bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression by intradermal administration of heparin of eosinophil accumulation but not oedema formation in inflammatory reactions in guinea‐pig skin
Authors: Teixeira M.M. , Hellewell P.G. 
Published: July 2012

Heparin is widely used in the treatment of thrombotic disorders and as an aid in surgery. Antiinflammatory effects of heparin have also been described. In this study, we have investigated the effects of locally‐injected heparin on the oedema formation and eosinophil accumulation induced by various inflammatory stimuli in guinea‐pig skin.
Heparin dose‐dependently suppressed the accumulation of 111In‐labelled eosinosphils induced by i.d. injection of zymosan‐activated plasma (ZAP). The 111In‐eosinophil accumulation induced by other inflammatory stimuli (compound 48/80, platelet activating factor, interleukin‐8 and in a passive cutaneous anaphylaxis reaction) was also suppressed by locally‐injected heparin.
Oedema formation in response to these same stimuli was not altered by the local injection of heparin.
Fucoidin, a negatively‐charged sulphated algal polymer, had no effect on the 111In‐eosinophil accumulation or oedema formation induced by ZAP. Nevertheless, fucoidin significantly suppressed the oedema formation induced by i.d. injection of cationic protein‐containing extracts of Schistosoma mansoni larvae. Heparin also inhibited oedema induced by the extracts, suggesting that both fucoidin and heparin were effectively neutralizing the cationic protein of the extracts to inhibit their oedema‐inducing activity.
Thus, heparin significantly inhibited the accumulation of 111In‐eosinophils, but not oedema formation, induced by various inflammatory stimuli. This, taken together with the lack of effect of fucoidin, suggests that heparin interferes with the process of eosinophil trafficking by a mechanism that does not depend on neutralisation of the charge of the stimulatory molecules.
Role of prostaglandins and nitric oxide in acute inflammatory reactions in guinea‐pig skin
Authors: Teixeira M.M. , Williams T.J. , Hellewell P.G. 
Published: July 2012

Oedema formation in skin is dependent on a synergism between mediators that increase vascular permeability and mediators that enhance local blood flow. Leukocyte accumulation is also enhanced by mediators that increase local blood flow. In this study, we have investigated whether nitric oxide (NO), an important endogenous vasodilator, could modulate oedema formation and leukocyte accumulation in guinea‐pig skin.
Local administration of the NO synthesis inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME), dose‐dependently inhibited the oedema formation induced in response to intradermal injection of bradykinin or histamine. l‐NAME, but not NG‐nitro‐d‐arginine methyl ester (d‐NAME), also inhibited oedema formation in response to i.d. injection of platelet‐activating factor (PAF), zymosan‐activated plasma (ZAP) and in a passive cutaneous anaphylactic (PCA) reaction.
N‐iminoethyl‐l‐ornithine (l‐NIO) was less effective and about 100 times less potent than l‐NAME in inhibiting bradykinin‐induced oedema formation. The cyclo‐oxygenase inhibitor, ibuprofen, had little effect on oedema responses induced by bradykinin, PAF and in a PCA reaction. On the other hand, histamine‐induced oedema formation was significantly suppressed by ibuprofen.
The inhibition by l‐NAME of bradykinin‐induced oedema formation was reversed by co‐injection of sodium nitroprusside (SNP) or prostaglandin E1 (PGE1).
L‐NAME inhibited 111In‐eosinophil and 111In‐neutrophil accumulation induced by i.d. injection of ZAP. 111In‐eosinophil accumulation induced by PAF and in the PCA reaction was also inhibited by l‐NAME but not by d‐NAME.
Co‐injection of SNP or PGE1, reversed the inhibition by l‐NAME of ZAP‐induced oedema formation and 111In‐neutrophil accumulation. SNP, but not PGE1, also reversed the effects of l‐NAME on ZAP‐induced 111In‐eosinophil accumulation.
l‐NAME caused a significant decrease in basal cutaneous blood flow when injected alone or with bradykinin. Again, SNP or PGE1 reversed the effects of l‐NAME suggesting that the inhibitory action of l‐NAME on oedema formation and cell accumulation was due to an inhibition of vasodilator tone in the microcirculation.
Thus, it appears that in guinea‐pig skin the inhibition of the production of endogenous NO inhibits both leukocyte accumulation and oedema formation induced by different mediators of inflammation. Since administration of l‐NAME also causes a local decrease in basal blood flow, we suggest that this is the mechanism by which it exerts anti‐inflammatory effects in this model.
Antagonism of levcromakalim by imidazoline‐ and guanidine‐derivatives in rat portal vein: involvement of the delayed rectifier
Authors: Ibbotson Timothy , Edwards Gillian , Weston Arthur H. 
Published: July 2012

