bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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.