bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the dihydropyridine Bay K 8644 on the release of [3H]‐noradrenaline from the rat isolated vas deferens
Authors: Ceña Valentin , Garcia Antonio G. , Khoyi Mohammad A. , Salaices Mercedes , Sanchez‐García Pedro
Published: July 2012

The effects of Bay K 8644 on the release of [3H]‐noradrenaline evoked by potassium, electrical stimulation or tyramine from the rat isolated vas deferens labelled with [3H]‐noradrenaline were investigated.

Bay K 8644 (1 μM) by itself did not affect the spontaneous release of tritium from the rat isolated vas deferens. However, it increased the calcium‐dependent release of tritium elicited by both high potassium (59 mM) and electrical field stimulation.

The exposure of rat vas deferens to phentolamine (10 μM) increased the release of tritium induced by potassium (59 mM) and electrical field stimulation. Bay K 8644 (1 μM) failed to increase further the release of tritium elicited by both stimuli in preparations previously treated with phentolamine (10 μM).

The calcium‐independent release of [3H]‐noradrenaline evoked by tyramine (10 μM) was not affected by Bay K 8644 (1 μM).

The results of our study support the view that α2‐adrenoceptors modulate noradrenaline release by restricting calcium influx into sympathetic nerve terminals through voltage‐dependent channels.
Solubilization and characterization of high and low affinity pirenzepine binding sites from rat cerebral cortex
Authors: Berrie Christopher P. , Birdsall Nigel J.M. , Hulme Edward C. , Keen Mary , Stockton Jane M.
Published: July 2012

An apparently monomeric form of the digitonin‐solubilized muscarinic acetylcholine receptor from the rat cerebral cortex retains a high affinity of 7 × 107 M−1 for pirenzepine.

Muscarinic receptor binding sites in the rat cerebral cortex with a low affinity for pirenzepine are solubilized with relatively little change in affinity.

The ability of pirenzepine to distinguish between subtypes of muscarinic binding site in the cerebral cortex is manifest in both the membrane‐bound and soluble state.
The selective antagonism of bradykinin action on rat isolated uterus by crude Mandevilla velutina extract
Authors: Calixto João B. , Nicolau Mauro , Yunes Rosendo A.
Published: July 2012

A crude aqueous alcoholic extract of Mandevilla velutina (Apocynaceae) rhizomes produced a concentration‐dependent displacement to the right of the concentration‐response curve to bradykinin (Bk) in the isolated uterus of the rat. Schild analysis of the data revealed a linear relationship (r = 0.99) and yielded a pA2 value of 3.3 + 0.08 (‐log g ml−1) but the slope differed significantly from unity. The anti‐Bk action was of rapid onset and was reversible upon washout. Contractions induced by acetylcholine, oxytocin, angiotensin II and BaCl2 were unaffected by the extract. This represents the first report of a selective Bk antagonist of plant origin. The isolation of the active principle(s) may result in a useful pharmacological tool for elucidating the physiological and physiopathological roles of endogenous Bk.
Effect of nicotine on blood flow, oxygen consumption and glucose uptake in the canine small intestine
Authors: Grayson J. , Oyebola D.D.O.
Published: July 2012

Resting blood flow, arterio‐venous glucose and oxygen (A‐V)O2 differences, glucose uptake and oxygen consumption by a segment of the upper jejunum were measured in anaesthetized dogs. Systemic arterial pressure was also measured.

The effect of nicotine infusion (25 μg kg−1 i.v., over 10 min) on these measurements was recorded in untreated dogs, in dogs treated with propranolol (0.5 mg kg−1) to produce β‐adrenoceptor blockade and in dogs after α1,‐adrenoceptor blockade with prazosin (0.2 mg kg−1).

Nicotine cause a significant pressor response during infusion and a hypotensive response during the post infusion period. Propranolol did not significantly affect these results. Jejunal blood flow increased in the first half of nicotine infusion in both the untreated and β‐blocked animals. Vascular resistance was reduced during nicotine infusion and the decrease persisted post infusion in the β‐blocked group.

In the untreated group (A‐V)O2 was significantly reduced during the first 5 min of nicotine infusion, thereafter it returned to control levels, then rose significantly above control level, post infusion. β‐Adrenoceptor blockade had little effect on these responses to nicotine. When oxygen consumption was calculated it was found that nicotine had little effect during or after infusion.

Nictine caused significant hyperglycaemia during and for about 1 h after infusion. Tissue release of glucose was occasionally observed following the infusion. β‐Adrenoceptor blockade reduced the hyperglycaemia caused by nicotine. β‐Blockade alone increased glucose uptake and nicotine caused a further three to four fold increase. Prazosin abolished the effects that were observed in the untreated and the α‐blocked animals.

The present findings, related to our previous observations on the effects of catecholamines on glucose uptake by the bowel, are consistent with the hypothesis that nicotine has its action on bowel glucose uptake or release through its well‐established action in releasing catecholamines and in activating β‐adrenoceptors. The responses are not related to oxygen utilization.
Electrophysiological actions of nicotine on substantia nigra single units
Authors: Clarke P.B.S. , Hommer D.W. , Pert A. , Skirboll L.R.
Published: July 2012

Extracellular recordings of single unit activity were made in the substantia nigra (SN) of chloral hydrate‐anaesthetized rats.

Dopaminergic neurones of the pars compacta (SNC) were stimulated by (—)‐nicotine bitartrate (1.0 mg k−1) given subcutaneously (s.c.). This action was prevented by the secondary amine mecamylamine HCl (2.0 mg kg−1 i.v.) but not by a ganglion‐blocking dose of the bisquaternary compound chlorisondamine Cl (0.1 mg kg−1 i.v.). Mecamylamine reduced the spontaneous activity of dopaminergic neurones.

Nicotine, when administered intravenously (2–128 μg kg−1 cumulative dose), also stimulated dopamine cells and this action was dose‐related.

