bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective IK blockade as an antiarrhythmic mechanism: effects of UK66,914 on ischaemia and reperfusion arrhythmias in rat and rabbit hearts
Authors: Rees Siân A. , Curtis Michael J. 
Published: July 2012

UK66,914 is a specific and selective blocker of the delayed rectifying potassium current (IK). The effectiveness of IK block as a mechanism for prevention of ischaemia‐ and reperfusion‐induced arrhythmias was tested by use of UK66,914: its actions in rat, a species deficient in cardiac IK were compared with its actions in rabbit, a species possessing functional cardiac IK. Antiarrhythmic actions in rabbit but none in rat is the only outcome possible if selective IK blockade is responsible for the antiarrhythmic actions of the drug during ischaemia and/or reperfusion.
During 30 min regional ischaemia, 0.3 and 1 μm UK66,914 had no influence on the incidence of ventricular fibrillation (VF) in rat (n = 9/group), values being 78% in controls, 100% in 0.3 μm‐treated hearts and 78% in 1.0 μm‐treated hearts (NS). UK66,914 also had no effect on reperfusion‐induced VF incidence (100% in each group), nor on the latency to onset of ischaemia‐ or reperfusion‐induced arrhythmias. In contrast, in rabbit (n = 13/group), similar concentrations of drug reduced the incidence of reperfusion‐induced VF from 77% in controls, to 38% and 31% (P < 0.05) respectively. The incidence of ischaemia‐induced arrhythmias was too low in controls to permit detection of an antiarrhythmic effect in rabbit; however no drug‐induced proarrhythmia was seen.
QT interval was not affected by UK66,914 in rat (NS), values (mean ± s.e.mean) being 114 ± 8, 121 ± 8, and 113 ± 6 ms in control, 0.3 and 1 μm groups respectively, 10 min after the onset of ischaemia. However, in the rabbit the same concentrations of UK66,914 produced concentration‐dependent widening of QT interval, values being 172 ± 14, 194 ± 9 (NS) and 233 ± 18 ms (P < 0.05), with increasing concentrations of drug, 10 min after the onset of ischaemia.
UK66,914 had no substantial effects on haemodynamics (heart rate, coronary flow or recovery of flow during reperfusion), at either concentration, in either species. Occluded zones sizes were similar with increasing concentrations of drug in rat (42 ± 4, 40 ± 2 and 40 ± 2% of total ventricular weight) and rabbit (46 ± 2, 43 ± 2 and 46 ± 3%). Thus, the species‐dependent antiarrhythmic effects of UK66,914 were not attributable to differences in these variables.
In conclusion, the rat versus rabbit data indicate that for UK66,914 to inhibit ventricular arrhythmias associated with reperfusion, IK blockade is sufficient and necessary. The rat data indicate that no antiarrhythmic effects occur with the drug during ischaemia when there is no scope for IK blockade. Whilst other mechanisms may be unlikely to be involved, they cannot be excluded completely. Together the rat and rabbit studies indicate that the antiarrhythmic effects of UK66,914 during ischaemia and reperfusion are adequately explained by IK blockade.
Differential sensitivity of antinociceptive assays to the bradykinin antagonist Hoe 140
Authors: Heapy Christopher G. , Shaw John S. , Farmer Susannah C. 
Published: July 2012

