bluuebunny/crossref_metadata_2025 huggingface dataset:
Excitatory neurotensin receptors on the smooth muscle of the rat fundus: possible implications in gastric motility
Authors: Huidobro‐Toro J. Pablo , Kullak Andreas
Published: July 2012

Picomolar concentrations of neurotensin caused concentration‐dependent contractions of the longitudinal musculature of the fundus of the rat stomach. The EC50 of neurotensin was approximately 1.5 nm. On a molar basis neurotensin was about 5–10 times more potent than 5‐hydroxytryptamine (5‐HT) and approximately 80 times as active as acetylcholine in producing similar contractions.

Studies with structurally related peptides indicated that whereas the carboxy terminal portion of neurotensin was essential for biological activity, a substantial part of its amino terminus end could be removed without affecting its potency. The EC50 for the neurotensin fragment 8–13 was identical to that of neurotensin, however its 1–8 or 1–11 fragments were completely inactive.

Tetrodotoxin did not modify the potency of neurotensin or structurally related analogues suggesting that the neurotensin receptor is probably located on the smooth muscle membrane. In addition, the potency of neurotensin in contracting the fundus was not modified by pretreatment with atropine, methysergide or diphenhydramine.

Fade to the contractile response of neurotensin was followed by the development of tachyphylaxis; desensitization was concentration‐dependent and characterized by a shift in the agonist concentration‐response curve to the right and downwards. Desensitization with a priming concentration of neurotensin (approx. EC50) caused a substantial blockade of its excitability.

There was cross‐desensitization between neurotensin and the contractile activity of neurotensin 8–13 or xenopsin, but not with angiotensin II, bradykinin, substance P, acetylcholine, 5‐HT or histamine.

Pretreatment of the fundus strip with verapamil 0.3–1 μm antagonized in a concentration‐dependent fashion the neurotensin‐induced contractions but not the muscular contractions caused by acetylcholine.

It is concluded that neurotensin activates a specific excitatory receptor probably located on the cell membrane of the smooth muscles of the rat fundus. In addition, we suggest that this receptor is somehow related to a voltage‐dependent calcium channel, sensitive to verapamil.
Modulation of [3H]‐dopamine released by different frequencies of stimulation from rabbit retina
Authors: Dubocovich Margarita L. , Hensler Julie G.
Published: July 2012

Rabbit retinal pieces were incubated with [3H]‐dopamine and superfused with Krebs solution. Calcium‐dependent tritium release was elicited twice within each experiment by electrical field stimulation (360 pulses, 2 ms, 20 mA) at frequencies of 1 Hz, 3 Hz, and 6 Hz. The evoked release of [3H]‐dopamine for the first period of stimulation (S1) was 2.09 ± 0.23% (n = 5) at 1 Hz and was of similar magnitude at all other frequencies of stimulation employed.

The D2‐dopamine receptor agonist, LY 171555 (quinpirole HCl; 0.01‐1 μM) added to the superfusion medium before the second period of stimulation, inhibited the calcium‐dependent release of [3H]‐dopamine in a concentration‐dependent manner, and was more potent the lower the stimulation frequency. The isomer of quinpirole, LY 181990 (0.01‐1 μM) did not inhibit the stimulation‐evoked overflow of tritium, regardless of concentration or stimulation frequency.

The stereoisomers of the D2‐dopamine receptor antagonist sulpiride (0.01–3 μM) increased the calcium‐dependent release of [3H]‐dopamine in a concentration‐dependent manner, being more potent the higher the frequency of stimulation. S‐sulpiride was more potent than R‐sulpiride at all stimulation frequencies. The inhibitory effect of quinpirole was stereoselectively antagonized by sulpiride, but not by LY 181990. The α‐adrenoceptor antagonist phentolamine (1 μM) did not modify the quinpirole‐induced inhibition of [3H]‐dopamine release.

When the synaptic concentration of dopamine was increased by the presence of the dopamine uptake inhibitor nomifensine (3 μM), the potency of the agonist quinpirole in inhibiting the release of [3H]‐dopamine elicited by field stimulation at 1 Hz (180 pulses) was decreased. In contrast, the potency of S‐sulpiride in enhancing the evoked release of [3H]‐dopamine was increased when nomifensine was present in the superfusion medium.

