bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the increase in vascular permeability induced by vascular permeability factor in vivo
Authors: Collins P.D. , Connolly D.T. , Williams T.J. 
Published: July 2012

Vascular permeability factor (VPF) is a protein secreted from a variety of human and rodent tumour and normal tissue cells. In addition to mediating angiogenesis and endothelial cell growth, VPF has been reported to be a potent mediator of increased microvascular permeability in vivo. In this study we have investigated these permeability changes in vivo using a quantitative model of local plasma leakage in rabbit skin.
Our results reveal that VPF is a potent mediator of plasma leakage which, in the rabbit, depends on a synergistic interaction with arteriolar vasodilators such as prostaglandin E2. The requirement for an exogenous vasodilator further suggests that VPF does not act to increase blood flow in this model.
We show that this response does not require the presence of circulating neutrophils and in this respect is similar to direct‐action permeability increasing mediators such as histamine and bradykinin. Similarly, the time course of plasma leakage induced by VPF resembles that of direct‐action mediators, where the greatest response occurs over the first 30 min. In contrast, the neutrophil‐dependent plasma leakage induced by the active component of zymosan‐activated plasma, C5ades arg, was maintained at a similar level over 2.5 h.
Further, using mediator antagonists and enzyme inhibitors we demonstrate that the mechanism of action of VPF is not via activation of histamine, kinin, or platelet‐activating factor pathways.
Counteraction of the rapid tolerance to 8‐OH‐DPAT‐induced corticosterone secretion in rats by activation of the GABAA receptor‐chloride channel complex
Authors: Kelder Diana , Ross Svante B. 
Published: July 2012

The effect of various classes of compounds on the rapidly developed tolerance to 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT)‐induced corticosterone secretion was examined.
Compounds activating the γ‐aminobutyric acidA (GABAA) receptor‐chloride complex, i.e. muscimol (3 mg kg−1), diazepam (5 mg kg−1), flunitrazepam (1 mg kg−1), sodium pentobarbitone (10–30 mg kg−1) and chlormethiazole ethane disulphonate (50 mg kg−1) counteracted the development of tolerance when injected before or simultaneously with, but not 15 min after 8‐OH‐DPAT.
At these doses the compounds produced an acute increase in serum corticosterone but had, with the exception of muscimol, no effect on the response to the challenge dose of 8‐OH‐DPAT 24 h later. Muscimol significantly decreased the response.
The GABAA chloride channel antagonist, picrotoxin (1 mg kg−1, s.c.), but not bicuculline (1 mg kg−1, i.p.) potentiated the development of tolerance to 8‐OH‐DPAT‐induced corticosterone secretion.
A number of compounds with widely differing pharmacological actions were examined and found to have no effect on the development of tolerance to 8‐OH‐DPAT‐induced corticosterone secretion.
Effects of chronic treatment with nitric oxide synthase inhibitors on regional haemodynamic responses to vasodilators in conscious Brattleboro rats
Authors: Gardiner Sheila M. , Kemp Philip A. , Bennett Terence 
Published: July 2012