Nicotine, administered intravenously, (2–128 μg kg−1 cumulative dose) markedly excited non‐dopamine cells in the pars reticulata (SNR) in a dose‐related manner. In rats pretreated with chlorisondamine (0.1 mg kg−1 i.v.), nicotine induced a small excitatory or depressant action, but the marked excitation was not seen. Mecamylamine (2 mg kg−1 i.v.) completely prevented the actions of nicotine.

The results are consistent with a direct excitatory action of nicotine on dopaminergic neurones of the substantia nigra pars compacta. The pronounced excitatory action of systemically administered nicotine on non‐dopamine cells of the pars reticulata appears to be of peripheral origin.
Excitatory effect of Clostridium perfringens alpha toxin on the rat isolated aorta
Authors: Fujii Yoshio , Nomura Shigemasa , Oshita Yoshitami , Sakurai Jun
Published: July 2012

Clostridium perfringens alpha toxin caused contraction of the isolated aorta of the rat in a dose‐dependent manner.

The contractile action caused by the toxin was inhibited or abolished by calcium antagonists such as nifedipine, verapamil and cinnarizine, or a Ca‐free medium, but was not affected by phentolamine, chlorpheniramine, atropine, tetrodotoxin or a low Na medium.

The toxin stimulated Ca uptake into the aorta in a dose‐dependent manner.

8‐N,N'‐diethylaminooctyl‐3,4,5‐trimethoxybenzoate (TMB‐8) blocked significantly both the toxin‐ and noradrenaline (NA)‐induced contractions.

Trifluoperazine (TFP) and N‐(6‐aminohexyl)‐5‐chloro‐l‐naphtharene sulphonamide (W‐7) did not affect the contractile activity of the toxin but blocked the NA‐induced contraction.

The toxin also stimulated the 32P phosphate labelling of phosphatidylinositol (PI) and phosphatidic acid (PA) in the preparation.

These results indicate that the toxin‐induced contraction, which is different from that induced by NA, is the result of a direct action of the toxin on the aorta and is due to an increased Ca2+ permeability across the smooth muscle membrane. It is suggested that the contractile response to the toxin is associated with activation of phospholipid metabolism and enhanced entry of Ca into the aorta.
Urinary kallikrein excretion during inhibition of endogenous angiotensin II in the pig
Authors: Binder Bernd R. , Maier Manfred , Rana Hemanta , Starlinger Michael , Zhegu Zydi
Published: July 2012

This study was performed to assess the possible contribution of endogenous angiotensin II (AII) to the regulation of urinary kallikrein excretion. The AII antagonist saralasin or the saline vehicle was infused into the aorta above the renal arteries of pigs under halothane‐O2/N2O anaesthesia. Systemic and renal functional parameters were followed for 140 min and during stimulation of the renin‐angiotensin system by haemorrhage.

Urinary kallikrein excretion, determined as kininogenase activity, was increased immediately upon both initiation and termination of the 2 h saralasin infusion into pigs not subjected to haemorrhage. Renal cortical blood flow (RCBF) was maintained in both saline and saralasin‐treated animals at blood pressures as low as 70 mm Hg, while glomerular filtration rate was dissociated during saralasin infusion. As long as RCBF was maintained, urinary kallikrein excretion rate was elevated during the progressive hypotension in both saline and saralasin‐treated animals.

These findings confirm a close relationship between the maintenance of RCBF and increased activity of the kallikrein‐kinin system whether or not AII is antagonized, and indicate that during haemorrhage the kallikrein‐kinin system is stimulated by a mechanism not involving AII.
Binding to serum α1‐acid glycoprotein and effect of β‐adrenoceptor antagonists in rats with inflammation
Authors: Belpaire F.M. , Bogaert M.G. , Mugabo P. , Rosseel M.T.
Published: July 2012

The β‐blocking effect of 4 β‐adrenoceptor antagonists with different pharmacokinetic properties was studied after intravenous and intraportal administration to control rats and to rats with experimental inflammation.

In rats with inflammation the effects of propranolol and oxprenolol, which are mainly bound to α‐acid glycoprotein (α1‐AGP), were significantly less after intravenous administration, but not after intraportal administration. In contrast, for metoprolol and atenolol, which are only negligibly serum bound, no difference was observed between control rats and rats with inflammation for either route of administration.

Total and unbound serum concentrations of propranolol were measured 20 min after intravenous and intraportal administration.

After intravenous administration, in the rats with inflammation total concentrations of propranolol were more than twice, and unbound concentrations less than half those of control rats. After intraportal administration the total concentrations were 8 times, and the unbound concentrations 3 times higher in the rats with inflammation.

There was a significant correlation between the β‐blocking effect and the unbound concentrations of propranolol after intravenous administration, but not after intraportal administration. The latter finding is probably because the unbound concentrations were supramaximal.
The effects of locally applied capsaicin on conduction in cutaneous nerves in four mammalian species
Authors: Baranowski Richard , Lynn Bruce , Pini Adrian
Published: July 2012

By examination of compound action potentials in the saphenous nerve of the anaesthetized rat it has been shown that capsaicin causes a rapid, dose‐dependent, failure of conduction in many C‐fibres when applied directly to the nerve. A large reduction in C‐fibre conduction occurs with concentrations as low as 110 μM. After a 15–30 min exposure to capsaicin, only partial recovery occurs in 1 h.

Similar block of C‐fibre conduction occurs in the ferret. However, only smaller, reversible, reductions in C‐fibre conduction were seen in the guinea‐pig and rabbit, even at the highest concentration of capsaicin used (33 mM).

A small reduction in the Aδ component of the compound action potential occurred in all four species. In the rat and ferret the effects were much less than those on C‐fibres.

