bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pharmacological study of oesophageal muscularis mucosae from the cat, dog and American opossum (Didelphis virginiana)
Authors: Christensen J. , Percy W. H. 
Published: July 2012

Strips of muscularis mucosae from the oesophagi of cat, dog and opossum have been studied to determine their responses to drugs and to electrical field stimulation.
All tissues were contracted by acetylcholine, histamine and, with the exception of strips of muscularis mucosae from the opossum proximal oesophagus, noradrenaline. The effects of acetylcholine and histamine were competitively antagonized by atropine (50 nM) and mepyramine (50 nM) and were abolished by atropine (1 μM) and mepyramine (1 μM) respectively. Contractile responses to noradrenaline were competitively antagonized by phentolamine (50 nM) but were converted to propranolol (50 nM)‐sensitive relaxations by phentolamine (1 μM). Relaxations were abolished by propranolol (1 μM).
Cholecystokinin octapeptide, gastrin 1 and vasoactive intestinal polypeptide were ineffective on any of the tissues examined. Substance P caused contractions in tissue from all three species. These effects were atropine and tetrodotoxin insensitive.
All tissues gave atropine (50 nM)‐ and tetrodotoxin (100 nM)‐sensitive contractions in response to electrical field stimulation. Contractions were not followed by relaxations and spontaneous mechanical activity was not suppressed between periods of stimulation. No evidence was obtained for the presence of non‐adrenergic, non‐cholinergic inhibitory innervation of the oesophageal muscularis mucosae in any species.
During electrical field stimulation noradrenaline always reduced the amplitude of evoked contractions and, with the exception of tissue from proximal opossum oesophagus, increased resting tension.
In opossum distal oesophageal muscularis mucosae, the effects of noradrenaline during electrical field stimulation were abolished by a 30 min pretreatment of the tissue with phentolamine (1 μM) and propranolol (1 μM). To achieve this in all other tissues, it was also necessary to use yohimbine (1 μM).
In all tissues where noradrenaline caused a phentolamine (1 μM)‐and propranolol (1 μM)‐resistant depression of electrically evoked responses, clonidine produced a yohimbine (1 μM)‐sensitive depression.
Evidence was obtained for the presence of excitatory α1‐and inhibitory α2‐ and β‐adrenoceptors. Inter‐species differences in their distribution are discussed.
Inhibition of vasoconstriction by frusemide in the rat
Authors: Gerkens John F. , Smith Anthony J. 
Published: July 2012

Mesenteric blood flow was measured in anaesthetized rats with a non‐cannulating electromagnetic flow probe around the superior mesenteric artery. Reductions in blood flow were produced by intravenous bolus injections of angiotensin II (1–300ng) and noradrenaline (3–300ng) before and after the administration of frusemide (5 mg kg−1, i.v.). Loss of volume after frusemide was prevented by either a urinary bladder‐intravenous shunt or replacement of urinary output by intravenous saline.
Frusemide administration caused a small increase in baseline blood pressure of 3.2 ± 1.3 mmHg (P<0.05) but did not change mesenteric blood flow. This dose of frusemide inhibited the vasoconstrictor responses to both angiotensin II and noradrenaline (P<0.01, two way analysis of variance). Responses to angiotensin II were inhibited to a greater extent.
Acute bilateral nephrectomy or treatment with indomethacin (2 mg kg−1, i.v.) completely prevented the inhibitory effect of frusemide on the responses to angiotensin II and noradrenaline.
To test whether frusemide‐induced increased endogenous levels of angiotensin II may be responsible for the effects of frusemide on the vasoconstrictor responses, a separate group of rats were not given frusemide but were infused with exogenous angiotensin II (12.5–25 ng kg−1 min−1). This produced a small increase in mean blood pressure (4.0± 1.4 mmHg, P<0.05) but did not change baseline mesenteric blood flow. Unlike frusemide, the responses to bolus injections of angiotensin II and noradrenaline were not changed by the infusion of angiotensin II.
It is suggested that frusemide may release directly or indirectly a prostanoid from the kidney (or a substance from the kidney which leads to the formation of a prostanoid) which inhibits constrictor responses in the peripheral vasculature.
Biological evaluation of substance P antagonists
Authors: Folkers K. , Håkanson R. , Hörig J. , Jie‐Cheng Xu , Leander S. 
Published: July 2012