The antinociceptive activity of the bradykinin (BK) BK2 receptor antagonist d‐Arg‐[Hyp3,Thi5,d‐Tic7,Oic8]BK (Hoe 140) was determined in a range of mouse abdominal constriction assays.
Hoe 140 potently inhibited the response induced by i.p. injection of 10 μg BK/mouse, and 1 μg BK/mouse in mice pre‐sensitized by i.p injection of prostaglandin E2 (PGE2). The ED50 values in these assays were 1.9 and 3.7 μg kg−1 respectively. This confirms that Hoe 140 is a potent antagonist of BK in vivo.
Hoe 140 produced potent, but incomplete inhibition of the responses evoked by i.p injection of kaolin or 0.25% acetic acid. ED25 values in these assays were 2.7 and 16.1 μg kg−1, and the maximum inhibition produced was 60% and 70% respectively.
At doses up to 1 mg kg−1, Hoe 140 was completely ineffective against the abdominal constriction response induced by zymosan. In contrast, morphine, ibuprofen and indomethacin had similar potencies against zymosan, kaolin and acetic acid‐induced abdominal constriction.
Although zymosan, acetic acid and kaolin all produce qualitatively similar responses, it is appears that they achieve this by different mechanisms. The extent to which BK is involved as a mediator differs between the various types of abdominal constriction assay.
Inhibitors of nitric oxide synthetase prevent castor‐oil‐induced diarrhoea in the rat
Authors: Mascolo N. , Izzo A.A. , Barbato F. , Capasso F. 
Published: July 2012

Castor oil (2 ml orally) produced copious diarrhoea in rats 3 h after its administration.
Pretreatment (intraperitoneal, i.p.) of rats with the NO synthesis inhibitors NG‐nitro‐l‐arginine methyl ester (l‐NAME, 1–25 mg kg−1) and NG‐monomethyl‐l‐arginine (l‐NMMA, 2.5–100 mg kg−1) inhibited or prevented castor‐oil‐induced diarrhoea. l‐Arginine (150–600 mg kg−1, i.p.) administered to rats pretreated with l‐NAME 10 mg kg−1, drastically reduced the antidiarrhoeal activity of l‐NAME in a dose‐related manner. d‐Arginine (900 mg kg−1) did not modify the protection by l‐NAME.
Pretreatment (i.p.) of rats with l‐NAME (2.5–25 mg kg−1) decreased the intestinal fluid accumulation and Na+ secretion induced by castor oil. l‐Arginine (600 mg kg−1) but not d‐arginine (900 mg kg−1) counteracted the inhibitory effect of l‐NAME (10 mg kg−1).
l‐NAME (10 and 25 mg kg−1) had no significant effect on the intestinal transit in normal rats or those given castor oil.
These results provide evidence that nitric oxide (NO) could play an important role in castor‐oil‐induced diarrhoea.
Renal imidazoline preferring sites and solute excretion in the rat
Authors: Allan D.R. , Penner S.B. , Smyth D.D. 
Published: July 2012

Moxonidine has been found to have an approximately 600 fold greater affinity for I1 imidazoline preferring sites as compared to α2‐adrenoceptors in the rat kidney. The effects of an intrarenal infusion of moxonidine in an anaesthetized rat preparation were investigated and contrasted with the effects previously reported for α2‐adrenoceptor stimulation.
An intrarenal infusion of moxonidine (1, 3 and 10 nmol kg−1 min−1) produced an increase in urine flow rate and sodium excretion. Moxonidine increased urine volume through an increase in osmolar clearance rather than an increase in free water clearance as previously reported for α2‐adrenoceptor stimulation.
The effects of moxonidine also appeared to be unique from the effects of α2‐adrenoceptor stimulation. An imidazoline preferring site specific blocking dose of idazoxan (0.3 mg kg−1), but not an α2‐adrenoceptor specific blocking dose of rauwolscine (0.3 mg kg−1) attenuated the renal effects of moxonidine (3 nmol kg−1 min−1). Moreover, unlike α2‐adrenoceptor agonists, the effects of moxonidine were not altered by prior treatment with a V2 vasopressin receptor antagonist.
These results indicate differences between stimulation of α2‐adrenoceptors and I1 imidazoline preferring sites in the rat kidney and suggest a direct physiological function of renal imidazoline preferring sites.
Redirection of arachidonic acid metabolism by ICI D1542: effects on thrombus formation in the coronary artery of the anaesthetized dog
Authors: McAuliffe S.J.G. , Moors J.A. , Snow H.M. , Wayne M. , Jessup R. 
Published: July 2012

