bluuebunny/crossref_metadata_2025_split huggingface dataset:
The action of excess potassium and calcium on ouabain‐evoked [3H]‐noradrenaline release from the rabbit pulmonary artery
Authors: Magyar Kálmán , Nguyen Tinh Thi , Török Tamás L. , Tóth Péter T. 
Published: July 2012

[3H]‐noradrenaline ([3H]‐NA) release from the main pulmonary artery of the rabbit has been measured in the presence of neuronal (cocaine, 3 × 10−5 M) and extraneuronal (corticosterone, 5 × 10−5 M) uptake blockers.
Removal of K from the external medium increased the [3H]‐NA release. In the absence of external K, ouabain (10−4 M) further enhanced the neurotransmitter release. The ‘K‐free’ stimulated [3H]‐NA release was inhibited by an increase of external Ca (7.5 mM), an action antagonized by ouabain.
After preperfusion of the preparations for 30 min with either excess K (23.6 mM) or excess Ca (7.5 mM), the ouabain‐stimulated [3H]‐NA release was inhibited by about 50%; the rates of inhibition did not differ significantly from each other. However, the characteristic initial delay before ouabain‐evoked neurotransmitter release was shortened in excess K, and prolonged in excess Ca‐containing solution.
When both excess K and Ca were applied together 30 min before ouabain perfusion, the action of ouabain in releasing neurotransmitter was also inhibited but the rate of inhibition did not differ significantly from that seen when K or Ca were applied separately. The action of K in shortening the initial delay was partly antagonized by Ca.
Excess Ca antagonized the inhibition of ouabain‐stimulated [3H]‐NA release caused by excess K when Ca and ouabain were applied together after 30 min preperfusion with excess K‐containing solution. Again excess Ca failed to inhibit the ouabain‐evoked neurotransmitter release if ouabain and excess K were applied together after excess Ca preperfusion (30 min). In both cases the initial delay of ouabain action was greatly shortened.
The results suggest a Na‐Ca competition at the external activation site of the nerve terminal sodium‐pump similar to that of Na‐K competition. Furthermore it seems that there is a sort of K‐Ca competition as well, suggested by the finding that excess Ca prevented the inhibition caused by excess K of ouabain‐evoked noradrenaline release and vice versa.
Comparison of the parasympatholytic activity of ACC‐9358 and disopyramide
Authors: Brown Barry S. , Gorczynski Richard J. , Reynolds Robert D. , Shaffer Joel E. 
Published: July 2012

ACC‐9358 (N‐[(3,5‐di(pyrrolidinylmethyl)‐4‐hydroxy)benzoyl]aniline) is a newly developed analogue of changrolin, an antiarrhythmic agent used in the Peoples Republic of China. Since changrolin and other antiarrhythmic agents exert parasympatholytic activity which may limit their clinical usefulness, it was of interest to examine the parasympatholytic effects of ACC‐9358. For comparative purposes we also studied the parasympatholytic activity of disopyramide.
In guinea‐pig isolated ileal strips, disopyramide, 3–30 μM, and ACC‐9358, 100–300 μM, competitively antagonized carbachol‐induced contractions with pA2 values of 5.78 and 4.17, respectively.
In guinea‐pig isolated right atria, disopyramide 3–30 μM, competitively antagonized methacholine‐induced slowing of spontaneous beating with a pA2 value of 5.99 whereas ACC‐9358, 3–300 μM, produced no significant muscarinic blockade in this preparation.
Disopyramide (1.9–15 mg kg−1, i.v.), but not ACC‐9358 (7.5‐1.5 mg kg−1, i.v.), significantly increased rat pupil diameter in vivo.
Disopyramide and ACC‐9358 blocked vagal‐induced reductions in heart rate in dogs anaesthetized with pentobarbitone. ED50 values were approximately 0.65 and 11.25 mg kg−1, respectively.
We conclude that ACC‐9358 possesses significantly less parasympatholytic activity than disopyramide.
The roles of prostaglandin endoperoxides, thromboxane A2 and adenosine diphosphate in collagen‐induced aggregation in man and the rat
Authors: Emms H. , Lewis G.P. 
Published: July 2012

