bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECTS ON RABBIT NODAL, ATRIAL, VENTRICULAR AND PURKINJE CELL POTENTIALS OF A NEW ANTIARRHYTHMIC DRUG, CIBENZOLINE, WHICH PROTECTS AGAINST ACTION POTENTIAL SHORTENING IN HYPOXIA
Authors: MILLAR J.S. , WILLIAMS E.M. VAUGHAN
Published: July 2012

The effects of cibenzoline (UP 339–01), a new anti‐arrhythmic drug, have been investigated in various cardiac tissues.

UP 339–01 produced a bradycardia, due partly to prolongation of the intracellularly recorded sinus node action potential duration (APD) and partly to depression of the maximum rate of depolarization (MRD). The slope of the slow diastolic depolarization was not significantly reduced.

UP 339–01 was not a β‐adrenoceptor antagonist.

UP 339–01 was negatively inotropic, and shifted the relation between [Ca2+]o and force of contractions to the right, and increased A‐H conduction time. It was concluded that UP 339–01 restricted slow inward current.

In all cardiac tissues depolarized by fast inward current, UP 339–01 caused a reduction in MRD and conduction velocity. The reduction was similar in atrial muscle, His and terminal Purkinje fibres, but in papillary muscle the effect was about half as great. On desheathed frog nerve UP 339–01 had a local anaesthetic potency slightly greater than that of procaine.

APD was significantly prolonged in a dose‐related manner in ventricular muscle but to a lesser extent in the bundle of His and atrial tissue. In terminal Purkinje fibres APD50 and APD90 were unaltered, but the transient outward current (‘notch’) was abolished, resulting in a lengthening of APD20.

The effective and functional refractory periods of the A—V node and right bundle branch were both lengthened by UP 339–01 in a dose‐related manner, and the difference between them was greatly increased.

UP 339–01 (2.63 μm) completely prevented the shortening of APD90 induced by hypoxia, and the shortening of APD50 and APD20 was much attenuated. There was no protection against hypoxic depression of contractions.

It was concluded that UP 339–01 is a highly active class 1 anti‐arrhythmic agent with additional class 3 and 4 properties.
THE ACTION OF PORCINE GLUCAGON ON THE MOTILITY OF THE CANINE DUODENUM AND JEJUNUM
Authors: EVANS D.F. , FOSTER G.E. , HARDCASTLE J.D. , JOHNSON F. , WRIGHT J.W.
Published: July 2012

Intravenous bolus doses of porcine glucagon of 0.001 −0.05 mg kg−1 caused intense stimulation of the duodenum and jejunum of the dog.

Intravenous infusion of porcine glucagon at 0.025 −0.05 mg kg−1 h−1 caused similar stimulation. In both cases the stimulation was phasic in nature.

Stimulation of the duodenum and jejunum following glucagon was accompanied by a decrease in frequency of the intestinal basic electrical rhythm (BER). No change was seen in the intervals between successive periods of phase III motor activity.
INHIBITION OF ADRENALINE‐INDUCED PLATELET AGGREGATION BY THE α‐ADRENOCEPTOR BLOCKING DRUG BENEXTRAMINE
Authors: BELLEAU B. , BENFEY B.G. , MELCHIORRE C. , MONTAMBAULT M.
Published: July 2012

The activity of the irreversible α‐adrenoceptor blocking drug, benextramine, was determined in human platelets.

Compared to its postsynaptic and presynaptic α‐adrenoceptor blocking potency, benextramine had a very low potency as an antagonist of adrenaline‐induced platelet aggregation.

The results confirm the previous observation with the irreversible α‐adrenoceptor blocking drug, phenoxybenzamine, that platelet α‐adrenoceptors differ from postsynaptic and presynaptic α‐adrenoceptors.
EFFECTS OF H2‐RECEPTOR ANTAGONISTS AND ANTICHOLINOCEPTOR DRUGS ON GASTRIC AND SALIVARY SECRETION INDUCED BY BETHANECHOL IN THE ANAESTHETIZED DOG
Authors: DALY M.J. , HUMPHRAY JANET M. , STABLES R.
Published: July 2012

The H2‐receptor antagonists, ranitidine and cimetidine, have been compared with, atropine and pirenzepine for their effects on gastric acid output, and on salivary secretion from the left parotid gland in the anaesthetized dog. Gastric and salivary secretions were elicited by intravenous infusion of bethanechol.

Atropine (0.3–1 Mg μg/kg) or pirenzepine (3–10 μg/kg) reduced both gastric and salivary secretions, pirenzepine showing little evidence of any selectivity for gastric secretion.

The H2‐receptor antagonists, ranitidine (30–1000 μg/kg) and cimetidine (100–3000 μg/kg), selectively inhibited gastric secretion and even at relatively high dose levels did not alter salivary volume.
ANTAGONISM OF THE THROMBOXANE‐SENSITIVE CONTRACTILE SYSTEMS OF THE RABBIT AORTA, DOG SAPHENOUS VEIN AND GUINEA‐PIG TRACHEA
Authors: JONES R.L. , PEESAPATI V. , WILSON N.H.
Published: July 2012

The thromboxane‐sensitive contractile systems in spirally‐cut preparations of the rabbit aorta, dog saphenous vein and guinea‐pig trachea have been compared. The full or partial agonist activities of a range of bicyclic ring analogues were found to be remarkably similar on the three preparations. In addition, EP 045, a prostanoid with a phenylsemicarbazone ω‐chain, blocked the action of both thromboxane A2 (TXA2) and the bicyclic ring analogues. Using 11,9‐epoxymethano prostaglandin H2 as the agonist, linear Schild plots with slopes close to unity were obtained on each preparation; this suggests a competitive type of antagonism.

