bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP‐dependent protein kinase I
Authors: Ny Lars , Pfeifer Alexander , Aszòdi Attila , Ahmad Marianne , Alm Per , Hedlund Petter , Fässler Reinhard , Andersson Karl‐Erik 
Published: January 2005

Guanosine 3′, 5′‐cyclic monophosphate (cyclic GMP)‐dependent kinase I (cGKI) is a major receptor for cyclic GMP in a variety of cells. Mice lacking cGKI exhibit multiple phenotypes, including severe defects in smooth muscle function. We have investigated the NO/cGMP‐ and vasoactive intestinal polypeptide (VIP)/adenosine 3′, 5′‐cyclic monophosphate (cyclic AMP)‐signalling pathways in the gastric fundus of wild type and cGKI‐deficient mice.
Using immunohistochemistry, similar staining patterns for NO‐synthase, cyclic GMP‐ and VIP‐immunoreactivities were found in wild type and cGKI‐deficient mice.
In isolated, endothelin‐1 (3 nM–3 μM)‐contracted, muscle strips from wild type mice, electrical field stimulation (1–16 Hz) caused a biphasic relaxation, one initial rapid, followed by a more slowly developing phase. In preparations from cGKI‐deficient mice only the slowly developing relaxation was observed.
The responses to the NO donor, SIN‐1 (10 nM–100 μM), and to 8‐Br‐cyclic GMP (10 nM–100 μM) were markedly impaired in strips from cGKI‐deficient mice, whereas the responses to VIP (0.1 nM–1 μM) and forskolin (0.1 nM–1 μM) were similar to those in wild type mice.
These results suggest that cGKI plays a central role in the NO/cGMP signalling cascade producing relaxation of mouse gastric fundus smooth muscle. Relaxant agents acting via the cyclic AMP‐pathway can exert their effects independently of cGKI.

British Journal of Pharmacology (2000) 129, 395–401; doi:10.1038/sj.bjp.0703061
Curcumin prevents adriamycin nephrotoxicity in rats
Authors: Venkatesan Narayanan , Punithavathi Durairaj , Arumugam Venkatesan 
Published: January 2005

The present study investigated the effect of curcumin on adriamycin (ADR) nephrosis in rats. The results indicate that ADR‐induced kidney injury was remarkably prevented by treatment with curcumin. Treatment with curcumin markedly protected against ADR‐induced proteinuria, albuminuria, hypoalbuminaemia and hyperlipidaemia. Similarly, curcumin inhibited ADR‐induced increase in urinary excretion of N‐acetyl‐β‐D‐glucosaminidase (a marker of renal tubular injury), fibronectin and glycosaminoglycan and plasma cholesterol. Curcumin restored renal function in ADR rats, as judged by the increase in GFR. The data also demonstrated that curcumin protected against ADR‐induced renal injury by suppressing oxidative stress and increasing kidney glutathione content and glutathione peroxidase activity. In like manner, curcumin abolished ADR‐stimulated kidney microsomal and mitochondrial lipid peroxidation. These data suggest that administration of curcumin is a promising approach in the treatment of nephrosis caused by ADR.British Journal of Pharmacology (2000) 129, 231–234; doi:10.1038/sj.bjp.0703067
Urothelium‐derived inhibitory factor(s) influences on detrusor muscle contractility in vitro
Authors: Hawthorn M H , Chapple C R , Cock M , Chess‐Williams R 
Published: January 2005