The effects of acute inhibition of nitric oxide (NO) synthase on cardiovascular responses to vasodilator challenges have already been described. We now report the responses to vasodilators during and after chronic NO synthase inhibition.
In conscious Brattleboro rats, the regional haemodynamic effects of 3 min infusions of acetylcholine (4 μg min−1), sodium nitroprusside (15 μg min−1) or adrenaline (0.2 μg min−1) were assessed (from areas under or over curves (AUC, AOC)) under control conditions, 6 and 72 h after the addition of the NO synthase inhibitor, NG‐monomethyl‐l‐arginine (l‐NMMA) to the drinking water (1 mg ml−1), and 6, 24 and 48 h after the withdrawal of l‐NMMA. In a separate group of Brattleboro rats, responses to acetylcholine, sodium nitroprusside and adrenaline were assessed before and 6 h after the onset of oral ingestion of the more potent nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME; 0.05 mg ml−1).
Acetylcholine caused renal vasodilatation (87 ± 11 units) and mesenteric vasoconstriction (−31 ± 5 units), sodium nitroprusside caused vasodilatation in renal (96 ± 12 units), mesenteric (222 ± 13 units) and hindquarters (49 ± 15 units) vascular beds, whereas adrenaline caused hindquarters vasodilatation (92 ± 8 units). Seventy two h after the onset of oral ingestion of l‐NMMA, acetylcholine had a decreased renal vasodilator (59 ± 9 units) effect, sodium nitroprusside had an increased renal vasodilator (142 ± 23 units) action, while adrenaline had a decreased hindquarters vasodilator (55 ± 6 units) influence. Twenty four h after withdrawal of l‐NMMA, the renal vasodilator effect of acetylcholine was greater than the control response (106 ± 14 units), but the regional haemodynamic effects of sodium nitroprusside and adrenaline were not different from those under control conditions. Hence, the increased renal vasodilator response to acetylcholine was probably due to changes in muscarinic receptor‐mediated mechanisms rather than to any increase in guanylyl cyclase or its sensitivity to NO.
Contractile and relaxant effects of phorbol ester in the intestinal smooth muscle of guinea‐pig taenia caeci
Authors: Mitsui Minori , Karaki Hideaki 
Published: July 2012

Effects of phorbol esters on the cytosolic Ca2+ level ([Ca2+]i) and muscle tension in the intestinal smooth muscle of guinea‐pig taenia caeci were examined.
12‐Deoxyphorbol 13‐isobutyrate (DPB, 1 μm) did not change the [Ca2+]i and tension in resting muscle.
In high K+‐stimulated muscle, 1 μm DPB transiently augmented the contraction and decreased [Ca2+]i. 12‐Deoxyphorbol 13‐isobutyrate 20‐acetate (1 μm) and phorbol 12, 13‐dibutyrate (1 μm) showed similar effects to DPB whereas phorbol 12‐myristate 13‐acetate (1 μm) and phorbol 12, 13‐didecanoate (1 μm) were ineffective.
DPB (1 μm) inhibited both [Ca2+]i and tension stimulated by 300 nm carbachol or 3 μm histamine. In the presence of a higher concentration of carbachol (1 μm), DPB decreased [Ca2+]i and transiently increased muscle tension.
In the muscle strips permeabilized with bacterial α‐toxin, 1 μm DPB shifted the Ca2+‐tension curve to the left. An inhibitor of protein kinase C, H‐7 (30 μm), inhibited the effect of DPB.
DPB did not change the high K+‐induced contraction in the muscle strips pretreated with 3 μm phorbol 12‐myristate 13‐acetate for 24 h.
These results suggest that activation of protein kinase C has dual effects; it augments contraction by increasing the Ca2+ sensitivity of the contractile elements and it inhibits contraction by decreasing [Ca2+]i.
S‐nitrosocysteine, but not sodium nitroprusside, produces apamin‐sensitive hyperpolarization in rat gastric fundus
Authors: Kitamura Kenji , Lian Qishen , Carl Andreas , Kuriyama Hirosi 
Published: July 2012