Five undeca‐ and six C‐terminal heptapeptide substance P (SP) analogues were tested for their capacity to block the contractile effect of SP on the guinea‐pig isolated taenia coli. They had one feature in common, namely substitutions in positions 7 and 9 in the SP molecule. In the majority of analogues D‐tryptophan was used for these substitutions.
All analogues tested were found to be competitive antagonists to exogenous SP and to be capable of blocking the electrically induced non‐cholinergic, non‐adrenergic neuronal contraction of the taenia.
Of the undecapeptides, (D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11) SP and (D‐Arg1, D‐Trp7,9, Leu11) SP (Spantide) had the highest pA2 value, 7.1–7.2, and the lowest IC50 value, 10−6 M. The pA2 values of the heptapeptides were generally lower.
Three of the most potent antagonists were tested for specificity and found to block the smooth muscle contraction induced by SP, physalaemin, eledoisin and bombesin but not that induced by bradykinin, carbachol, 5‐hydroxytryptamine, histamine, prostaglandins and vasopressin.
The SP antagonists were also tested for spasmogenic effect on the taenia and for their capacity to release histamine from rat isolated peritoneal mast cells. The spasmogenic activity displayed by most of the SP antagonists tested is likely to be related to their ability to release histamine since the contractile response was reduced by mepyramine, a histamine H1‐receptor antagonist.
(D‐Arg1, D‐Trp7, 9, Leu11) SP was notable for combining a high antagonistic potency with a weak spasmogenic effect (and poor histamine releasing effect).
Purinoceptor mediated stimulation of prostacyclin release in the porcine pulmonary vasculature
Authors: Hellewell Paul G. , Pearson Jeremy D. 
Published: July 2012

Prostacyclin (PGI2) release from the piglet isolated perfused lung was measured by radioimmunoassay of 6‐keto‐PGF1α in the venous effluent.
Basal release of PGI2 was transiently stimulated up to 30 fold, in a dose‐dependent manner, by bolus injections of ATP (0.03–3 μmol). A continuous infusion of ATP also produced a transient response.
Dose‐response curves for purinergic stimulation of PGI2 release showed that ADP was equipotent with ATP, while AMP and adenosine were virtually inactive.
The non‐hydrolyzable ATP analogue, ATP‐γ‐S, elicited PGI2 release of similar magnitude and duration to that of ATP, suggesting that pulmonary catabolism of ATP is not required to induce PGI2 release.
The results suggest that the porcine pulmonary vasculature possesses P2‐purinoceptors through which the synthesis and release of PGI2 can be mediated.
Pro‐ and anti‐convulsant properties of PK 11195, a ligand for benzodiazepine binding sites: development of tolerance
Authors: File Sandra E. 
Published: July 2012