In rat whole portal veins, guanabenz (100 nm to 10 μm) and antazoline (100 nm to 100 μm) each increased the amplitude, frequency and duration of spontaneous contractions. In addition, guanabenz (30 μm) and antazoline (30 μm) each antagonized the ability of levcromakalim (3 nm to 10 μm) to inhibit the spontaneous contractions of this tissue.
Whole‐cell voltage‐clamp recordings were made from freshly‐isolated rat portal vein cells dispersed by a collagenase/pronase enzyme treatment. The ability of several agents (antazoline, cirazoline, clonidine, guanabenz and phentolamine, each containing an imidazoline or guanidine moiety), to modulate potassium (K) currents and to inhibit the actions of levcromakalim was investigated.
Antazoline, cirazoline, clonidine, guanabenz and phentolamine (each at a concentration of 30 μm) had little effect on control non‐inactivating currents but inhibited the delayed‐rectifier current, IK(V).
Levcromakalim (1 μm) induced a non‐inactivating current, IK(ATP), and also inhibited the delayed rectifier current, IK(V).
Glibenclamide (1 μm) had no effect on control delayed rectifier or non‐inactivating currents, but it inhibited the simultaneous induction of IK(ATP) and reduction of IK(V) produced by levcromakalim (1 μm).
Antazoline, cirazoline, clonidine and guanabenz (each at a concentration of 30 μm) prevented the induction of IK(ATP) by levcromakalim (1 μm). Phentolamine (30 μm) and clonidine (30 μm) each inhibited the IK(ATP) generated by levcromakalim (1 μm).
It is concluded that a variety of agents which possess either an imidazoline (antazoline, cirazoline, clonidine and phentolamine) or a guanidine (guanabenz) moiety within their structure inhibit the delayed rectifier current, IK(V). This action may thus be mediated via a so‐called non‐adrenoceptor imidazoline binding site. Furthermore, the ability of these ligands to inhibit IK(V) and to antagonize both the induction of IK(ATP) and the vasorelaxation produced by levcromakalim is consistent with the view that the channel (KATP) which underlies IK(ATP) is a voltage‐insensitive state of the delayed rectifier K‐channel (KV).
The guinea‐pig distal colon ‐ a sensitive preparation for the investigation of 5‐HT4 receptor‐mediated contractions
Authors: Wardle Kay A. , Sanger Gareth J. 
Published: July 2012