The function of the bladder urothelium in modulating contractile responses of the underlying detrusor smooth muscle to muscarinic stimulation has been examined in the pig bladder. Saturation curves for [3H]‐QNB binding demonstrated a greater muscarinic receptor density in the urothelium than in the detrusor smooth muscle. The presence of an intact urothelium on isolated bladder strips inhibited contractions induced by carbachol but not KCl. Contractions of a urothelium‐denuded muscle strip were inhibited in the presence of a second bladder strip with an intact urothelium, but not if the second strip was denuded. The urothelium‐induced inhibition of contractions was not prevented in the presence of L‐NOARG, methylene blue, indomethacin, propranolol, suramin, TEA or apamin. The data suggest the presence of a diffusable, urothelium‐derived inhibitory factor, which could not be identified but appears to be neither nitric oxide, a cyclo‐oxygenase product, a catecholamine, adenosine, GABA nor an EDHF sensitive to apamin.British Journal of Pharmacology (2000) 129, 416–419; doi:10.1038/sj.bjp.0703068
Characterization of prostanoid receptors mediating inhibition of histamine release from anti‐IgE‐activated rat peritoneal mast cells
Authors: Chan C L , Jones R L , Lau H Y A 
Published: January 2005

Prostanoid receptors mediating inhibition of anti‐IgE induced histamine release from rat peritoneal mast cells have been characterized pharmacologically. PGD2 and the specific DP receptor agonists BW 245C and ZK 118182 were the most potent inhibitors with half‐maximal concentrations of 0.26, 0.06 and 0.02 μM respectively. The maximum inhibition attainable was 60–65% with 10−5 M BW 245C and ZK 118182.
Among several EP receptor agonists investigated, only PGE2 and the EP2/EP3 receptor agonist misoprostol induced significant inhibition (46.8±4.7% at 10−4 M and 18.7±6.8% at 10−5 M respectively). The IP receptor agonists cicaprost and iloprost were both less potent than the DP agonists in inhibiting histamine release (45.2±3.3% and 35.1±2.5% inhibition respectively at 10−5 M), whereas PGF2α and the TP receptor agonist U‐46619 were only marginally effective.
The EP4/TP receptor antagonist AH 23848 failed to affect the inhibitory actions of PGD2 or PGE2 even at 10−5 M, whereas the DP/EP1/EP2 receptor antagonist AH 6809 slightly enhanced the effect of PGD2 at 10−6 M.
At concentrations of 3×10−6 to 10−5 M, the putative DP receptor antagonist ZK 138357 dose‐dependently suppressed the inhibitory activities of the DP agonists, PGE2 and cicaprost. The antagonism of ZK 138357 against the DP receptor agonists appeared to be competitive with pA2 values of around six.
In conclusion, these data support our earlier proposal that an inhibitory DP receptor is the predominant prostanoid receptor in rat peritoneal mast cell. The properties of this receptor in relation to putative DP receptor subtypes reported in the literature are discussed.

British Journal of Pharmacology (2000) 129, 589–597; doi:10.1038/sj.bjp.0703072
A novel anionic conductance affects action potential duration in isolated rat ventricular myocytes
Authors: Spencer C Ian , Uchida Wataru , Kozlowski Roland Z 
Published: January 2005

Effects of extracellular anions were studied in electrophysiological experiments on freshly isolated rat ventricular myocytes. Under current‐clamp, action potential duration (APD) was prolonged by reducing the extracellular Cl− concentration and shortened by replacement of extracellular Cl− with I−. Under voltage‐clamp, membrane potential steps or ramps evoked an anionic background current (IAB) carried by either Cl−, Br−, I− or NO3−. Activation of IAB was Ca2+‐ and cyclic AMP‐independent, and was unaffected by cell shrinkage. IAB was insensitive to stilbene and fenamate anion transport blockers at concentrations that inhibit Ca2+‐, cyclic AMP‐ and swelling‐activated Cl− currents in ventricular cells of other mammals. These results suggest that IAB may be carried by a novel class of Cl− channel. Correlation of anion substitution experiments on membrane current and action potentials revealed that IAB could play a major role in controlling rat ventricular APD. These findings have important implications for those studying cardiac Cl− channels as potential targets for novel antiarrythmic agents.British Journal of Pharmacology (2000) 129, 235–238; doi:10.1038/sj.bjp.0703074
Somatostatin‐induced control of cytosolic free calcium in pituitary tumour cells
Authors: Petrucci Cristina , Cervia Davide , Buzzi Marco , Biondi Carla , Bagnoli Paola 
Published: January 2005

