first process (half‐time 21 s) amounted to 93% and the second (half‐time 5 min 50 s) to 7% of the total uptake. The development of the positive inotropic effect of theophylline was about four times faster than even the rapid component of the uptake of the drug into the myocardium.

The amount of theophylline accumulated in myocardial tissue (after 10 min perfusion) increased proportionally with theophylline concentrations in the perfusion media and no signs of saturation were detected. The tissue‐medium ratio did not exceed 1. The water content of the myocardial tissue amounted to about 80% at all theophylline concentrations examined.

The uptake of theophylline (3 mg/ml) was diminished by 9.2% after pretreatment of the hearts with caffeine (1 mg/ml). Theophylline uptake was also decreased by 13.5% when caffeine‐pretreated hearts were perfused with a solution containing theophylline (300 μg/ml) plus caffeine (1 mg/ml).

Theophylline release from the hearts was also very rapid. The efflux curve was composed of three components (half‐times: 24 s; 1 min 24 s; 6 min 18 seconds). The intercepts of the linear portions of the efflux curve occurred at 61%, 38% and 1%, respectively. Contractile force and theophylline content in myocardial tissue declined in a similar manner.

It is concluded that theophylline enters myocardial tissue very rapidly by passive diffusion. Theophylline distributes itself in the heart as freely as in the perfusion medium. A very small amount may be bound within the cell in a relatively specific way.

It seems possible that the positive inotropic effect of theophylline is partly due to an action of the drug on intracellular calcium binding or storage sites. However, the principal action of theophylline is assumed to be on the sarcolemma where it increases calcium influx from the extracellular space. This conclusion is based on the fact that the time courses of the increase in contractile force and of theophylline uptake into the cell were dissimilar.
THE PHARMACOKINETICS OF NEOSTIGMINE AND 3‐HYDROXYPHENYLTRIMETHYLAMMONIUM IN THE RAT: DOSE‐DEPENDENT EFFECTS AFTER PORTAL VEIN ADMINISTRATION
Authors: BARBER H.E. , BOURNE G.R.
Published: July 2012

The elimination kinetics of [14C]‐neostigmine iodide and [14C]‐3‐hydroxyphenyltrimethylammonium iodide (3‐OH PTMA) have been studied in the rat.

The presence of a renal secretory pathway for neostigmine and 3‐OH PTMA has been confirmed.

For neostigmine and 3‐OH PTMA, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that both compounds are subject to extensive metabolism during the first passage through the liver.

Neostigmine was eliminated by dose‐independent kinetics after jugular vein administration but dose‐dependent after portal vein administration. In the latter case the fraction eliminated as neostigmine increased with increasing dose. This increase was not accompanied by any change in the fraction of the metabolites eliminated.

After portal vein administration of 3‐OH PTMA, the fraction of the dose eliminated as 3‐OH PTMA also increased with increasing dose. This change was accompanied by a decrease in the fraction of the metabolites eliminated which were excreted at a constant rate.
METABOLIC AND CARDIOVASCULAR EFFECTS OF ISOPRENALINE AND SALBUTAMOL IN THE DOG
Authors: KELLY J.G. , SHANKS R.G.
Published: July 2012

The intravenous infusion of isoprenaline and salbutamol into the greyhound increased heart rate and levels of free fatty acids, lactic acid and glucose.

On terminating the infusions of isoprenaline the changes produced declined rapidly but the effects produced by salbutamol were more persistent. When high doses of salbutamol had been infused, glucose and lactic acid levels in fact increased during the 20 min following the infusions.

These results support suggestions that, in the dog, lipolysis is mediated by β1 ‐adrenoceptors and liver glycogenolysis by β2 ‐adrenoceptors. The β‐adrenoceptors mediating muscle glycogenolysis could not be assigned unequivocally to either subtype.

The differences in the behaviour of isoprenaline and salbutamol in the period following the infusions are considered to be due partly to slower removal of salbutamol. Increases in lactic acid levels after infusion of large amounts of salbutamol may be secondary to the persistence of high glucose levels.
PHARMACOLOGICAL STUDIES ON SURUGATOXIN, THE TOXIC PRINCIPLE FROM JAPANESE IVORY MOLLUSC (Babylonia japonica)
Authors: HAYASHI E. , YAMADA S.
Published: July 2012

Some pharmacological properties of surugatoxin (SGTX), a purified toxic substance from the Japanese ivory mollusc (Babylonia japonica), have been investigated. SGTX (50 nmol/kg i.v.) produced a prolonged fall of blood pressure in anaesthetized cats. This hypotensive effect was neither blocked by atropine and propranolol nor by spinal cord transection.

SGTX (37‐50 nmol/kg i.v.) inhibited the hypertensive and hypotensive response to 1, 1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) and to electrical stimulation of the splanchnic and vagal nerve, whereas it usually augmented the hypertensive response to adrenaline and to 4‐(m‐hlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride (McN‐A‐343) in anaesthetized cats.