The effects of simultaneous redirection of arachidonic acid metabolism, by inhibition of thromboxane A2 (TXA2) synthase and blockade of the platelet thromboxane A2 receptor (TP‐receptor), was examined on the rate of thrombus formation in a stenosed coronary artery with damaged endothelium in an anaesthetized dog.
Redirection of arachidonic acid metabolism was achieved by intravenous doses of ICI D1542, a selective and potent inhibitor of TXA2 synthase and the TP‐receptor.
Redirection of arachidonic acid metabolism was demonstrated in whole blood, stimulated ex vivo by collagen. The ED50 for inhibition of TXB2 production was 7.1 μg kg−1, i.v.; there were corresponding increases in the production of the eicosanoids prostaglandin D2 (PGD2), PGE2 and PGF2α.
Thrombus formation was inhibited by D1542 (ED50 0.55 μg kg−1, i.v.), but could be restarted by an intravenous infusion of adrenaline (0.2–38 μg kg−1 min−1, i.v.). In the presence of the maximum effective dose of D1542 (1 mg kg−1, i.v.) a 190 fold increase in the infusion rate of adrenaline was required to restore thrombus formation.
In the presence of D1542, removal of endoperoxide metabolites by inhibition of cyclo‐oxygenase with aspirin (5 mg kg−1, i.v.) caused thrombus formation to restart, indicating the ability of the endoperoxide metabolites to inhibit thrombus formation in vivo.
These results indicate that, in the stenosed and damaged coronary artery of the dog, redirection of arachidonic acid metabolism by D1542 is more effective at preventing thrombus formation than inhibition of cyclo‐oxygenase by aspirin.
The spinal antinociceptive activity of the α2‐adrenoceptor agonist, xylazine in sheep
Authors: Kyles A.E. , Waterman A.E. , Livingston A. 
Published: July 2012

The intrathecal administration of xylazine (100 μg), via a chronic indwelling, cervical intrathecal catheter, produced a marked elevation of the mechanical nociceptive thresholds in the sheep. This antinociceptive effect was abolished by the prior intrathecal administration of the α2‐adrenoceptor antagonist, idazoxan.
The intrathecal administration of the selective α2‐antagonists, idazoxan (100 μg) and RX811059 (33 μg), significantly attenuated the antinociceptive activity of intravenous xylazine, with a 60–65% reduction in the area under the antinociceptive curve. The intrathecal administration of the antagonists alone had no significant effect on nociceptive thresholds.
Examination of the distribution of tritiated idazoxan (25 μCi in 100 μl) indicated that the site of action of the drug was limited to the cervical spinal cord after intrathecal administration.
These studies demonstrate that a significant proportion of the antinociceptive effect of systemically administered xylazine is mediated by spinal α2‐adrenoceptors.
Quinapril treatment and arterial smooth muscle responses in spontaneously hypertensive rats
Authors: Arvola Pertti , Ruskoaho Heikki , Wuorela Heikki , Pekki Anu , Vapaatalo Heikki , Pörsti Ilkka 
Published: July 2012

The effects of long‐term angiotensin‐converting enzyme inhibition with quinapril on arterial function were studied in spontaneously hypertensive rats, Wistar‐Kyoto rats serving as normotensive controls.
Adult hypertensive animals were treated with quinapril (10 mg kg−1 day−1) for 15 weeks, which reduced their blood pressure and the concentrations of atrial natriuretic peptide in plasma and ventricular tissue to a level comparable with that in normotensive rats.
Responses of mesenteric arterial rings in vitro were examined at the end of the study. Compared with normotensive and untreated hypertensive rats, responses to noradrenaline were attenuated in hypertensive animals on quinapril, both force of contraction and sensitivity being reduced. Quinapril also attenuated maximal contractions but not sensitivity to potassium chloride. Nifedipine less effectively inhibited vascular contractions in normotensive and quinapril‐treated than in untreated hypertensive rats.
Arterial relaxation responses by endothelium‐dependent (acetylcholine) and endothelium‐independent (sodium nitrite, isoprenaline) mechanisms were similar in normotensive and quinapril‐treated rats and more pronounced than in untreated hypertensive rats.
Cell membrane permeability to ions was evaluated by means of potassium‐free solution‐induced contractions of endothelium‐denuded denervated arterial rings. These responses were comparable in normotensive and quinapril‐treated rats and less marked than in untreated hypertensive rats.
Intracellular free calcium concentrations in platelets and lymphocytes, measured by the fluorescent indicator quin‐2, were similar in normotensive and quinapril‐treated rats and lower than in untreated hypertensive rats.
In conclusion, quinapril treatment improved relaxation responses and attenuated contractions in arterial smooth muscle of hypertensive rats. These changes may be explained by diminished cytosolic free calcium concentration, reduced cell membrane permeability, and alterations in dihydropyridine‐sensitive calcium channels following long‐term angiotensin‐converting enzyme inhibition.
Effects of dicentrine on haemodynamic, plasma lipid, lipoprotein level and vascular reactivity in hyperlipidaemic rats
Authors: Yu Sheu‐Meei , Kang Ya‐Fei , Chen Chien‐Chih , Teng Che‐Ming 
Published: July 2012