At high doses, small reversible effects were also seen on the fastest conducting Aαβ component of the compound action potential in the rat, rabbit and guinea‐pig; no effects were seen on the Aαβ fibres in the ferret.

Decreases in amplitude of the compound action potential were accompanied by some slowing of conduction in most cases. The slowing was less than 5% except for the rat Aαβ and C‐fibres and the ferret C‐fibres where 9–15% changes occurred at the highest doses of capsaicin.

Opening the connective tissue sheath of the nerve did not significantly increase the effectiveness of capsaicin.
Pressure reversal of alphaxalone/alphadolone and methohexitone in tadpoles: evidence for different molecular sites for general anaesthesia
Authors: Halsey Michael J. , Wardley‐Smith Bridget , Wood Steven
Published: July 2012

Tadpoles were used to study quantitative interactions between high pressure and two intravenous anaesthetics, alphaxalone/alphadolone and methohexitone.

The potencies of the two agents were decreased by high pressure but to different extents. The maximum effect was seen in the pressure range 70–130 atmospheres absolute (ATA). The increases in the normobaric anaesthetizing concentration (ED50) required at 100 ATA were alphaxalone/alphadolone:405 ± 5 (s.d.)%; methohexitone:658 ± 80 (s.d.)%.

For both alphaxalone/alphadalone and methohexitone, the curves obtained when the increase in ED50 was plotted against increasing pressure showed plateaux at pressures above 70 ATA.

These data support the concept of the two intravenous drugs causing general anaesthesia by the occupation of separate molecular ‘sites’ with different but finite capacities.
The effect of α2‐adrenoceptor agonists on the acid secretory responses of rat isolated gastric mucosa to electrical field stimulation
Authors: Dettmar P.W. , Lord J.A.H.
Published: July 2012

The effects of clonidine, UK‐14,304, noradrenaline, para‐aminoclonidine and phenylephrine were examined on the acid secretory response of the rat isolated gastric mucosa preparation to electrical field stimulation.

Clonidine, UK‐14,304, noradrenaline and para‐aminoclonidine but not phenylephrine (10 μM) reduced the response of the gastric mucosa stimulated at 2.5 Hz; gastric mucosae stimulated at higher frequencies were insensitive to the action of these α2‐adrenoceptor agonists.

The inhibitory effect of the selective α2‐adrenoceptor agonist UK‐14,304 was antagonized by idazoxan but not by prazosin.

These findings indicate that clonidine and other α2‐adrenoceptor agents inhibit the acid secretory response of the rat gastric mucosa to electrical field stimulation by an action at α2‐adrenoceptors, which are probably located on cholinergic nerve terminals.
Inhibition of calcium channels by harmaline and other harmala alkaloids in vascular and intestinal smooth muscles
Authors: Karaki H. , Kishimoto T. , Ozaki H. , Sakata K. , Umeno H. , Urakawa N.
Published: July 2012

Effects of harmaline and other harmala alkaloids on the contractions induced in the vascular smooth muscle of rabbit aorta and intestinal smooth muscle of taenia isolated from guinea‐pig caecum were examined.

In rabbit isolated aorta, harmaline inhibited the sustained contraction induced by 65.4 mM K+ with an IC50 (concentration needed for 50% inhibition) of 4.6 × 10−5 M. This inhibitory effect on high K+‐induced contraction was antagonized by raising the concentration of external Ca2+ but not by Bay K 8644, a Ca2+ channel facilitator. Harmaline also inhibited the sustained contraction induced by noradrenaline (10−6 M) with an IC50 of 7.6 × 10−5 M. The inhibitory effects on noradrenaline‐induced contractions were not antagonized by raising the external Ca2+ concentrations or by Bay K 8644.

In guinea‐pig taenia, harmaline inhibited the 45.4 mM K+‐induced contraction with an IC50 of 6.8 × 10−5 M and the carbachol (10−6 M)‐induced contraction with an IC50 of 7.0 × 10−5 M. The inhibitory effects on both high K+‐ and carbachol‐induced contractions were antagonized by raising the external Ca2+ concentrations but not by Bay K 8644.

Harmaline, at the concentrations needed to inhibit the muscle contraction, inhibited the increase in 45Ca2+ uptake induced by high K+, noradrenaline and carbachol in aorta and taenia.

Harmaline did not change the cellular Na+ and ATP contents in resting and high K+ stimulated taenia.

Other harmala alkaloids also inhibited the contractions in these smooth muscles. The order of the inhibitory potency was 6‐methoxyharman = harmine > harmaline = 2‐methylharmine = harmane > 6‐methoxyharmalan > harmalol = harmol for the contractions induced by high K+ in aorta and taenia and by carbachol in taenia, and 2‐methylharmine > 6‐methoxyharman > 6‐methoxyharmalan = harmol = harmalol = harmane > harmine > harmaline for the contraction induced by noradrenaline in aorta.

These results suggest that harmaline inhibits the contractile response of rabbit aorta and guinea‐pig taenia by inhibiting different types of Ca2+ channel. The structure‐activity relationship indicates that the potency and selectivity of the inhibitory effects on these channels are varied by modification of the structure of this alkaloid.
The effects of noradrenaline, B‐HT 920, methoxamine, angiotensin II and vasopressin on mean circulatory filling pressure in conscious rats
Authors: Pang C.C.Y. , Tabrizchi R.
Published: July 2012

The effects of vasoactive substances on mean circulatory filling pressure (MCFP), an index of total body venous tone, were determined in conscious rats.

Cumulative doses of saline (0.9% w/v NaCl solution), methoxamine (α1‐adrenoceptor agonist), B‐HT 920 (α2‐adrenoceptor agonist) noradrenaline and vasopressin, and individual doses of angiotensin II (AII), were infused into the rats. Mean arterial pressure (MAP), MCFP and heart rate (HR) were determined before and during the plateau responses to infusions of the vasoactive substances.

