bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative analysis of the vagal stimulation of gastric acid secretion in rodent isolated stomach preparations
Authors: Welsh Nicola J. , Shankley Nigel P. , Black James W. 
Published: July 2012

Electrical field stimulation produced a tetrodotoxin‐sensitive, frequency‐dependent, release of acid from isolated, lumen‐perfused, stomach preparations from mouse, immature rat and guinea‐pig.
In the guinea‐pig and mouse preparations, the frequency‐dependent response was abolished by hexamethonium, acetylcholine (ACh) muscarinic (M) and histamine H2‐receptor blockade, consistent with the hypothesis that the vagal ACh acts indirectly by stimulating the release of endogenous histamine.
In contrast, in the rat preparation the frequency‐dependent response was partially refractory to all of these inhibitors. However, a combination of H2‐ and ACh M‐receptor blockade did abolish the effect.
We conclude that vagal‐stimulated acid secretion in the rat, unlike the other two species, behaves as though there is a direct innervation of the oxyntic cells by either cholinergic or noncholinergic neurones.
Evoked noradrenaline release in the rabbit ear artery: enhancement by purines, attenuation by neuropeptide Y and lack of effect of calcitonin gene‐related peptide
Authors: Maynard K.I. , Burnstock G. 
Published: July 2012

Adenosine (30 μm) and its analogues 5′‐N‐ethylcarboxaminoadenosine (5 and 30 μm) and l‐phenylisopropyladenosine (5 and 30 μm), potentiated the evoked but not spontaneous release of tritiated noradrenaline in the rabbit central ear artery.
Prejunctional inhibition of the evoked but not spontaneous release of tritiated noradrenaline by 100 nm neuropeptide Y is greater at 2 min than at 10 min after superfusion of the peptide.
Calcitonin gene‐related peptide (2.63 to 263 nm) did not affect the evoked or spontaneous release of tritiated noradrenaline in this preparation.
These results are discussed in terms of prejunctional modulation of sympathetic transmission in the rabbit central ear artery.
Role of endopeptidase 3.4.24.16 in the catabolism of neurotensin, in vivo, in the vascularly perfused dog ileum
Authors: Barelli H. , Fox‐Threlkeld J.E.T. , Dive V. , Daniel E.E. , Vincent J.P. , Checler F. 
Published: July 2012

The degradation of tritiated and unlabelled neurotensin (NT) following close intra‐arterial infusion of the peptides in ileal segments of anaesthetized dogs was examined.
Intact NT and its catabolites recovered in the venous effluents were purified by chromatography on Sep‐Pak columns followed by reverse‐phase h.p.l.c. and identified by their retention times or by radioimmunoassay.
The half‐life of neurotensin was estimated to be between 2 and 6 min. Four labelled catabolites, corresponding to free tyrosine, neurotensin (1–8), neurotensin (1–10) and neurotensin (1–11), were detected.
Neurotensin (1–11) was mainly generated by a phosphoramidon‐sensitive cleavage, probably elicited by endopeptidase 24–11.
Two endopeptidase 3.4.24.16 inhibitors, phosphodiepryl 03 and the dipeptide Pro‐Ile, dose‐dependently potentiated the recovery of intact neurotensin. Furthermore, both agents inhibited the formation of neurotensin (1–10), the product that results from the hydrolysis of neurotensin by purified endopeptidase 3.4.24.16. In contrast, the endopeptidase 3.4.24.15 inhibitor Cpp‐AAY‐pAB neither protected neurotensin from degradation nor modifed the production of neurotensin (1–10).
Our study is the first evidence to indicate that endopeptidase 3.4.24.16 contributes to the catabolism of neurotensin, in vivo, in the dog intestine.
Studies of the nucleoside transporter inhibitor, draflazine, in the human myocardium
Authors: Böhm Michael , Weinhold Christian , Schwinger Robert H.G. , Müller‐Ehmsen Jochen , Böhm Dieter , Reichenspurner Hermann , Reichart Bruno , Erdmann Erland 
Published: July 2012