Analogues of prostaglandin D2 (PGD2), PGE2 and PGF2α also contracted the three smooth muscle preparations; those analogues containing a 16‐p‐halophenoxy residue were highly active. On the rabbit aorta, EP 045 completely blocked the contractile actions of these agonists, perhaps indicating a single type of prostanoid receptor in this tissue. On the dog saphenous vein PGD2, PGE2 and 15‐methyl PGE2 exhibited relaxant activity when the tissue was partially contracted with either a thromboxane agonist or noradrenaline. On the guinea‐pig trachea 16,16‐dimethyl PGE2 and the 16‐p‐chlorophenoxy analogue of PGE2 were potent contractile agents whose action was not blocked by EP 045. PGE2 and 15‐methyl PGE2 showed similar properties but exhibited relaxant activity with increasing concentrations in the organ bath. Our results indicate the presence of three types of prostanoid receptors in the guinea‐pig trachea: thromboxane‐ and PGE‐sensitive systems mediating contraction and a PGE‐sensitive system mediating relaxation.

The similarity of the thromboxane‐sensitive systems in the three smooth muscle preparations is discussed with particular reference to the differences in the equilibrium dissociation constants for EP 045.
SELECTIVE DEPRESSION OF SYNAPTIC TRANSMISSION OF SPINAL NEURONES IN THE CAT BY A NEW CENTRALLY ACTING MUSCLE RELAXANT, 5‐CHLORO‐4‐(2‐IMIDAZOLIN‐2‐YL‐AMINO)‐2, 1, 3‐BENZOTHIODAZOLE (DS103–282)
Authors: DAVIES JOHN
Published: July 2012

The effects of a new muscle relaxant, 5‐chloro‐(2‐imidazolin‐2‐yl‐amino)‐2, 1, 3‐benzothiodazole (DS103–282) have been examined on segmental reflexes and responses of single neurones in the spinal cord of the anaesthetized cat to stimulation of peripheral afferents, ventral roots, acetylcholine and various amino acids. Drugs were administered intravenously and/or iontophoretically.

Polysynaptic reflexes were depressed in a dose‐dependent manner by 0.01–0.1 mg/kg DS103–282 whereas monosynaptic reflexes were relatively insensitive to this agent.

In studies on single dorsal horn neurones, iontophoretically and intravenously administered DS103–282 depressed synaptic excitatory responses, polysynaptic responses being much more sensitive to this agent than monosynaptic responses. In contrast (−)‐baclofen preferentially reduced monosynaptic excitation.

Doses or ejecting currents of DS103–282 which greatly depressed polysynaptic excitatory responses also reduced spontaneous firing of neurones, but either had no effect or minimal depressant effects on responses to iotophoretically administered excitant amino acids. Acetylcholine‐induced excitation of Renshaw cells was depressed by iontophoretically (but not intravenously) administered DS103–282, although ventral root‐evoked responses of these cells were insensitive to this agent.

Inhibition of spinal neurones by stimulation of peripheral nerves or by iontophoresis of γ‐aminobutyric acid or glycine was unaffected by DS103–282.

These results indicate that DS103–282 preferentially depresses peripherally evoked polysynaptic excitation of spinal neurones probably by an action on the terminals of excitatory interneurones.
COMPARISON OF THE VASODILATOR ACTION OF DOPAMINE AND DOPAMINE AGONISTS IN THE RENAL AND CORONARY BEDS OF THE DOG
Authors: LANG W.J. , WOODMAN O.L.
Published: July 2012

The effects of dopamine and the dopamine receptor agonists, SK&F 38393 and bromocriptine, on renal and coronary blood flow in the anaesthetized dog were examined. Dopamine was found to dilate both vascular beds, whereas SK&F 38393 increased renal blood flow but did not have any dilator activity in the coronary vasculature. Bromocriptine did not cause vasodilatation in either vascular bed.

The vasodilator responses to dopamine and SK&F 38393 were significantly reduced by the dopamine receptor antagonists, ergometrine or metoclopramide.

It is proposed that the selective action of SK&F 38393 on the renal vasculature suggests that the dopamine receptors of the renal and coronary vascular beds may be of different types.
THE α‐ AND β‐ADRENOCEPTOR BLOCKING POTENCIES OF LABETALOL AND ITS INDIVIDUAL STEREOISOMERS IN ANAESTHETIZED DOGS AND IN ISOLATED TISSUES
Authors: BRITTAIN R.T. , DREW G.M. , LEVY G.P.
Published: July 2012

The antagonist potencies of labetalol and each of its four stereoisomers have been compared at α1‐, β1‐ and β2‐adrenoceptors in anaesthetized dogs and in isolated tissues.

The RR stereoisomer is a potent, non‐selective antagonist at β‐adrenoceptors but has only weak α1‐adrenoceptor blocking activity.

The SR stereoisomer was the most potent antagonist at α1‐adrenoceptors, and it also had similar potency as an antagonist at β‐adrenoceptors.

The α‐ and β‐adrenoceptor blocking profile of the RS stereoisomer is intermediate between that of the RR and SR, but the SS stereoisomer is a relatively weak antagonist at both α‐ and β‐adrenoceptors.