To investigate the pharmacological properties of the membrane hyperpolarization induced by electrical field stimulation (EFS), sodium nitroprusside (SNP) and S‐nitrosocysteine (NO‐Cys) in circular smooth muscle cells of the rat gastric fundus (forestomach), the effects of various potassium channel blockers on these hyperpolarizations were investigated.
EFS (50 μs, 20 Hz, 3 pulses, 10–50 V) produced inhibitory junction potentials (i.j.ps), in the presence of atropine (1 μm) and guanethidine (1 μm). NO‐Cys and SNP produced hyperpolarization of the membrane in the rat gastric fundus. l‐NG‐nitroarginine (l‐NNA) inhibited the i.j.ps, but not the hyperpolarization induced by NO‐Cys and SNP. This inhibitory action of l‐NNA on the i.j.ps was partly reversed by subsequent application of l‐arginine (1 mm) but not by d‐arginine.
Oxyhaemoglobin (Oxy‐Hb; 5 μm) inhibited these hyperpolarizations, although a higher concentration of Oxy‐Hb was required to inhibit the SNP‐induced hyperpolarization. Hydroquinone (50 μm) inhibited only the hyperpolarization induced by NO‐Cys.
Apamin (1 μm) partly inhibited i.j.ps and NO‐Cys‐induced hyperpolarization, but not the SNP‐induced hyperpolarization. Tetraethylammonium (TEA; 1 mm), 4‐aminopyridine (4‐AP; 1 mm) or glibenclamide (1 μm) did not affect hyperpolarization induced by NO‐Cys and SNP.
8‐Bromo cyclic guanosine 3′:5′‐monophosphate (1 mm) also produced hyperpolarization. Apamin (1 μm), TEA (1 mm) and glibenclamide (5 μm) all failed to inhibit this hyperpolarization.
These results indicate that NO‐Cys and EFS hyperpolarize the membrane by activating apamin‐sensitive and TEA‐resistant K+ channels and favour the hypothesis that a NO‐liberating substance may act as a neurotransmitter in non‐adrenergic, non‐cholinergic (NANC) neurones in the rat forestomach. Our results also suggest that increase in cyclic GMP may cause apamin‐resistant hyperpolarization but the apamin‐sensitive hyperpolarization is mediated by another mechanism.
A2‐purinoceptor‐mediated relaxation in the guinea‐pig coronary vasculature: a role for nitric oxide
Authors: Vials Amanda , Burnstock Geoffrey 
Published: July 2012

The Langendorff heart preparation was used to investigate the mechanism of action of the endothelium‐dependent vasodilatation evoked by adenosine and its analogues in the guinea‐pig coronary vasculature.
The relative order of potency of adenosine and its analogues in causing a reduction in perfusion pressure was d‐5′‐(N‐ethylcarboxamide)adenosine (NECA) = 2‐[p‐(2‐carboxyethyl)phenylethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS 21680)>R‐N6‐(2‐phenylisopropyl)adenosine (R‐PIA) = adenosine = 2‐chloroadenosine (2‐CA)>S‐N6‐(2‐phenylisopropyl)adenosine (S‐PIA) = N6‐cyclopentyl‐adenosine (CPA); thus suggesting the presence of A2‐purinoceptors in this preparation.
8‐(p‐Sulphophenyl)theophylline (8‐PSPT; 3 × 10−5 m) significantly reduced both the maximum amplitude and area of the vasodilatation produced in response to adenosine (5 × 10−10 − 5 × 10−8 mol) without having any effect on the response to the P2‐purinoceptor agonist, 2‐methylthioATP. The relaxation induced by adenosine (5 × 10−12 − 5 × 10−8 mol) was unaffected by the selective A1‐purinoceptor antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX; 10−8 m). This antagonist profile suggests that only A2‐purinoceptors are present in the guinea‐pig coronary vasculature.
The areas of the vasodilator response to adenosine (5 × 10−10 − 5 × 10−7 mol), NECA (5 × 10−12 − 5 × 10−7 mol) and CGS 21680 (5 × 10−12 − 5 × 10−10 mol) were significantly reduced by NG‐nitro‐l‐arginine methyl ester (l‐NAME; 3 × 10−5 m). The amplitude of the responses to low concentrations of adenosine (5 × 10−10 − 5 × 10−9 mol), NECA (5 × 10−11 mol) and CGS 21680 (5 × 10−11 − 5 × 10−9 mol) were significantly reduced by l‐NAME (3 × 10−5 m).
l‐Arginine (1.5 × 10−3m) significantly reversed the inhibition, by l‐NAME (3 × 10−5m), of the relaxant response to adenosine (5 × 10−8 mol), NECA (5 × 10−9 mol) and CGS 21680 (5 × 10−11 mol).
Indomethacin (10−6 m) did not inhibit the response to adenosine, except at low doses (5 × 10−11 − 5 × 10−10 mol).
It is concluded that in the guinea‐pig coronary vasculature, while a major part of the vasodilator action of adenosine is probably directly via A2‐receptors on the smooth muscle, activation of a subpopulation of A2‐purinoceptors on endothelial cells by adenosine and its analogues induces relaxation via production of nitric oxide; prostanoids appear to play a minimal role in the relaxation induced by adenosine as in most other preparations.
Effects of prolonged application of isoprenaline on intracellular free magnesium concentration in isolated heart of rat
Authors: Nishimura H. , Matsubara T. , Ikoma Y. , Nakayama S. , Sakamoto N. 
Published: July 2012