The infusions of all the agonists caused a dose‐dependent increase in MAP and a decrease in HR. The infusion of saline affected neither MAP nor HR.

The infusions of saline and methoxamine did not affect MCFP while the infusions of B‐HT 920, noradrenaline and AII increased MCFP. MCFP was slightly increased during the infusion of high doses of vasopressin.

It was concluded that receptors for the α2‐adrenoceptor agonist and AII are involved in the control of venous tone. Receptors for the α1‐adrenoceptor agonist and vasopressin are not important for the control of venous tone.
The effects of epithelium removal on the sensitivity of guinea‐pig isolated trachealis to bronchodilator drugs
Authors: Farmer S.G. , Fedan J.S. , Hay D.W.P. , Raeburn D.
Published: July 2012

Mechanical removal of the epithelium increased the sensitivity of tracheal strips to isoprenaline, sodium nitroprusside, and to adenosine (only in the presence of inhibitors of its uptake and metabolism). Epithelium removal was without effect on sensitivity to salbutamol or papaverine.

Preincubation of tracheal strips with an inhibitor of extraneuronal uptake, corticosterone (50 μM), had no effect on tissue sensitivity to either salbutamol or papaverine. However, the steroid both increased sensitivity to isoprenaline, and abolished the effect of epithelium removal on sensitivity to this catecholamine.

These results suggest that in the guinea‐pig, the tracheal epithelium is a major source of extraneuronal uptake for catecholamines. Furthermore, the increase in trachealis sensitivity to isoprenaline following epithelium removal is probably due to loss of these sites of extraneuronal uptake.

The fact that sensitivity to salbutamol, papaverine and adenosine (in the absence of metabolic inhibitors) was not increased by denuding the epithelium indicates that loss of a diffusion barrier to drugs is not the mechanism of increased sensitivity.

Adenosine (and possibly nitroprusside) may cause the epithelium to release a smooth muscle excitatory factor. Thus, removal of the epithelium attenuates this excitatory influence and enhances smooth muscle responsiveness to adenosine.

These results provide further evidence that the epithelium has an important role in modulating the sensitivity of guinea‐pig trachealis to drugs.
Effects of inhibitors of arachidonic acid metabolism on Paf‐induced gastric mucosal necrosis and haemoconcentration
Authors: Wallace John L. , Whittle Brendan J.R.
Published: July 2012

The effects of several inhibitors of arachidonic acid metabolism on gastric necrosis, hypotension, haemoconcentration, leukopenia and plasma exudation induced by platelet‐activating factor (Paf) were studied in the rat.

A 10 min intravenous infusion of Paf (100 ng kg−1 min−1) caused extensive gastric damage and a marked fall in systemic blood pressure which had not recovered to basal levels 30 min after the infusion had been terminated. Paf also caused significant haemoconcentration, plasma exudation and transient leukopenia.

Pretreatment with dexamethasone (0.2 or 2 mg kg−1 s.c.) or prednisolone (20 mg kg−1 s.c.) two hours before Paf significantly reduced the gastric damage and accelerated the recovery of blood pressure after the Paf infusion. Likewise, BW755C (50 mg kg−1 p.o.) significantly reduced the gastric damage.

Acute pretreatment with dexamethasone (2 mg kg−1 i.v.) 15 min before Paf, or with indomethacin (5 mg kg−1 s.c.), acetylsalicylic acid (10 mg kg−1 i.v.) or 1‐benzylimidazole (50 mg kg−1 s.c.) did not significantly affect the gastric damage induced by Paf.

The Paf‐induced haemoconcentration and plasma exudation were significantly reduced by pretreatment with prednisolone (20 mg kg−1 s.c.) or BW755C (50 mg kg−1 p.o.), while Paf‐induced leukopenia was unaffected by either drug.

These studies indicate that cyclo‐oxygenase products of arachidonic acid are unlikely to contribute significantly to the gastric damage or the prolonged hypotension induced by Paf. The ability of corticosteroids and BW755C to reduce the gastric damage, haemoconcentration and plasma exudation suggests that lipoxygenase products of arachidonic acid may contribute to these actions of Paf.
The binding of pirenzepine to digitonin‐solubilized muscarinic acetylcholine receptors from the rat myocardium
Authors: Birdsall N.J.M. , Hulme E.C. , Keen M.
Published: July 2012

The binding of pirenzepine to digitonin‐solubilized rat myocardial muscarinic acetylcholine receptors has been examined at 4°C.

Solubilization produced only small changes in the binding of N‐methylscopolamine and atropine. In contrast to the low affinity binding of pirenzepine found to be present in the membranes, high affinity binding was detected in the soluble preparation. In both preparations, pirenzepine binding was complex.

High affinity pirenzepine binding (KD ∼ 3 × 10−8M) to the soluble myocardial receptors could be monitored directly using [3H]‐pirenzepine.

[3H]‐pirenzepine‐labelled soluble myocardial receptors have a sedimentation coefficient of 11.1 s. This indicates that [3H]‐pirenzepine binds predominantly to the uncoupled form of the receptor. However, [3H]‐ pirenzepine‐agonist competition experiments indicated that the high affinity pirenzepine binding sites are capable of coupling with a guanosine 5′‐triphosphate (GTP)‐binding protein. Pirenzepine affinities for the soluble myocardial receptors were unaffected by their state of association with the GTP‐binding proteins found in the heart.

The equilibrium binding properties of the soluble cortical and myocardial receptors were very similar. However, the binding kinetics of the myocardial receptor were much slower.

