bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the rapid component of the delayed‐rectifier K+ current by therapeutic concentrations of the antispasmodic agent terodiline
Authors: Jones Stephen E , Ogura Toshitsugu , Shuba Lesya M , McDonald Terence F 
Published: January 2005

Prolongation of the QT interval and malignant ventricular arrhythmia have been observed in patients administered terodiline for urinary incontinence. Since this adverse reaction might be caused by inhibition of delayed‐rectifier K+ current (IK), we investigated whether clinically relevant (10 μm) concentrations of the drug modify IK in guinea‐pig ventricular myocytes.
Myocytes superfused with normal Tyrode's solution were pulsed from −40 mV to more positive test potentials (V) for 0.2–1 s to elicit tail IK on repolarization and measure tail IK‐V relationships. IKr was distinguished from IKs by its sensitivity to the selective blocker E4031.
Inhibition of IKr by 5 μm E4031 was completely occluded by pretreatment with 3 μm terodiline. In addition, action potential lengthening by E4031 in guinea‐pig papillary muscles (29±3%) was abolished (3±2%) (P < 0.001) by terodiline pretreatment.
Inhibition of IKr by terodiline appeared to be voltage‐independent, and the parameters of the Hill equation describing the inhibition were IC50=0.7 μm and nH=1.6. High concentrations of the drug also affect IKs; in experiments with K+‐free Tyrode's, 10 μm terodiline inhibited tail IKs by 27±3% (n = 5) (P < 0.001).
These data suggest that QT lengthening at therapeutic concentrations of the drug (≈amp;1.5 μm) is primarily due to inhibition of IKr. Inhibition of other K+ currents such as IKs is likely to be important at higher concentrations.

British Journal of Pharmacology (1998) 125, 1138–1143; doi:10.1038/sj.bjp.0702173
Impaired function of alpha‐2 adrenoceptors in smooth muscle of mesenteric arteries from spontaneously hypertensive rats
Authors: Feres Teresa , Borges Antonio Carlos R , Silva Eneida G , Paiva Antonio C M , Paiva Therezinha B 
Published: January 2005

The α2‐adrenoceptor function in mesenteric arteries of spontaneously hypertensive rats (SHR) was investigated by comparing membrane potential changes in response to adrenergic agonists in preparations from female SHR, Wistar‐Kyoto (WKY) and normotensive Wistar rats (NWR).
Resting membrane potential was found to be less negative in mesenteric arteries from SHR than in those from NWR and WKY. Apamin induced a decrease in the membrane potential of mesenteric artery rings without endothelium from NWR and WKY, but had no effects in those from SHR. Both UK 14,304 and adrenaline, in the presence of prazosin, induced a hyperpolarization that was significantly lower in de‐endothelialized mesenteric rings from SHR than in those from NWR and WKY. In mesenteric rings with endothelium, however, similar hyperpolarization was observed in the three strains.
In NWR mesenteric rings with endothelium the hyperpolarization induced by activation of α2‐adrenoceptors was abolished by apamin, whereas in intact SHR mesenteric rings this hyperpolarization was slightly reduced by apamin and more efficiently reduced by Nω‐nitro‐l‐arginine.
It is concluded that the activity of potassium channels coupled to α2‐adrenoceptors is altered in the smooth muscle cells of SHR mesenteric arteries, contributing to their less negative membrane potential. On the other hand, the endothelial α2‐receptors are functioning in mesenteric vessels from SHR and their stimulation induces a hyperpolarization mainly through the release of nitric oxide.

British Journal of Pharmacology (1998) 125, 1144–1149; doi:10.1038/sj.bjp.0702177
The mechanism by which aminoglycoside antibiotics cause vasodilation of canine cerebral arteries
Authors: Gergawy Mourad , Vollrath Bozena , Cook David 
Published: January 2005

The effects of aminoglycoside antibiotics were examined in canine cerebral arteries and in cultured cerebrovascular smooth muscle cells stimulated with oxyhemoglobin (OxyHb), a blood constituent which has been implicated in the pathogenesis of cerebrovascular spasm.
In cerebral arterial rings precontracted with OxyHb (10 μm), the aminoglycosides caused a concentration‐dependent decrease in isometric tension. The EC50s for the relaxation were 0.46±0.1 mm (n = 6), 0.53±0.08 mm (n = 12), 1.6±0.3 mm (n = 7) and 3.9±0.5 mm (n = 5) for neomycin, gentamicin, streptomycin and kanamycin, respectively. This order of potency corresponds approximately to the number of positive charges in the molecules.
The aminoglycosides also inhibited the contractions to prostaglandin F2α (1 μm) and depolarizing concentrations of potassium chloride (60 mm). The order of potency was neomycin>gentamicin>streptomycin>kanamycin.
The relaxation was maintained in vascular preparations denuded of endothelium.
Neomycin (5 mm) abolished the Ca2+‐independent contraction to PGF2α.
In Fura‐2‐loaded cerebrovascular smooth muscle cells, OxyHb (1 μm) significantly enhanced the concentration of intracellular calcium ([Ca2+]i) by 330%. The administration of neomycin, gentamicin, kanamycin and streptomycin in concentrations corresponding to the EC50 from contractility studies, reduced the effects of OxyHb on [Ca2+]i by about 50% to 221±35 nm (n = 7), 270±31 nm (n = 7), 229±33 nm (n = 6) and 240±6 nm (n = 5), respectively.
These results suggests that the effects of the aminoglycosides on the OxyHb‐induced contraction and the long‐term increase in [Ca2+]i, may arise from several effects, including inhibition of PLC, protection of calcium extrusion mechanisms, and interference with the process of [Ca2+]i accumulation.

