bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spontaneous release of large packets of noradrenaline from sympathetic nerve terminals in rat mesenteric arteries in vitro
Authors: Brock James A , Dunn William R , Boyd Nicola S F , Wong Danny K Y 
Published: January 2005

Continuous amperometry was used to monitor noradrenaline (NA) release from sympathetic nerves supplying rat mesenteric arteries in vitro. During electrical stimulation the amplitude of oxidation currents evoked by successive stimuli varied over a small range, with occasional events of larger amplitude. In the absence of stimulation, spontaneous oxidation currents (s.o.cs) were recorded. The frequency of s.o.cs was increased by α‐latrotoxin (1 nM). This agent also increased the frequency of spontaneous excitatory junction potentials (s.e.j.ps), which monitor the packeted release of adenosine 5′ triphosphate (ATP). The frequency of s.o.cs recorded 20–25 min after applying α‐latrotoxin was about four times the control value, but that of s.e.j.ps was about 30 times the control value. The findings suggest that continuous amperometry can detect the spontaneous packeted release of NA, probably from large dense‐cored vesicles. In contrast, s.e.j.ps monitor spontaneous release of neurotransmitter (ATP) from a different store, most likely the small dense‐cored vesicles.British Journal of Pharmacology (2000) 131, 1507–1511; doi:10.1038/sj.bjp.0703733
Effect of protease‐activated receptor (PAR)‐1, −2 and −4‐activating peptides, thrombin and trypsin in rat isolated airways
Authors: Chow Jean M , Moffatt James D , Cocks Thomas M 
Published: January 2005

Mechanisms of relaxation and contraction to protease‐activated receptor‐ (PAR) tethered ligand peptides (SFLLRN/TFLLR, SLIGRL and GYPGKF (all C‐terminally amidated) for PAR1, PAR2 and PAR4, respectively) and enzymes (thrombin and trypsin) were investigated in isolated segments of rat trachea, main and first order intrapulmonary bronchi.
In airway segments previously exposed to SLIGRL, SFLLRN caused contractions that were potentiated by indomethacin, but were independent of mast cell degranulation. Contractions to TFLLR in the intrapulmonary bronchi were similarly potentiated by indomethacin.
SLIGRL caused epithelium‐dependent relaxations which were unaffected by NG‐nitro‐L‐arginine, 1‐H‐oxodiazol‐[1,2,4]‐[4,3‐a]quinoxaline‐1‐one or zinc‐protoporphyrin‐IX but were abolished by haemoglobin in all three regions of the airways. Relaxations to SLIGRL were markedly attenuated by indomethacin only in the main and intrapulmonary bronchi.
GYPGKF caused epithelium‐dependent relaxations in all three regions of the airway which were only significantly inhibited by indomethacin in the intrapulmonary bronchi.
In general, thrombin and trypsin failed to cause any response in the airways tested.
Intense PAR2‐immunoreactivity was observed on airway epithelium. PAR1‐immunoreactivity was faint on airway epithelium and smooth muscle, but was prevalent in mast cells.
These findings indicate that PAR2 and possibly PAR4 present on rat airway epithelia mediate smooth muscle relaxation via cyclo‐oxygenase‐dependent and ‐independent mechanisms. PAR1‐mediated contractions were most likely due to activation of smooth muscle receptors. The general failure of thrombin and trypsin to cause responses which may have been due to endogenous protease inhibitors, highlights the need for caution in assessing pathophysiological roles for PARs if only enzymes are used to activate PARs.