It is concluded that, although most of the α1‐adrenoceptor blocking activity of labetalol is attributable to the SR stereoisomer and nearly all of its β‐adrenoceptor blocking activity resides in the RR stereoisomer, each of the stereoisomers contributes to the overall pharmacological profile of labetalol.
Ethanol produces coronary vasospasm: evidence for a direct action of ethanol on vascular muscle
Authors: Altura B.M. , Altura B.T. , Carella A.
Published: July 2012

The effects of ethanol and acetaldehyde on basal tension of canine small and large coronary arteries were examined in vitro. Ethanol in a concentration as little as 8.5 mm can induce threshold contractions of coronary arteries. High concentrations of ethanol produce concentration‐dependent coronary vasospasms equivalent to those induced by supra‐maximal concentrations of KCl. Acetaldehyde (10−5 to 10−2m) resulted in concentration‐dependent relaxation of basal tone. Use of a variety of pharmacological antagonists (i.e., phentolamine, methysergide, diphenhydramine, metiamide, propranolol and indomethacin) did not attenuate or prevent the spasmogenic actions of ethanol. These findings could help to explain why alcohol can induce cardiac depression, arrhythmias, cardiomyopathy and the higher than normal incidence of sudden death observed in ‘binge’ drinkers.
Opioid agonist and antagonist behavioural effects of buprenorphine
Authors: Leander J. David
Published: July 2012

The agonist and antagonist effects of a range of bupenorphine doses (0.08–20 mg/kg) were studied on the responding of pigeons under a multiple fixed‐ratio, fixed‐interval schedule of grain presentation. Various doses (0.02–10 mg/kg) of buprenorphine were also tested in pigeons trained to discriminate between injections of 0.05 mg/kg of fentanyl and injections of distilled water.

Buprenorphine, over a broad dose range (0.08–5 mg/kg), increased the rates of responding in the fixed‐interval component of the multiple schedule and disrupted patterning of responding within the fixed‐interval, without affecting fixed‐ratio responding even at a dose of 40 mg/kg. The effects of some of the high doses on fixed‐interval responding were still evident one and two days after buprenorphine injection.

Doses of buprenorphine which produced increases in fixed‐interval responding were also effective as antagonists of the behavioural depression produced by 40 mg/kg of morphine, and were discriminated as fentanyl‐like by pigeons trained to discriminate between injections of fentanyl and injections of water.

These results show that buprenorphine produces marked agonist and antagonist effects over an extremely broad dose range without producing behavioural depressant effects.
The characteristics of inhibition of histamine release from human lung fragments by sodium cromoglycate, salbutamol and chlorpromazine
Authors: Church Martin K. , Young Kevin D.
Published: July 2012

Three drugs have been tested for activity against antigen‐induced histamine release from passively sensitized human lung fragments after increasing periods of pre‐incubation before challenge.

After 30 s pre‐incubation, sodium cromoglycate inhibited histamine release in the concentration range 0.2–200 μm, producing a maximum inhibition of 33.0%. As the pretreatment period was extended, tolerance developed in a dose‐related manner, resulting in a 48.3% and 82.8% loss of activity of the 200 μm dose after 60 min and 19 h pre‐incubation, respectively. Tolerance was independent of extracellular calcium and was poorly reversible. Lung tissue desensitized to cromoglycate was cross‐tolerant to the related drug, bufrolin, but not to salbutamol or chlorpromazine.

In acute studies, salbutamol (0.03–3.0 μm) produced dose‐related inhibition of histamine release, with a maximum inhibition of 72.2%. The effect was blocked stereoselectively by 1 μm propranolol, suggesting that it occurred through an interaction with lung β‐adrenoceptors. Increasing the pre‐incubation time with salbutamol from 30 s to 19 h did not produce tolerance. Inhibition produced by incubation with salbutamol for 19 h was totally prevented when propranolol was added at the beginning of the pre‐incubation period, indicating that it resulted from stimulation of β‐receptors and not from a non‐specific or toxic effect. However, studies of reversibility of effect through washing or late addition of propranolol did indicate some change in the nature of salbutamol inhibition with time.

Chlorpromazine was a weak inhibitor of immunological histamine release. A 100 μm concentration was ineffective after 30 s pre‐incubation but its activity increased with time. Pre‐incubation of lung fragments with this concentration for 1 h or longer, or with a 1 mm dose for a shorter period, provoked histamine release in the absence of antigen. Effects of chlorpromazine were not reversed by washing.

The different characteristics shown by sodium cromoglycate, salbutamol and chlorpromazine indicate that these drugs inhibit histamine release by interfering with the secretory mechanisms in different ways.
Effect of nifedipine on constriction of human tracheal strips in vitro
Authors: Drazen Jeffrey M. , Fanta Christopher H. , Lacouture Peter G.
Published: July 2012

Autopsy specimens of human trachealis muscle were used to investigate the effect of the calcium channel blocker, nifedipine, on airway smooth muscle constriction. With these tracheal strips, two consecutive cumulative concentration‐effect curves to histamine (0.1–100 μm) obtained at a 60 min interval were highly reproducible.

We examined the effects of adding nifedipine (2.9 μm) to the incubation medium before the second histamine response. The concentration‐effect relationships determined after nifedipine incubation were significantly different from control: the response to 100 μm histamine was reduced by approximately one‐half (to 2.53 ± 0.6 g; P < 0.025), and the concentration of histamine causing 40% of the maximal control contraction (EC40) increased nearly ten fold (to 36.9 ± 10.5 μm; P < 0.02).

In two additional tracheal strips submaximally constricted with 10 μm histamine, nifedipine 2.9 μm caused complete relaxation to resting tension or below.

These results indicate a direct inhibitory effect of nifedipine on airway smooth muscle constriction and partial dependence of human trachealis muscle on calcium ion fluxes for initiation and maintenance of contraction. In addition, the results suggest a potential mechanism for the inhibitory effects of calcium channel blocking drugs in exercise‐induced asthma.
Effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive isomer in endotoxic shock in the rat
Authors: Anderegg Katherine , Anzeveno Peter , Cook James A. , Halushka Perry V. , McCarthy James , Wagner Eugene , Wise William C.
Published: July 2012

We investigated the effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive ortho isomer on arachidonic acid metabolism and pathophysiological sequelae of endotoxic shock. In vehicle‐treated rats, 30 min after intravenous S. enteritidis endotoxin (15 mg/kg), plasma iTxB2 (the stable metabolite of thromboxane A2) increased from non‐detectable levels (< 100 pg/ml) to 763 ± 250 pg/ml (n = 10). Plasma i6‐keto‐PGF1α (the stable metabolite of prostacyclin, PGI2) increased to 1850 ± 426 pg/ml, (n = 9) and plasma iPGE increased to 2350 = 560 (n = 5). Pretreatment with the pyridine active (PA) meta isomer (30 mg/kg i.p.) significantly (P < 0.05) suppressed iTxB2 to 390 ± 31 pg/ml (n = 10) although 6‐keto‐PGF1α levels (1294 ± 358 pg/ml, n = 5) and plasma iPGE (2847 ± 1103 pg/ml, n = 5) were not significantly different from the shocked control values. In contrast, pretreatment with, the pyridine inactive (PI) ortho isomer did not significantly affect endotoxin‐induced iTxB2 (1431 ± 194 pg/ml, n = 5) or i6‐keto‐PGF1α synthesis (628 ± 266 pg/ml, n = 5).