Experiments were designed to characterize pharmacologically the contractile responses to 5‐hydroxytryptamine (5‐HT) in the guinea‐pig isolated distal colon longitudinal muscle‐myenteric plexus preparation (LMMP).
In the presence of methiothepin (100 nm) and granisetron (1 μm), 5‐HT (10 pm −‐ 10 nm) produced concentration‐dependent contractile responses of the guinea‐pig distal colon LMMP, with a pEC50 of 9.2 ± 0.08.
Responses to 5‐HT were mimicked by a series of tryptamine analogues, with the following rank order of potency; 5‐HT > 5‐MeOT >> 5‐CT > tryptamine > 2‐Me‐5‐HT. All were found to be full agonists.
Responses to 5‐HT were also mimicked by a series of substituted benzamide analogues. Their rank order of potency was 5‐HT > renzapride > cisapride > (S)‐zacopride > (R)‐zacopride > metoclopramide. All were full agonists relative to 5‐HT.
The benzimidazolone derivatives, BIMU 1 and BIMU 8 were approximately equipotent partial agonists (intrinsic activities of 0.8 ± 0.07 and 0.5 ± 0.08 respectively) in the guinea‐pig distal colon.
Tropisetron produced a rightward displacement of the 5‐HT concentration‐effect curve, yielding an apparent pA2 of 6.4 ± 0.1. The slope of the Schild plot (1.3 ± 0.1) was significantly greater than unity.
SDZ 205 557 produced a concentration‐dependent shift to the right of the 5‐HT concentration‐response curve, yielding an estimated pA2 of 7.8 ± 0.1 and a slope which did not significantly deviate from unity. SDZ 205 557 produced similar pKB estimates (7.3–7.9) when tested against 5‐MeOT, renzapride and 5‐CT, indicating a common site of action.
The pharmacological profile of the 5‐HT‐evoked contractions of the guinea‐pig distal colon LMMP are consistent with activity at the 5‐HT4 receptor. Furthermore, of the models of this receptor described in the literature, the guinea‐pig distal colon appears to be the most sensitive model to date, making it a useful tool in the investigation of 5‐HT4 receptor‐mediated events.
Profile of capsaicin‐induced mouse ear oedema as neurogenic inflammatory model: comparison with arachidonic acid‐induced ear oedema
Authors: Inoue Hideo , Nagata Nobuyuki , Koshihara Yasuko 
Published: July 2012

We have investigated the mechanism of capsaicin‐induced mouse ear oedema compared with that of arachidonic acid (AA)‐induced ear oedema, and evaluated the possible involvement of neuropeptides in the development of capsaicin‐induced oedema.
Topical application of capsaicin (0.1–1.0 mg per ear) to the ear of mice produced immediate vasodilatation and erythema followed by the development of oedema which was maximal at 30 min after the treatment. This oedema was of shorter duration with less swelling than AA‐induced oedema (2.0 mg per ear).
Capsaicin‐induced ear oedema was unaffected when inhibitors of arachidonate metabolites including platelet activating factor (PAF) were administered before capsaicin (250 μg per ear) application, while these agents significantly prevented AA‐induced oedema. Dexamethasone, histamine H1 and/or 5‐hydroxytryptamine (5‐HT) antagonists, and substance P (SP) antagonists were effective in inhibiting both models. Furthermore, a Ca2+‐channel blocker and the capsaicin inhibitor, ruthenium red, were effective inhibitors of capsaicin oedema but had no effect on AA‐induced oedema.
Phosphoramidon (50 μg kg−1, i.v.), an endopeptidase inhibitor, markedly (P < 0.001) enhanced only capsaicin‐induced ear oedema, but bestatin (0.5 mg kg−1, i.v.), an aminopeptidase, failed to enhance oedema formation.
Neuropeptides (1–100 pmol per site) such as rat calcitonin gene‐related peptide (CGRP), SP, neurokinin A (NKA), and vasoactive intestinal peptide (VIP), which are released from capsaicin‐sensitive neurones, caused ear oedema by intradermal injection. Furthermore, a synergistic effect of CGRP (10 fmol per site) and SP (10 pmol per site) on oedema formation was observed.
The oedema induced by neuropeptides was significantly (P < 0.05 or P < 0.001) inhibited when cyproheptadine (20 mg kg−1, p.o.), a histamine H1 and 5‐HT antagonist, was administered before injection. In contrast, nifedipine (50 mg kg−1, p.o.), a Ca2+‐channel blocker, and indomethacin (10 mg kg−1, p.o., except for NKA), a cyclo‐oxygenase inhibitor, had little effect on neuropeptide‐induced oedema.
These results suggest that the mechanism of capsaicin‐induced ear oedema is different from that of AA‐induced oedema and suggest that the development of capsaicin‐induced ear oedema is primarily mediated by neuropeptides. The neuropeptides released after activation of sensory nerves cause an increase of vascular permeability by interactions with endothelial cells and by histamine (and 5‐HT) release from mast cells.
Effect of activation on adhesion of flowing neutrophils to cultured endothelium: time course and inhibition by a calcium channel blocker (nitrendipine)
Authors: Perry I. , Buttrum S.M. , Nash G.B. 
Published: July 2012