British Journal of Pharmacology (2000) 131, 1584–1591; doi:10.1038/sj.bjp.0703738
Angiotensin‐converting enzyme (ACE) inhibition attenuates insulin‐like growth factor‐I (IGF‐I) induced cardiac fibroblast proliferation
Authors: Van Eickels Martin , Vetter Hans , Grohé Christian 
Published: January 2005

The effects of angiotensin‐converting enzyme (ACE) inhibition and angiotensin type 1 (AT1) receptor blockade on insulin‐like growth factor‐I (IGF‐I) induced proliferation and immediate‐early‐gene expression of neonatal rat cardiac fibroblasts were investigated. Moreover the role of the IGF‐I receptor (IGF‐IR) in this process was evaluated.
IGF‐I (10−9–10−7 M) stimulated neonatal rat cardiac fibroblast growth in a dose‐dependent fashion (maximum: 3.5±0.1 fold, 10−7 M), as determined by 5‐bromo‐2′‐deoxyuridine (BrdU) incorporation. ACE inhibition or AT1 receptor blockade attenuated the IGF‐I (10−7 M) induced neonatal rat cardiac fibroblast growth in a concentration‐dependent fashion (moexiprilat: 50±2%, enalaprilat: 31±2%, CV11974; 58±1%, all: 10−7 M).
IGF‐I stimulated cellular growth was accompanied by an upregulation of the immediate early genes c‐Fos (2.4±0.3 fold), Egr‐1 (4.7±1.1 fold) and Sp1 (6.2±0.7 fold). IGF‐I induced expression was completely inhibited by ACE inhibition or AT1 receptor blockade.
Stimulation with IGF‐I or Ang II (10−7 M) increased IGF‐IR expression 5.7±0.5 fold and 3.6±0.5 fold respectively. The IGF‐I induced overexpression of the IGF‐IR was reduced by ACE inhibition with moexiprilat (10−7 M) by 79±7% and by AT1 receptor blockade with CV11974 (10−7 M) by 79±5%.
These data demonstrate that the mitogenic action of IGF‐I in neonatal rat cardiac fibroblasts is in part mediated by activation of the renin‐angiotensin system (RAS) with subsequent upregulation of IGF‐IR expression. This observation has important implications for the treatment of cardiac diseases with ACE inhibitors alone and their combination with IGF‐I or growth hormone.

British Journal of Pharmacology (2000) 131, 1592–1596; doi:10.1038/sj.bjp.0703740
Lack of run‐down of smooth muscle P2X receptor currents recorded with the amphotericin permeabilized patch technique, physiological and pharmacological characterization of the properties of mesenteric artery P2X receptor ion channels
Authors: Lewis C J , Evans R J 
Published: January 2005

Immunoreactivity for P2X1, P2X4 and P2X5 receptor subtypes was detected in the smooth muscle cell layer of second and third order rat mesenteric arteries immunoreactivity, for P2X2, P2X3, P2X6 and P2X7 receptors was below the level of detection in the smooth muscle layer.
P2X receptor‐mediated currents were recorded in patch clamp studies on acutely dissociated mesenteric artery smooth muscle cells. Purinergic agonists evoked transient inward currents that decayed rapidly in the continued presence of agonist (τ∼200 ms). Standard whole cell responses to repeated applications of agonist at 5 min intervals ran down. Run‐down was unaffected by changes in extracellular calcium concentration, intracellular calcium buffering or the inclusion of ATP and GTP in the pipette solution.
Run‐down was overcome and reproducible responses to purinergic agonists were recorded using the amphotericin permeabilized patch recording configuration.
The rank order of potency at the P2X receptor was ATP=2 methylthio ATP>α,β‐methylene ATP>CTP=l‐β,γ‐methylene ATP. Only ATP and 2meSATP were full agonists. The P2 receptor antagonists suramin and PPADS inhibited P2X receptor‐mediated currents with IC50s of 4 μM and 70 nM respectively.
These results provide further characterization of artery P2X receptors and demonstrate that the properties are dominated by a P2X1‐like receptor phenotype. No evidence could be found for a phenotype corresponding to homomeric P2X4 or P2X5 receptors or to heteromeric P2X1/5 receptors and the functional role of these receptors in arteries remains unclear.