Ro 5–4864 is a benzodiazepine that differs from diazepam only in a p‐chloro substituent and yet is inactive at the classical CNS binding sites. However it is a potent ligand for the peripheral type of benzodiazepine binding sites. PK 11195 is an isoquinoline carboxamide derivative that potently displaces [3H]‐Ro 5–4864 from its binding sites.
PK 11195 (30–60 mg kg−1) significantly reduced the incidence of convulsions caused by Ro 5–4864 (30 mg kg−1). PK 11195 (up to 120 mg kg−1) was ineffective at counteracting seizures caused by the convulsant benzodiazepine Ro 5–3663, although this dose did increase the latency to seize after injection with pentylenetetrazole. PK 11195 had no anticonvulsant actions against picrotoxin, and at 60 mg kg−1 reduced the latency to seize. This possible proconvulsant property of the isoquinoline was further explored.
PK 11195 (30–90 mg kg−1) had proconvulsant actions when combined with subconvulsant doses of strychnine and picrotoxin, but had none when combined with pentylenetetrazole.
No significant tolerance developed to the anticonvulsant action of PK 11195 (30 mg kg−1) even after 25 days of dosing daily. In contrast, there was rapid tolerance (within 5 days) to the proconvulsant action of PK 11195 (60 mg kg−1) with picrotoxin (3 mg kg−1).
There was no cross‐tolerance between the anticonvulsant actions of diazepam and PK 11195, which suggests that these two drugs act at different sites, as would be predicted from the results of the binding studies.
The possible sites of action and clinical relevance of these effects are discussed.
Evidence for the lack of interaction between (±)‐ 1‐O‐octadecyl‐2‐acetylglyceryl‐3‐phosphorylcholine and α‐adrenoceptors in vivo and in vitro
Authors: Cervoni P. , Goldstein B.M. , Herzlinger H. , Lai F.M. , Quirk G.J. 
Published: July 2012

The interactions of (±)‐1‐O‐octadecyl‐2‐acetylglyceryl‐3‐phosphorylcholine (octadecyl‐AGPC) with α‐adrenoceptors were studied in rat mesenteric artery, cat nictitating membrane and on the blood pressure of the cat and spontaneously hypertensive (SH) rat.
Using a direct radioligand α‐adrenoceptor binding assay in particulate fractions of rat mesenteric arteries, octadecyl‐AGPC was found to be 5 × 107 and 75 times less potent than prazosin and noradrenaline (NA), respectively, in displacing (2,6‐dimethoxyphenoxyethyl)‐aminomethyl‐1,4‐benzodioxane ([3H]‐WB 4101 — a selective probe for the identification of α‐adrenoceptors).
In the cat, intravenous infusions of octadecyl‐AGPC, which produce a hypotensive response, did not attenuate nictitating membrane contractions in vivo in response to intravenous injections of NA, adrenaline (Ad) or to electrical stimulation of the postganglionic fibres of the superior cervical ganglion. In these experiments, the pressor responses to NA or Ad were not affected by octadecyl‐AGPC. Phentolamine, on the other hand, attenuated nictitating membrane contractions and blood pressure responses to Ad or NA.
In the SH rat, octadecyl‐AGPC decreased mean arterial blood pressure (MABP). After an intravenous dose of phentolamine which lowered MABP, the depressor response to octadecyl‐AGPC was reduced. When MABP in the phentolamine‐treated SH rat was restored to its initial level with an infusion of angiotensin II (AII), the depressor response to octadecyl‐AGPC was restored to its original magnitude. The effectiveness of α‐adrenoceptor blockade under these experimental conditions was monitored with intravenous NA and Ad.
Thus, based on radioligand binding studies and pharmacological studies, it is concluded that octadecyl‐AGPC lacks the ability to interact with α‐adrenoceptors.
Negative inotropic effect of somatostatin in guinea‐pig atrial fibres
Authors: Diez J. , Tamargo J. , Valenzuela C. 
Published: July 2012

The effect of somatostatin (SS, 1 × 10−7M‐5 × 10−6 M) was studied on the electrical and mechanical properties of isolated atria of the guinea‐pig.
On spontaneously beating right atria, SS produced a dose‐dependent negative inotropic effect which was accompanied by a decrease in atrial rate and a prolongation of the sinus node recovery time.
In electrically driven left atria, SS produced a dose‐dependent negative inotropic effect which occurred concomitantly with a decrease in the amplitude and duration of the plateau phase of the action potential of atrial fibres.
SS also decreased the amplitude and maximum rate of depolarization of the slow action potential as well as the amplitude of the slow contractions induced by isoprenaline and caffeine in K‐depolarized atrial fibres.
The negative inotropic effect of SS varied with the concentration of Ca and Na in the bathing media and the frequency of stimulation.
SS, 1 × 10−6 M and 5 × 10−6 M, decreased 45Ca uptake in electrically driven atria.
All these results suggest that the negative inotropic effect produced by SS on rat isolated atria is related to its ability to reduce Ca influx via the slow inward Ca current.
Evidence for an A2‐subtype adenosine receptor on pancreatic glucagon secreting cells
Authors: Chapal J. , Loubatières‐Mariani M.M. , Petit P. , Roye M. 
Published: July 2012