Close intra‐arterial injection of SGTX (6.2‐12.3 nmol/kg) to the superior cervical ganglion blocked the contractile response of the nictitating membrane to preganglionic stimulation of cervical sympathetic nerve or injected DMPP, but not to postganglionic stimulation or to injected adrenaline and McN‐A‐343.

SGTX affected neither the indirectly nor the directly stimulated response of the rat isolated phrenic nerve‐diaphragm at concentrations less than 12.3 MM.

The effect of SGTX on the contractile response to some agonists and on the twitch response to transmural stimulation in the guinea‐pig isolated ileum was investigated. At <12.3 MM SGTX did not depress responses to acetylcholine or histamine. The curves for nicotine‐ and DMPP‐induced contractions were shifted to the right and depressed gradually as the concentration of SGTX was increased (12.3 nM‐1.23 μM). SGTX partially inhibited the contraction induced by 5‐hydroxytryptamine and the transmurally‐stimulated twitch response.

These results suggest that SGTX has a ganglion‐blocking action. The mode of anti‐nicotinic action of SGTX in the guinea‐pig isolated ileum seems to differ from that of hexamethonium and tetraethylammonium and to resemble more closely that of mecamylamine.
INFLUENCE OF COCAINE AND SODIUM ON BRETYLIUM UPTAKE BY RESERPINE‐TREATED GUINEA‐PIG LEFT ATRIUM
Authors: GARCÍA A.G. , SÁNCHEZ‐GARCÍA P.
Published: July 2012

The effects of cocaine and sodium on bretylium uptake into sympathetic nerve terminals were investigated in the reserpine‐treated guinea‐pig left atrium. The ability of bretylium pretreatment to increase the retention of noradrenaline was used as an index of bretylium uptake. Such increased retention has been assessed both by direct measurement and by the ability of tyramine to produce an inotropic response.

The restoration of the response to tyramine after incubation with noradrenaline was abolished when the atrium was pretreated with bretylium in the presence of cocaine. When bretylium was added before cocaine, or when α‐methyl‐noradrenaline (not a substrate for monoamine oxidase) was used for incubation, the responses to tyramine were restored in the normal way.

Bretylium greatly enhanced the retention of [3 H]‐noradrenaline; when bretylium was added in the presence of cocaine, [3 H]‐noradrenaline retention was severely impaired.

Pretreatment with bretylium in a low‐sodium (25 μM) or sodium‐free medium significantly decreased the retention of [3 H]‐noradrenaline, as compared with the control.

Potassium deprivation did not modify the enhanced retention of [3 H]‐noradrenaline induced by bretylium pretreatment.

Bretylium was released from the nerve terminals by exposure of the preparation to a sodium‐free medium or to a solution containing calcium 50 mM, leading to a considerable decrease in [3 H]‐noradrenaline retention.

The results are consistent with the view that both cocaine and sodium deprivation block the uptake of bretylium by the adrenergic nerve terminals, and that bretylium is probably taken up by a mechanism similar to or identical with the uptake system for noradrenaline and other amines.
STUDIES ON THE MECHANISM OF ACTION OF A NEW Ca2+ ANTAGONIST, 8‐(N,N‐DIETHYLAMINO)OCTYL 3,4,5‐TRIMETHOXYBENZOATE HYDROCHLORIDE IN SMOOTH AND SKELETAL MUSCLES
Authors: CHIOU C. Y. , MALAGODI MARJORIE H.
Published: July 2012

The rabbit aortic strip, guinea‐pig ileum and rabbit skeletal muscle sarcoplasmic reticulum preparations were used to determine at which sites and in what manner 8‐(N,N‐diethylamino)‐octyl 3,4,5‐trimethoxybenzoate (TMB‐8) interferes with Ca2+ availability in smooth and skeletal muscles.

TMB‐8 (50 μM) significantly inhibited equivalent responses of the rabbit aortic strip to KCl and noradrenaline.

TMB‐8 (65 μM) produced no significant alteration in the extracellular space of the guinea‐pig ileum as measured with [3 H]‐sorbitol.

The resting cellular Ca2+ influx as well as the resting 45 Ca2+ efflux in the guinea‐pig ileum preparation were significantly inhibited by TMB‐8 (65 μM).

TMB‐8 (5 μM and 50 μM) had no significant effect on the uptake of 45 Ca2+ by the sarcoplasmic reticulum preparation of skeletal muscle; however, TMB‐8 (5 μM) did significantly inhibit the caffeine (20 μ)‐induced release of 45 Ca2+ from this preparation.

It is concluded that TMB‐8 reduces Ca2+ availability in smooth and skeletal muscles by stabilizing Ca2+ binding to cellular Ca2+ stores and thereby inhibits the release of this Ca2+ by contractile stimuli.
ON THE ACTIONS OF COMPOUNDS RELATED TO DOPAMINE AT A NEUROSECRETORY SYNAPSE
Authors: GINSBORG B.L. , TURNBULL K.W. , HOUSE C.R.
Published: July 2012

The effects of a number of substances related to dopamine, including all its methylated derivatives, were investigated on the membrane potential and response to nerve stimulation of cockroach salivary gland cells.