British Journal of Pharmacology (2000) 131, 1659–1666; doi:10.1038/sj.bjp.0703744
Relationships between the Na+/K+ pump and ATP and ADP content in mouse pancreatic islets: effects of meglitinide and glibenclamide
Authors: Elmi Adrian , Idahl Lars‐Åke , Sehlin Janove 
Published: January 2005

We have previously demonstrated that both D‐glucose and glibenclamide stimulate the Na+/K+ pump and suggested that this may be part of the membrane repolarization process, following the primary depolarization by these agents. The aim of this study was to investigate whether the non‐sulphonylurea meglitinide (HB 699) exerts similar effects as glibenclamide or glucose on the islet Na+/K+ pump and if effects of meglitinide or glibenclamide on this pump activity is paralleled by changes in islet ATP content and/or ATP/ADP ratio.
The acyl‐amino‐alkyl benzoic acid derivative, meglitinide, stimulated the islet ouabain‐sensitive portion of 86Rb+ influx (Na+/K+ pump) by 53%, while the ouabain‐resistant portion was inhibited by 70%. The stimulatory effect was not additive to that caused by D‐glucose, suggesting that both agents may activate the Na+/K+ pump via the same mechanism.
Glibenclamide (10 μM) decreased the islet ATP and ADP content as well as the ATP/ADP ratio at 0 mM glucose. These effects were no longer observed at 10 mM glucose.
Meglitinide (10 or 50 μM) lowered the islet ATP and ADP content at 0 mM glucose without affecting the ATP/ADP ratio. At 10 mM glucose, however, 10 μM of the drug reduced the islet ATP content but not the ATP/ADP ratio, while 50 μM of the drug, besides lowering the ATP content, also reduced the ATP/ADP ratio.
Diazoxide (0.5 mM) increased the islet ATP content in the absence of glucose, an effect not seen in the presence of 10 mM glucose.
The rate of glucose oxidation at 1, 10 or 20 mM of the sugar was not affected by glibenclamide (0.1–10 μM) and at 10 or 20 mM of the sugar not affected by meglitinide (1–100 μM).
These results suggest that glibenclamide and meglitinide lower the islet ATP level by indirectly activating the β‐cell Na+/K+ pump, which is a major consumer of ATP in the islets, while diazoxide increases the ATP level due to inhibition of the pump.

British Journal of Pharmacology (2000) 131, 1700–1706; doi:10.1038/sj.bjp.0703745
Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase‐inhibitor
Authors: Hamada Tetsuo , Arima Nobuyuki , Shindo Miki , Sugama Kazushige , Sasaguri Yasuyuki 
Published: January 2005

BAY 12‐9566 (4‐[4‐(chlorophenyl)phenyl]‐4‐oxo‐2S‐(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that selectively inhibits MMP‐2, MMP‐3 and MMP‐9 isozymes. We study the effect of BAY 12‐9566 on inflammation and cartilage destruction in adjuvant‐induced arthritis (AA) in rats.
Rats were injected with adjuvant and treated for 21 days with vehicle, Indomethacin or BAY 12‐9566. AA was assessed: by measuring arthritic index, paw volume, urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr); by examining joint inflammation; and by microscopic morphometry of articular cartilages.
Oral treatment of rats for 22 days with 50 mg kg−1 body weight/d BAY 12‐9566 showed decreased AA as determined by improvement in body weight gain (P<0.01), arthritic index (P<0.05) and swelling of paws contralateral to the adjuvant injection site (P<0.05). Neutrophil infiltration and collagen degradation were also significantly lower (P<0.01) in this treatment group. Cartilage destruction was successfully suppressed (P<0.01) in rats treated with either 50 mg kg−1 body weight/d BAY 12‐9566 or 1 mg kg−1 body weight/d Indomethacin.
These results indicate that BAY 12‐9566 successfully suppressed inflammation and cartilage destruction in rats with AA. Moreover, these results also suggested that MMP‐2, MMP‐3 and MMP‐9 are involved in arthritic diseases such as rheumatoid arthritis.