Picomolar concentrations of the hormone melatonin (0.1–10 nM) inhibited the calcium‐dependent release of [3H]‐dopamine from rabbit retina with the same potency regardless of the frequency of stimulation applied (1 Hz, 3 Hz or 6 Hz).

The potency of D2‐dopamine receptor agonists and antagonists in modifying [3H]‐dopamine release from rabbit retina appears to depend on the synaptic concentration of dopamine which is altered by the frequency of stimulation, and by the dopamine uptake inhibitor nomifensine. At lower synaptic concentrations of the transmitter dopamine the receptor agonist quinpirole was more potent in inhibiting [3H]‐dopamine release, while the receptor antagonist sulpiride was more potent in enhancing [3H]‐dopamine release the higher the synaptic concentration of dopamine. In contrast, the potency of melatonin in inhibiting [3H]‐dopamine release was not altered by the frequency of stimulation, or by frequency‐dependent changes in the biophase concentration cf the transmitter dopamine.
The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels
Authors: Weir Sheila W. , Weston A.H.
Published: July 2012

The effects of the antihypertensive agent BRL 34915 on a variety of responses of the aorta and portal vein of the rat have been compared with those of nicorandil.

On portal vein, BRL 34915 (0.01–50 × 10−6 M) and nicorandil (0.1–500 × 10−6 M) abolished spontaneous mechanical activity and reduced mechanical responses to noradrenaline (0.1–100 × 10−6 M) and K+ (5–20 × 10−3 M) but had little inhibitory effect on responses to K+ (40–80 × 10−3 M). The onset of the reduced responses to noradrenaline was delayed by both agents.

On portal vein, BRL 34915 (0.1–50 × 10−6 M) and nicorandil (0.5–500 × 10−6 M) abolished spontaneous electrical and mechanical activity, hyperpolarized the smooth muscle cells to a value close to their calculated potassium equilibrium potential and increased the 86Rb efflux rate coefficient.

On aorta, BRL34915 (0.2‐0.8 × 10−6 M) and nicorandil (8–32 × 10−6 M) reduced mechanical responses to noradrenaline (0.001‐1 × 10−6 M) and K+ (5–20 × 10−3 M) but had little inhibitory effect on responses to K+ (40–80 × 10−3 M).

On aorta, BRL 34915 (0.2‐0.8 × 10−6 M) increased the 86Rb efflux rate coefficient whereas nicorandil (8–32 × 10−6 M) was without effect.

It is concluded that the inhibitory actions of BRL 34915 on both aorta and portal vein result from the opening of membrane potassium channels. The resulting membrane shunt inhibits the effects of excitatory agents. The inhibitory effects of nicorandil result from a combination of the opening of potassium channels together with an additional, undefined action.
Adenosine‐modulation of cholinergic and non‐adrenergic non‐cholinergic neurotransmission in the rabbit iris sphincter
Authors: Gustafsson Lars E. , Wiklund N. Peter
Published: July 2012

The characteristics of smooth muscle responses to transmural nerve stimulation in the rabbit iris sphincter were examined.

Transmural stimulation elicited a composite contractile response that could be divided in two phases. Atropine abolished the phase I contraction and inhibited the phase II contraction. The atropine‐resistant component of the phase II contraction which was unaltered by sympathetic denervation, was mimicked by substance P and abolished by capsaicin.

Adenosine inhibited the phase I contraction. The adenosine analogue L‐N6‐phenylisopropyladenosine (L‐PIA) was more potent than 5′‐N‐ethylcarboxamideadenosine (NECA) in mimicking this adenosine effect.

By contrast, adenosine enhanced the phase II contraction in non‐pretreated preparations, as well as the atropine‐resistant capsaicin‐sensitive part of this contraction. Here, NECA was more potent than L‐PIA.

Adenosine, NECA, L‐PIA and D‐PIA also enhanced the atropine‐sensitive component of the phase II contraction, as well as the contractile response to exogenous acetylcholine or carbachol, but not to exogenous substance P. In this respect, L‐PIA was the most powerful adenosine analogue with at least 10 fold higher potency than D‐PIA.

The adenosine antagonist 8‐p‐sulphophenyltheophylline enhanced the phase I contraction and decreased the capsaicin‐sensitive non‐adrenergic non‐cholinergic component of the phase II contraction.