Only N‐methyldopamine (epinine), N,N‐dimethyldopamine and N,N‐dimethylnoradrenaline, all with unsubstituted hydroxyl groups, directly resembled dopamine in producing a hyperpolarization which could be as large as that caused by maximal nerve stimulation. During the continued presence of these substances the hyperpolarization waned and responses to nerve stimulation declined.

Many of the compounds caused one or both of two other effects, namely an increase in the rate of ‘spontaneous miniature hyperpolarizations’ and an enhancement of the submaximal responses to single nerve stimuli. There were no obvious structural requirements for these effects.
ACTIONS OF CARBON TETRACHLORIDE, HEXACHLOROETHANE AND THE PRODUCTS OF THEIR METABOLISM IN SHEEP ON Fasciola hepatica
Authors: BARTLET A.L.
Published: July 2012

An in vitro preparation of Fasciola hepatica is described which responded to electrical stimulation with tetanic spasms. Both carbon tetrachloride (20–500 nl/ml), and its metabolite chloroform (50–1000 nl/ml), produced contractions in the preparation which extinguished the responses to electrical stimulation. It is suggested that the spasmogenic action of carbon tetrachloride and its metabolite may contribute to the fasciolifugal action of the drug.

Hexachloroethane, another fasciolifuge, had very little effect in the preparation. However, penta‐chloroethane and tetrachloroethylene, the main products of the metabolism of hexachloroethane in sheep, were potent spasmogens in preparations of Fasciola hepatica. Pentachloroethane was about twice as potent as carbon tetrachloride.

Tetrodotoxin (2 μg/ml) did not antagonize the responses of the preparation to electrical stimulation or carbon tetrachloride.
A POSSIBLE MODULATORY ROLE FOR PROSTACYCLIN (PGI2) IN IgGa‐INDUCED RELEASE OF SLOW‐REACTING SUBSTANCE OF ANAPHYLAXIS IN RATS
Authors: BURKA J.F. , GARLAND L.G.
Published: July 2012

Antigen challenge in vivo of rat peritoneal cells (enriched with monocytes and polymorphonuclear leucocytes) passively sensitized 2 h previously with homologous antibody of the IgGa class released large amounts of slow‐reacting substance of anaphylaxis (SRS‐A, 1739 ± 59 u/ml) into the peritoneal fluid. This reaction was strongly inhibited by prostacyclin (PGI2, ED50 = 0.5 μg/kg i.p.) and by isoprenaline (ED50 = 0.2 μg/kg i.p.) but prostaglandins E1, E2 and 6‐oxo‐prostaglandin F1α were only weak inhibitors. Indomethacin (10 mg/kg, orally) augmented by 30% the release of SRS‐A, whereas thromboxane B2 (50 μg/kg i.p.) had no effect. Lowering the antigen (ovalbumin) dosage from 400 μg/ml to 10 μg/ml reduced the control release of SRS‐A by 70% and increased the inhibitory effect of prostaglandins I2, E1 and isoprenaline. Augmentation of release by indomethacin remained unchanged. These preliminary data suggested that endogenous prostacyclin may modulate the anaphylactic release of SRS‐A from rat peritoneal cells.
A CENTRALLY MEDIATED PROLONGED HYPOTENSION PRODUCED BY OXOTREMORINE OR PILOCARPINE
Authors: DAGE R.C
Published: July 2012

Oxotremorine, methyloxotremorine, pilocarpine or arecoline were given intravenously to anaesthetized cats, dogs or rats, and intraperitoneally to conscious normotensive and spontaneously hypertensive rats, pretreated with doses of methylatropine that completely blocked peripheral muscarinic receptors, to ascertain their effects on blood pressure and heart rate.

Oxotremorine but not methyloxotremorine produced a prolonged hypotension in cats and dogs but not in rats. Heart rate was not changed. Pilocarpine, although less potent, produced an identical effect, whereas the effect of arecoline was short by comparison. The hypotensive effect of these drugs was reversed by atropine.

In dogs, oxotremorine produced a prolonged hypotension with no change in heart rate or cardiac output.

A decrease in spontaneous sympathetic nerve activity accompanied the hypotension in cats. Both effects were reversed by atropine but could be reinvoked by large doses of oxotremorine.

The oxotremorine‐induced hypotension in cats was not altered by decerebration but was abolished by high cervical spinal section.

The results indicate that the prolonged hypotension elicited by oxotremorine is mediated by an action at muscarinic receptors in the brain stem resulting in a decrease in sympathetic nerve activity and peripheral resistance but not heart rate or cardiac output.
N‐ARALKYL SUBSTITUTION INCREASES THE AFFINITY OF ADRENERGIC DRUGS FOR THE α‐ADRENOCEPTOR IN RAT LIVER
Authors: AGGERBECK MARTINE , GUELLAEN GEORGES , HANOUNE JACQUES
Published: July 2012

The α‐adrenoceptor of rat liver plasma membranes was studied by use of the specificα‐antagonist [3H]‐dihydroergocryptine ([3H]‐DHEC). Catecholamines and adrenergic compounds displayed an order of affinity that is typical of anα‐receptor. Nevertheless, protokylol, a potent β‐adrenoceptor agonist, exhibited a higher affinity than that of adrenaline forα‐sites. This result might be due to its bulky substituent on the amino group.