The aim of the present study was to determine the effect of the nucleoside transporter inhibitor, draflazine, on the force of contraction in human myocardium and the affinity of the compound for the nucleoside transporter. Nucleoside transport inhibitors, like draflazine, are of potential importance for cardiopreservation of donor hearts for heart transplantation.
Functional experiments were performed in isolated electrically driven (1 Hz, 1.8 mmol l−1 Ca2+) human atrial trabeculae and ventricular papillary muscle strips. The affinity of draflazine for the myocardial nucleoside transporter was studied in isolated membranes from human ventricular myocardium and human erythrocytes in radioligand binding experiments using [3H]‐nitrobenzylthioinosine ([3H]‐NBTI). Dipyridamole was studied for comparison.
In membranes from human myocardium and erythrocytes, [3H]‐NTBI labelled 1.18 pmol mg−1 protein and 23.0 pmol mg−1 protein, respectively, nucleoside transporter molecules with a KD value of 0.8 nmol l−1. Draflazine concentration‐dependently inhibited binding of [3H]‐NBTI to myocardial and erythrocyte membranes with a Ki‐value of 4.5 nmol l−1. The potency as judged from the Ki values was ten times greater than that of dipyridamole in both myocardial and erythrocyte membranes.
Draflazine, at concentrations up to 100 μmol l−1, did not produce negative inotropic effects in atrial and ventricular myocardium.(−)‐N6‐phenylisopropyladenosine (R‐PIA) and carbachol did not reduce force of contraction in ventricular myocardium, but exerted concentration‐dependent direct negative inotropic effects in atrial myocardium.
The data provide evidence that draflazine specifically binds to the nucleoside transporter of the human heart and erythrocytes with high affinity. The compound does not produce negative inotropic effects at concentrations as high as 100 μmol l−1.
Draflazine could be a useful agent for cardiopreservation because it does not produce cardiodepressant effects. Thus, it may be possible to perfuse explanted hearts directly with this agent without the hazard of cardiodepression.
The renal functional responses to 5‐HT1A receptor agonist, flesinoxan, in anaesthetized, normotensive rat
Authors: Chamienia Andrzej L. , Johns Edward J. 
Published: July 2012

The present study was designed to examine the effects of a centrally acting 5‐HT1A receptor agonist, flesinoxan, on the cardiovascular system and renal haemodynamics and excretory function.
In chloralose‐urethane anaesthetized Wistar rats, i.v. administration of bolus doses of flesinoxan, at 30, 100, 300 and 1000 μg kg−1, caused significant, dose‐dependent decreases in mean arterial pressure, of 33 ± 2 mmHg (P < 0.001) and heart rate of 57 ± 9 beats min−1 (P < 0.001) at the highest dose used. Despite this substantial fall in perfusion pressure there were no meaningful changes in the renal excretion of water and sodium. In a second group of rats, reduction of renal perfusion pressure mechanically to the same values as observed in rats given flesinoxan (i.e. 100, 92, 84 and 76 mmHg) produced reductions in urine flow, absolute and fractional sodium excretions reaching a maximum of 74, 86 and 84% respectively (all P < 0.001) at the lowest pressure. These reductions were significantly larger than those seen in the previous group of animals.
In the group of rats subjected to renal denervation, flesinoxan produced changes in blood pressure and heart rate which were not different from those observed in intact animals. However, the reduction in pressure was accompanied by significant decreases in urine flow of 71%, absolute sodium excretion of 68% and fractional sodium excretion of 67% (all P < 0.001) at the highest dose, which were all significantly greater than the changes seen in the innervated animals but were not different from those observed when renal perfusion pressure was reduced mechanically.
The findings of this investigation showed that flesinoxan was effective in lowering blood pressure and heart rate in the anaesthetized rat, which was probably due to decreased sympathetic nerve activity. Renal excretion of water and sodium was well preserved in the face of the flesinoxan‐induced hypotension. The maintenance of fluid excretion with flesinoxan appeared to be mediated via changes in renal nerve activity, since it did not occur when the kidney was denervated.
Modulatory effects of NMDA on phosphoinositide responses evoked by the metabotropic glutamate receptor agonist 1S,3R‐ACPD in neonatal rat cerebral cortex
Authors: Challiss R.A. John , Mistry Rajendra , Gray David W. , Nahorski Stefan R. 
Published: July 2012