The effects of a 5′‐substituted analogue of adenosine, 5′‐N‐ethylcarboxamidoadenosine (NECA) have been studied on glucagon secretion in vitro, using the isolated pancreas of the rat perfused in the presence of glucose (2.8 mM).
NECA provoked a peak of glucagon secretion, the kinetics of which were comparable to those previously obtained with adenosine. The effect was concentration‐dependent and appeared at nanomolar concentrations. The EC50 was approximately 4 × 10−8 M.
A comparison of relative potency between adenosine and NECA showed that NECA was about 800 fold more potent than adenosine in inducing glucagon secretion.
Theophylline (50 μM) considerably decreased the peak of glucagon secretion induced by 1.65 μM NECA and totally suppressed the effect of 16.5 nM NECA. These results indicate the involvement of an adenosine receptor.
These and other previous results (low stereoselectivity of N6‐phenylisopropyladenosine) provide evidence for an adenosine receptor of the A2‐subtype being involved in glucagon secretion.
The effects of methyl β‐carboline‐3‐carboxylate on social interaction and locomotor activity when microinjected into the nucleus raphé dorsalis of the rat
Authors: Hindley S.W. , Hobbs A. , Paterson I.A. , Roberts M.H.T. 
Published: July 2012

Intraperitoneal and intracerebral injections of methyl β‐carboline‐3‐carboxylate (βCCM) and intracerebral injections of RO 15–1788 were given to rats. The performance of the rats in the social interaction test was measured to determine if changes in social interaction induced by βCCM were mediated in part by the nucleus raphé dorsalis (NRD).
Intraperitoneal injections of βCCM, 2 and 4 mg kg−1, reduced social interaction.
Intracerebral microinjections of βCCM (10‐0.1 ng in 0.5 μl) into the NRD reduced social interaction. Injections outside the NRD did not have this effect.
Intracerebral microinjections of RO 15–1788 (1 ng in 0.5 μl) into the NRD had no effect when given alone, but blocked the reduction in social interaction caused by intracerebral or intraperitoneal injections of βCCM.
No effect was observed when R 15–1788 was microinjected into sites outside the NRD.
Changes in social interaction may reflect changes in anxiety. The NRD may be one of the important sites for the expression of the anxiogenic actions of βCCM.
Dopexamine: a novel agonist at peripheral dopamine receptors and β2‐adrenoceptors
Authors: Brown R.A. , Dixon J. , Farmer J.B. , Hall Janet C. , Humphries R.G. , Ince F. , O'Connor S.E. , Simpson W.T. , Smith G.W. 
Published: July 2012