In rat pituitary tumour cells (GC cells), spontaneous oscillations of the intracellular concentration of Ca2+ ([Ca2+]i) induce growth hormone (GH) secretion that is inhibited by octreotide, a somatostatin (SRIF) agonist which binds to SRIF subtype (sst) receptor 2. The effects of its functional activation on the control of [Ca2+]i were investigated using fluorimetric measurements of [Ca2+]i.
SRIF decreases the basal [Ca2+]i and the [Ca2+]i rise in response to forskolin (FSK) through the inhibition of L‐type voltage‐dependent Ca2+ channels.
Pretreatment with octreotide or with L‐Tyr8Cyanamid 154806, a sst2 receptor antagonist, abolishes the SRIF‐induced inhibition of [Ca2+]i. Octreotide is known to operate through agonist‐induced desensitization, while the antagonist operates through receptor blockade.
sst1 and sst2 receptor‐immunoreactivities (‐IRs) are localized to cell membranes. sst2, but not sst1 receptor‐IR, internalizes after cell exposure to octreotide.
SRIF‐induced inhibition of basal [Ca2+]i or FSK‐induced Ca2+ entry is blocked by pertussis toxin (PTX).
FSK‐induced cyclic AMP accumulation is only partially decreased by SRIF or octreotide, indicating that sst2 receptors are coupled to intracellular pathways other than adenylyl cyclase (AC) inhibition.
In the presence of H‐89, an inhibitor of cyclic AMP‐dependent protein kinase (PKA), SRIF‐induced inhibition of basal [Ca2+]i is still present, although reduced in amplitude.
SRIF inhibits [Ca2+]i by activating sst2 receptors. Inhibition of AC activity is only partly responsible for this effect, and other transduction pathways may be involved.

British Journal of Pharmacology (2000) 129, 471–484; doi:10.1038/sj.bjp.0703075
Evidence against potassium as an endothelium‐derived hyperpolarizing factor in rat mesenteric small arteries
Authors: Lacy Peter S , Pilkington Gemma , Hanvesakul Rajesh , Fish Helen J , Boyle John P , Thurston Herbert 
Published: January 2005

Endothelium‐derived hyperpolarizing factor (EDHF) has recently been identified as potassium released from endothelial cells into the myo‐endothelial space. The present study was designed to test this hypothesis.
In rat small mesenteric arteries, mounted in a wire myograph, relaxation to acetylcholine or potassium was not significantly changed following incubation with oxadiazolo‐quinoxalin‐1‐one (ODQ, 4 μM) and indomethacin (10 μM, n=9).
Maximal relaxations to acetylcholine occurred in all arteries, were maintained and were significantly greater (P<0.01, n=9) than the transient relaxations to potassium, which only occurred in 30–40% of vessels.
Removal of the vascular endothelium abolished relaxant responses both to potassium and acetylcholine (P<0.005, n=9).
Compared with responses in 5.5 mM potassium PSS, relaxation responses to added potassium in arteries maintained in 1.5 mM potassium PSS were more marked and were not dependent on the presence of an intact endothelium (n=8).
Incubation with BaCl2 (50 μM) significantly inhibited the maximal relaxant response to potassium in the presence of an intact endothelium in 5.5 mM potassium PSS (P<0.05, n=4), but had no effect on relaxation of de‐endothelialized preparations in 1.5 mM potassium PSS (n=5).
Treatment with ouabain (0.1 mM) abolished the relaxant response to potassium in 1.5 mM potassium PSS (P<0.001, n=9), but only partly inhibited the maximal relaxant response to acetylcholine in 5.5 mM potassium PSS (P<0.01, n=5).
These data show that at physiological concentrations of potassium an intact endothelium is necessary for potassium‐induced relaxation in rat mesenteric arteries. Furthermore, the response to potassium is clearly different to that from acetylcholine, indicating that potassium does not mimic EDHF released by acetylcholine in these arteries.