Pretreatment of rats with the Tx synthetase inhibitor, PA, significantly enhanced (P < 0.05) survival and prevented splanchnic infarction relative to both endotoxin shocked control rats and those pretreated with the PI isomer.

Significantly reduced lysosomal labilization, hepatocellular dysfunction and elevations in serum fibrin/fibrinogen degradation products were seen only in groups pretreated with the PA isomer.

The beneficial effects of the latter compound in Endotoxic shock thus appear to be due to inhibition of Tx synthesis, since its ortho isomer did not inhibit TxA2 synthesis nor did it protect against endotoxic shock.
A study on the membrane depolarization of skeletal muscles caused by a scorpion toxin, sea anemone toxin II and crotamine and the interaction between toxins
Authors: Chang C.C. , Hong S.J. , Su M.J.
Published: July 2012

Quinquestriatus toxin (QTX) isolated from the venom of a scorpion (Leiurus quinquestriatus) and sea anemone (Anemonia sulcata) toxin II enhanced the twitch response of the rat and mouse diaphragms and like crotamine (isolated from the venom of Crotalus durissus terrificus) caused spontaneous fasciculation of the muscle.

Trains of action potentials in muscles at 70–250 Hz, which could not be antagonized by (+)‐tubocurarine, were triggered by single stimulation or occurred spontaneously after treatment with these toxins.

QTX and toxin II prolonged the rat muscle action potential 3 to 4 fold whereas crotamine prolonged the action potential by only 30%.

The membrane potential was depolarized from about −82 mV to −55 mV by crotamine 2 μg ml−1, −41 mV by toxin II 5 μg ml−1 and to −50 mV by QTX 1 μg ml−1. The concentrations to induce 50% maximal depolarization (K0.5) were 0.07, 0.15 and > 0.4 μg ml−1, respectively, for QTX, crotamine and toxin II, whereas the rates of depolarization were in the order toxin II > crotamine > QTX. The depolarizing effects of crotamine and QTX, but not of toxin II, were saturable.

The depolarizing effects of all three toxins were irreversible whereas the membrane potential could be restored by tetrodotoxin non‐competitively.

Simultaneous treatment with crotamine and QTX or crotamine and toxin II at concentrations below K0.5 caused only additive effects on depolarization.

When the muscle was depolarized by pretreating with a saturating concentration of crotamine, the onset of depolarization by QTX was greatly retarded whereas that by toxin II was unaffected. Action potentials were further prolonged in both cases.

It is inferred that all three peptide toxins act at sites on the sodium channel and the binding sites for QTX and crotamine overlap to a considerable extent. On the other hand, the site for toxin II appears not to overlap with that of crotamine but may overlap with that of QTX.
Pharmacological mapping of regional effects in the rabbit heart of some new antiarrhythmic drugs
Authors: Millar J.S. , Willams E.M. Vaughan
Published: July 2012

In vitro preparations of rabbit heart were made from which measurements of effective refractory period (ERP), atrio‐Hisian (A‐H) and His‐Purkinje (H‐P) conduction times could be obtained, analogous to electrophysiological measurements customarily carried out in vivo.

Intracellular potentials also were recorded from the sino‐atrial (SA) node, atrium, bundle of His, preterminal Purkinje fibres and papillary muscles.

The effects of a range of concentrations of three new antiarrhythmic drugs, melperone, cibenzoline and alinidine were compared, the lower concentrations studied corresponding to clinical levels.

At low concentrations the effects of melperone, inducing bradycardia and lengthening ERP, could be attributed to prolongation of action potential duration (APD) in the sinus node and atrial and ventricular tissues. The slope of slow diastolic depolarization was not altered, nor was there any change in A‐H or H‐P conduction time, or in maximum rate of depolarization (MRD).

At higher concentrations melperone had a substantial class 1 action, but there was no negative inotropic effect, or other evidence of restriction of slow inward current.

Cibenzoline was primarily a class 1 agent but also lengthened APD to some extent in the SA node and in atrial and ventricular muscle, but not in Purkinje fibres. APD thus became more uniform along the ventricular conducting pathway.

Cibenzoline also depressed contractions and increased A‐H conduction time, implying restriction of slow inward current. The bradycardia could thus be attributed to a slowing of both depolarization and repolarization in the SA node, without any change in slope of the slow diastolic depolarization. Conduction time was increased in all tissues.

Alinidine greatly reduced the slope of the slow diastolic depolarization and slightly lengthened APD in the SA node. MRD was also reduced in the SA node, and A‐H conduction time was increased, implying some restriction of slow inward current. However, there was no negative inotropic effect.

Alinidine had no significant effect on MRD in atrium, ventricle or Purkinje cells, nor was H‐P conduction time altered, implying absence of effect on fast inward current. APD was moderately lengthened in atrium and ventricle but not in Purkinje cells.