Further displacement experiments between [3H]‐DHEC and four pairs of drugs differently substituted on the amino group (isoprenaline vs Cc‐25, orciprenaline vs fenoterol, AH 3474 vs labetalol, pindolol vs hydroxybenzylpindolol) provided evidence that N‐alkyl substitution decreased the affinity forα‐sites (20 μm < KD < 500 μm), whereas an N‐aralkyl one increased the affinity (0.17 μm < KD < 4.6 μm).

It is concluded that a substitution on the amino group by a bulky, hydrophobic moiety enhances the affinity of drugs for the α‐adrenoceptors.
DIRECT VASODILATATION BY LABETALOL IN ANAESTHETIZED DOGS
Authors: DAGE RICHARD C. , HSIEH CHIH PENG
Published: July 2012

The effects of several doses of labetalol (0.03 to 1 mg/kg) given intravenously and into the vertebral artery were examined in anaesthetized dogs. Labetalol produced no immediate (5 min) change in blood pressure or heart rate when given by either route, with one exception. Heart rate increased after the first dose (0.03 mg/kg i.v.) of labetalol. By contrast, clonidine (1 μg/kg) elicited an immediate and prolonged fall in blood pressure and heart rate when given into the vertebral artery, but not intravenously.

In the isolated perfused gracilis muscle of the dog, following α‐ and β‐adrenoceptor blockade, intra‐arterial injections of labetalol (0.3 to 10 mg) or diazoxide (0.3 to 1 mg) produced decreases in perfusion pressure that were dose‐related in both magnitude and duration. The doses of labetalol and diazoxide required to produce a half‐maximal vasodilatation were 1.5 mg and 0.7 mg respectively.

In adrenalectomized, vagotomized spinal dogs, both labetalol (0.1 to 1 mg/kg i.v.) and hydralazine (1 mg/kg i.v.) elicited a fall in blood pressure without changing heart rate or cardiac output.

These results suggest that the hypotension produced by systemically administered labetalol does not involve an action in the brain. It may involve instead a direct vasodilatation of resistance blood vessels, since labetalol in sufficient amounts, directly dilates resistance vessels and lowers blood pressure in dogs devoid of adrenergic tone. Direct vasodilatation may be a component of the hypotensive action of labetalol.
HYPERMOTILITY OF THE AMPHETAMINE TYPE INDUCED BY A CONSTITUENT OF KHAT LEAVES
Authors: KALIX PETER
Published: July 2012

Khat leaves, widely used as a stimulant in East Africa and the Arab Peninsula, contain the alkaloid, (−)‐cathinone. The effects of this substance on the locomotor activity of rats were compared to those of (+)‐amphetamine. Both substances were found to induce a similar degree of hypermotility. Furthermore, the effect of (−)‐cathinone on the locomotor behaviour of hypophysectomized rats was analogous to that reported for (+)‐amphetamine in such animals. The results support the claim that the symptoms caused by the chewing of khat are amphetamine‐like.
CORONARY VASOCONSTRICTION BY LOCALLY ADMINISTERED ACETYLCHOLINE, CARBACHOL AND BETHANECHOL IN ISOLATED, DONOR‐PERFUSED, RAT HEARTS
Authors: SAKAI K.
Published: July 2012

Experiments were carried out on rat isolated heart preparations in which the coronary vasculature was perfused through the aorta at a constant flow rate with arterial blood from donor animals. Single doses of drugs were injected into the aortic cannula.

Small doses of acetylcholine, carbachol or bethanechol decreased perfusion pressure (PP) without markedly affecting left ventricular pressure (LVP) and heart rate (HR); larger doses of these drugs increased PP (vasoconstriction), and decreased LVP and HR in a dose‐dependent manner.

Acetylcholine, carbachol and bethanechol had almost no effects when perfused through the aorta in such a way as to exclude the coronary vessels.

Coronary vasoconstriction in response to acetylcholine, carbachol and bethanechol was not significantly affected by reserpine pretreatment, phentolamine or hexamethonium, but was antagonized by small doses of atropine.

From these results it is concluded that in the coronary vasculature of the rat, the receptors involved in the vasoconstrictor actions of acetylcholine, carbachol and bethanechol are muscarinic.
CHARACTERISTICS OF 5‐HYDROXYTRYPTAMINE TRANSPORT IN PANCREATIC ISLETS
Authors: LINDSTRÖM PER , SEHLIN JANOVE , TÄLJEDAL INGE‐BERT
Published: July 2012

Transmembrane transport of 3H‐labelled 5‐hydroxytryptamine (5‐HT) by isolated pancreatic islets of non‐inbred ob/ob mice was studied.

5‐HT was vigorously accumulated in a temperature‐dependent way by the islet cells.