The effects of aspirin, carboxyheptylimidazole (CHI) and creatine phosphate/creatine phosphokinase (CP/CPK) on platelet aggregation and thromboxane B2 (TxB2) formation induced by collagen have been examined in vitro. Platelets from two species, man and the rat, have been used.
In man, aspirin and CHI abolished TxB2 production but only partially inhibited aggregation. CP/CPK partially inhibited aggregation and TxB2 formation.
In the rat, aspirin and CHI abolished TxB2 formation but had no effect on aggregation. CP/CPK completely inhibited aggregation and partially inhibited TxB2 generation.
In man, collagen‐induced aggregation is largely dependent on ADP and to a lesser extent on arachidonate metabolites whereas, in the rat, ADP alone mediates aggregation induced by this agonist.
The results with CP/CPK suggest that TxB2 formation is dependent either on the prior release of platelet ADP or on aggregation itself rather than being responsible for the aggregation response.
Selective enhancement of histamine H1‐receptor responses in guinea‐pig ileal smooth muscle by 1,4‐dithiothreitol
Authors: Donaldson J. , Hill S.J. 
Published: July 2012

1,4‐Dithiothreitol (DTT; 1 mM, 30 min preincubation) produced a small, non‐specific potentiation of spasmogenic activity in longitudinal muscle strips of guinea‐pig small intestine.
A direct comparison of contractile responses elicited by histamine and a range of H1‐ and non‐H1‐receptor agonists indicated that DTT produced a significantly greater potentiation of H1‐receptor responses.
This apparently selective increase in tissue sensitivity to histamine H1‐preceptor agonists did not appear to be a consequence of the inhibition of histamine N‐methyl transferase or diamine oxidase activity. Potentiation of the responses to histamine by DTT was still observed in the presence of SKF 91488 (10 μM) and aminoguanidine (1 μM).
The potentiation elicited by DTT was readily reversed by the sulphydryl oxidizing agent dithiobis‐(2‐nitrobenzoic acid) (DTNB). This suggests that the mechanism of action of DTT involves the reduction of disulphide bonds.
Exposure of ileal smooth muscle to DTT following desensitization with histamine (100 × EC50 [‐ DTT]) resulted in a 6.9 ± 0.7 fold shift of the concentration‐response curve to lower agonist concentrations. Conversely, following potentiation of the response to histamine with DTT, exposure of the tissue to desensitizing concentrations of histamine resulted in a dextral shift of the dose‐response curve (dose ratio = 39.5 ± 1.2) to higher agonist concentrations.
The results of this study suggest that DTT may be a useful tool with which to investigate histamine H1‐receptor mechanisms in ileal smooth muscle.
Effect of vasoactive peptides on prostacyclin synthesis in man
Authors: Barrow Susan E. , Dollery Colin T. , Heavey Dennis J. , Hickling Nicola E. , Ritter James M. , Vial Janet 
Published: July 2012

Bradykinin, angiotensin II, arginine vasopressin (AVP) or des‐amino‐D‐arginine vasopressin (DDAVP) were administered by intravenous infusion to 10 healthy men.
The concentration of 6‐oxo‐prostaglandin F1α (6‐oxo‐PGF1α), the stable hydrolysis product of prostacyclin (PGI2), was measured in plasma using gas chromatography/negative ion chemical ionisation mass spectrometry.
Dose‐related increases in plasma concentrations of 6‐oxo‐PGF1α occurred during administration of bradykinin (100–3200 ng kg−1 min−1). The concentrations of 6‐oxo‐PGF1α rose from baseline values in the range < 1.0–4.9 pg ml−1 to 24.9–47.6 pg ml−1 at maximum tolerated infusion rates.
There were no changes in the concentrations of 6‐oxo‐PGF1α during administration of angiotensin II, AVP or DDAVP at infusion rates which caused haemodynamic changes.
Selective inhibition of monoamine oxidase type B by MDL 72145 increases the central effects of L‐DOPA without modifying its cardiovascular effects
Authors: Fozard John R. , Palfreyman Michael G. , Robin Marc , Zreika Monique 
Published: July 2012

The potential of a new, potent, irreversible and selective inhibitor of monoamine oxidase type B, (E)‐2‐(3,4‐dimethoxyphenyl)‐3‐fluorallyamine (MDL 72145), to augment the effects of L‐DOPA in an animal model which reproduces the biochemical defect of Parkinson's disease has been evaluated.
In rats bearing unilateral 6‐hydroxydopamine lesions of the nigro‐striatal dopamine pathways, both MDL 72145 and clorgyline, a selective inhibitor of MAO A, augmented the contralateral turning response to L‐DOPA combined with carbidopa.
The potential of inhibitors of MAO to interact adversely in the periphery with L‐DOPA was investigated in the pithed rat; L‐DOPA was given either intravenously or intraduodenally.
Clorgyline consistently potentiated L‐DOPA when given 18 h before testing. Neither MDL 72145 nor the selective inhibitor of MAO B, L‐deprenyl, augmented the cardiovascular effects of intraduodenally administered L‐DOPA.
The data provide no reason to suppose that MDL 72145 would be very different in clinical use from L‐deprenyl which is both effective and well‐tolerated as an adjunct to the L‐DOPA‐based therapy of Parkinson's disease.
Third Report on the Organization of Pharmacology in Great Britain
Authors: Bakhle Y.S. , Morton I.K.M. , Straughan D.W. , Webster R.A. 
Published: July 2012