The effects of dicentrine on haemodynamic, plasma lipid, lipoprotein level and vascular reactivity were investigated in Wistar‐Kyoto (WKY) and spontaneously hypertensive (SH) rats, fed a high fat‐high cholesterol diet.
In high fat‐high cholesterol (HF‐HC) diet fed WKY and SH rats, oral administration of dicentrine (5 and 10 mg kg−1, twice a day) for 4 weeks caused significant reductions in total plasma cholesterol (CE) by reducing the low density lipoprotein (LDL) fraction, and reductions in total plasma triglyceride (TG) by reducing the very low density lipoprotein (VLDL) fraction.
Dicentrine therapy was associated with increased high density lipoprotein (HDL)‐cholesterol levels; thus the ratio of total plasma cholesterol to HDL‐cholesterol was improved.
In HF‐HC diet fed conscious WKY and SH rats, oral administration of dicentrine (5 and 10 mg kg−1, twice a day) also evoked dose‐related decreases in mean arterial pressure (MAP) which were of greater magnitude in SH rats. Neither dose of dicentrine caused a significant change in heart rate (HR).
The aortic arches from SH rats fed the HF‐HC diet for 8 weeks were significantly more affected by the atherosclerotic lesions than the abdominal aortae and renal arteries of WKY and SH rats. Oral administration of dicentrine (5 and 10 mg kg−1) for 4 weeks did not diminish the atherosclerotic lesion areas in WKY and SH rats.
In aortae of the hyperlipidaemic rats, significantly attenuated EC50 values and augmented maximal responses for phenylephrine‐induced contraction were obtained. Endothelium‐dependent relaxation to acetylcholine was abolished, while endothelium‐independent relaxation to nitroprusside was well preserved. Dicentrine therapy caused significantly augmented EC50 values and attenuated maximal responses for phenylephrine‐induced contraction in hyperlipidaemic rats. However, dicentrine neither prevented the impaired relaxation to acetylcholine, nor affected the relaxation to nitroprusside during atherosclerosis progression.
It is concluded that dicentrine decreases MAP, plasma CE, LDL‐CE, plasma TG, VLDL‐TG, vascular hyperreactivity to phenylephrine and increases HDL‐CE levels. Dicentrine may thus hold potential for the reduction of two of the major risk factors, hypertension and hyperlipidaemia, for cardiovascular disease.
Cellular mechanism of U78517F in the protection of porcine coronary artery endothelial cells from oxygen radical‐induced damage
Authors: Maeda Kaori , Kimura Masaaki , Hayashi Shigehiro 
Published: July 2012