Dopexamine is an agonist at peripheral dopamine receptors and at β2‐adrenoceptors.
Dopexamine has approximately one‐third the potency of dopamine in stimulating the vascular DA1‐receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 × 10−8 mol kg−1 (i.a.).
Prejunctional DA2‐receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC50 of 1.15 × 10−6 M) and of neurogenic tachycardia in the cat (ID50 of 5.4 × 10−8 mol kg−1, i.v.), with a potency six and four times less respectively than that of dopamine.
By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the β2‐adrenoceptor of the guinea‐pig isolated tracheal chain, with an EC50 of 1.5 × 10−6 M.
Both dopexamine and dopamine are weak agonists at the guinea‐pig atrial β1‐adrenoceptor over the concentration range 10−7 to 10−4 M, but dopexamine has an intrinsic activity of only 0.16 relative to dopamine.
Dopexamine does not stimulate postjunctional α1 or α2‐adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline.
Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea‐pig isolated perfused heart at doses of up to 10−5 mol, which is a thousand times the minimum cardiostimulant dose.
The combination of agonist properties at peripheral dopamine receptors and at β2‐adrenoceptors, with little or no activity at α‐ and β1‐adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.
The effects of dopexamine on the cardiovascular system of the dog
Authors: Brown R.A. , Farmer J.B. , Hall Janet C. , Humphries R.G. , O'Connor S.E. , Smith G.W. 
Published: July 2012

The cardiovascular effects of dopexamine and dopamine were compared in the anaesthetized and conscious dog by the use of intravenous infusions over the dose range 3 × 10−9 − 10−7 mol kg−1 min−1.
In the anaesthetized dog, dopexamine produced a dose‐related fall in blood pressure due to peripheral vasodilatation and a small rise in heart rate and contractility. By contrast, dopamine did not significantly reduce blood pressure but produced a larger dose‐related increase in contractility. At the highest infusion rate (10−7 mol kg−1 min−1) blood pressure and heart rate were increased by dopamine.
Dopexamine dilated the renal and mesenteric vascular beds with a potency similar to that of dopamine. Femoral vascular responses produced by both agents were inconsistent but the highest infusion rate of dopamine did produce vasoconstriction.
With the aid of selective receptor antagonists (haloperidol, propranolol and bulbocapnine) the vasodepressor activity of dopexamine was shown to be mediated by stimulation of DA2‐, β‐ and DA1‐receptors. The cardiac stimulation and renal vasodilatation produced by both compounds were due to stimulation of β‐adrenoceptors and DA1‐receptors respectively.
In the conscious dog, intravenous infusion of dopexamine caused a dose‐related fall in blood pressure, renal vasodilatation and an increase in cardiac contractility and heart rate. Dopamine also increased cardiac contractility, and renal blood flow due to renal vasodilatation but without affecting heart rate. At the highest infusion rate, blood pressure was increased.
Dopexamine and dopamine produced a similar incidence of panting and repetitive licking at 3 × 10−8 mol kg−1 min−1 and emesis at 10−7 mol kg−1 min−1, due to stimulation of dopamine receptors in the chemoreceptor trigger zone.
Dopexamine produces a different cardiovascular profile from dopamine in the anaesthetized and conscious dog. Both compounds reduce renal vascular resistance, but in contrast to dopamine, dopexamine reduces afterload and produces only mild inotropic stimulation. These differences reflect contrasting activity at adrenoceptors.
Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus
Authors: Gage Peter W. , Robertson Brian 
Published: July 2012

Spontaneous inhibitory postsynaptic currents (i.p.s.cs) were recorded in voltage‐clamped CA1 neurones in rat hippocampal slices.
The exponential decay of i.p.s.cs was prolonged by concentrations of sodium pentobarbitone as low as 50 μM. With concentrations up to 100 μM, there was no change in the amplitude or rise time of the currents but current amplitude was depressed at 200 μM. The prolongation of currents increased with drug concentration within the range tested (50 to 200 μM).
Halothane, at concentrations from 1 to 5%, also increased the time constant of decay of i.p.s.cs. The effect increased with concentration and was fully reversible.
Ketamine, at a concentration of 0.5 mM, increased the time constant of decay of i.p.s.cs by 50 to 80% and the effect was reversible.
Ethanol (10–200 mM), nitrous oxide (75–80%), and caffeine (10 μM‐5 mM) had no detectable effect on the i.p.s.cs.
It is suggested that pentobarbitone, halothane and ketamine increase the time constant of decay of the i.p.s.cs by stabilizing the open state of channels activated by γ‐aminobutyric acid.
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.