The results presented in this Report on the Organization of Pharmacology in the United Kingdom are based on replies to questionnaires sent out in 1983. In addition to academic and industrial research and development (R&D) departments we also surveyed industrial departments of toxicology, sales, clinical liaison and medical information, as well as specialized research units with no formal teaching function. The overall response rate was 87%.
Since the last Report in 1971, the total number of pharmacologists has doubled to 2220, and they are now almost equally distributed between Universities and Industry. The most striking feature has been a major (3 fold) increase in the total number of industrial pharmacologists to 1014. In contrast, there was only a 1.3 fold increase in the number (99) of pharmacologists in established academic posts, over half of which are in the new departments of clinical pharmacology.
Of the established pharmacologists in academic departments only 8% were less than 30 years of age and 22% over 50, whereas in industrial R&D departments the corresponding figures were 44% and 6% respectively. Since 1971 the proportion of pharmacy graduates in established academic or industrial R&D posts has fallen from 30% to 13% but the proportion with a medical qualification is almost unchanged.
In academic departments, there was a net loss of established staff during 1982 and 1983 compared with a net gain of almost 100 appointments in industrial departments. The major single cause of academic pharmacologists leaving posts was early retirement, whilst in the industrial sector the major single destination was another industrial department.
In 1983, 227 students graduated with a special B.Sc. degree in Pharmacology compared with 67 in 1971. The same period saw a decline in pharmacy students specializing in pharmacology (293 to 204) and the emergence of Joint Honours courses that include pharmacology.
Pharmacology students who graduated in 1983 were also sent a questionnaire. From those responding (57%) over 90% were satisfied with their course and over 80% considered it adequate preparation for their future occupation.
At the time of the survey in 1983, only 8% of students graduating in 1982 were unemployed, but all of the 1982 postgraduates were employed.
Pilot experiments on the actions of drugs injected into the human corpus cavernosum penis
Authors: Brindley G.S. 
Published: July 2012

Seven drugs that are known to relax smooth muscle (phenoxybenzamine, phentolamine, thymoxamine, imipramine, verapamil, papaverine, naftidrofuryl) caused erection when injected intracavernosally.
Salbutamol, hydralazine, lignocaine and bupivacaine caused tumidity but not erection.
Metaraminol and guanethidine caused shrinkage followed by tumidity.
Neostigmine, atropine, propranolol and idazoxan had no effect in the doses tried.
It is argued that the seven drugs that cause erection do so by relaxing vascular and trabecular smooth muscle within the cavernosal space, and that the two that cause shrinkage of the penis do so by constricting vascular and trabecular smooth muscle within the cavernosal space.
It is argued that muscarinic and β‐adrenergic transmission play no important part in erectile mechanisms within the corpora cavernosa.
Papaverine, phenoxybenzamine and metaraminol, given intracavernosally, are already used therapeutically. Uses are suggested for thymoxamine, phentolamine, verapamil and guanethidine.
Opioids increase potassium conductance in submucous neurones of guinea‐pig caecum by activating δ‐receptors
Authors: Mihara Satoshi , North R. Alan 
Published: July 2012

Intracellular records were made from neurones in the submucous plexus of the guinea‐pig caecum.
[Met5]enkephalin, [Leu5]enkephalin, [D‐Ala2,D‐Leu5]enkephalin (DADLE) and [D‐Ser2,Leu5]enkephalin‐Thr (DSLET) hyperpolarized the membrane when applied in concentrations of 30 nM‐10 μM. Normorphine, [D‐Ala2, MePhe4,Gly5]enkephalin‐ol (DAGO), [D‐Ala2,MePhe4,Met(0)5]enkephalin‐ol (FK33824), dynorphin A and tifluadom had no effect at concentrations up to 10 μM.
The hyperpolarization resulted from an increase in the membrane potassium conductance.
Hyperpolarizations induced by [Met5]enkephalin were antagonized competitively by naloxone and by N‐bisallyl[aminoisobutyrate2'3, Leu5]enkephalin (ICI 174864). The Schild plots for these antagonisms had slopes not different from one, and the dissociation equilibrium constants among individual neurones were 5–50 nM for naloxone and 5–60 nM for ICI 174864.
The results indicate that the opioid receptors on guinea‐pig submucous neurones which are coupled to potassium channels are of the δ‐type.
Actions of the verapamil analogues, anipamil and ronipamil, against ischaemia‐induced arrhythmias in conscious rats
Authors: Curtis M.J. , Walker M.J.A. , Yuswack T. 
Published: July 2012