Adhesion of neutrophils to vascular endothelium plays an important role in inflammation and thrombosis. Modulation of adhesion may be therapeutic in these conditions.
A flow model was used to quantify adhesion of neutrophils to human cultured umbilical vein endothelial cells. The time course of the neutrophil response to activation by N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP, 10−7 m) was studied and the inhibitory effects of the calcium‐channel blockers, nitrendipine and nifedipine, were investigated.
Neutrophils adhered firmly to the endothelial cells without rolling, but initial attachment was highly dependent on shear stress; doubling the stress from 0.05 to 0.1Pa decreased the number of neutrophils adhering by over 80%.
Adhesion rapidly increased after activation of neutrophils by fMLP, peaking at 1–3 min post‐treatment, and then decreased over the next 10–12 min. A monoclonal antibody to the β2‐integrin component CD18 inhibited adhesion by over 80% for activated or unactivated cells.
The Ca‐channel blocker, nitrendipine, but not nifedipine, significantly inhibited the fMLP‐induced increase of adhesion in a dose‐dependent manner (10−8 to 10−6 m). Dihydropyridines may be useful agents for modifying neutrophil function.
Mediation of the hypotensive action of systemic clonidine in the rat by α2‐adrenoceptors
Authors: Hieble J. Paul , Kolpak David C. 
Published: July 2012

During the past few years it has been shown that the sympatholytic effect resulting from localized microinjection of clonidine and other imidazolines into the rostral ventrolateral medulla (RVL) results from activation of ‘imidazoline’ receptors (I1 receptors) rather than from an α2‐adrenoceptor‐mediated effect.
The relative contributions of these two receptor systems to the hypotensive action of systemically administered clonidine have not been studied. Clonidine has afffinity for both I1 and α2‐adrenoceptors; guanabenz represents a useful pharmacological tool, since it activates only the α2‐adrenoceptor.
Antagonists acting at both I1 and α2‐adrenoceptors (idazoxan) and at only α2‐adrenoceptors (SK&F 86466; 6‐chloro‐3‐methyl‐2,3,4,5‐tetrahydro‐3‐benzazepine) are available. Idazoxan (1 mg kg−1, i.v.) and SK&F 86466 (3 mg kg−1, i.v.) produced an equivalent degree of blockade of the pressor response to guanabenz or clonidine in the pithed rat, a response mediated by the α2‐adrenoceptor.
Guanabenz (30 μg kg−1, i.v.) and clonidine (10 μg kg−1, i.v.) lowered blood pressure in the chloralose‐anaesthetized spontaneously hypertensive rat by 48 ± 4.6 mmHg and 44 ± 5.4 mmHg, respectively; this response, for either agonist, was blocked by both idazoxan and SK&F 86466.
These data show that the hypotensive effect of intravenously administered clonidine results from activation of central α2‐adrenoceptors, with no significant contribution from an I1‐mediated effect. Thus clonidine can lower blood pressure by different receptor mechanisms, dependent on the route of administration.
Insulin‐mediated sensitization of adenylyl cyclase activation
Authors: Feldman Ross D. 
Published: July 2012