It appears that the membrane environment can affect the affinity of pirenzepine for the rat myocardial muscarinic receptor. Removal of the constraint by solubilization allows the expression of high affinity pirenzepine binding.
Identification of 6‐oxo‐prostaglandin E1 as a naturally occurring prostanoid generated by rat lung
Authors: Berry C.N. , Griffiths R.J. , Hoult J.R.S. , Moore P.K. , Taylor G.W.
Published: July 2012

The spontaneous release of prostanoids from rat isolated perfused lungs was studied after acid/organic extraction of perfusates by bioassay, radioimmunoassay, thin layer and high performance liquid chromatographic methods and by gas chromatography‐negative ion mass spectroscopy (g.c.‐n.i.m.s.).

An acid/organic extractable anti‐aggregatory vasodilator prostaglandin which inhibited the twitch response of the field‐stimulated guinea‐pig vas deferens was released from the Krebs‐perfused rat lung in nanogram amounts similar to those of other detected prostanoids. Parallel biological assay suggested that this prostaglandin had very closely similar pharmacological activity to authentic 6‐oxo‐prostaglandin E1 (6‐oxo‐PGE1), a metabolite of prostacyclin (PGI2) generated by the action of the enzyme 9‐hydroxyprostaglandin dehydrogenase (9‐PGDH).

6‐oxo‐PGE1 was identified conclusively in extracts of rat lung perfusate by thin layer chromatography, high performance liquid chromatography and g.c./m.s. combined with bioassay (inhibition of platelet aggregation), and its covalent structure was defined by g.c. negative ion chemical ionization mass spectroscopy.

The rank order of spontaneous release of prostanoids (measured by radioimmunoassay) from the perfused rat lung was 6‐oxo‐PGF1α > thromboxane B2 (TXB2) > PGE2 > 6‐oxo‐PGE1 (measured biologically) > PGF2α. Release of all five prostanoids was inhibited by indomethacin, but only that of 6‐oxo‐PGE1 was inhibited by naringenin.

Rat lung 100,000 g cytosolic supernatants contained 9‐PGDH activity capable of removing 9β‐tritium from labelled prostacyclin and forming an acid/organic extractable 6‐oxo‐PGE1‐like anti‐aggregatory substance. This 9‐PGDH activity was inhibited by naringenin (IC50 10.3 μM).

The relevance of these findings to the possible physiological role of 6‐OXO‐PGE1 in the lung is discussed, and we propose that 6‐oxo‐PGE1 should be accorded the status of a physiologically relevant, naturally occurring metabolite of arachidonic acid.
The inhibitory action of 5‐hydroxytryptamine on gastric secretory function in rats
Authors: Cho C.H. , Ogle C.W.
Published: July 2012

The inhibitory action of 5‐hydroxytryptamine (5‐HT) on gastric function was studied in vagotomized rats.

5‐HT (0.6, 1 or 5 mg kg−1, s.c.) dose‐dependently reduced gastric acid secretion evoked by histamine, pentagastrin or methacholine. Pepsin secretion induced by pentagastrin or methacholine was also depressed by 5‐HT.

Basal secretion of both acid and pepsin was not significantly affected by any of the three 5‐HT doses.

Indomethacin pretreatment, which significantly decreased gastric mucosal prostaglandin E2 content, did not modify the inhibitory effects of 5‐HT on histamine‐induced acid secretion, nor did phentolamine or propranolol.

This study suggests that 5‐HT inhibits gastric secretory function through mechanisms other than by sympathetic influence or increased prostaglandin synthesis. The inhibitory action appears not to be vagus‐dependent. Other mechanisms of action are discussed.
Changes in mechanical responses of vascular smooth muscles to acetylcholine, noradrenaline and high‐potassium solution in hypercholesterolemic rabbits
Authors: Ibengwe Joshwa K. , Suzuki Hikaru
Published: July 2012

Mechanical responses produced by high potassium solution (high‐[K]), noradrenaline (NA) and acetylcholine (ACh) were observed in the thoracic aorta and the main pulmonary artery isolated from control and hypercholesterolemic rabbits.

In the hypercholesterolemic rabbit, these tissues showed increased contractile sensitivity to high‐[K], in comparison with those from the control rabbit. In tissues from the control rabbit, mechanical removal of the endothelium did not change the contraction to high‐[K].

The amplitudes of the contractions produced by NA were decreased in tissues from the hypercholesterolemic rabbit, while they were enhanced after removal of the endothelium in tissues from the control rabbit.

The endothelium‐dependent relaxant response to ACh observed in tissues from the control rabbit was diminished, abolished or changed to a contraction in tissues from the hypercholesterolemic rabbit.

It is concluded that in vascular tissues from the rabbit, an increase in contractile sensitivity to high‐[K], a decrease in sensitivity to NA and dysfunction of the endothelium to ACh are induced by feeding a high‐cholesterol diet and these changes in the vascular tissues may thus be involved in the hypertension observed during diet‐induced atherosclerogenesis.
A tachykinin antagonist inhibits gastric emptying and gastrointestinal transit in the rat
Authors: Holzer P. , Holzer‐Petsche U. , Leander S.
Published: July 2012

The effect of a substance P antagonist, [D‐Pro2, D‐Trp7,9]‐substance P (SPA), on gastric emptying and gastrointestinal transit in the rat was studied in order to elucidate a possible physiological role of endogenous substance P and other tachykinins in gastrointestinal motility. SPA was given by intraperitoneal injection concurrently with the intragastric administration of a test meal containing charcoal and 51Cr.

Examination 15 min after the test meal showed that SPA (0.13‐1.3 μmol kg−1) inhibited gastric emptying and gastrointestinal transit in a dose‐dependent manner.

The inhibitory effect of SPA on gastric emptying and gastrointestinal transit remained unchanged after pretreatment of rats with mepyramine (8.7 μmol kg−1) plus cimetidine (19.8 μmol kg−1) or with guanethidine (67 μmol kg−1).

Since a full examination of SPA as a specific tachykinin antagonist was not possible in vivo, SPA was also tested on circular muscle strips from the rat gastric corpus in vitro. Submaximal contractions in response to bombesin or bethanechol were not reduced by SPA (50 μM), whereas those in response to substance P were inhibited.