British Journal of Pharmacology (2000) 129, 605–611; doi:10.1038/sj.bjp.0703076
Extracellular nucleotides activate the p38‐stress‐activated protein kinase cascade in glomerular mesangial cells
Authors: Huwiler Andrea , Wartmann Markus , Van Den Bosch Henk , Pfeilschifter Josef 
Published: January 2005

Extracellular ATP and UTP have been reported to activate a nucleotide receptor (P2Y2‐receptor) that mediates arachidonic acid release with subsequent prostaglandin formation, a reaction critically depending on the activity of a cytosolic phospholipase A2. In addition, extracellular nucleotides trigger activation of the classical mitogen‐activated protein kinase (MAPK) cascade and cell proliferation as well as of the stress‐activated protein kinase (SAPK) cascade.
In this study, we report that ATP and UTP are also able to activate the p38‐MAPK pathway as measured by phosphorylation of the p38‐MAPK and its upstream activators MKK3/6, as well as phosphorylation of the transcription factor ATF2 in a immunocomplex‐kinase assay.
Time courses reveal that ATP and UTP induce a rapid and transient activation of the p38‐MAPK activity with a maximal activation after 5 min of stimulation which declined to control levels over the next 20 min.
A series of ATP and UPT analogues were tested for their ability to stimulate p38‐MAPK activity. UTP and ATP were very effective analogues to activate p38‐MAPK, whereas ADP and γ‐thio‐ATP had only moderate activating effects. 2‐Methyl‐thio‐ATP, βγ‐imido‐ATP, AMP, adenosine and UDP had no significant effects of p38‐MAPK activity. In addition, the extracellular nucleotide‐mediated effect on p38‐MAPK was almost completely blocked by 1 mM of suramin, a putative P2‐purinoceptor antagonist.
In summary, these results demonstrate for the first time that extracellular nucleotides are able to activate the MKK3/6‐ p38‐MAPK cascade most likely via the P2Y2‐receptor. Moreover, this finding implies that all three MAPK subtypes are signalling candidates for extracellular nucleotide‐stimulated cell responses.

British Journal of Pharmacology (2000) 129, 612–618; doi:10.1038/sj.bjp.0703077
The novel immunosuppressant SDZ‐RAD protects rat brain slices from cyclosporine‐induced reduction of high‐energy phosphates
Authors: Serkova Natalie , Litt Lawrence , Leibfritz Dieter , Hausen Bernard , Morris Randall E , James Thomas L , Benet Leslie Z , Christians Uwe 
Published: January 2005

SDZ‐RAD, 40‐O‐(2‐hydroxyethyl)‐rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ‐RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side‐effect of cyclosporine.
We studied the effect of SDZ‐RAD and its combination with cyclosporine on high‐energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using 31P‐magnetic resonance spectroscopy (MRS).
Cyclosporine significantly reduced high‐energy phosphates after 2 h in a dose‐dependent manner (100 μg l−1: 93±3% of control (NTP), 91±3% (PCr); 500 μg l−1: 84±2% (NTP), 73±2 (PCr); 5000 μg l−1: 68±3% (NTP), 55±5% (PCr); n=6; P<0.02).
In contrast, after perfusion for 2 h, SDZ‐RAD (500 μg l−1 and 5000 μg l−1) significantly increased high‐energy phosphate concentrations in the brain slices (P<0.02). Even at the lowest concentration, SDZ‐RAD protected brain energy metabolism against cyclosporine toxicity: 100 μg l−1 SDZ‐RAD+5000 μg l−1 cyclosporine: 86±3% (NTP), 83±7% (PCr), n = 3, P<0.03 compared to cyclosporine alone. 5As evaluated using an algorithm based on Loewe isobolograms, the effects of SDZ‐RAD/ cyclosporine combinations on brain energy reduction were antagonistic. Both drugs were found in mitochondria using h.p.l.c‐MS analysis.
We conclude that cyclosporine inhibits mitochondrial high‐energy phosphate metabolism, which can be antagonized by SDZ‐RAD.