It was concluded that the effects of the drugs in the sinus node and on ERP and on A‐H and H‐P conduction times could be accounted for by their selective cellular actions in different regions of the heart.
Behavioural hyperactivity in rats treated with selective monoamine oxidase inhibitors and LM 5008, a selective 5‐hydroxytryptamine uptake blocker
Authors: Ashkenazi R. , Finberg J.P.M. , Youdim M.B.H.
Published: July 2012

The administration of 4‐[2‐(3‐indolyl)ethyl]piperidine (LM 5008), a selective 5‐hydroxytryptamine (5‐HT) uptake blocker to rats pretreated with tranylcypromine (Tcp) resulted in a behavioural syndrome of locomotor hyperactivity which is indistinguishable from that following combined treatment with Tcp and l‐tryptophan.

A similar behavioural response was elicited by the administration of LM 5008 to rats pretreated with 5‐hydroxytryptophan.

The response to LM 5008 after monoamine oxidase (MAO) inhibition was abolished by pretreatment with p‐chlorophenylalanine, indicating the involvement of 5‐HT in producing the hyperactivity syndrome.

The administration of imipramine and chlorimipramine in combination with Tcp also resulted in hyperactivity, but these drugs were much less potent than LM 5008 in producing the syndrome.

In contrast to l‐tryptophan, which can produce hyperactivity only after the inhibition of both type A and type B MAO, LM 5008 can elicit the syndrome after selective inhibition of MAO type A only but not after inhibition of MAO type B.

The behavioural results indicate that when MAO type A is inhibited, LM 5008 treatment elicits hyperactivity by preventing the availability of 5‐HT to be metabolized by MAO‐B component.
Contraction and increase in tissue calcium content induced by maitotoxin, the most potent known marine toxin, in intestinal smooth muscle
Authors: Ohizumi Yasushi , Yasumoto Takeshi
Published: July 2012

Maitotoxin (MTX), the most potent known marine toxin, isolated from toxic dinoflagellates and poisonous fish, caused a dose‐dependent contraction of the guinea‐pig isolated ileum and taenia caeci at concentrations of 100 pg to 30 ng/ml. These contractile responses to MTX (3 ng/ml) in both tissues were abolished by incubation in Ca2+‐free solution and were markedly inhibited by treatment with methoxyverapamil (D600), but were not affected by tetrodotoxin and atropine. Furthermore, MTX markedly elevated tissue Ca2+ content of the taenia caeci. These results suggest that MTX activates Ca2+ channels in the smooth muscle membrane of both tissues to increase Ca2+ influx and thus induces contractions.
α1‐Adrenoceptor agonist activity of α2‐adrenoceptor antagonists in the pithed rat preparation
Authors: Paciorek P.M. , Shepperson N.B.
Published: July 2012

The selective α2‐adrenoceptor antagonist, RX781094, evoked a dose‐related pressor response in the pithed rat preparation when administered in bolus doses by the intravenous route. This response was enhanced following depletion of endogenous amines by reserpine, and inhibited by the selective α1‐adrenoceptor antagonist, prazosin. Two other selective α2‐adrenoceptor antagonists, Wy 26703 and Wy 26392, had no marked effect on the blood pressure of this preparation. Pretreatment of the preparation with Wy 26703 had no significant effect on the pressor response evoked by RX781094.

It is concluded that RX781094 is an α1‐adrenoceptor agonist at similar doses to those at which it exhibits α2‐adrenoceptor antagonist properties. The agonist activity exhibited by RX781094 is not a general property of all α2‐adrenoceptor antagonists and should be considered when this compound is employed as an α2‐adrenoceptor antagonist.
Effect of angiotensin II and 5‐hydroxytryptamine on the vessels of the human foetal cotyledon
Authors: Abramovich D.R. , Page K.R. , Wright F.
Published: July 2012

The actions of angiotensin II (AT II) and 5‐hydroxytryptamine (5‐HT) on the vessels of the human isolated, perfused, cotyledon were examined in vitro.

The cotyledonary vessels were shown to respond to both AT II and 5‐HT over the range 10−8 to 10−4M.

The preparation was found to be more responsive to AT II than 5‐HT.

The findings confirm that the responsiveness of the cotyledonary vessels differs from the vessels of the umbilical cord, and that this behaviour does not depend upon the integrity of the endothelium associated with these vessels.
Evidence of poor conduction of muscle excitation in the longitudinal axis of guinea‐pig isolated trachea
Authors: Dixon J.S. , Small R.C.
Published: July 2012

Mechanical activity was recorded from one segment of guinea‐pig trachealis muscle while intracellular electrical activity was simultaneously recorded from a contiguous segment. When the tissue was stimulated by 1–32 mmol/l tetraethylammonium (TEA) it became clear that the electrical and mechanical records were not directly correlated.

Dual recording of mechanical activity from two contiguous segments of trachealis revealed that one tissue segment could exhibit phasic activity whilst the other could exhibit tonic activity, despite exposure to the same concentration of TEA.

Histological studies revealed that the trachealis muscle was organized into bundles largely separated from one another by spaces filled with connective tissue. However, muscle bundles branched and formed anastomotic connections with near neighbours.

It is concluded that the cell to cell spread of muscle excitation is very poor along the longitudinal axis of the trachea. The trachealis muscle as a whole does not function as a single unit. Rather it may represent a series of effector units each comprising a small number of smooth muscle bundles.
The determination of presynaptic pA2 values of yohimbine and phentolamine on the perfused rat heart under conditions of negligible autoinhibition
Authors: Fuder Hermann , Muscholl Erich , Spemann Romeo
Published: July 2012

Rat isolated perfused hearts with the right sympathetic nerves attached were loaded with [3H]‐(—)‐noradrenaline. The nerves were stimulated with up to 40 trains of 10 pulses every min at 1 Hz, and the evoked increases of [3H]‐noradrenaline overflow into the perfusate, of right atrial tension development and ventricular beating frequency were measured.

Oxymetazoline inhibited the evoked transmitter overflow (IC50: 10 nM) and decreased the postsynaptic responses in a concentration‐dependent manner. It behaved as a full agonist in abolishing the evoked transmitter overflow.