The results suggest that SPA inhibits gastric emptying and gastrointestinal transit by interfering with the action of tachykinins released from enteric nerves and that endogenous tachykinins are involved in the regulation of gastrointestinal motility.
Systemic baclofen stimulates gastric motility and secretion via a central action in the rat
Authors: Andrews P.L.R. , Wood K.L.
Published: July 2012

Intravenous (0.5 mg kg−1) or subcutaneous (2–16 mg kg−1) administration of the γ‐aminobutyric acid (GABA) analogue baclofen resulted in a stimulation of gastric motility and secretion in the rat, anaesthetized with urethane.

The motility response to subcutaneous injection was dose‐related.

This effect was abolished by vagotomy or atropine. There was no response to baclofen in decerebrate animals.

These results indicate that systemic baclofen, probably acting at a site rostral to the brainstem, stimulates gastric motility and acid secretion by a vagally‐dependent mechanism.
Selective inhibition by ethylisopropylamiloride of the positive inotropic effect evoked by low concentrations of ouabain in rat isolated ventricles
Authors: Finet Michel , Godfraind Théophile
Published: July 2012

The biphasic positive inotropic effect of ouabain has been studied in rat ventricular strips in the presence of ethylisopropylamiloride (EIPA) an inhibitor of Na+/H+ exchange.

EIPA (10–20 μM) depressed dose‐dependently the high affinity component of the ouabain inotropic effect, whereas it did not significantly modify the low affinity inotropic effect related to high concentrations of ouabain.

At the EIPA concentrations studied, there was no observable modification of the inotropic effect of Bay K 8644 (10 nM, 0.3 μM) or of isoprenaline (10 nM, 1 μM).

These results indicate that the inotropic effect of ouabain resulting from its interaction with high affinity sites is selectively sensitive to EIPA.
On the mechanisms of k‐opioid‐induced diuresis
Authors: Blackburn T.P. , Borkowski K.R. , Friend J. , Rance M.J.
Published: July 2012

In conscious saline loaded rats, the k‐opioid agonists tifluadom, U50488, and ethylketocyclazocine, given subcutaneously, induced a characteristic diuresis which could be antagonized by naloxone.

Bilateral adrenal demedullation significantly reduced adrenal gland catecholamine content and plasma adrenaline levels, but did not significantly affect plasma corticosterone levels, indicating that the adrenal cortex remained both intact and functional.

Seven days following bilateral adrenal demedullation, the subcutaneous administration of the k‐agonists no longer induced diuresis. However, demedullation did not affect the diuretic response to frusemide or clonidine, nor did it affect the antidiuretic response induced by the μ‐opioid agonists morphine and buprenorphine.

Adrenal catecholamines do not appear to be involved in k‐opioid‐induced diuresis, since pretreatment with propranolol, prazosin and idazoxan did not affect the diuretic response in intact animals.

The results indicate a link between the adrenal medulla and k‐opioid‐induced diuresis and suggest that a peripheral mechanism may also be involved in mediating this effect.
Muscarinic agonists block five different potassium conductances in guinea‐pig sympathetic neurones
Authors: Cassell J.F. , McLachlan Elspeth M.
Published: July 2012

Muscarinic excitation of sympathetic ganglion cells has usually been thought to result from inhibition of an outward K+ current, the M current, although in other neurones several conductances have been shown to be blocked by muscarinic agonists. We report that, as well as resting K+ conductance, all of four different K+ conductances, two voltage‐dependent (M currents and A currents) and two calcium‐dependent (responsible for slow and very slow afterhyperpolarizations), present in different sub‐types of guinea‐pig sympathetic neurones, are inhibited by the muscarinic agonists, bethanechol and muscarine. All of these effects increase neurone excitability and can lead to repetitive discharge.
Renal effects of gastrin C‐terminal tetrapeptide (as pentagastrin) and cholecystokinin octapeptide in conscious rabbit and man
Authors: Calam J. , Gordon D. , Peart W.S. , Taylor S.A. , Unwin R.J.
Published: July 2012

Pentagastrin and cholecystokinin octapeptide (CCK8) were infused i.v. at three different doses in two sets of 4 conscious rabbits following a repeated measurements design (130, 1,300 and 13,000 pmol kg−1 min−1 pentagastrin; 5, 50 and 450 pmol kg−1 min−1 CCK8). In man, two different doses of pentagastrin (13 and 65 pmol kg−1 min−1) were infused in two groups of 6 subjects, and CCK8 (2 pmol kg−1 min−1) in a third group. According to published human postprandial levels, plasma CCK8‐like immunoreactivity concentrations were supraphysiological at all doses infused.

In the rabbit, pentagastrin produced a dose‐related fall in urine flow and free water clearance, but no significant change in systemic and renal haemodynamics, electrolyte excretion and measured plasma constituents; however, in human subjects, pentagastrin increased renal sodium excretion and reduced potassium excretion but did not change glomerular filtration rate.

In the rabbit, CCK8 produced a dose‐related fall in plasma renin activity, plasma calcium concentration and mean arterial blood pressure; dose‐dependent increases in effective renal plasma flow, glomerular filtration rate and renal sodium excretion. In man, changes in sodium and potassium excretion similar to pentagastrin were observed; there were no significant changes in plasma renin activity, plasma calcium concentration, blood pressure, effective renal plasma flow or glomerular filtration rate.

The pharmacological renal effects of pentagastrin in conscious water‐loaded rabbits resemble vasopressin. In contrast, CCK8′s most striking effect was vasodilatation and was unusual in inhibiting rather than stimulating renin release. In man the net changes in urine composition found during infusion of these peptides are similar to those produced by the potassium‐sparing diuretics, amiloride and triamterene. However the generally weak renal effects observed, even at pharmacological doses, indicate that these peptides are unlikely to influence renal function under normal physiological conditions.
An investigation of the role of adrenergic innervation in the regulation of the extraneuronal uptake of [3H]‐isoprenaline into rat vasa deferentia and atria
Authors: Morton A.J.
Published: July 2012

Destruction of adrenergic nerves by neonatal guanethidine treatment did not affect the extraneuronal accumulation of [3H]‐isoprenaline by adult vasa deferentia or atria.