The effect of NMDA‐receptor stimulation on phosphoinositide signalling in response to the metabotropic glutamate receptor agonist 1‐aminocyclopentane‐1S,3R‐dicarboxylic acid (1S,3R‐ACPD) has been examined in neonatal rat cerebral cortex slices.
Total [3H]‐inositol phosphate ([3H]‐InsPx) accumulation, in the presence of 5 mm LiCl, in [3H]‐inositol pre‐labelled slices was concentration‐dependently increased by 1S,3R‐ACPD (EC50 16.6 μm) and, at a maximally effective concentration, 1S,3R‐ACPD (300 μm) increased [3H]‐InsPx accumulation by 12.8 fold over basal values.
[3H]‐InsPx accumulation stimulated by 1S,1R‐ACPD was enhanced by low concentrations of NMDA (3–30 μm), but not by higher concentrations (> 30 μm). [3H]‐InsPx accumulations stimulated by 1S,3R‐ACPD in the absence or presence of 10 μm NMDA were linear with time, at least over the 15 min period examined; however, in the presence of 100 μm NMDA the initial enhancement of 1S,3R‐ACPD‐stimulated phosphoinositide hydrolysis progressively decreased with time.
In the presence of a maximal enhancing concentration of NMDA (10 μm), the response to 1S,3R‐ACPD (300 μm) was increased 1.9 fold and the EC50 for agonist‐stimulated [3H]‐InsPx accumulation decreased about 4 fold. The enhanced response to the metabotropic agonist was concentration‐dependently inhibited by competitive and uncompetitive antagonists of NMDA‐receptor activation.
1S,3R‐ACPD also stimulated inositol 1,4,5‐trisphosphate (Ins(1,4,5)P3) mass accumulation with an initial peak response (5–6 fold over basal) at 15 s decaying to a smaller (2 fold), but persistent elevated accumulation (1–10 min).
Co‐addition of 10 or 100 μm NMDA enhanced the initial peak Ins(1,4,5)P3 response to 1S,3R‐ACPD. However, the enhancing effect was only maintained over 10 min in the presence of 10 μm NMDA, whilst in contrast, 100 μm NMDA ceased to cause a significant enhancement of the metabotropic response by 5 min and completely suppressed 1S,3R‐ACPD‐stimulated Ins(1,4,5)P3 accumulation at 10 min.
Both basal and 1S,3R‐ACPD‐stimulated Ins(1,4,5)P3 accumulations were reduced when slices were incubated in nominally Ca2+‐free medium. Under these conditions only a concentration‐dependent enhancement of the response was observed (EC50 for NMDA facilitation of 1S,3R‐ACPD‐stimulated Ins(1,4,5)P3 accumulation of 32 μm).
These experiments have revealed that at low concentrations, NMDA can dramatically potentiate 1S,3R‐ACPD‐stimulated phosphoinositide hydrolysis, probably by a Ca2+‐dependent facilitation of agonist‐stimulated phosphoinositide‐specific phospholipase C activity. Higher concentrations of NMDA result in time‐dependent inhibition of the metabotropic agonist‐stimulated response. We believe the former effect could be fundamental in glutamate receptor ‘cross‐talk’, whereas the latter may reflect a Ca2+‐dependent neurotoxic effect of NMDA on the neonatal cerebral cortex slices.
Cardiovascular and behavioural effects of centrally administered tachykinins in the rat: characterization of receptors with selective antagonists
Authors: Picard Pierre , Regoli Domenico , Couture Réjean 
Published: July 2012