The aim of this study was to clarify the role of lipid peroxidation in cellular injury as assessed by lactate dehydrogenase (LDH) release from cultured coronary artery endothelial cells of the pig. Cells exposed to H2O2 at concentrations of 0.1 to 20 mm or to a xanthine and xanthine oxidase (X/XO) reaction mixture released LDH into the medium. Significant release from X/XO‐treated cells took place with a delay of 2 h.
Superoxide dismutase (SOD), catalase or dimethylthiourea attenuated the release of LDH from X/XO‐treated cells. Similarly the putative inhibitor of lipid peroxidation, U78517F attenuated the release of LDH by X/XO with an IC50 of 0.08 μm.
H2O2 was continuously produced by the addition of X/XO to the medium alone. However, in the presence of endothelial cells, H2O2 was eliminated at 1 h. U78517F had no effect on either process.
The oxygen radical‐induced release of LDH was associated with malondialdehyde (MDA) formation. U78517F inhibited the formation of MDA with an IC50 of 0.27 μm.
Reduction of the Ca2+ concentration in the incubation medium from 1.6 mm to 0.016 mm markedly attenuated the release of LDH from endothelial cells. Nifedipine (1 μm) did not attenuate the LDH release from the cells.
It is likely that porcine coronary artery endothelial cells can be thus injured by oxygen radicals presumably through hydroxyl radicals formed and consequent lipid peroxidation, and that the extracellular Ca2+ concentration plays an important role in the genesis of such endothelial cell damage.
Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide
Authors: Semba Jun'ichi , Curzon Gerald Curzon , Patsalos Philip N. 
Published: July 2012

The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter‐relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats.
Milacemide dose‐dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug.
Pretreatment with l‐deprenyl (2 mg kg−1), a specific inhibitor of monoamine oxidase type B (MAO‐B), almost completely prevented the formation of glycinamide and increased milacemide accumulation in CSF. Tmax and t1/2 were significantly increased and Cmax and AUC values were decreased for glycinamide compared to controls. Pretreatment with clorgyline (5 mg kg−1), a specific inhibitor of MAO‐type A, only moderately decreased glycinamide Cmax and AUC values.
After milacemide administration (100, 200 and 400 mg kg−1, i.p.) serum and CSF milacemide concentrations rose linearly and dose‐dependently. Serum glycinamide concentrations exhibited small dose‐dependent rises but these were not linearly related. In contrast, CSF glycinamide concentrations rose linearly and dose‐dependently with Cmax values 2.5, 3.2 and 4.1 times greater than the corresponding values for serum glycinamide after giving 100, 200 and 400 mg kg−1 respectively of milacemide.
Serum glycine concentrations were unaffected but CSF concentrations increased dose‐dependently and these were significant at the higher milacemide doses (200 and 400 mg kg−1). Animals given 400 mg kg−1 milacemide had glycine values which were still significantly elevated 7 h later.
In conclusion, serum milacemide rapidly enters and equilibrates with the CNS compartment where it is metabolised primarily by MAO‐B to glycinamide and finally to glycine. Metabolism in the peripheral compartment is negligible.
Endothelin‐3‐induced relaxation of rat thoracic aorta: a role for nitric oxide formation
Authors: Moritoki Hideki , Miyano Hiroaki , Takeuchi Shougo , Yamaguchi Mari , Hisayama Tetsuhiro , Kondoh Wataru 
Published: July 2012

Endothelin‐3 (ET‐3) at concentrations below those which caused contraction (30 nm) elicited endothelium‐dependent relaxation followed by rebound contraction in rat isolated thoracic aorta.
Endothelin‐1 also relaxed the rat aorta with a similar potency.
The nitric oxide (NO) synthase inhibitor, NG‐nitro l‐arginine, the radical scavenger, haemoglobin and the soluble guanylate cyclase inhibitor, methylene blue, each inhibited the ET‐3‐induced relaxation.
The calmodulin inhibitor, calmidazolium, considerably attenuated the relaxation caused by ET‐3 without affecting that to nitroprusside.
Concentrations of ET‐3 that were necessary to induce the relaxation also caused concentration‐dependent elevation of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels.
NG‐nitro l‐arginine, haemoglobin, methylene blue, calmidazolium and removal of the endothelium completely abolished ET‐3‐stimulated cyclic GMP production.
These results suggest that ET‐3 triggers NO formation possibly via ETB receptors on the endothelium to activate soluble guanylate cyclase, which in turn stimulates cyclic GMP production and smooth muscle relaxation. The enzyme contributing to the NO formation may be of the calcium/calmodulin‐dependent, constitutive type.
Effects of phospholipase A2 inhibitors on coupling of α2‐adrenoceptors to inwardly rectifying potassium currents in guinea‐pig submucosal neurones
Authors: Evans R.J. , Surprenant A. 
Published: July 2012