Two analogues of verapamil, ronipamil and anipamil, were tested for their ability to reduce arrhythmias induced by occlusion of the left anterior descending coronary artery in conscious rats.
Only anipamil (50 and 150 mg kg−1 orally) produced a statistically significant reduction in arrhythmias; it was most effective against ventricular fibrillation. Ronipamil at the same doses had limited antiarrhythmic actions.
Only anipamil delayed the development of ECG signs of ischaemia, while both drugs reduced the magnitude of such changes.
Anipamil has a more favourable ratio of antiarrhythmic to hypotensive effects when compared with verapamil.
Development of tolerance to the inhibitory effects of ethanol in the rat isolated vas deferens: effect of acute and chronic ethanol administration in vivo
Authors: DeTurck Kathryn H. , Pohorecky Larissa A. 
Published: July 2012

Contractions of the rat vas deferens elicited by the addition of noradrenaline (NA), K+‐depolarizing solutions or by electrical stimulation were recorded before and after incubation with ethanol 181 mM.
In tissues from untreated rats, the contractions were inhibited 40–50% by such exposure.
Injection of ethanol (2 g kg−1) significantly attenuated ethanol's reduction of peak tension generated by the lowest concentration of NA (10−4 mM).
Chronic administration of ethanol, 18‐14 g kg−1 daily for two weeks, resulted in significant tolerance to ethanol. Tissues of treated animals demonstrated ethanol‐induced decreases of roughly one‐half those of the maltose dextrin (isocaloric) and water (fluid control) groups.
This tolerance persisted for at least 48 h after ethanol treatment had been terminated.
Overall, the data suggest that ethanol acts both pre‐ and postsynaptically to produce acute inhibition of smooth muscle contractions or tolerance to these actions upon chronic exposure.
The origin of (+)‐tubocurarine resistance in dystrophic mice
Authors: Kelly S.S. , Morgan G.P. , Smith J.W. 
Published: July 2012

Intracellular recording, twitch responses and radio‐ligand binding techniques were used to study the causes of resistance to (+)‐tubocurarine (curare) of extensor digitorum longus (EDL) muscles from dystrophic mice (129 ReJ/strain).
The indirectly evoked twitch response of muscles from dystrophic mice was more resistant to block by curare than the twitch response of muscles from normal littermates. The IC50 (concentration producing 50% inhibition of stimulus‐evoked contractions) values for the curare block of muscle twitch were 0.78 ± 0.03 μM and 1.32 ± 0.05 μM (mean ± 95% confidence limits) for muscles from normal and dystrophic mice, respectively.
There was no difference between muscles from normal and dystrophic mice in the number of α‐bungarotoxin binding sites per endplate.
The amplitudes of both spontaneous miniature endplate potentials (m.e.p.ps) in unblocked preparations and of evoked endplate potentials (e.p.ps) in 1.91 μM curare were greater in muscles from dystrophic mice than in muscles from normal mice. The ratio dystrophic/normal was greater for the e.p.p. amplitudes than for the m.e.p.p. amplitudes.
The quantum content of e.p.ps in magnesium‐blocked and in cut‐fibre preparations was greater in muscles from dystrophic mice than in muscles from normal littermates. Calculation of the binomial parameters n and p in the cut‐fibre preparations indicated that this increased quantum content was caused by an increase in the value of p.
It is concluded that at least part of the increased resistance to curare of the indirectly evoked twitch response of muscles from dystrophic mice is due to an increase in the quantum content of e.p.ps in these muscles.
α‐Adrenoceptor involvement in catecholamine‐induced hyperglycaemia in conscious fasted rabbits
Authors: Moratinos J. , Olmedilla B. , de Pablos I. , Vigueras M.D. 
Published: July 2012