Insulin may be an important regulator of vascular function. We have previously studied lymphocyte β‐adrenoceptors as a model for the human vascular β‐adrenoceptor. To examine the effects of insulin on human β‐adrenoceptor responsiveness, adenylyl cyclase activity, cyclic AMP‐dependent protein kinase activity and β‐adrenoceptor radioligand binding assays were performed on permeabilized mononuclear leukocytes.
With acute exposure to insulin in vitro, followed by washing and permeabilization there was a dose‐dependent increase in both lymphocyte NaF‐stimulated activity and β‐adrenoceptor‐stimulated adenylyl cyclase activity paralleling an increase in β‐adrenoceptor‐stimulated protein kinase A activity. Manganese‐, forskolin‐ and forskolin plus guanylimidodiphosphate‐stimulated adenylyl cyclase activities were not altered by insulin pretreatment. Additionally, mononulcear leukocyte β‐adrenoceptor density, proportion of externalized receptors and receptor affinity for agonist were not altered.
The data indicate that acute exposure to insulin sensitizes G‐protein‐stimulated adenylyl cyclase activity. These findings suggest a potential role for insulin in the regulation of β‐adrenoceptor responsiveness in man.
Tacrine‐induced increase in the release of spontaneous high quantal content events in Torpedo electric organ
Authors: Cantí Carles , Martí Eulàlia , Marsal Jordi , Solsona Carles 
Published: July 2012

The anticholinesterases, tacrine (100 μm) and physostigmine (60 μm) had different effects on the amplitude distribution and kinetics of miniature endplate currents (m.e.p.cs) recorded extracellularly from the electric organ of Torpedo marmorata.
Tacrine increased the ratio of giant miniatures (larger than 4 mV of amplitude) to more than 20% of recorded spontaneous events. In the presence of physostigmine such events represented only 4%.
Both tacrine and physostigmine increased the rise time and the decay phase of normal‐sized m.e.p.cs when compared to control conditions. Both effects were significantly greater for tacrine.
We have tested the specificity of the tacrine effect on ectoenzyme activities associated with plasma membranes of these pure cholinergic nerve endings. Tacrine does not act unspecifically on every ectoenzyme, because it is not able to block the ectoapyrase activity even at a concentration 100 fold greater than that required to inhibit 94% of AChE.
We conclude that the differential effects of tacrine and physostigmine can be explained in terms of undetermined presynaptic actions of tacrine, while comparable effects of the two compounds can be explained through a shared anticholinesterase activity.
Chloride secretion in response to guanylin in colonic epithelia from normal and transgenic cystic fibrosis mice
Authors: Cuthbert A.W. , Hickman Margaret E. , MacVinish Lesley J. , Evans M.J. , Colledge W.H. , Ratcliff Rosemary , Seale P.W. , Humphrey P.P.A. 
Published: July 2012

Guanylin, a 15 amino acid endogenous gut peptide, increased the short circuit current (SCC) in the epithelium of the mouse colon, but only when applied to the apical and not the basolateral surface.
By use of selective blockers of epithelial ion transport and modification of the bathing solution, it was concluded that guanylin increased electrogenic chloride secretion but also had a minor effect on electrogenic sodium absorption. In addition there were small residual currents which remained unresolved.
The threshold concentration of guanylin causing a SCC increase was less than 50 nm, but at concentrations 40 times greater no indication of a maximally effective concentration was found.
Two guanylin isomers with the same amino acid sequence but with the disulphide bridges joined in an alternate fashion showed no activity. Thus only guanylin with the greatest structural homology to heat stable enterotoxin (STa) showed biological activity.
The action of guanylin was virtually eliminated in colonic epithelia from transgenic cystic fibrosis (CF) mice. As these animals lack the chloride channel coded by the CF gene sequence, it is likely that the final effector process in murine colonic epithelia involves the CFTR (cystic fibrosis transmembrane conductance regulator) chloride channel.
Opportunistic infections of the gut generating STa lead to diarrhoeal conditions via an action of the toxin on apical guanylin receptors. Thus, as discussed, the CF heterozygote may have a genetic advantage in this circumstance.
β1‐ and β2‐adrenoceptor antagonist activities of ICI‐215001, a putative β3‐adrenoceptor agonist
Authors: Tesfamariam Belay , Allen Guy T. 
Published: July 2012