The effect of prolonged application of isoprenaline on intracellular free‐Mg2+ concentration ([Mg2+]i) was examined by use of 31P‐nuclear magnetic resonance (31P‐n.m.r.) in rat isolated hearts. Left ventricular pressure (LVP) was simultaneously measured.
[Mg2+]i was estimated from the separation of the α‐ and β‐ATP peaks, using the dissociation constant of MgATP 38 μm (established previously). In normal (phosphate‐free, Krebs‐Henseleit) solution, [Mg2+]i was approximately 0.4 mm.
When isoprenaline was applied for 100 min, a transient increase in [Mg2+]i was observed during the initial 25 min, whilst concentrations of ATP ([ATP]) and phosphocreatine ([PCr]) decreased and [Pi] correspondingly increased. During the subsequent 75 min of isoprenaline application, [Mg2+]i decreased below its resting levels. Washout of isoprenaline restored [Mg2+]i and [PCr], but [ATP] remained low. These changes elicited by isoprenaline were not observed in the presence of propranolol, a typical α‐adrenoceptor blocker.
Isoprenaline increased both LVP and heart rate. The increased LVP and heart rate slowly returned to lower values during prolonged application of isoprenaline, but remained higher than those before application.
The transient rise in [Mg2+]i elicited by isoprenaline could be attributed to the decrease in [ATP] resulting in a release of Mg2+. The subsequent decrease in [Mg2+]i during the prolonged applications suggests that β‐adrenoceptor stimulation itself facilitates Mg2+‐extruding mechanism(s).
Functional importance of cholinergic and purinergic neurotransmission for micturition contraction in the normal, unanaesthetized rat
Authors: Igawa Yasuhiko , Mattiasson Anders , Andersson Karl‐Erik 
Published: July 2012

The cholinergic and purinergic neurotransmission involved in micturition in the normal, unanaesthetized rat was investigated by means of continuous cystometry.
ATP (1 and 5 mg kg−1), administered intra‐arterially (i.a.) close to the bladder, produced rapid, phasic, dose‐dependent increases in bladder pressure with micturition immediately after injection. The micturition pressure of the following spontaneous voidings increased, and bladder capacity, micturition volume, and residual volume decreased. Pretreatment with α,β‐methylene ATP (1 mg kg−1, i.a.) blocked the effects of ATP (5 mg kg−1).
α,β‐Methylene ATP (0.25, 0.5 and 1 mg kg−1, i.a.) produced rapid, phasic, increases in bladder pressure with micturition immediately after injection. The effects of α,β‐methylene ATP (0.25 mg kg−1, i.a.) were not affected by pretreatment with indomethacin (0.5–2 mg kg−1, i.a.). The micturition pressure of the subsequent spontaneous voidings decreased, and bladder capacity and residual volume increased.
Carbachol (5–50 μg kg−1, i.a.) produced rapid, sustained, dose‐dependent increases in bladder pressure with micturition, and then increased basal pressure, threshold pressure, and micturition pressure, and decreased bladder capacity and micturition volume during the following spontaneous voidings.
Atropine (1 mg kg−1, i.a.) decreased micturition pressure and micturition volume, but did not induce dribbling incontinence. Micturition contractions still occurred after the injection, but changed in appearance and were of shorter duration than before. In the presence of atropine (1mg kg−1, i.a.), α,β‐methylene ATP (1 mg kg−1, i.a.) produced initially a phasic increase in bladder pressure with micturition and then dribbling incontinence in all animals tested.
After blockade of the micturition reflex with morphine (10 μg intrathecally), ATP (5 mg kg−1, i.a.), α,β‐methylene ATP (0.25–1 mg kg−1, i.a.), and carbachol (5–500 μg kg−1, i.a.) were unable to empty the bladder.
The results suggest that drug‐induced bladder emptying in the normal, unanaesthetized rat requires an intact micturition reflex and they support the view that the two physiologically important transmitters involved in micturition are acetylcholine and ATP.
Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta
Authors: Ivorra M. Dolores , Lugnier Claire , Catret Maria , Anselmi Elsa , Cortes Diego , D'Ocon Pilar 
Published: July 2012