Studies of the concentration‐dependence of [3H]‐5‐HT uptake revealed complex kinetics with one component being saturated at 1 to 3 um 5‐HT (apparent association constant 0.6 × 106 m−1) and the other non‐saturated up to 1 mm 5‐HT.

The saturable uptake was inhibited by Na+‐deficiency and metabolic poisoning with 2,4‐dinitro‐phenol and antimycin A, whereas the non‐saturable component was not affected.

Omission of K+, Ca2+ or Mg2+ did not affect the uptake rate.

It is concluded that 5‐HT is taken up by pancreatic β‐cells by mechanisms very similar to those observed in thrombocytes and neurones.
UNEXPECTED ANTAGONISM IN THE RAT VAS DEFERENS BY BENZOMORPHANS WHICH ARE AGONISTS IN OTHER PHARMACOLOGICAL TESTS
Authors: GILLAN MAUREEN G.C. , KOSTERLITZ HANS W. , MAGNAN JACQUES
Published: July 2012

The benzomorphans, ethylketazocine, bremazocine and MR 2034 are pure agonists in the guinea‐pig ileum and mouse vas deferens but are competitive antagonists without agonist activity in the rat vas deferens.
SEDATIVE ACTIVITY OF CANNABIS IN RELATION TO ITS Δ‘‐trans‐TETRAHYDROCANNABINOL AND CANNABIDIOL CONTENT
Authors: PICKENS JOAN T.
Published: July 2012

The oral sedative potencies of cannabis herb, crude ethanolic and petroleum‐ether fractions, were assayed against Δ′‐trans‐tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h.

The THC contents of the extracts were determined chemically by gas‐liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis herb, which contained THC but no CBD, was 4.47 and for ethanolic and petroleum‐ether extracts, 5.26 and 4.39, respectively.

The sedative potency expressed as SDA50, the dose required to give 50% effect over 6 h, was 1.06 (0.98 to 1.15) mg/kg for THC; 4.72 (4.22 to 5.27) mg/kg for cannabidiol and 1.26 (1.22 to 1.80) mg/kg for chlorpromazine.

An infusion of cannabis herb made with boiling water was shown to have sedative activity of very low potency.

When the cannabinoids were completely extracted from a sample of herb with petroleum‐ether the aqueous and ethanolic extracts of the marc had some sedative activity; but the 70% ethanolic fraction had none.

The sedative activity of THC, cannabis herb and a water soluble fraction is blocked by aspirin, a cyclo‐oxygenase inhibitor, and restored by prostaglandin E2 (PGE2).

The sedative effect of chlorpromazine is not blocked by aspirin.
AFFINITIES OF THE PROTONATED AND NON‐PROTONATED FORMS OF HYOSCINE AND HYOSCINE N‐OXIDE FOR MUSCARINIC RECEPTORS OF THE GUINEA‐PIG ILEUM AND A COMPARISON OF THEIR SIZE IN SOLUTION WITH THAT OF ATROPINE
Authors: BARLOW R.B. , WINTER ELIZABETH A.
Published: July 2012

At 37°C in 0.1 m NaCl the pKa of hyoscine (10 mm) is 7.53; the non‐protonated form has about one‐tenth of the affinity (log K = 8.58) of the protonated form (log K = 9.58) for muscarine‐sensitive receptors of the guinea‐pig ileum at 37°C.

In the same conditions the pKa of hyoscine N‐oxide is 5.78 and the non‐protonated form is inactive on the ileum whereas the protonated form is highly active with log K estimated to be 9.9, at least as active as hyoscine methobromide (log K = 9.85).

Hyoscine methobromide appears to occupy less space in water than atropine methobromide; hyoscine hydrochloride occupies less space than hyoscyamine hydrochloride: the non‐protonated forms are slightly bigger. Hyoscine N‐oxide hydrobromide is slightly smaller than hyoscine methobromide but the removal of the proton is accompanied by a reduction in volume, such as is seen with other zwitterions.

These differences in volume indicate a reduction in entropy on solution which may allow a greater increase in entropy on binding to receptors and hence greater affinity. The higher activity of hyoscine itself could also be due to the presence of the N‐methyl group in the axial position, rather than equatorial as in hyoscyamine or atropine.

The different position of the N‐methyl group may partly explain why the pKa of hyoscine is 2 units lower than that of hyoscyamine or atropine. It is also probable that the unionized form of hyoscine is stabilized by hydration.

Although hyoscine N‐oxide is only weakly active at pH 7.6, it is present in a highly active form in the acid environment of the stomach and so might be expected to act selectively at this site.
DOWN‐REGULATION OF THE SODIUM PUMP FOLLOWING CHRONIC EXPOSURE OF HeLa CELLS AND CHICK EMBRYO HEART CELLS TO OUABAIN
Authors: AITON J.F. , LAMB J.F. , OGDEN P.
Published: July 2012

HeLa cells and primary cultures of embryonic chick heart cells were grown in medium containing low concentrations of ouabain for 24 h.

Compared with normal cells, cells grown in ouabain have fewer free sodium pump sites, an increased intracellular sodium concentration and a decreased intracellular potassium concentration. The cells are able to maintain their intracellular ion contents because the remaining pump sites have an increased turnover rate.