We conclude that adenosine inhibited the nerve‐induced cholinergic twitch (phase I) responses by action at prejunctional A1‐receptors. Furthermore, adenosine enhanced the phase II contractile responses via postjunctional enhancement of the cholinergic transmission by action at A1‐receptors, and via enhancement of the non‐adrenergic non‐cholinergic transmission by action at presumably prejunctional A2 receptors.
Effects of calcium antagonistic drugs on the electrical activity of rabbit sino‐atrial node
Authors: Molyvdas Paschalis‐Adam , Sperelakis Nick
Published: July 2012

The effects of several calcium antagonistic drugs (slow channel blockers), mesudipine, FR‐34235 (nilvadipine), nifedipine, and verapamil, were compared on the naturally‐occurring slow action potentials (APs) of the isolated spontaneously‐contracting sinoatrial (SA)‐node of the rabbit.

Mesudipine, at 1 × 10−8 M, had little or no effect on the AP parameters and beating frequency. At 1 × 10−7 M, mesudipine depressed the amplitude, + V̇max and frequency of the APs. A higher concentration of mesudipine (3 × 10−7 M) completely blocked the slow APs.

The concentration of FR‐34235 required for 50% depression of V̇max was 3 × 10−8 M, and complete block required 1 × 10−7 M.

The verapamil and nifedipine concentrations required for complete block were 1 × 10−6 M and 1 × 10−7 M, respectively.

The cells blocked by these drugs were depolarized to about − 40 mV.

Cells blocked and depolarized by the drugs responded to intensive field stimulation with a transient after‐hyperpolarization, followed by damped oscillations.

When [Ca]o was elevated from 1.8 mM to 5.4 mM, full block required a higher concentration of mesudipine (1 × 10−6 M) and FR‐34235 (1 × 10−6 M).

The order of potency of the drugs tested was: nifedipine = FR‐34235 > mesudipine > verapamil.

The effects of mesudipine, FR‐34235, and nifedipine were easily reversible upon washout for 10 min, whereas those of verapamil required longer periods.

The results indicate that the slow channel blockers, mesudipine, FR‐34235, nifedipine, and verapamil depress the APs and automaticity of the SA‐node.
Positive inotropic action of saponins on isolated atrial and papillary muscles from the guinea‐pig
Authors: Enomoto Yoshikazu , Ito Katsuaki , Kawagoe Yasushi , Mono Yasunori , Yamasaki Yasundo
Published: July 2012

The effects of several saponins of animal and plant origin on the contractile activity of atrial and papillary muscles of the guinea‐pig were tested. In a concentration of 1 × 10−5 M, holothurin‐A (HL‐A), holothurin‐B, echinoside‐A, echinoside‐B and sakuraso‐saponin (Saku) exhibited positive inotropic and chronotropic actions whereas desacyl‐jego‐saponin and ginsenoside‐Rd did not.

Saponins having a positive inotropic action caused haemolysis of rabbit erythrocytes whereas those without inotropic action did not cause haemolysis.

The positive inotropic action of saponins was not affected by practolol, chlorpheniramine, cimetidine and indomethacin.

Verapamil (10−6 M) inhibited the inotropic actions due to HL‐A and isoprenaline (10−8 M) to the same extent but had a small efect on those due to ouabain (10−7 M).

In high K+ (30 mM K+) medium where the action potential and the contraction were depressed, HL‐A, Saku and isoprenaline restored the action potential and the contraction of the ‘slow response’ type whereas ouabain failed to do so.

In normal medium HL‐A and Saku reduced the resting membrane potential by 15–20 mV.

These results suggest that modification of the Ca channel is involved in the positive inotropic action of saponins.
Stereoselective accumulation of hydroxylated metabolites of amphetamine in rat striatum and hypothalamus
Authors: Dougan D.F.H. , Duffield A.M. , Duffield P.H. , Wade D.N.
Published: July 2012

The stereoselective accumulation of α‐methyl‐p‐tyramine (AMPT) and α‐methyl‐p‐octopamine (AMPO) in rat striatum and hypothalamus after acute and chronic administration of the (+)‐and (−)‐isomers of amphetamine (Amphet) and the acute administration of (+)‐ and (−)‐AMPT has been investigated by chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.).