In the present study we assessed the activity of antioquine, a bisbenzyltetrahydroisoquinoline alkaloid isolated from Pseudoxandra sclerocarpa, by examining its effects on the contractile activity of rat isolated aorta, specific binding of [3H]‐(+)‐cis‐diltiazem, [3H]‐nitrendipine and [3H]‐prazosin to cerebral cortical membranes and the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta.
Contractions in rat aorta induced by high concentrations of KCl (80 mm) and noradrenaline (1 μm) were inhibited by antioquine in a concentration‐dependent manner (0.1 μm– 300 μm). The alkaloid appeared more potent against KCl‐induced contractions. This inhibitory effect was observed at both 37°C and 25°C.
Paradoxically, at the highest concentration tested (300 μm) antioquine induced a contractile response of similar magnitude in the presence and absence of extracellular calcium, at 37°C. This activity was greatly attenuated at 25°C. Antioquine‐induced contractions were not inhibited by prazosin (0.1 μm), nifedipine (1 μm) or diltiazem (100 μm). On the contrary, prazosin and nifedipine slightly increased the contractions in the presence of extracellular calcium. Papaverine (100 μm) partially inhibited the contractile response to antioquine both in the presence and absence of extracellular calcium.
At 25°C, in Ca2+‐free solution, antioquine (300 μm) did not modify the contractile response (phasic and tonic) evoked by noradrenaline, but increased the phasic contraction induced by caffeine. At 37°C, the contraction elicited by antioquine made it impossible to observe the noradrenaline‐induced one.
Antioquine showed affinity for the [3H]‐prazosin binding site and for the [3H]‐(+)‐cis‐diltiazem binding site of the Ca2+‐channel receptor complex, but had no effect at the dihydropyridine binding site in rat cerebral cortex.
Antioquine weakly inhibited some PDE forms isolated from bovine aorta: a CaM‐PDE (PDE I) which preferentially hydrolyzes cyclic GMP and is activated by calmodulin, and a rolipram‐sensitive cyclic AMP‐PDE (PDE IV) which hydrolyzed cyclic AMP. Antioquine did not exert any inhibitory effect on the other forms of PDE, a cyclic GMP selective form (PDE V) and a low Km cyclic AMP‐PDE that is inhibited by cyclic GMP (CGI‐PDE, PDE III).
The present work provides evidence that antioquine has properties both as a calcium entry blocker (possibly through the benzodiazepine recognition site in the calcium channel) and as a contractile agent. Its mechanism of action as a contractile agent is not related to Ca2+‐entry and is hypothetically similar to that of calyculin‐A or okadaic acid. The possible involvement of α‐adrenoceptors in this paradoxical effect cannot be excluded. The rigidity of the molecule provides an interesting model for analyzing this contractile mechanism and the intracellular processes involved.
On the high affinity binding site for [3H]‐1,3‐dipropyl‐8‐cyclopentylxanthine in frog brain membranes
Authors: Oliveira J.C. , Sebastião A.M. , Ribeiro J.A. 
Published: July 2012