When cells that have been chronically exposed to ouabain are returned to normal growth medium, the sodium pump site numbers increase; the recovery process begins within 6 to 8 h and is complete within 24 h. Recovery of pump site numbers is primarily dependent upon de novo protein synthesis since the protein synthesis inhibitor, cycloheximide, prevents recovery.
ACTIVITY OF CANNABIS IN RELATION TO ITS Δ‘‐trans‐TETRAHYDROCANNABINOL CONTENT
Authors: FAIRBAIRN J.W. , PICKENS JOAN T.
Published: July 2012

Conditions have been worked out for a reliable estimation of the cataleptic activity of Δ′‐trans‐tetrahydrocannabinol (THC) after oral administration to mice, using the ring test over a period of 6 h.

By this method, the activity of cannabis herb and 5 crude fractions were measured against THC; at the same time the THC contents were determined chemically.

The B/C ratio (biological activity divided by chemical assay) was calculated for each. With cannabis herb the value was 3.3 and with extracts prepared with ethanol or 70% ethanol the values ranged from 3.2 to 7.1, indicating that in all samples the activity was much higher than would be expected from their THC content.

The cannabinoids were completely extracted from a sample of herb using petroleum spirit and the marc examined for a possible synergist. Surprisingly, it contained a powerful inhibitor of the action of THC, which could be restored by intraperitoneal prostaglandin E2 (3 μg/kg). Some crude fractions had inhibitory activities about 10 times that of aspirin.

In contrast, the petroleum spirit extract (referred to in 4) had a surprisingly high B/C ratio of 23, indicating that a powerful synergist of THC activity is present.

The net effect of the herb and ethanol extracts is probably due to a balance of synergist and inhibitor.
THE EFFECT OF TAURINE ON HIGH POTASSIUM‐ AND NORADRENALINE‐INDUCED CONTRACTION IN RABBIT EAR ARTERY
Authors: FRANCONI FLAVIA , GIOTTI ALBERTO , MANZINI STEFANO , MARTINI FLAVIO , STENDARDI ISABELLA , ZILLETTI LUCILLA
Published: July 2012

Intraluminal administration of taurine (40 mm) did not affect the contractile tone of rabbit isolated ear artery.

Taurine (10–80 mm) exerted a powerful concentration‐dependent, vasodilator action in arteries contracted with high potassium medium.

In the same experimental conditions, the taurine analogues β‐alanine and homotaurine, had no effect.

Taurine (40–80 mm) did not affect in a significant manner the tonic component of the noradrenaline (5 × 10−6m)‐induced contraction.

When noradrenaline (5 × 10−6m) was followed by the administration of high potassium medium a further increase in intraluminal pressure was observed. Under these conditions taurine (40 mm) reversed specifically the component due to the high potassium medium.
The effect of McN‐A‐343 on muscarinic receptors in the cerebral cortex and heart
Authors: Birdsall N.J.M. , Burgen A.S.V. , Hulme E.C. , Stockton J.M. , Zigmond M.J.
Published: July 2012

McN‐A‐343 behaves as a competitive agonist in binding to muscarinic receptors in the cerebral cortex. In its interaction with myocardial muscarinic receptors it is not competitive but it retains features of agonist binding.
Forskolin activation of an identified peptide‐sensitive motoneurone in Aplysia
Authors: Ram J.L.
Published: July 2012

Activation of a physiological response by the adenylate cyclase activator, forskolin, has been suggested as a new criterion for testing the role of cyclic AMP. In Aplysia, motoneurone B16, which innervates muscle 15, is activated by the peptide egg‐laying hormone (ELH). In high magnesium‐low calcium medium, used to block synaptic activity, forskolin produced a similar response to ELH. Forskolin, at a concentration of 100 μm, consistently activated the ELH‐sensitive neurone; vehicle produced no response while 30 μm forskolin usually produced lower levels of activity than 100 μm. The data are consistent with cyclic AMP mediation of the ELH response.
Spasmolytic effect of cadmium and cadmium uptake in aorta
Authors: Nasu Tetsuyuki
Published: July 2012

The relationship between inhibition of tension by Cd2+ in aorta and the kinetics of cadmium uptake and efflux was studied. Cd2+ (0.01–0.5 mm) inhibited the contraction of aorta to high‐K+ (30 mm) in a dose‐dependent manner.

The high‐K+‐induced tension completely returned to control values after 60 min washing with a solution containing 5 mm disodium edetate (EDTA) or 5 mm cysteine, following a treatment with 0.5 mm Cd2+ for 30 min; after washing with normal medium only 15% of the control response returned.

Cadmium uptake increased with an increase of the Cd2+ concentration (0.01–0.5 mm).

Aortae preincubated with 0.5 mm Cd2+ for 60 min were washed subsequently with a medium containing 5 mm EDTA or 5 mm cysteine. About 5% of the original tissue cadmium was retained after washing with EDTA or cysteine.