Yohimbine up to 1 μM neither enhanced the evoked [3H]‐noradrenaline overflow nor the postsynaptic parameters. Phentolamine (1 μM) caused a transient, minor (<30%) increase in [3H]‐noradrenaline overflow.

Yohimbine (0.03–1.0 μM) and phentolamine (0.1–5.0 μM) shifted to the right the concentration‐response curve of oxymetazoline for the inhibition of [3H]‐noradrenaline overflow in response to nerve stimulation without depressing the maxima. The pA2 values were 7.82 and 7.52, respectively.

Yohimbine (0.1 μM) also antagonized the decrease induced by oxymetazoline in the postsynaptic responses to nerve stimulation.

The results confirm the existence of presynaptic inhibitory α2‐adrenoceptors at the adrenergic nerve fibres of the rat heart in vitro. Under the stimulation and perfusion conditions selected, the released endogenous transmitter apparently does not activate a negative feedback mechanism, thus permitting the determination of pA2 values.
Acetal phosphatidic acids: novel platelet aggregating agents
Authors: Brammer J. Preston , Maguire M. Helen , Walaszek E.J. , Wiley R.A.
Published: July 2012

Palmitaldehyde, olealdehyde and linolealdehyde acetal phosphatidic acids induced rapid shape change and dose‐dependent biphasic aggregation of human platelets in platelet‐rich plasma; aggregation was reversible at low doses and irreversible at high doses of the acetal phosphatidic acids. The palmitaldehyde congener elicited monophasic dose‐dependent aggregation of sheep platelets in platelet‐rich plasma.

The threshold concentration for palmitaldehyde acetal phosphatidic acid (PGAP)‐induced platelet aggregation was 2.5–5 μM for human platelets and 0.25–0.5 μM for sheep platelets. PGAP was 4–5 times as potent versus human platelets as the olealdehyde and linolealdehyde acetal phosphatidic acids, which were equipotent.

PGAP‐induced irreversible aggregation of [14C]‐5‐hydroxytryptamine ([14C]‐5‐HT)‐labelled human platelets in platelet‐rich plasma was accompanied by release of 44.0 ± 2.4% (s.e.) of the platelet [14C]‐5‐HT; reversible aggregation was not associated with release. In contrast, PGAP‐induced release of [14C]‐5‐HT‐labelled sheep platelets was dose‐dependent.

The adenosine diphosphate (ADP) antagonist, 2‐methylthio‐AMP, and the cyclo‐oxygenase inhibitor, aspirin, abolished PGAP‐induced second phase aggregation and release in human platelets but did not affect the first, reversible, phase of aggregation. Both the first and second phases of PGAP‐induced aggregation were abolished by chlorpromazine, by the phospholipase A2 inhibitor, mepacrine, and by nmolar concentrations of prostaglandin E1 (PGE1); these agents abolished the second, but not the first phase of ADP‐induced aggregation.

The related phospholipids, lecithin, lysolecithin and phosphatidic acid, at < 100 μM, neither induced aggregation of human platelets in platelet‐rich plasma, nor modified PGAP‐induced aggregation; 1‐palmityl lysophosphatidic acid elicited aggregation of human platelets at a threshold concentration of 100 μM.

It is concluded that the acetal phosphatidic acids induce platelet aggregation per se by direct action at the platelet membrane, and that the acetal function is of primary importance in their potent platelet‐stimulating activity. Moreover, as the acetal phosphatidic acids are the major components of the smooth muscle‐contracting acidic phospholipid tissue extract ‘Darmstoff’ (Vogt, 1949), their potent platelet‐aggregating properties may be of physiological or pathological significance.
Gold‐containing drugs and the control of proteolytic enzymes
Authors: Rohozková D. , Steven F.S.
Published: July 2012

NaAuCl4 and aurothioglucose inhibited trypsin in free solution without the need of a carrier molecule.

NaAuCl4, aurothioglucose, aurothiomalate, auranofin and chloro(triethyl phosphine) gold all inhibited the trypsin‐like neutral protease on the surface of Ehrlich ascites tumour cell membranes equally well.

Crude cathepsin preparations were activated by low concentrations of dithiothreitol and also by aurothioglucose, due to the displacement of an inhibitor.

Thiol‐activated cathepsins were inhibited by each of the gold derivatives. The gold could be withdrawn from the enzyme by incremental additions of thiols such as reduced glutathione and cysteine with regeneration of enzymic activity.

Lineweaver‐Burk plots of kinetic data indicated that gold acted as a non‐competitive inhibitor of cathepsins.

A naturally occurring inhibitor of cathepsins was extracted from cartilage. The mechanism of inhibition was again shown to be a thiol‐disulphide exchange, the disulphide being provided by the inhibitor and the thiol being provided by the enzyme.

The role of gold in the attempted control of proteolysis in rheumatoid arthritis is briefly discussed in terms of reversible exchange reactions involving gold thiols, disulphides and cartilage inhibitors of proteolytic enzymes.
Sedative effects of PK 9084 and PK 8165, alone and in combination with chlordiazepoxide
Authors: File Sandra E.
Published: July 2012

The sedative effects in rats of two phenylquinolines, PK 9084 and PK 8165 (5–50 mg/kg), were examined in a holeboard: both when given alone and when given in conjunction with chlordiazepoxide (5 mg/kg).

Both phenylquinolines produced significant dose‐related decreases in locomotor activity and rearing, with an ED50 about twice that for chlordiazepoxide.

When the phenylquinolines were combined with chlordiazepoxide the degree of sedation was equal to that seen with either drug given alone, whichever produced the greater sedation; the sedative effects of the two drugs were never additive.

PK 9084 (10 and 50 mg kg) significantly reduced rectal temperature, as did chlordiazepoxide (5 mg/kg), but there was no addition nor interaction of their effects.