British Journal of Pharmacology (2000) 129, 485–492; doi:10.1038/sj.bjp.0703079
No contractile effect for 5‐HT1D and 5‐HT1F receptor agonists in human and bovine cerebral arteries: similarity with human coronary artery
Authors: Bouchelet Isabelle , Case Bruce , Olivier André , Hamel Edith 
Published: January 2005

Using subtype‐selective 5‐HT1 receptor agonists and/or the 5‐HT1 receptor antagonist GR127935, we characterized in vitro the 5‐HT receptor that mediates the contraction of human and bovine cerebral arteries. Further, we investigated which sumatriptan‐sensitive receptors are present in human coronary artery by reverse‐transcriptase polymerase chain reaction (RT–PCR).
Agonists with affinity at the 5‐HT1B receptor, such as sumatriptan, alniditan and/or IS‐159, elicited dose‐dependent contraction in both human and bovine cerebral arteries. They behaved as full agonists at the sumatriptan‐sensitive 5‐HT1 receptors in both species. In contrast, PNU‐109291 and LY344864, selective agonists at 5‐HT1D and 5‐HT1F receptors, respectively, were devoid of any significant vasocontractile activity in cerebral arteries, or did not affect the sumatriptan‐induced vasocontraction. The rank order of agonist potency was similar in both species and could be summarized as 5‐HT=alniditan>sumatriptan=IS‐159>>>PNU‐109291=LY344864.
In bovine cerebral arteries, the 5‐HT1 receptor antagonist GR127935 dose‐dependently inhibited the vasoconstrictions elicited by both 5‐HT and sumatriptan, with respective pA2 values of 8.0 and 8.6.
RT–PCR studies in human coronary arteries showed a strong signal for the 5‐HT1B receptor while message for the 5‐HT1F receptor was weak and less frequently detected. Expression of 5‐HT1D receptor mRNA was not detected in any sample.
The present results demonstrate that the triptan‐induced contraction in brain vessels is mediated exclusively by the 5‐HT1B receptor, which is also present in a majority of human coronary arteries. These results suggest that selective 5‐HT1D and 5‐HT1F receptor agonists might represent new antimigraine drugs devoid of cerebro‐ and cardiovascular effects.

British Journal of Pharmacology (2000) 129, 501–508; doi:10.1038/sj.bjp.0703081
Antihyperglycemic action of isoferulic acid in streptozotocin‐induced diabetic rats
Authors: Liu I‐Min , Hsu Feng‐Lin , Chen Chieh‐Fu , Cheng Juei‐Tang 
Published: January 2005

Wistar rats with streptozotocin‐induced diabetes (STZ‐diabetic rats), which is similar to human insulin‐dependent diabetic mellitus (IDDM), were employed to investigate the antihyperglycemic action of isoferulic acid.
A single intravenous injection of isoferulic acid decreased the plasma glucose in a dose‐dependent manner in the STZ‐diabetic rats. Repeated intravenous administration of STZ‐diabetic rats with isoferulic acid (5.0 mg kg−1) also resulted in the lowering of plasma glucose after one day.
Stimulatory effects of isoferulic acid on the glucose uptake and glycogen synthesis in soleus muscles isolated from STZ‐diabetic rats were also obtained indicating an increase of glucose utilization following isoferulic acid treatment which was not dependent on insulin.
The mRNA level of glucose transporter subtype 4 form (GLUT4) in soleus muscle was raised by isoferulic acid after repeated treatment for 1 day in STZ‐diabetic rats. Similar repeated treatment with isoferulic acid reversed the elevated mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ‐diabetic rats to the normal level. However, expression of GLUT4 and PEPCK genes in nondiabetic rats were not influenced by similar treatment with isoferulic acid.
These results suggest that isoferulic acid can inhibit hepatic gluconeogenesis and/or increase the glucose utilization in peripheral tissue to lower plasma glucose in diabetic rats lacking insulin.