It is suggested that Cd2+ binds chiefly to the surface membrane of aorta. It seems possible that the quantity bound is correlated with the degree of inhibition of tension.
Blood pressure changes in spontaneously hypertensive rats correlate with aortic prostacyclin formation
Authors: Fahr A. , Förster W. , Taube Ch.
Published: July 2012

The relationship between the blood pressure fall, induced by antihypertensive drugs or bleeding, and the formation of prostacyclin (PGI2)‐like activity in the thoracic aorta of spontaneously hypertensive rats has been investigated. Inhibition of ADP‐induced platelet aggregation was used to assess PGI2‐like activity.

The decreases in blood pressure produced by clonidine, dihydralazine and prazosin were associated with increases of PGI2‐like activity of 50–80%. The increase in PGI2‐like activity correlated well with the blood pressure decrease, independently of the mechanism of the fall in blood pressure.
The role of histamine receptors in the release of renin
Authors: Gerber J.G. , Nies A.S.
Published: July 2012

The effect of intrarenal histamine, dimaprit (H2‐agonist) and 2‐(2‐pyridyl) ethylamine (H1‐agonist) on renin release was examined in anaesthetized dogs.

In dogs with intact kidneys, histamine and dimaprit administration resulted in renal vasodilatation, a two fold increase in urinary sodium excretion, and no change in renal renin release. 2(2‐Pyridyl) ethylamine administration resulted in renal vasodilatation, a 25% decrease in urinary sodium excretion and a significant increase in renin release.

In dogs with non‐filtering kidneys, dimaprit administration resulted in renal vasodilatation and a significant increase in renin release, while 2(2‐pyridyl) ethylamine administration resulted in renal vasodilatation but no change in renin release.

Our data suggest that histamine is a potential participant in the release of renin through stimulation of H2‐receptors, but it is a weak agonist.

In addition, the direct effect of histamine analogues on renin release is modulated by their effects on electrolyte excretion probably by influencing the renal chemoreceptor release of renin mediated by the macula densa.
Classification of β‐adrenoceptors in isolated bronchus of the pig
Authors: Goldie Roy G. , Paterson James W. , Wale Janet L.
Published: July 2012

(±)‐Isoprenaline (Iso), (−)‐adrenaline (Ad), (−)‐noradrenaline (NA), the β2‐selective adrenoceptor agonist (±)‐fenoterol (Fen) and the β1‐selective adrenoceptor agonist (±)‐RO363 caused concentration‐dependent relaxation of preparations of pig bronchus pre‐contracted with carbachol 40 ng/ml (0.22 μM). Iso, Ad, NA and Fen caused complete relaxation of carbachol‐induced tone, but RO363 caused relaxation equivalent to only 59% of the maximal response to Iso.

When relaxation responses to these amines were plotted as a % of their maximal effects, comparison of EC50 values showed that the order of potency was RO363 > Iso > NA > Fen > Ad (14.4:4.6:1:0.4:0.3).

pA2 values determined for the β‐adrenoceptor antagonists propranolol (non‐selective) and atenolol (β1‐selective), or the partial agonist salbutamol (β2‐selective) using Iso as agonist were 8.3, 7.3 and 4.4 respectively. The pA2 value for atenolol using RO363 as the agonist was 7.6.

These results indicate that porcine bronchus contains a homogeneous population of β1‐adrenoceptors.
H1‐histamine receptors may mediate the contractile response of guinea‐pig ileum to ‘histamine‐free’ splenic extracts
Authors: Ainz L.F. , Casis E. , de Gandarias J.M. , Gil‐Rodrigo C.E. , de Gandarias J.J. Goiriena
Published: July 2012

A water‐soluble splenic factor, which produces a contractile response of the guinea‐pig ileum, that is resistant to cholinoceptor and adrenoceptor antagonists is described.

The ileal contractions elicited by the splenic extract showed some significant differences from those elicited by 5‐hydroxytryptamine. The responses to splenic extract were not affected by the D‐tryptamine‐receptor antagonist, methysergide.

The effect of the splenic extract on the guinea‐pig ileum was similar to that of histamine. The H1‐histamine antagonists, (+)‐chloropheniramine and diphenhydramine, caused a parallel shift to the right of the splenic extract dose‐response curve without suppression of the maximum response. A pA2 value of 8.97 ± 0.03 for (+)‐chlorpheniramine and 7.55 ± 0.1 for diphenhydramine was calculated.

Significant histamine levels, as determined by fluorometric methods, could not be detected in the splenic extract. Likewise, the splenic factor did not release histamine from the intestinal preparation.

These results support the view that: (i) the splenic factor acts through H1‐histamine receptors; (ii) it is not histamine; (iii) it does not have any histamine releasing effect on the ileal smooth muscle.
Inhibition of lymphocyte activation by gold sodium thiomalate
Authors: Hopkins Stephen J. , Jayson Malcolm I.V. , Van der Zeil Peter
Published: July 2012

Activation of lymphoid cells by both T and B cell mitogens was inhibited by gold sodium thiomalate (GST).

The action of GST did not appear to be exerted at early stages of lymphocyte activation.

Inhibition by GST was sustained throughout 4 days of culture.