Both phenylquinolines also reduced exploratory head‐dipping, as did chlordiazepoxide, but in combination they antagonized each other's effects.

The classification of the phenylquinolines as non‐sedative anxiolytics, acting as agonists at the benzodiazepine receptors needs revision.
Characteristics of conditioned taste aversion produced by nicotine in rats
Authors: Kumar R. , Pratt J. A. , Stolerman I.P.
Published: July 2012

Nicotine produced conditioned taste aversions in rats which were directly related to the dose of nicotine and to the number of conditioning trials.

The tobacco alkaloid (−)‐nicotine was four to five times as potent as its stereoisomer, (+)‐nicotine.

Mecamylamine but not hexamethonium blocked the development of taste aversions produced by nicotine.

Mecamylamine did not block the development of taste aversions produced by apomorphine.

Prolonged treatment with mecamylamine prior to conditioning did not produce supersensitivity to nicotine.
Release of acetylcholine at the motor endplate of the rat — evidence against a muscarinic acetylcholine autoreceptor
Authors: Häggblad J. , Heilbronn E.
Published: July 2012

The effect of some drugs on the release of endogenous acetylcholine from the phrenic nerve‐hemidiaphragm preparation of the rat was measured. Muscarinic ligands had no effect. 8‐Br‐cyclic GMP, a penetrating analogue of cyclic guanosine 3′,5′‐monophosphate (cyclic GMP) was also without effect. 8‐Br‐cyclic AMP somewhat enhanced the basal release while the potassium‐induced release remained unaltered.

In supersensitivity experiments, no specific binding of ligand [3H]‐quinuclidinylbenzilate ([3H]‐QNB) was found in homogenates of the diaphragm, either before or after atropine treatment, while concomitant binding studies in the CNS demonstrated the expected increase in muscarinic binding sites after atropine.

Our conclusion is that muscarinic acetylcholine receptors are probably absent from the presynaptic motor endplate area of the rat. Certain preliminary results suggest that a presynaptic nicotinic mechanism might be involved in the release of acetylcholine.
The possible mechanism of protection induced by dexamethasone against sudden death due to coronary ligation in conscious rats
Authors: Koltai M. , Leprán I. , Nemecz Gy. , Szekeres L.
Published: July 2012

Rat isolated peritoneal cells (107 cells ml−1) incubated in the presence of dexamethasone (3 × 10−9 m, for 90 min) were shown to release some factor(s), having a mol. wt. of 15 k, as determined by size exclusion chromatography, which inhibited phospholipase A2 activity and offered significant protection against sudden death due to post‐infarction arrhythmias in conscious rats pre‐treated with actinomycin D (0.5 mg kg−1 i.v. 4 h before coronary ligation). This observation suggests that the cardioprotective effect of glucocorticoids in acute myocardial infarction may result from the de novo synthesis of macrocortin, an antiphospholipase protein.
The β‐adrenoceptor of pig coronary arteries: determination of β1 and β2 subtypes by radioligand binding
Authors: Schwartz Jean , Velly Jeanne
Published: July 2012

β‐Adrenoceptors of pig coronary arteries were investigated by the use of a new ligand, 125iodocyanopindolol (ICYP) in binding studies.

Inhibition of ICYP binding by betaxolol (a selective β1‐antagonist), zinterol (a selective β2‐agonist) and ICI 118551 (a selective β2‐blocking drug) resulted in non‐linear Scatchard plots, suggesting that both β‐adrenoceptor subtypes are present in pig coronary arteries.

Computer analysis of the data gave a β1:β2‐adrenoceptor ratio of approximately 65:35.
Effects of α‐adrenoceptor antagonists on clonidine‐induced inhibition of insulin secretion by isolated pancreatic islets
Authors: Langer Joachim , Panten Uwe , Zielmann Siegfried
Published: July 2012

The effects of clonidine, yohimbine, corynanthine and prazosin on glucose‐induced insulin secretion by incubated or perifused mouse pancreatic islets were investigated.

Clonidine (0.1 μm) inhibited glucose‐induced insulin secretion alone and in the presence of yohimbine (0.1 μm), corynanthine (10 μm) or prazosin (1 μm).

In higher concentrations, yohimbine (1–10 μm) antagonized the inhibitory effect of clonidine (0.1 μm) upon glucose‐induced insulin secretion by incubated islets and by perifused islets.

The results support the view that adrenergic inhibition of insulin secretion is mediated by α2‐adrenoceptors on pancreatic β‐cells.
In vivo, noradrenaline is a substrate for rat brain monoamine oxidase A and B
Authors: Youdim M.B.H.
Published: July 2012

In vivo clorgyline (5 mg/kg) and (‐)‐deprenyl (5 mg/kg) selectively inhibit monoamine oxidase (MAO) type A and B activities in rat brain hypothalamus and caudate nucleus using 5‐hydroxytryptamine (5‐HT), noradrenaline (NA), and β‐phenylethylamine (PEA) as substrates.

Clorgyline induces a significant increase in NA concentrations of hypothalamus and caudate nucleus; however (‐)‐deprenyl is without effect.

The combination of clorgyline and (‐)‐deprenyl at the above doses completely inhibits both forms of MAO, resulting in an even greater increase in NA levels in both brain areas than observed with clorgyline. The non‐selective inhibitor tranylcypromine (5 mg/kg) produced a similar effect.

Rats pretreated with the selective or the non‐selective inhibitors but given l‐DOPA (50 mg/kg) have a similar pattern of brain NA, but its concentrations are higher in both brain regions.