In conscious fasted rabbits an intravenous infusion of phenylephrine (20 μg kg−1 min−1) induced hyperglycaemia. The increase in blood glucose was accompanied by a modest increase in insulin secretion and a reduction of liver glycogen. Muscle glycogen and blood lactate levels were not altered by treatment with phenylephrine.
Prazosin, 1 mg kg−1 s.c, partially attenuated phenylephrine‐induced hyperglycaemia.
Phenoxybenzamine infusion (16.6 μg kg−1 min−1) for 15 min suppressed the increase in blood glucose and the reduction in liver glycogen evoked by phenylephrine. This α‐adrenoceptor blocker also clearly attenuated the blood glucose elevation observed on infusing adrenaline at 0.3 μg kg−1 min−1.
Blockade by phenoxybenzamine of phenylephrine‐ and adrenaline‐induced hyperglycaemia was not accompanied by a significant increase in immunoreactive insulin plasma levels.
Yohimbine infused at a rate of 20 μg kg−1 min−1, also completely blocked phenylephrine‐induced hyperglycaemia. This suppressor effect was accompanied by a marked rebound in insulin secretion.
It is concluded that in normal fasted rabbits stimulation of α‐adrenoceptors induces hyperglycaemia. The increase in blood glucose depends mainly on liver glycogenolysis and inhibition of insulin secretion. Separate blockade of each component suffices to reduce α‐adrenoceptor‐mediated hyperglycaemia.
An examination of 5‐hydroxytryptamine receptors in human saphenous vein
Authors: Docherty James R. , Hyland Lisa 
Published: July 2012

We have examined the effects of antagonists on the isometric contraction of the human saphenous vein produced by 5‐hydroxytryptamine (5‐HT).
The 5‐HT2‐antagonist ketanserin (1 μM) had little effect on the lower part of the concentration‐response curve to 5‐HT, but markedly shifted the upper part of the curve.
Yohimbine caused an approximately parallel shift of the concentration‐response curve to 5‐HT, with a pA2 of 5.48, much lower than its pA2 against noradrenaline in the absence (6.36) or presence (7.06) of cocaine.
It is concluded that there are two components to the contractile response to 5‐HT in human saphenous vein: at low concentrations 5‐HT activates a yohimbine‐sensitive receptor, and at higher concentrations 5‐HT activates a 5‐HT2‐receptor.
Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine
Authors: Giachetti A. , Giraldo E. , Ladinsky H. , Montagna E. 
Published: July 2012

The selectivity profiles of the muscarinic receptor antagonists dicyclomine and trihexyphenidyl have been examined in binding and functional studies and compared with those of pirenzepine and atropine.
Dicyclomine, trihexyphenidyl and pirenzepine demonstrated the highest affinity for the M1 muscarinic receptor subtype as revealed in competition experiments against [3H]‐pirenzepine labelling of cortical membranes. Their affinity values lay in a narrow range (3.7–14 nM) approaching that of atropine (1.6 nM).
Competition experiments against [3H]‐N‐methylscopolamine in cardiac and glandular (salivary) membranes revealed differences between the drugs examined. Dicyclomine, trihexyphenidyl and pirenzepine displayed low affinity for the cardiac and intermediate affinity for the glandular receptors. Thus, the drugs appeared to discriminate between the M1 (cortical) and the peripheral muscarinic subtypes (cardiac and glandular). However, atropine displayed similar affinities for either subtype with IC50s varying only slightly (1.6‐4.6 nM). The rank order of selectivity was: pirenzepine > dicyclomine > trihexyphenidyl > atropine.
Mirroring the binding data, pirenzepine, dicyclomine and trihexyphenidyl showed a tenfold greater ability at inhibiting M1‐preceptor mediated ganglionic responses (McN A‐343 pressor effect in pithed rats and nictitating membrane contraction in cats) than at inhibiting peripheral muscarinic responses in the heart and cardiovascular smooth muscle (vagal bradycardia in rats and cats and vagally‐induced vasodilatation in cats).
The muscarinic antagonists so far examined can be categorized into two groups. Trihexyphenidyl, dicyclomine and pirenzepine, included in one group, are characterized by a higher affinity for the neuronal (M1) muscarinic receptor, hence they antagonize functional responses mediated by the M1 subtype. Atropine, a member of the other group, shows essentially no selectivity.
Differentiation of M1 and peripheral muscarinic receptor subtypes appears to be a property not confined to tricyclics such as pirenzepine but shared by diverse chemical structures. Both trihexyphenidyl and dicyclomine appear to be useful pharmacological tools in the classification of muscarinic receptor subtypes.