The effects of intracerebroventricular (i.c.v.) injection of selective and potent NK1 (RP 67580), NK2 (SR 48968) and NK3 (R 486, [Trp7, β‐Ala8]NKA(4–10)) receptor antagonists were assessed on the cardiovascular and behavioural responses elicited by the i.c.v. injection of substance P (SP), neurokinin A (NKA) or [MePhe7]neurokinin B ([MePhe7]NKB) in the conscious freely moving rat.
SP, NKA and [MePhe7]NKB (5–650 pmol) evoked dose‐dependent increases in mean arterial blood pressure (MAP) and heart rate (HR) with the rank order of potency SP > NKA > [MePhe7]NKB. The cardiovascular responses were accompanied by excessive face washing, grooming and wet dog shakes.
The cardiovascular effects and face washing behaviour induced by SP (25 pmol) were significantly reduced by the pre‐injection (i.c.v., 5 min earlier) of RP 67580 (6.5 nmol). However, this antagonist failed to affect the central effects of 25 pmol NKA or [MePhe7]NKB.
The cardiovascular and behavioural responses (except for wet dog shakes) elicited by NKA (25 pmol) were significantly reduced by 6.5 nmol SR 48968. However, the latter antagonist had no effect on the SP or [MePhe7]NKB‐mediated responses.
Both cardiovascular and behavioural effects produced by either SP or NKA (25 pmol) were completely abolished when rats were pretreated with a combination of RP 67580 (6.5 nmol) and SR 48968 (6.5 nmol), yet this combination of antagonists failed to modify the central effects of [MePhe7]NKB.
R 486 (6.5 nmol) inhibited the cardiovascular effects as well as wet dog shakes produced by [MePhe7]NKB, but it was inactive against the responses induced by either SP or NKA.
None of the tachykinin receptor antagonists or agonists caused motor impairment or respiratory distress. All antagonists blocked in a reversible manner and were devoid of intrinsic activity except R 486 (6.5 nmol) which produced a transient increase of MAP and HR.
These results suggest that the central effects of SP, NKA and [MePhe7]NKB are primarily mediated by central NK1, NK2 and NK3 receptors, respectively. However, a minor activation of NK2 receptors by SP and NK1 receptors by NKA was seen during blockade of both receptors. This study therefore supports the existence of functional NK1, NK2 and NK3 receptors in the adult rat brain.
Pharmacological relevance of peripheral type benzodiazepine receptors on motor nerve and skeletal muscle
Authors: Chiou L.C. , Chang C.C. 
Published: July 2012

Effects of agonists and antagonists of peripheral and central benzodiazepine receptors (pBZR and cBZR) on neuromuscular transmission were studied in mouse isolated phrenic nerve‐diaphragm preparations.
Ro5–4864, a pBZR agonist, had no effect on the neuromuscular transmission but increased muscle contractility and antagonized the tetanic fade induced by neostigmine.
Ro5–4864 inhibited the regenerative tonic endplate depolarization caused by repetitive stimulation in the presence of neostigmine without affecting the amplitude and decay time of miniature and evoked single endplate potentials.
All the effects of Ro5–4864 were shared by PK11195, a pBZR antagonist, but not by clonazepam and flumazenil, a cBZR agonist and antagonist, respectively.
It is suggested that peripheral type benzodiazepine receptors modulate presynaptic function and muscle contraction.
The influence of the trigeminal ganglion on carotid blood flow in anaesthetized guinea‐pigs
Authors: Beattie D.T. , Connor H.E. 
Published: July 2012