The inhibitory effect of GST was reduced at low serum concentrations.

Sodium thiomalate and sodium chloroaurate were also able to inhibit lymphocyte activation.
Antagonism of tetrodotoxin‐ and procaine‐induced axonal blockade by adenine nucleotides in the frog sciatic nerve
Authors: Ribeiro J. A. , Sebastião A.M.
Published: July 2012

The effects of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine on compound action potentials were investigated in de‐sheathed frog‐sciatic nerve preparations.

ATP and ADP but not adenosine antagonized the inhibitory action of tetrodotoxin (TTX) on nerve conduction. AMP had little or no antagonistic effect on TTX‐induced axonal block. ATP was more effective than ADP. The effects of the nucleotides were related to the degree of the TTX‐induced inhibition and were more evident where the blockade was more intense.

ATP and ADP but not adenosine antagonized the procaine‐induced axonal blockade which, in some experiments, was completely reversed by these nucleotides. ATP and ADP were of similar potency.

The axonal blockade induced by pentobarbitone was not antagonized by ATP, ADP, AMP or adenosine.

The possibility that ATP stimulates a TTX‐sensitive sodium channel is discussed.
Relationship between structure of phenothiazine analogues and their activity on platelet calcium fluxes
Authors: Enouf J. , Lévy‐Toledano S.
Published: July 2012

Phenothiazine analogues have been tested for their effect on calcium uptake into platelet membrane vesicles and on ionophore‐induced platelet activation, both phenomena being Ca2+‐dependent.

Both calcium uptake into membrane vesicles and ionophore‐induced platelet activation were inhibited by the drugs.

Evidence for two inhibitors as potent as chlorpromazine and trifluoperazine was found.

These drugs are apparently competitive inhibitors of calcium uptake.

A structure‐activity relationship has been established.

The data suggest that the phenothiazines are able to inhibit calmodulin‐insensitive calcium uptake of platelet membrane vesicles and that therefore they cannot be assumed to be selective inhibitors of calmodulin interactions under all circumstances.
The effects of ryanodine, EGTA and low‐sodium on action potentials in rat and guinea‐pig ventricular myocytes: evidence for two inward currents during the plateau
Authors: Mitchell Mary R. , Powell T. , Terrar D.A. , Twist V.W.
Published: July 2012

Action potentials were recorded from single cells isolated from rat and guinea‐pig ventricular muscle. In rat cells the repolarization showed two distinct phases, referred to as the early and late phases. In guinea‐pig cells there was a maintained plateau.

Reducing external sodium by replacement with lithium or choline suppressed the late phase of the action potential in rat cells, and shortened the plateau of the action potential in guinea‐pig cells.

Intracellular EGTA abolished contraction while suppressing the late phase of the action potential in rat cells, and shortening the plateau in guinea‐pig cells.

Ryanodine (1 μm), which is thought to inhibit the release of calcium from internal stores, suppressed contraction and the late phase of the action potential in rat cells. In guinea‐pig cells, there was no substantial effect of ryanodine (1 μm) on either contraction or the time course of the action potential.

The late phase of the action potential in rat cells was suppressed by increasing the external potassium concentration to 12 mm, and enhanced by reducing external potassium to 1.2 mm

It is concluded that an inward current activated by internal calcium contributes to the late phase of the action potential in rat cells, and to the plateau in guinea‐pig cells. Two possibilities are a current arising from electrogenic sodium‐calcium exchange, and a current through ion channels activated by calcium. The effects of reducing external sodium would be consistent with either mechanism. The contribution of such an inward current would be expected to be modified by outward currents through a rectifying potassium conductance which varies with external potassium concentration. In the rat, but not the guinea‐pig, the rise in internal calcium which activates the inward current seems to be largely dependent on ryanodine‐sensitive release of calcium from internal stores.
Dual population of GABAA and GABAB receptors in rat pars intermedia demonstrated by release of αMSH caused by barium ions
Authors: Demeneix Barbara A. , Desaulles Eric , Feltz Paul , Loeffler Jean‐Philippe
Published: July 2012

We have studied the effects of selective GABAA and GABAB agonists on α‐melanophore stimulating hormone (αMSH) release from intact rat neurointermediate lobes (NIL) in vitro. Agonist effects were tested against either basal αMSH output or BaCl2 (5 mM)‐evoked release.

GABA (50 μM) produced a biphasic effect on basal release, with an enhancement followed by inhibition of release. The enhancement but not the inhibition was blocked by bicuculline methiodide (100 μM).

Baclofen (10 μM), a specific GABAB agonist, reduced the basal and Ba2+‐evoked hormonal release in a stereospecific manner. (−)−Baclofen (5 μM) was active whereas the (+)‐isomer was inactive at the same concentration.

Isoguvacine (50 μM) a specific GABAA agonist, potentiated the Ba2+‐evoked release of αMSH. GABA (50 μM) mimicked this effect, and its action was antagonized by bicuculline methiodide (200 μM).

The results suggest that both GABAA and GABAB receptors are present on the endocrine cells of the intermediate lobe.