British Journal of Pharmacology (2000) 131, 1513–1520; doi:10.1038/sj.bjp.0703751
Mechanisms of vasorelaxation induced by eicosapentaenoic acid (20:5n‐3) in WKY rat aorta
Authors: Engler Mary B , Engler Marguerite M , Browne Amanda , Sun Yi‐Ping , Sievers Richard 
Published: January 2005

The vasorelaxant activity of eicosapentaenoic acid (EPA, 20:5n‐3), the omega‐3 polyunsaturated fatty acid, was investigated in isolated Wistar Kyoto (WKY) rat aortae by measuring isometric tension.
Eicosapentaenoic acid (1–100 μM) relaxed rat aortae contracted with high K+ (80 mM) or noradrenaline (NA, 1 μM) in a concentration‐dependent manner. Contractions induced by Bay K 8644 or increasing concentrations of calcium were unaffected by EPA.
The relaxant effect of EPA (3–100 μM) was significantly inhibited by indomethacin (10 μM), the cyclo‐oxygenase inhibitor, but not by the nitric oxide (NO) synthesis inhibitor, Nω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME, 100 μM). Removal of the endothelium did not alter EPA‐induced relaxations.
In Ca2+‐free, EGTA 2 mM solution, EPA (10–30 μM significantly inhibited NA‐sustained contractions. Incubation with EPA (5, 10 μM) diminished both NA‐induced (1 μM) phasic and sustained contractions.
The vasorelaxant effects of EPA (30 μM) on NA‐induced (1 μM) contractions were significantly inhibited by the K+ channel blocker, glibenclamide (10 μM), but not tetraethylammonium (1 mM). Moreover, indomethacin and glibenclamide combined significantly inhibited EPA‐induced (1–100 μM) responses.
These results indicate EPA exerts its endothelium‐independent vasorelaxant effects in WKY rat aortae through production of prostanoids which activate K+ATP channels. Inhibition of Ca2+ mobilization from intracellular pools and influx through the non‐L‐type, but not the L‐type, Ca2+ channel are also possible mechanisms action of EPA's.

British Journal of Pharmacology (2000) 131, 1793–1799; doi:10.1038/sj.bjp.0703754
Ivermectin excretion by isolated functionally intact brain endothelial capillaries
Authors: Nobmann Stephanie , Bauer Björn , Fricker Gert 
Published: January 2005

Functionally intact brain endothelial capillaries were isolated from porcine brain. p‐Glycoprotein was localized at the lumenal membrane of intact capillaries by immunohistochemistry using a murine monoclonal antibody and a secondary FITC fluorescent labelled anti‐mouse IgG. Western blot staining of p‐glycoprotein in isolated endothelial cells confirmed the immunohistochemistry.Excretion of the fluorescent labelled anthelmintic drug Ivermectin (BODIPY‐Ivermectin) was studied in the isolated brain endothelial capillaries. Drug accumulation in the capillary lumen was visualized by fluorescence confocal laser scanning microscopy and was measured by image analysis. Secretion of BODIPY‐Ivermectin into the capillary lumen exhibited characteristics of specific and energy‐dependent transport. Steady state lumenal fluorescence intensity averaged 1.6 times cellular fluorescence and was reduced 3 – 4 times below cellular levels when metabolism was inhibited by NaCN.BODIPY‐Ivermectin secretion was inhibited in a concentration‐dependent manner by unlabeled Ivermectin. In addition, lumenal but not cellular fluorescence intensity was significantly decreased when capillaries were incubated with PSC‐833, Cyclosporin A or Verapamil, all inhibitors of p‐glycoprotein. Conversely, unlabelled Ivermectin reduced the p‐glycoprotein (Pgp)‐mediated secretion of a fluorescent derivative of Verapamil, (BODIPY‐Verapamil).BODIPY‐Ivermectin secretion was not affected in the presence of Leucotriene C4(LTC4), a potent inhibitor of multidrug resistance related protein (mrp)‐mediated transport processes. In addition, excretion of Fluorescein‐Methotrexate, an mrp‐substrate, was not inhibited by Ivermectin.Uptake experiments with isolated porcine brain capillary cells showing increased cellular uptake of BODIPY‐Ivermectin in the presence of unlabelled drug or PSC‐833 supported the findings of a Pgp interaction in intact capillaries.The data are consistent with BODIPY‐Ivermectin and Ivermectin being transported across the lumenal membrane of brain capillaries. For the first time Pgp‐interaction of Ivermectin at the blood brain barrier is demonstrated on a cellular level in an intact vascular tissue.British Journal of Pharmacology(2001)132, 722–728; doi:10.1038/sj.bjp.0703762
Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome
Authors: Studenik Christian R , Zhou Zhengfeng , January Craig T 
Published: January 2005