The influence of the trigeminal ganglion on the carotid circulation has been investigated by measuring electrical stimulation‐induced alterations in carotid arterial blood flow and resistance in anaesthetized guinea‐pigs. The effects of several receptor antagonists were assessed to determine which neurotransmitters are involved in regulating carotid blood flow.
Arterial blood pressure and carotid vascular resistance were reduced by electrical stimulation (0.5 mA, 1 ms, 5 Hz, 60 s) of the trigeminal ganglion ipsilateral to the carotid artery from which flow was measured. No consistent effect of electrical stimulation on carotid blood flow was observed. However, when guinea‐pigs were pretreated with guanethidine (30 mg kg−1, s.c, 24 h prior to experiments), stimulation produced little change in blood pressure, while carotid blood flow was increased and vascular resistance decreased, consistent with vasodilatation in the cranial circulation. Stimulation of the trigeminal ganglion contralateral to the carotid artery from which blood flow was measured, had little effect on either carotid blood flow or vascular resistance.
In animals pretreated with guanethidine, intravenous administration of the vasoactive intestinal polypeptide (VIP) receptor antagonist, [p‐Cl‐d‐Phe6,Leu17]‐VIP (50 μg kg−1) significantly attenuated the increase in carotid blood flow and decrease in carotid vascular resistance evoked by trigeminal ganglion stimulation. Responses evoked by trigeminal ganglion stimulation were, however, unaffected by intravenous injection of the tachykinin NK1 receptor antagonists, GR82334 (0.3 mg kg−1) and CP‐99,994 (0.4 mg kg−1), calcitonin gene‐related peptide (CGRP) receptor antagonist, CGRP8–37 (0.9 mg kg−1) and the ganglion blocking agent, hexamethonium (10 mg kg−1).
It is concluded that in the guanethidine‐pretreated guinea‐pig, electrical stimulation of the trigeminal ganglion increases carotid blood flow and produces an accompanying decrease in carotid vascular resistance, consistent with the dilatation of carotid blood vessels. The transmitter mediating this effect is most likely to be VIP.
Comparative effects of anti‐platelet agents as adjuncts to tissue plasminogen activator in a dog model of occlusive coronary thrombosis
Authors: McAuliffe S.J.G. , Moors J.A. , Jones H.B. 
Published: July 2012

This study compares a cyclo‐oxygenase inhibitor (aspirin), a 5‐HT2 antagonist (ZM170809) and a combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) as adjuncts to tissue plasminogen activator (rt‐PA).
Application of an anodal current (332 ± 4.1 μA) to the stenosed left circumflex coronary artery of 20 anaesthetized dogs produced a stable platelet‐rich occlusive thrombus.
After initial i.v. administration of recombinant human tissue type plasminogen activator (rt‐PA, 3 mg bolus + 2 mg kg−1 h−1 for 30 min) thrombolysis occurred in 15 out of 20 dogs. All 15 dogs reoccluded.
The second i.v. administration of rt‐PA in the presence of either aspirin, ZM170809, ZD1542 or saline resulted in thrombolysis in all 20 dogs.
Both the combined thromboxane synthase inhibitor/receptor antagonist (ZD1542) and 5‐HT2 antagonist (ZM170809) significantly (P < 0.05) reduced the time taken to lyse the thrombus compared with the saline group. The times were 14.4 ± 2.7 min, 18.0 ± 3.9 min and 36.8 ± 6.2 min for ZD1542, ZM170809 and saline respectively.
Aspirin did not offer any additional benefit to using rt‐PA alone. The times to thrombolysis were 36.8 ± 8.4 min for aspirin and 36.8 ± 6.2 min for the saline group.
The number of dogs in which the circumflex coronary artery reoccluded within 60 min of terminating the second infusion of rt‐PA were five for saline, four for aspirin, two for ZD1542 and two for ZM170809.
These results indicate that both ZD1542 and ZM170809 are more effective adjuncts than aspirin in thombolysis and may provide an improvement in current clinical practice.
Further characterization of 5‐hydroxytryptamine receptors (putative 5‐HT2B) in rat stomach fundus longitudinal muscle
Authors: Baxter Gordon S. , Murphy Olive E. , Blackburn Thomas P. 
Published: July 2012