Radioligand binding properties of the adenosine receptor ligands, [3H]‐1,3‐dipropyl‐8‐cyclopentylxanthine ([3H]‐DPCPX), and [3H]‐R‐phenylisopropyladenosine ([3H]‐R‐PIA) were investigated in frog brain membranes.
The specific binding of the adenosine antagonist, [3H]‐DPCPX to frog brain membranes showed one binding site with Kd and Bmax values of 43.8 nm and 0.238 ± 0.016 pmol mg−1 protein, respectively. Guanosine 5′‐triphosphate (GTP, 100 μm) decreased to 72 ± 7% and Mg2+ (8 mm) increased to 121 ± 3% [3H]‐DPCPX (40 nm) binding to frog brain membranes.
[3H]‐DPCPX saturation binding experiments performed in the presence of Mg2+ (8 mm), or in the presence of GTP showed that Mg2+ ions decreased the Kd value of [3H]‐DPCPX to 14 nm, and GTP increased this value to 65.6 nm. Bmax values were not significantly (P > 0.05) modified (0.261 ± 0.018 pmol mg−1 protein, with Mg2+, and 0.266 ± 0.026 pmol mg−1 protein, in presence of GTP) by the presence of Mg2+ or GTP.
The specific binding of [3H]‐R‐PIA (15 nm) was decreased to 37 ± 6% by GTP (100 μm) and increased to 123 ± 4% by Mg2+ (8 mm). [3H]‐R‐PIA saturation binding experiments performed in the presence of Mg2+ (8 mm) showed one binding site with Kd and Bmax values of 0.9 nm and 0.229 ± 0.008 pmol mg−1 of protein, respectively.
The concentration‐inhibition curves of adenosine agonists and antagonists versus [3H]‐DPCPX binding showed the following order of potencies: CPA > R‐PIA ≃ NECA > S‐PIA > > CGS 21680, for the agonists, and XAC ≃ DPCPX > > XCC > PACPX, for the antagonists.
The present results suggest that the adenosine binding site in the frog brain membranes is G‐protein coupled, but that the antagonist affinities and the pharmacological profile is different from the A1 or A2 adenosine receptors.
The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs
Authors: Wainwright C.L. , Parratt J.R. , Van Belle H. 
Published: July 2012

The effect of R75231, an inhibitor of purine nucleoside transport, were examined on ischaemic arrhythmias in anaesthetized pigs.
In closed chest pigs (n = 4), R75231 exerted a moderate dose‐dependent decrease in mean arterial blood pressure (from 97 ± 4 mmHg to 95 ± 4, 90 ± 1 and 83 ± 2 mmHg at 25, 50 and 100 μg kg−1 respectively) and produced a dose‐related shift to the left of the blood pressure dose‐response curve to intravenous bolus doses of adenosine. The degree of inhibition of adenosine uptake by R75231, assessed ex vivo in erythrocyte suspensions, was 43 ± 5%, 64 ± 13 and 114 ± 15% at doses of 25, 50 and 100 μg kg−1 respectively.
In open chest pigs, intravenous injection of R75231 (50 μg kg−1; n = 6 and 100 μg kg−1; n = 10) induced a dose‐related decrease in both systolic and diastolic arterial blood pressure which was more marked than in closed‐chest pigs (mean pressure 86 ± 4 to 70 ± 2 mmHg and 88 ± 6 to 60 ± 6 mmHg with 50 and 100 μg kg−1 respectively), without affecting heart rate or myocardial contractility. Coronary artery occlusion in these pigs caused a secondary decrease in blood pressure. This was not observed in controls (n = 10). The lower dose of R75231 did not exert any antifibrillatory effects, whereas the higher dose significantly reduced the incidence of ventricular fibrillation, from 80% in control pigs to 30%. Neither dose modified the incidence of ventricular tachycardia (33% and 40% with 50 and 100 μg kg−1 respectively, compared to 30% in controls) or had any effect on the total number of ventricular ectopic beats (85 ± 47 and 130 ± 31 vs 110 ± 19 in controls). R75231, at a dose of 100 μg kg−1, also attenuated the ischaemia‐induced shortening of QRS‐interval, but neither dose modified the ST‐segment depression seen following occlusion.
These results show that the nucleoside transport inhibitor, R75231, exerts an antifibrillatory effect in a model of severe myocardial ischaemia in a dose which completely inhibits adenosine uptake ex vivo. However, while this agent has minimal haemodynamic effects in closed chest animals, the reduction in blood pressure induced by R75231 in open‐chest pigs cannot be excluded as a possible contributory mechanism of the antiarrhythmic effects of this drug.