Long OT syndrome has many causes from both acquired and congenital disorders. For the congenital disorders, their presentation and disease course are not identical. We studied two pharmacological models of long QT syndrome (LQT) to identify differences in cellular electrophysiological properties that may account for this. LQT2 was simulated by suppression of the rapidly activating delayed rectifier potassium current (IKr) with the drug E‐4031, and LQT3 was simulated by slowing of the sodium current (INa) decay with the toxin ATX II.
Single rabbit ventricular cell action potentials were studied using the amphotericin B perforated patch clamp technique. Action potential and early afterdepolarization (EAD) properties were rigorously defined by the frequency power spectra obtained with fast Fourier transforms.
The E‐4031 (n=43 myocytes) and ATX II (n=50 myocytes) models produced different effects on action potential and EAD properties. The major differences are that ATX II, compared with E‐4031, caused greater action potential prolongation, more positive plateau voltages, lower amplitude EADs with less negative take‐off potentials, greater time to the EAD peak voltage, and longer duration EADs. Despite causing greater action potential prolongation, the incidence of EAD induction was much less with the ATX II model (28%) than with the E‐4031 model (84%). Thus these two pharmacological models have strikingly different cellular electrophysiological properties.
Our findings provide cellular mechanisms that may account for some differences in the clinical presentation of LQT2 and LQT3.

British Journal of Pharmacology (2001) 132, 85–92; doi:10.1038/sj.bjp.0703770
Combined blockade of endothelin‐1 and thromboxane A2 receptors against postischaemic contractile dysfunction in rat hearts
Authors: Hornstein Pius S , Zaugg Christian E , Zhu Peili , Allegrini Peter R , Buser Peter T 
Published: January 2005

Endothelin‐1 (ET‐1) may play a role in myocardial ischaemia/reperfusion injury because both the release and vasoconstrictor effect of ET‐1 are increased after ischaemia. Since the increased vasoconstrictor effect of ET‐1 can be mediated by ET‐1‐induced release of thromboxane A2 (TXA2), the aim of this study was to test whether combined blockade of ET and TXA2 receptors protects the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion.
Bosentan (antagonist for ETA and ETB receptors, 1 μM based on concentration‐response curves of ET‐1), SQ 30,741 (antagonist of TXA2 receptors, 0.1 μM), or the combination thereof was administered to isolated perfused rat hearts undergoing 15 min of global ischaemia and 60 min of reperfusion.
Neither bosentan or SQ 30,741 alone, nor the combination thereof, improved the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischaemia‐induced acidosis but this did not translate into a measurable effect on haemodynamic or metabolic variables.
Thus, combined blockade of ET and TXA2 receptors does not protect the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding suggests that neither ET‐1 nor ET‐1‐induced release of TXA2 play a major role in the postischaemic recovery of the cardiac contractile function and energy metabolism.