The present study was undertaken to isolate and characterize pharmacologically homogeneous populations of 5‐hydroxytryptamine (5‐HT) receptors from a possible mixed receptor population mediating contraction of the longitudinal muscle of rat stomach fundus. Our aim was to extend the pharmacological characterization of the 5‐HT2B receptor which is reported to be expressed in this preparation.
To minimize spontaneous activity and any influence of circular muscle on the contractile response, narrow (1–1.5 × 20 mm) segments of mucosa‐denuded longitudinal muscle were used. Under these conditions, blockade of monoamine oxidase with pargyline (100 μm for 15 min) caused a leftward displacement of concentration‐effect curves for both 5‐methoxytryptamine (5‐MeO‐T) and tryptamine. Neither pargyline nor a number of uptake inhibitors affected responses to 5‐HT.
In pargyline pretreated preparations, the order of potency of a number of tryptamine analogues was as follows: 5‐MeO‐T≥α‐Me‐5‐HT≥ 5‐HT> 5‐carboxamidotryptamine (5‐CT)> tryptamine>2‐Me‐5‐HT. In addition several ligands known to act as agonists at either 5‐HT2A or 5‐HT2C receptors including 1‐m‐chlorophenylpiperazine (m‐CPP), Ru 24969, MK 212 and SCH 23390 were also agonists in rat fundus whilst sumatriptan, renzapride and 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) were very weak or inactive. With the exception of 2‐Me‐5‐HT and m‐CPP, most agonists produced monophasic concentration‐effect curves consistent with an interaction at a single site. High concentrations of 2‐Me‐5‐HT evoked relaxations which were blocked by phentolamine (1 μm) suggesting an interaction with α‐adrenoceptors. m‐CPP often evoked biphasic concentration‐effect curves with a second contractile phase which was insensitive to yohimbine at concentrations higher than required for antagonism of responses to 5‐HT.
LY 53857, methiothepin, methysergide, ritanserin and ICI 170809 were potent but non‐surmountable antagonists of 5‐HT in rat fundus. In contrast, several ligands behaved as surmountable antagonists with the following order of potency: rauwolscine > yohimbine = mesulergine ≥ mianserin = SB 204070 ≥ WY 26703 ≥ SB 200646 > pirenpirone ≥ renzapride. DAU 6285, granisetron, spiperone, ketanserin, phentolamine and GR 127935 did not affect responses to 5‐HT at concentrations up to 1 μm. The agonist and concentration independent profile of antagonism supported a single site interaction for both agonists and antagonists.
We conclude that despite small differences concerning the enantiomeric selectivity and affinity of rauwolscine and yohimbine, the close pharmacological identity of 5‐HT receptors in rat stomach fundus and the recently cloned 5‐HT2B receptor is maintained. SB 200646, which demonstrates some selectivity for 5‐HT receptors in rat stomach fundus, should provide a useful ligand for confirmation of this view and allow discrimination of 5‐HT2B function both in vitro and in vivo.
Effects of phosphodiesterase isoenzyme inhibitors on cutaneous inflammation in the guinea‐pig
Authors: Teixeira M.M. , Rossi A.G. , Williams T.J. , Hellewell P.G. 
Published: July 2012

Inflammation is central to the pathophysiology of asthma. The recent findings that different inflammatory cells may express different phosphodiesterase (PDE) isoenzymes have centred attention on inhibitors of these isoenzymes as new drugs for the treatment of asthma. In this study, we investigated the effect of different PDE isoenzyme inhibitors on the accumulation of 111In‐labelled eosinophils and local oedema formation at sites of allergic‐ and mediator‐induced inflammation in guinea‐pig skin.
Systemic treatment with SK&F 94120, a type III PDE inhibitor, or zaprinast, a type V PDE inhibitor, had no effect on the 111In‐eosinophil accumulation and oedema formation induced by i.d. injection of zymosan‐activated plasma (ZAP), PAF, histamine or in a passive cutaneous anaphylaxis (PCA) reaction.
Systemic treatment with rolipram, a type IV PDE inhibitor, effectively inhibited 111In‐eosinophil accumulation induced by ZAP, PAF, histamine and in a PCA reaction. However, oedema formation measured in the same sites was not affected. Systemic administration of higher doses of theophylline produced similar results. In contrast, 111In‐neutrophil accumulation induced by ZAP or in a PCA reaction was not altered by systemic treatment with rolipram.
Locally‐injected rolipram had little effect on 111In‐eosinophil accumulation and oedema formation induced by histamine, PAF and in a PCA reaction.
These data show that systemic, but not local, treatment with rolipram effectively inhibits allergic‐ and mediator‐induced 111In‐eosinophil accumulation but not oedema formation or 111In‐neutrophil accumulation. This, taken together with the potent inhibitory effects of PDE type IV inhibitors on eosinophil function in vitro, suggest that this class of drugs may be beneficial in disease states such as asthma where eosinophils are thought to play a major pathophysiological role.