Neither pre‐nor post‐ganglionic denervation of vasa deferentia resulted in a significant change in extraneuronal accumulation of [3H]‐isoprenaline.

The appearance and subsequent development of extraneuronal uptake in embryonic and newborn rats did not appear to be dependent on a fully developed or functional adrenergic innervation.

Decreasing plasma catecholamine levels by adrenal demedullation did not have an effect on extraneuronal uptake.

Chronic cold exposure (7 days) significantly increased plasma levels of adrenaline, and there was a significant decrease in the corticosterone‐sensitive extraneuronal uptake of [3H]‐isoprenaline into atria. After 14 days in the cold, plasma adrenaline levels had fallen, and were no longer significantly different from control levels.

The extraneuronal uptake of [3H]‐isoprenaline into atria after 14 days cold exposure was no longer different from that of control atria. There did not appear to be a direct correlation between plasma catecholamines and extraneuronal accumulation of [3H]‐isoprenaline.

Neither the presence of adrenergic nerves nor plasma catecholamines appear to play a major role in the regulation of extraneuronal uptake by atria and vasa deferentia of the rat.
Effects of sympathetic stimulation and applied catecholamines on mechanical and electrical responses to stimulation of the vagus nerve in guinea‐pig isolated trachea
Authors: McCaig Dorothy J.
Published: July 2012

Mechanical and electrical responses to stimulation of the vagus nerve were studied in the isolated, innervated trachea of the guinea‐pig.

In approximately half the preparations tested, the amplitudes of mechanical constrictor responses to stimulation of the vagus were reduced substantially during a period of sympathetic stimulation. Vagal responses were unaltered in the remainder.

In single trachealis cells, stimulation of the vagus nerve or sympathetic stellate ganglion elicited depolarization and hyperpolarization, respectively. Vagally‐mediated depolarization was decreased, unchanged or increased in amplitude after a period of sympathetic stimulation.

Isoprenaline almost abolished mechanical responses induced by stimulation of the vagus, and this effect was blocked by propranolol.

Noradrenaline attenuated markedly vagal mechanical responses also, and this effect was blocked by a combination of propranolol and phentolamine.

Both noradrenaline and isoprenaline hyperpolarized single trachealis cells and greatly reduced the amplitude of vagally‐mediated depolarization.

Neither sympathetic stimulation nor applied catecholamines altered mechanical responses to applied acetylcholine, strongly suggesting that their effects on vagal responses are predominantly presynaptic.
Differing electrophysiological effects of class IA, IB and IC antiarrhythmic drugs on guinea‐pig sinoatrial node
Authors: Campbell Terence
Published: July 2012

Standard microelectrode techniques were used to study the effects of class IA (quinidine, disopyramide, procainamide), IB (lignocaine, mexiletine, tocainide) and IC (flecainide, encainide, lorcainide) antiarrhythmic drugs on action potentials in spontaneously beating sino‐atrial node cells from guinea‐pigs.

The IA drugs all produced significant slowing of spontaneous rate in therapeutic concentrations. The IB agents did so only in concentrations well above therapeutic levels and the IC drugs were of intermediate potency.

All nine drugs markedly slowed the repolarization rate and this was the major mechanism of sinus slowing for the IA and IC compounds. The IB drugs shared this effect but prolongation of phase 4 by reduction of the slope of diastolic depolarization was also a prominent feature of their action.
The novel anticonvulsant MK‐801 binds to the activated state of the N‐methyl‐d‐aspartate receptor in rat brain
Authors: Foster Alan C. , Wong Erik H.F.
Published: July 2012

The influence of endogenous and exogenous acidic amino acids on the binding of [3H]‐MK‐801, a selective, non‐competitive antagonist of N‐methyl‐d‐aspartate (NMDA) receptors, has been investigated in rat cerebral cortex crude synaptic membranes (CSM).

Removal of endogenous glutamate and aspartate from CSM by repeated washing reduced the affinity of [3H]‐MK‐801 for its binding site (with no change in the total number of binding sites) and increased NMDA‐sensitive l‐[3H]‐glutamate binding.

In washed CSM, competitive NMDA antagonists of the dl‐α‐amino‐ω‐phosphonocarboxylate series reduced [3H]‐MK‐801 binding and NMDA‐sensitive L‐[3H]‐glutamate binding, the most active compounds being 2‐amino‐5‐phosphonovalerate (AP5) and 2‐amino‐7‐phosphono‐heptanoate (AP7).

Exogenous excitatory amino acid agonists enhanced the binding of [3H]‐MK‐801 to washed CSM by up to 700%. A selective involvement of NMDA receptors in these effects was indicated by the excellent correlation between EC50s for stimulation of [3H]‐MK‐801 binding and IC50s for inhibition of NMDA‐sensitive l‐[3H]‐glutamate binding in the same membranes.

The selective, competitive NMDA receptor antagonist D‐AP5 blocked the l‐glutamate‐induced increase in [3H]‐MK‐801 binding in a competitive manner with a pA2 value of 6.0.