British Journal of Pharmacology (2001) 132, 234–240; doi:10.1038/sj.bjp.0703773
Multiple P2X receptors on guinea‐pig pelvic ganglion neurons exhibit novel pharmacological properties
Authors: Zhong Yu , Dunn Philip M , Burnstock Geoffrey 
Published: January 2005

Application of ATP and α,β‐methylene ATP (αβmeATP) to voltage‐clamped guinea‐pig pelvic neurons produced three types of inward currents. A fast‐desensitizing response was present in 5% (25/660) of neurons, 70% gave slowly‐desensitizing currents, and the remainder had biphasic responses.
Slowly‐desensitizing responses were characterized pharmacologically. The response to αβmeATP 100 μM was 46±27% (range 0 – 100%) of that evoked by ATP 100 μM in the same cell. Cross‐desensitization indicated the presence of αβmeATP‐sensitive and ‐insensitive receptors.
The concentration‐response curve for αβmeATP had an EC50 of 55 μM, and a Hill coefficient of 0.99, while at the αβmeATP‐insensitive receptor, ATP had an EC50 of 73 μM, with a Hill coefficient of 1.78.
The response to αβmeATP was blocked by pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), suramin and Cibacron blue. However, the αβmeATP‐insensitive receptor was inhibited by PPADS, but not by the other two antagonists.
2′‐ (or 3′‐) O‐trinitrophenyl‐ATP was 10 times more potent in inhibiting responses to αβmeATP than to ATP (at the αβmeATP‐insensitive receptor).
Lowering extracellular pH potentiated responses to αβmeATP and ATP, while raising pH attenuated them.
Co‐application of Zn2+ (3 – 300 μM) inhibited the responses to αβmeATP and ATP, with IC50 values of 286 and 60 μM, respectively.
In conclusion, unlike rat and mouse pelvic ganglion neurons, which only express P2X2 homomers, at least three distinct P2X receptors are present in guinea‐pig pelvic neurons, probably homomeric P2X2, P2X3 and heteromeric P2X2/3 receptors. However, some of the novel pharmacological properties observed suggest that the guinea‐pig P2X receptor subtypes may differ from their rat orthologues.

British Journal of Pharmacology (2001) 132, 221–233; doi:10.1038/sj.bjp.0703778
Function of cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 in the ductus arteriosus from foetal lamb: differential development and change by oxygen and endotoxin
Authors: Coceani F , Ackerley C , Seidlitz E , Kelsey L 
Published: January 2005

Prenatal patency of the ductus arteriosus is maintained mainly by prostaglandin(PG) E2. Here we have examined the relative importance of cyclo‐oxygenase‐1 (COX1) and cyclo‐oxygenase‐2 (COX2) for PGE2 formation in the foetal lamb ductus (0.65 gestation onwards).
Using fluorescence microscopy and immunogold staining, COX1 appeared more abundant than COX2 in endothelial and smooth muscle cells, and this difference was greater before‐term. Inside muscle cells, COX1 and COX2 immunoreactivity was located primarily in the perinuclear region. Endotoxin, given to the lamb in utero (∼0.1 μg kg−1), caused COX2 upregulation, while an opposite effect with disappearance of the enzyme followed endotoxin treatment in vitro (100 ng ml−1). COX1 immunoreactivity remained virtually unchanged with either treatment; however, this isoform as well as any induced COX2 migrated towards the outer cytoplasm.
The COX2 inhibitor L‐745,337 (1 – 10 μM) contracted the isolated ductus at term, the response being almost as high as that to indomethacin (dual COX1/COX2 inhibitor) over the same dose‐range. Conversely, L‐745,337 was relatively less effective in the premature.
Pretreatment of the premature in vivo with endotoxin enhanced the contraction of the ductus to L‐745,337, while in vitro endotoxin had a variable effect.
The premature ductus exhibited a stronger contraction to L‐745,337 following exposure to oxygen. On the other hand, the oxygen contraction, which is modest before‐term, was enhanced by L‐745,337.
We conclude that COX1 and COX2 develop unevenly in the ductus. While both enzymes contribute to PGE2 formation at term, COX1 is the major isoform in the premature. COX2, however, may acquire greater importance before‐term following physiological and pathophysiological stimuli.

British Journal of Pharmacology (2001) 132, 241–251; doi:10.1038/sj.bjp.0703779