Two h after the administration of (+)‐ or (−)‐AMPT (5 mg kg−1 i.p.), the concentrations of the isomers in striatal tissue were approximately equal; 18 h later, the concentration of the (+)‐isomer was 10 times that of the (−)‐isomer.

The concentrations of AMPO in the striatum and hypothalamus 20 h after administration of (+)‐AMPT were 68 ng g−1 and 484 ng g−1 respectively. After the administration of the (−)‐isomer of AMPT, small quantities of AMPO were detected in both brain areas.

Twenty h after the last of 7 daily injections of (+)‐Amphet (5 mg kg−1, i.p.), the concentration of AMPO in the hypothalamus was 5.4 times the concentration at 20 h after one injection. In the striatum, the corresponding ratio for AMPO was 3.5 and for AMPT was 2.5.

These data indicate that, although both isomers of AMPT formed from Amphet administered systemically, cross the blood brain barrier, the (+)‐isomers AMPT and AMPO are preferentially stored in striatal and hypothalamic aminergic nerve terminals.

The accumulations of AMPT and AMPO in rat striatum and hypothalamus after chronic administration of Amphet demonstrates that these metabolites persist in neuronal storage in these brain areas for days after administration. The half‐lives of (+)‐AMPT and (+)‐AMPO in striatal neuronal storage, calculated from this data, were 1.5 days and 2.5 days, respectively. The corresponding half‐life for hypothalamic (+)‐AMPO was 7 days.

These findings suggest the involvement of accumulated AMPT and AMPO in the development of behavioural augmentation to repeated injections of Amphet (Randrup & Munkvad, 1970).
Pharmacological analysis of the inhibition by pirenzepine and atropine of vagal‐stimulated acid secretion in the isolated stomach of the mouse
Authors: Black J.W. , Shankley N.P.
Published: July 2012

The muscarinic receptors involved in the vagal stimulation of gastric acid secretion in the mouse isolated stomach assay have been examined by analysing the effects of pirenzepine and atropine on fully‐defined frequency‐effect curves.

Both atropine and pirenzepine produced concentration‐dependent inhibition of vagal‐stimulated acid secretion in a manner consistent with a model describing competitive antagonism of endogenous acetylcholine, which was assumed to be released by vagal stimulation.

The results obtained are quite compatible with the hypothesis that vagal stimulation involves muscarinic receptors which are homogeneous with those previously found on histamine and oxyntic cells in the mouse stomach assay.

These results find no evidence for muscarinic receptor heterogeneity and reinforce the hypothesis that the selectivity of pirenzepine in vivo relative to atropine is due to the loss of atropine into the gastric secretion.
Characterization of prostanoid relaxant/inhibitory receptors (ψ) using a highly selective agonist, TR4979
Authors: Gardiner P.J.
Published: July 2012

TR4979, an analogue of prostaglandin E1 (PGE1) was evaluated on respiratory and non‐respiratory isolated tissues known to contain heterogeneous or homogeneous populations of the two classes of prostanoid (prostaglandins and thromboxanes) receptors. These receptors are classified as ‘χ’ the contractant/stimulant receptor with ‘χ1,2,3’ being three subdivisions and ‘ψ’ the relaxant/inhibitory receptor(s).

On a respiratory tissue (cat trachea) containing predominantly ‘ψ’‐receptors, TR4979 was 26 times less potent than PGE1 or PGE2.

On other respiratory tissues known to contain mixtures of the ‘χ1,2.3’‐ and ‘ψ’‐receptors (guinea‐pig trachea and lung strip, cat lung strip and human bronchial muscle), TR4979 consistently acted as a potent relaxant whereas PGE2 and to a lesser extent PGE1 had significant contractant activities.

Human pregnant uterus, guinea‐pig and rat pseudo‐pregnant uteri, rat colon and fundic strips and chick ileum are known to contain one or more of the three subclasses of the ‘χ’‐receptor. TR4979 (10−9 − 10−5 M) was inactive on all these tissues whereas all of the reference prostanoids were contractants of varying potencies.

PGE, and histamine‐induced contractions of the guinea‐pig isolated ileum were both noncompetitively antagonized by increasing concentrations of TR4979 suggesting that ‘ψ’‐receptors also exist on this tissue.