Noradrenaline hyperpolarizes guinea‐pig submucosal neurones by opening inwardly rectifying potassium channels. Intracellular recordings were made from submucosal neurones and the possible involvement of the phospholipase A2 pathway in this response was examined.
The non‐specific phospholipase A2 inhibitors, quinacrine (10 μm) and 4‐bromophenacyl bromide (4‐BPB, 10 μm) inhibited nerve‐evoked inhibitory synaptic potentials (i.p.s.ps) and hyperpolarizations to somatostatin and UK 14304. Quinacrine and 4‐BPB also blocked the inward rectification present in current‐voltage curves in the absence of somatostatin or UK 14304.
The more selective phospholipase A2 inhibitor, cyclosporin A (10 μm) and the lipoxygenase and cyclo‐oxygenase inhibitor, eicosatetraynoic acid (ETYA, 20 μm) and nordihydroguairetic acid (NDGA, 20 μm) did not alter i.p.s.ps or hyperpolarizations to UK 14304.
Exogenously applied arachidonic acid (1–300 μm) did not mimic the i.p.s.p. or the hyperpolarization to UK 14304.
We conclude that arachidonic acid or its eicosanoid metabolites produced by phospholipase A2 stimulation are unlikely to be involved in the receptor G‐protein coupled activation of potassium currents in submucosal neurones. The inhibition of the noradrenaline‐induced hyperpolarization by quinacrine and 4‐BPB is most likely due primarily to blockade of the basal inwardly rectifying potassium conductance present in these neurones.
Monocrotaline pyrrole‐induced changes in angiotensin‐converting enzyme activity of cultured pulmonary artery endothelial cells
Authors: Hoorn Cindy M. , Roth Robert A. 
Published: July 2012

Changes in the structural and functional integrity of endothelium have been recognized as relatively early features of delayed and progressive pulmonary vascular injury caused by the pyrrolizidine alkaloid, monocrotaline (MCT). Although a number of investigators have evaluated angiotensin‐converting enzyme (ACE) activity in the lungs of rats treated with MCT, the exact nature of changes in activity of this enzyme and the role they may play in MCT pneumotoxicity remain controversial.
We examined the direct effects of monocrotaline pyrrole (MCTP), a toxic metabolite of MCT, on cultured endothelial cell ACE activity. Post‐confluent monolayers of porcine or bovine pulmonary artery endothelial cells (PECs or BECs, respectively) were treated with a single administration of MCTP at time 0; then they were examined for their ability to degrade the synthetic peptide, [3H]‐benzoyl‐Phe‐Ala‐Pro.
In PECs, which are relatively insensitive to the direct cytolytic effects of MCTP, monolayer ACE activity was unchanged initially but gradually decreased within 4 days after treatment with a high concentration of MCTP (150 μm). This decrease was transient, and PEC monolayer ACE activity returned to the control value by 10 days post treatment.
BEC monolayer ACE activity was also unchanged initially but rapidly declined within 4 days after MCTP treatment and remained depressed throughout the post treatment period. BECs were quite sensitive to the cytolytic effects of MCTP and the decline in ACE activity occurred coincident with the decrease in monolayer cellularity and appearance of marked cytotoxicity.
We conclude that high concentrations of MCTP decrease endothelial ACE activity. The decline in ACE activity is delayed and the magnitude and duration of the decrease corresponds to the degree of MCTP‐induced cytotoxicity. This suggests that altered endothelial ACE activity is unlikely to be a direct effect of MCTP on the enzyme but may reflect the delayed cell injury which results from exposure to this compound.