The results indicate that although in vitro NA may be an exclusive substrate for MAO type A, in vivo, when this enzyme form is selectively inhibited, NA at high concentrations can be a substrate for MAO type B.
Rapid degradation of [3H]‐substance P in guinea‐pig ileum and rat vas deferens in vitro
Authors: Watson Stephen P.
Published: July 2012

The degradation of [3H]‐substance P was monitored in guinea‐pig ileum and rat vas deferens. Substantial and rapid metabolism occurred in both tissues within the time course of the pharmacological responses; for example, after 1 min more than 50% of the extracted tritium from both tissues was present in the form of metabolites.

[3H]‐inulin was used to estimate the rate of equilibration of the extracellular space of guinea‐pig ileum longitudinal muscle and rat vas deferens with the bath fluid; half‐lives of 30 s and 5 min respectively were observed.

These two factors combine to give different concentrations of substance P in the biophase of the tissues. The peak concentration of substance P reached in the guinea‐pig ileum longitudinal muscle was approximately five times higher than in the rat vas deferens.

An analogue of substance P, [3H]‐DiMe‐C7, was found to be stable in both tissues.

These results are discussed in the light of the suggested existence of multiple receptors for substance P, based on agonist potency differences.
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate
Authors: Anis N.A. , Berry S.C. , Burton N.R. , Lodge D.
Published: July 2012

The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone‐anaesthetized cats and rats.

Both ketamine and phencyclidine selectively blocked excitation by N‐methyl‐aspartate (NMA) with little effect on excitation by quisqualate and kainate.

Ketamine reduced responses to L‐aspartate somewhat more than those of l‐glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other.

On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root‐evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation.

Intravenous ketamine, 2.5–20 mg/kg, and phencyclidine, 0.2–0.5 mg/kg, also selectively blocked excitation of neurones by NMA.

Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or γ‐aminobutyricacid (GABA).

The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.
Glucocorticoid protection against PAF‐acether toxicity in mice
Authors: Myers Adam , Ramey Estelle , Ramwell Peter
Published: July 2012

Intravenous platelet activating factor (PAF‐acether, 10 to 25 μg/kg body weight) produced dose‐dependent mortality in both male and female mice.

Pretreatment with indomethacin (50 mg/kg), verapamil (40 mg/kg) or nifedipine (4 mg/kg) failed to inhibit the lethal effect of 20 μg/kg PAF‐acether. This suggests that neither arachidonate cyclo‐oxygenase products nor availability of extracellular Ca2+ mediate the toxic action.

In contrast, pretreatment with 100 mg/kg cortisone acetate (s.c.) daily for four days exerted a highly protective effect, i.e. 100% and 93% survival in males and females, compared to 13% and 7% respectively, in untreated animals.

PAF‐acether‐induced death may be a useful model for the in vivo evaluation of pharmacological agents in anaphylactic shock.
Endothelium‐dependent relaxation induced by angiotensin II and histamine in isolated arteries of dog
Authors: Toda Noboru
Published: July 2012

In helical strips of dog renal and mesenteric arteries pre‐contracted with prostaglandin F2α (PGF2α), endothelium‐dependent relaxations were investigated. Removal of the endothelium was shown histologically by staining with silver nitrate and functionally by testing the inability of acetylcholine to induce arterial relaxations.

When the endothelium was removed, relaxation of renal arteries to angiotensin (Ang) II was markedly suppressed, whereas relaxations induced by PGI2 or isoprenaline were attenuated only slightly. Removal of the endothelium attenuated the relaxant response of mesenteric arteries to histamine but did not significantly alter the response to PGI2.

Treatment with indomethacin caused an additional attenuation of the relaxant response to histamine or a reversal of the Ang II‐induced relaxation to a contraction in the arterial strips, from which the endothelium had been removed.

Relaxation of renal arteries induced by Ang II and of mesenteric arteries induced by histamine is postulated to result from PGI2 released from the arterial wall. Therefore, it appears that the endothelium is a major site but not the only site responsible for drug‐induced release of PGI2.
Contractions of rat uterine smooth muscle induced by acetylcholine and angiotensin II in Ca2+‐free medium
Authors: Lalanne C. , Mironneau C. , Mironneau J. , Savineau J.P.
Published: July 2012

The effects of acetylcholine (ACh, 10−4m) and angiotensin II (Ang II, 10−6 M) have been studied on the mechanical and electrical activities of rat myometrial strips perfused in Ca2+‐free EGTA‐containing solutions.

Both ACh and Ang II produced transient contractions, the amplitude of which can be taken as a measurement of the amount of Ca2+ present in a drug‐sensitive Ca2+ store. The degree of filling of this store depended on the external Ca2+ concentration, and on the presence of contractile responses during the Ca2+ loading period. The existence of two pathways (either direct or transcytoplasmic) is suggested for Ca2+ uptake into the internal Ca2+ store.

The rate of filling of the Ca2+ store in 2.1 mm‐Ca2+‐containing solution was faster (time to half‐maximal response, t1/2 = 29 ± 2.2s, n = 4) than the rate of depletion in Ca2+‐free solution (t1/2 = 3 ± 0.3 min, n = 3). The gradual depletion of this store was much slower at 18°C than at 35°C, and in the presence of vanadate which is known to inhibit Ca2+‐ATPases.

Methoxyverapamil (D600, 10−6‐10−5m) had no appreciable effect on the direct Ca2+ uptake or on the release of Ca2+ from the store by ACh and Ang II. Mn2+ (10−3m) completely inhibited the direct pathway to the internal Ca2+ store and also reduced the release of Ca2+.

ACh and Ang II induced repetitive depolarizations close to zero potential which did not parallel the transient contractions as a function of the time of perfusion in Ca2+‐free solution. Applications of 2 mm EGTA, 135 mm K+ or Ca2+ antagonists which suppressed or reduced the drug‐induced depolarizations did not affect appreciably the drug‐induced contractions.

These results suggest that myometrial cells have an intracellular Ca2+ store sensitive to different stimulus substances. This store is not affected by depolarization of the plasma membrane and is certainly different from that described in voltage‐clamp experiments.