British Journal of Pharmacology (2000) 129, 631–636; doi:10.1038/sj.bjp.0703082
Effects of some isoprostanes on the human umbilical artery in vitro
Authors: Oliveira L , Stallwood N A , Crankshaw D J 
Published: January 2005

Cumulative concentration‐effect curves for the selective prostanoid TP receptor agonist U46619 and six isoprostanes were constructed in the human isolated umbilical artery.
All compounds except 8‐iso‐PGF3α produced concentration‐dependent contractions. The contractile response to the isoprostanes increased with each cumulative addition up to a point, after which subsequent addition reduced the contraction below the previous level. This [downturn] in the concentration‐effect curve did not occur with U46619.
The potencies of the compounds tested were as follows (pEC50±s.e.mean): U46619, 6.7±0.2; 8‐iso‐PGE2, 6.5±0.1; 8‐iso‐PGF2α, 5.8±0.2; 8‐iso‐PGE1, 5.4±0.1; 8‐iso‐PGF1α, 5.0±0.1; 8‐iso‐PGF2β> 4.8; 8‐iso‐PGF3α>> 4.8 (n=4–17). Neither 8‐iso‐PGF2β nor 8‐iso‐PGF3α at 44 μM had a significant effect on cumulative concentration‐effect curves to U46619.
The selective TP receptor antagonist GR32191 (0.1 μM) caused rightward shifts in the concentration‐effect curves to all the active compounds. pA2 values for GR32191 against U46619, 8‐iso‐PGE2, 8‐iso‐PGF2α, 8‐iso‐PGE1 were 7.6±0.2, 9±1, 8.2±0.3 and 7.7±0.3, respectively (n=4).
Neither Nω‐nitro‐L‐arginine methyl ester (100 μM) nor the selective DP receptor antagonist BW A868C (50 nM) affected the complex concentration‐effect curve to 8‐iso‐PGE2 (n=3).
Stable contractions to U46619 (1–3 μM) were unaffected by anandamide at concentrations up to 60 μM.

British Journal of Pharmacology (2000) 129, 509–514; doi:10.1038/sj.bjp.0703083
Mechanisms of 17 β‐oestradiol induced vasodilatation in isolated pressurized rat small arteries
Authors: Shaw Linda , Taggart Michael J , Austin Clare 
Published: January 2005

The influence of 17 β‐oestradiol on pressurized isolated rat mesenteric and coronary small arteries was investigated.
17 β‐oestradiol caused rapid (t1.0<5 mins) concentration‐dependent relaxations of pre‐contracted pressurized (50 mmHg) isolated rat mesenteric and coronary arteries. Similar responses were observed in both vessel types. Significant relaxations were only observed at concentrations exceeding 3 μM.
The vasodilatory responses in both types of artery were unaffected by 10 μM L‐nitro arginine (L‐NNA) alone or in the presence of 10 μM indomethacin, inhibitors of nitric oxide and prostaglandin synthesis respectively. They were also unaffected by the pre‐contracting agent used i.e. high K+ or U46619 (a thromboxane analogue).
Neither the oestrogen receptor antagonist ICI 182,780 (10 μM) nor the protein synthesis inhibitor cycloheximide (100 μM) had any effect on the responses of mesenteric arteries to 17 β‐oestradiol.
17 α‐oestradiol had only a minor effect on mesenteric arterial diameter over a concentration range similar to the effective vasodilatory range for 17 β‐oestradiol.
Membrane impermeant 17 β‐oestradiol conjugated to bovine serum albumin (β‐oestradiol‐17hemisuccinate‐BSA) (E‐H‐BSA) resulted in a vasodilatation of pressurized arteries.
Wortmannin, an inhibitor of myosin light chain kinase, near maximally relaxed pressurized mesenteric arteries although the time course for the response was significantly slower than that for 17 β‐oestradiol.
These results taken together suggest that the acute effects of 17 β‐oestradiol on isolated pressurized arterial tone may be due to effects directly on the vascular smooth muscle via non‐genomic mechanisms that involve a stereospecific interaction at the plasma membrane.

British Journal of Pharmacology (2000) 129, 555–565; doi:10.1038/sj.bjp.0703084