The present study was undertaken to characterize the β3‐adrenoceptor agonist activity of ICI‐215001 and to determine whether it exhibits additional activities on β1‐ and β2‐adrenoceptors in isolated spontaneously beating atrium, trachea and ileum of guinea‐pig.
In guinea‐pig atrium, isoprenaline, a non‐selective β‐adrenoceptor agonist, caused concentration‐dependent, positive chronotropic effects that were inhibited by atenolol, a selective β1‐antagonist. ICI‐215001 also competitively antagonized the increase in heart rate caused by isoprenaline.
ICI‐215001 exhibited low intrinsic activity at increasing the beating rate of atrium and no activity on resting or induced tone of tracheal strips.
In strips of guinea‐pig trachea, contracted submaximally with carbachol, isoprenaline, caused concentration‐dependent relaxations. Both ICI‐118551, a selective β2‐adrenoceptor antagonist, and ICI‐215001 competitively inhibited the relaxations caused by isoprenaline.
In isolated strips of guinea‐pig ileum longitudinal smooth muscle contracted with histamine, isoprenaline and ICI‐215001 caused relaxations which were inhibited by alprenolol, a β‐adrenoceptor antagonist with modest affinity for β3‐adrenoceptors, but were resistant to ICI‐118551 and atenolol.
These results indicate that ICI‐215001 exhibits β3‐adrenoceptor agonist activity as demonstrated by relaxations mediated via atypical β‐adrenoceptors in the longitudinal smooth muscle of guinea‐pig ileum. Further, the studies demonstrate that ICI‐215001 can act as an antagonist at β1‐ and β2‐adrenoceptors in situations where its intrinsic agonist activity is low.
Ontogenic increase in PGE2 and PGF2α receptor density in brain microvessels of pigs
Authors: Li D.Y. , Varma D.R. , Chemtob S. 
Published: July 2012

The hypothesis that the relative vasoconstrictor ineffectiveness of prostaglandin E2 (PGE2) and PGF2α on cerebral vessels of newborn pigs might be due to fewer receptors for these prostanoids was tested by comparing receptors for PGE2 (EP) and PGF2α (FP) in cerebral microvessels from newborn and adult pigs.
Specific binding of [3H]‐PGE2 and [3H]‐PGF2α to membranes prepared from brain microvessels showed that EP and FP receptor density (Bmax) in tissues from newborn animals was less than 50% of that determined in tissues from adults. By contrast, estimates of affinity (KD) were unchanged.
Specifically bound [3H]‐PGE2 to brain microvessels from both the newborn and adult was displaced by AH 6809 (EP1‐selective antagonist) by 80–90%, and only by approximately 30–35% by both 11‐deoxy PGE1 (EP2/EP3 agonist) and M&B 28,767 (EP3 agonist); butaprost (EP2 agonist) was completely ineffective.
PGE2, 17‐phenyl trinor PGE2 (EP1 agonist), PGF2α and fenprostalene (PGF2α analogue) caused significantly less increase in inositol 1,4,5‐triphosphate (IP3) in brain microvessels from the newborn than in those from adult pigs. The stimulation of IP3 by PGE2 and 17‐phenyl trinor PGE2 was almost completely inhibited by the EP1 antagonist, AH 6809.
PGE2, 11‐deoxy PGE1 and M&B 28,767 produced small reduction of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) production in adult vessels but no effect in newborn tissues.
The lower density of EP and FP receptors in microvessels of newborn pigs compared to adults may explain the reduced ability of PGE2 and PGF2α to stimulate production of IP3 in tissues from newborn animals. This in turn, may provide an explanation for previous observations demonstrating that these prostanoids elicit contraction of adult cerebral microvessels, but exert minimal effects on these vessels in newborn animals.