These results seem to reflect a molecular interaction between two distinct components of the NMDA receptor complex: the transmitter recognition site and the site through which MK‐801 exerts its antagonist effects, possibly the ion channel.
Effects of cations on binding, in membrane suspensions, of various opioids at μ‐sites of rabbit cerebellum and κ‐sites of guinea‐pig cerebellum
Authors: Kosterlitz H.W. , Paterson S.J. , Robson L.E. , Traynor J.R.
Published: July 2012

At the μ‐sites of rabbit cerebellum, NaC1, LiC1, KCl, choline chloride and MnCl2 were tested for potentiation and inhibition of the binding of several opioids. Naloxone, (–)‐bremazocine and diprenorphine are μ‐antagonists in pharmacological assays and their binding is potentiated by the lower concentrations and inhibited by the higher concentrations of NaCl. The binding of the agonists [3H]‐[d‐Ala2, MePhe4, Gly‐ol5]enkephalin and [3H]‐dihydromorphine is inhibited. MnCl2/potentiates the binding of the agonist [3H]‐[d‐Ala2, MePhe4, Gly‐ol5]enkephalin but not the binding of the antagonists. The thresholds of inhibition and slopes of the dose‐response curves for inhibition by MnCl2 and LiCl vary. This finding may indicate that potentiating effects of MnCl2 and LiCl are masked by simultaneous inhibition.

At the κ‐sites of guinea‐pig cerebellum, NaCl, KCl and MnCl2 inhibit the binding of [3H]‐dynorphin A (1–8), [3H]‐dynorphin A (1–9), [3H]‐(–)‐bremazocine, [3H]‐tifluadom, and [3H]‐diprenorphine. NaCl also causes a small potentiation of the binding of [3H]‐diprenorphine, which is a κ‐agonist in the guinea‐pig myenteric plexus but a κ‐antagonist in the rabbit vas deferens. The slopes of the inhibitory dose‐response curves and the thresholds of inhibition vary with the different ligands. Therefore some potentiating effects may have been masked.

The results support the view that NaCl, and perhaps LiCl, but not KCl and choline chloride, potentiate the binding of μ‐antagonists but not the binding of μ‐agonists. It is not yet possible to decide whether, at the κ‐site, there is a similar differentiation of the binding of agonists and antagonists.
Increase in acetylcholine concentrations in the brain of ‘old’ rats following treatment with pyrithioxin (Encephabol)
Authors: Martin K.J. , Vyas S.
Published: July 2012

Treatment of old rats, for two to three weeks, with pyrithioxin led to an increase in the levels of endogenous acetylcholine (ACh) in the cortex and the striatum but not in the hippocampus.

Pretreatment of old rats with pyrithioxin also increased the resting release and the K+‐stimulated release of radioactive ACh from brain slices in vitro.
Adamantane derivatives: a new class of insulin secretagogues
Authors: Garrino M.G. , Henquin J.C.
Published: July 2012

Adamantane derivatives were found to increase insulin release in vitro. Mouse islets were used to study the mechanisms and molecular requirements of that hitherto unrecognised property.

At a non‐stimulatory concentration of glucose (3 mm), 1‐adamantanamine (1 mm) reversibly inhibited 86Rb efflux from islet cells, depolarized the β‐cell membrane, induced electrical activity, stimulated 45Ca uptake and efflux, and triggered insulin release. Omission of extracellular Ca2+ abolished the secretory response but only partially inhibited the acceleration of 45Ca efflux.

At a stimulatory concentration of glucose (10 mm), 1‐adamantanamine reversibly increased 86Rb efflux, potentiated electrical activity (lengthening of the slow waves with spikes), augmented 45Ca uptake and efflux, and increased insulin release. The effects of adamantanamine were dose‐dependent, with a threshold concentration of 10 μm for stimulation of release.

2‐Adamantanamine was as potent as 1‐adamantanamine. In contrast, substitution of the amino group by a carboxyl group (1‐adamantanecarboxylic acid) decreased the effectiveness by about 65%, and substitution by a hydroxyl group (1‐adamantanol) suppressed it.

It is concluded that adamantane derivatives bearing an amino group decrease K+ permeability of the β‐cell membrane and thereby cause depolarization. This activates voltage‐dependent Ca channels, permits Ca2+ influx and eventually stimulates insulin release. They may also mobilize cellular Ca2+, but this effect is not sufficient to cause release.
Tyr‐MIF‐1 attenuates antinociceptive responses induced by three models of stress‐analgesia
Authors: Galina Z. Harry , Kastin Abba J.
Published: July 2012

Tyr‐MIF‐1 (Tyr‐Pro‐Leu‐Gly‐NH2), a biologically active brain peptide, has previously been shown to antagonize the analgesia induced by morphine.

In this report experiments are described in which mice were tested on the hot‐plate in three models of antinociception—shock, novel environment, and warm‐water swim—after the administration of various doses of Tyr‐MIF‐1 without any exogenous opiates.

The peptide reduced the antinociception produced by all three methods of inducing endogenous antinociception.

These results add further support for the existence of peptides like Tyr‐MIF‐1 that act as opiate antagonists.
The effect of platelet activating factor on pulmonary β‐adrenoceptors
Authors: Barnes P.J. , Grandordy B.M. , Page C.P. , Rhoden K.J. , Robertson D.N.
Published: July 2012

An intravenous infusion of platelet activating factor (Paf) in the guinea‐pig elicits an increase in bronchial responsiveness to the spasmogens, histamine and bombesin.

Airways obstruction induced by bombesin in Paf‐treated animals is poorly reversed by isoprenaline compared to comparable airways obstruction induced by bombesin in vehicle‐treated animals.

Isoprenaline induced a comparable dose‐related relaxation in vitro of tracheal smooth muscle isolated from Paf‐ and vehicle‐treated animals.

No change in β‐adrenoceptor numbers or binding affinity was observed in lungs removed from Paf‐treated animals in comparison with those from vehicle‐treated animals, or after direct incubation with Paf in vitro.

The reduced bronchodilator responsiveness to isoprenaline in Paf‐treated animals is not related to changes in pulmonary β‐adrenoceptor function. These results suggest that non‐spasmogenic elements may contribute to airways obstruction induced in hyper‐responsive animals.