TR4979 is a highly selective agonist of prostanoid ‘ψ’ (relaxant/inhibitory)‐receptors which at present have been demonstrated to exist mainly in the lung. This prostaglandin analogue is a useful new selective pharmacological tool for revealing as yet unidentified prostanoid ‘ψ’‐receptors and actions in a wide range of non‐respiratory tissues/organs such as the guinea‐pig ileum.
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.
Stereospecific inhibition of 5‐HT‐induced increase of intracellular free calcium by (+)‐ and (−)‐desmethoxyverapamil in human platelets
Authors: Bruns Christian , Marmé Dieter , Osswald Hartmut
Published: July 2012

The concentration of intracellular free calcium [Ca2+]i in human platelets was measured by the quin‐2 method. 5‐Hydroxytryptamine (5‐HT) at 10−5 M induced a rapid transient increase of [Ca2+]i which was antagonized by 10−7 M ketanserin or cyproheptadine. The verapamil derivative, desmethoxyverapamil (D 888), showed stereospecific inhibition of the 5‐HT‐induced [Ca2+]i increase. The IC50 for (−)‐D 888 was approx. 2 × 10−8 M; (+)‐D 888 was almost 50 times less potent.
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.
Impairment of protein synthesis in the rat uterus following intrauterine delivery of indomethacin
Authors: Hurst P.R. , Peplow P.V.
Published: July 2012

When indomethacin was incorporated into a slow‐release preparation (initial content 1.6 mg drug) and placed in one horn of the rat uterus, a significant decrease in protein synthesis occurred for this horn in comparison with control animals (as determined by the incorporation of radioactive leucine) at three different times after insertion. Decreases of 20, 21 % at the two times of dioestrus and 28% at the time of oestrus selected were determined. No significant reduction in protein synthesis was found for the contralateral horn, although there was a tendency for it to be lowered at the earliest time of examination when two complete oestrous cycles had passed following insertion.

Measurement of the uptake of radioactive leucine by the uterine horns showed no change in response to indomethacin delivery compared to the control animals with silastic implants, and suggested that the transport system for this amino acid in cells of the uterine horns was not affected by the drug.

It was apparent that in instances when the protein synthesis of the uterine horn was impaired by indomethacin that a decrease in RNA/DNA ratio existed. At the latest time examined, no alteration in DNA content occurred in the indomethacin‐influenced horn but there was a significant reduction in RNA content.

For a small proportion of the animals with indomethacin‐releasing preparations there was a tendency to show a lengthening of the oestrous cycle over the first three cycles following insertion. Whether this was due to a direct effect of indomethacin on the ovaries or an effect caused by decreased concentrations of prostaglandins in the uterus was unknown.

These results provide further evidence that non‐steroidal anti‐inflammatory drugs can interfere with the synthesis of macromolecular substances, and that such changes need to be taken into account when considering the overall effect of these drugs on tissues and organs.
Kinetics of the generation and action of chemical mediators in zymosan‐induced inflammation of the rabbit peritoneal cavity
Authors: Forrest M.J. , Jose P.J. , Williams T.J.
Published: July 2012

Acute inflammation was induced by intraperitoneal injection of zymosan (yeast cell walls) in the rabbit.

Peritoneal inflammation was monitored by the local accumulation of intravenously‐injected Evans blue dye (which binds to plasma albumin) and of polymorphonuclear leukocytes (PMNLs).

The zymosan‐induced exudate fluid contained a microvascular permeability‐increasing factor or factors which, unlike histamine and bradykinin, had a long duration of action when tested in rabbit skin and was dependent on circulating PMNLs.

Using radioimmunossay, high levels of rabbit C5a, or C5a des Arg, were detected in the exudate fluid and accounted for much of the permeability‐increasing activity, as judged by skin bioassay after separation on Sephadex G‐100.

The vasodilator prostaglandin, prostaglandin I2 (PGI2), was generated in the inflammatory reaction, as judged by the presence of high levels of 6‐oxo‐PGF1α detected in the exudate by radioimmunossay. However, in contrast to observations in rabbit skin, inhibition of prostaglandin generation had a relatively small effect on peritoneal oedema formation.

C5a and C5a des Arg increase microvascular permeability by a PMNL‐dependent mechanism in the rabbit. However, in response to zymosan, protein leakage was detected considerably earlier than PMNL accumulation. A hypothesis to account for this difference is proposed.
Presynaptic muscarinic and α‐adrenoceptor‐mediated regulation of GABA release from my enteric neurones of the guinea‐pig small intestine
Authors: Hashimoto S. , Tanaka C. , Taniyama K.
Published: July 2012

The effects of cholinomimetic and sympathomimetic drugs on the release of [3H]‐γ‐aminobutyric acid ([3H]‐GABA) evoked by high K+ from the isolated small intestine of the guinea‐pig were investigated, in the presence of tetrodotoxin.

Acetylcholine and oxotremorine, at concentrations ranging from 10−9 to 10−6 M inhibited the evoked release of [3H]‐GABA in a concentration‐dependent manner, while nicotine was without effect. Scopolamine and pirenzepine inhibited the effect of oxotremorine, while hexamethonium had no effect. The IC50 values for scopolamine and pirenzepine of the oxotremorine (3 × 10−8 M)‐induced inhibition were 1.02 × 10−9 M and 9.78 × 10−10 M, respectively.

Noradrenaline, but not isoprenaline inhibited the evoked release of [3H]‐GABA. Clonidine (10−10 − 10−6 M) reduced the evoked release of [3H]‐GABA in a concentration‐dependent manner, but phenylephrine had no effect. The inhibitory effect of clonidine was antagonized by yohimbine but not by prazosin.

These findings provide evidence for the localization of M1‐ muscarinic and α2‐ adrenoceptors on GABAergic nerve terminals and their involvement in the presynaptic control of the release of GABA from the guinea‐pig small intestine.
Electrophysiology of neuroeffector transmission in the isolated, innervated trachea of the guinea‐pig
Authors: McCaig Dorothy J.
Published: July 2012

Intracellular recordings were made from cells of the guinea‐pig trachealis muscle. Some cells were electrically quiescent while others exhibited spontaneous slow waves.

In quiescent cells, stimulation of the cervical vagus nerve evoked transient depolarization. Occasionally there was a single depolarization, but more often there were several fluctuations in potential.

In spontaneously active cells, vagal stimulation induced a transient increase in amplitude of the slow waves without affecting their frequency.

Depolarizing responses could be obtained with a single pulse applied to the vagus nerve, and responses increased in amplitude with number of pulses (up to 16 pulses), and with frequency of stimulation (up to 20 Hz). Depolarization did not give rise to spike discharge.

Responses to vagal stimulation were blocked by atropine.

In the presence of neostigmine, vagally‐mediated depolarization was augmented and abortive spikes were observed in a number of cells.

In quiescent cells, repetitive stimulation of the sympathetic stellate ganglion evoked slight hyperpolarization.

In spontaneously active cells, sympathetic stimulation evoked attenuation, or temporary cessation of slow wave discharge, with or without hyperpolarization.

Sympathetic‐induced hyperpolarization and suppression of slow waves were both blocked by propranolol, but unaffected by phentolamine.

Electrical changes associated with sympathetic stimulation may be of minor importance in the initiation of relaxation.
Abnormal vascular phosphoinositide hydrolysis in the spontaneously hypertensive rat
Authors: Heagerty A.M. , Ollerenshaw J.D. , Swales J.D.
Published: July 2012

The production of [3H]‐inositol phosphates was studied in labelled segments of aorta from spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) controls at 5 and 19 weeks, either unstimulated or in the presence of noradrenaline.

Basal hydrolysis of inositol phospholipids was significantly enhanced in young SHR (P < 0.05) compared to controls but this difference was no longer detected at 19 weeks.

Noradrenaline increased [3H]‐inositol phosphate accumulation in both SHR and WKY, but maximal hydrolysis was significantly greater in WKY (P < 0.01), although the ED50 was similar in both groups of animals.

These data demonstrate that phosphatidylinositide hydrolysis is enhanced in the young hypertensive rat at the time blood pressure is rising, but that this activity has declined by the time hypertension has reached an established phase. In addition, α1‐agonist induction of inositol phospholipid hydrolysis differs in the two species of animals, being reduced in genetically mature hypertensive rats.