British Journal of Pharmacology (1998) 125, 1150–1157; doi:10.1038/sj.bjp.0702180
Comparison of two soluble guanylyl cyclase inhibitors, methylene blue and ODQ, on sodium nitroprusside‐induced relaxation in guinea‐pig trachea
Authors: Hwang Tsong‐Long , Wu Chin‐Chung , Teng Che‐Ming 
Published: January 2005

To clarify further the role of cyclic GMP in mediating the relaxant response in guinea‐pig trachea induced by sodium nitroprusside (SNP), the effects of soluble guanylyl cyclase inhibitors, methylene blue and 1H‐[1,2,4]oxadiazolo[4,3,‐a]quinoxalin‐1‐one (ODQ) on SNP‐induced muscle relaxation and cyclic GMP accumulation were determined.
SNP (0.3–100 μm) evoked a concentration‐dependent relaxation of guinea‐pig isolated tracheas precontracted with 0.3 μm carbachol. Preincubation of the preparations with methylene blue (10, 30 and 100 μm) resulted in a slight but concentration‐dependent prevention of the relaxant response to SNP. In contrast, the relaxation to SNP was extensively prevented by 3 μm ODQ and almost abolished by 10 μm ODQ.
SNP (30 μm) induced a significant elevation of cyclic GMP accumulation (from 1.34±0.14 to 5.39±0.28 pmol mg−1 protein, n = 5; P < 0.001), which was partially attenuated by 100 μm methylene blue (3.11±0.51 pmol mg−1 protein, n = 5; P < 0.05), whereas completely abolished by 10 μm ODQ (1.31±0.28 pmol mg−1 protein, n = 5; P < 0.001).
Methylene blue, but not ODQ and Nω‐nitro‐l‐arginine methyl ester (l‐NAME), caused a concentration‐dependent contraction in the tracheal preparation. The tension produced by 100 μm methylene blue was 41.8±4.3% (0.3 μm carbachol as 100%; n=12). Moreover, the non‐selective muscarinic receptor antagonist atropine and the M3‐selective antagonist 4‐diphenylacetoxy‐N‐methylpiperidine methiodine greatly inhibited the contractile effect evoked by methylene blue (100 μm).
In conclusion, this study provides substantial evidence that SNP‐induced muscle relaxation in guinea‐pig trachea is completely via a cyclic GMP‐dependent mechanism. Furthermore, ODQ, but not methylene blue, will likely become an important tool in differentiating between cyclic GMP‐dependent and ‐independent effects of nitric oxide.

British Journal of Pharmacology (1998) 125, 1158–1163; doi:10.1038/sj.bjp.0702181
The central action of the 5‐HT2 receptor agonist 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI) on cardiac inotropy and vascular resistance in the anaesthetized cat
Authors: Ramage Andrew G , de Burgh Daly M 
Published: January 2005

Experiments were carried out to determine the effects of the application of the selective 5‐HT2 receptor agonist DOI intravenously (in the presence of the peripherally acting 5‐HT2 receptor antagonist, BW501C67, 1 mg kg−1, i.v.) or to the ‘glycine sensitive area’ of the ventral surface (30 μg each side) on the left ventricular inotropic (left ventricular dP/dt max) and vascularly isolated hindlimb responses in anaesthetized cats. For the ventral surface experiments, NMDA (10 μg each side) was applied to act as a positive control. In all experiments heart rate and mean arterial blood pressure were held constant to exclude any secondary effects caused by changes in these variables.
DOI (n = 6) i.v or on the ventral surface had no effect on left ventricular dP/dt max but caused a significant increase in hindlimb perfusion pressure of 40±9 and 50±14 mmHg, respectively. Respiration was unaffected. NMDA (n = 6), applied to the ventral surface, caused significant increases in both left ventricular dP/dt max and hindlimb perfusion pressure of 1950±349 mmHg s−1 and 69±17 mmHg respectively, with no associated change in left ventricular end‐diastolic pressure. The amplitude of respiratory movements increased.
It is concluded that activation of 5‐HT2 receptors at the level of the rostral ventrolateral medulla (RVLM) excites sympathetic premotor neurons and/or their antecedents controlling hindlimb vascular resistance but not those controlling the inotropic effects on the left ventricle.

British Journal of Pharmacology (1998) 125, 1172–1179; doi:10.1038/sj.bjp.0702183
Kinetics of leukocyte‐induced changes in endothelial barrier function
Authors: Gautam N , Hedqvist P , Lindbom L 
Published: January 2005

Extravasation of polymorphonuclear leukocytes (PMN) and associated plasma leakage are key events in the inflammatory process. The kinetics of PMN‐induced changes in endothelial barrier function were studied by means of confluent monolayers of bovine aorta or human umbilical vein endothelial cells (EC), cultured on permeable membranes and mounted in a two‐compartment diffusion chamber. The model permitted continuous measurement of transendothelial electrical resistance (TEER), and analysis of protein efflux and PMN migration across the EC monolayer.
Transendothelial chemotactic stimulation (fMLP or LTB4) of PMN resting on EC in the upper compartment induced a prompt decline in TEER, followed by an increase in protein flux and transmigration of PMN. Adding the chemoattractant together with PMN in the upper compartment provoked adhesion of PMN, fall in TEER and increase in protein permeability, but no transmigration of PMN, whereas inhibition of PMN adhesion to EC by pretreatment with anti‐CD18 mAb prevented all responses to chemotactic stimulation.
Chemoattractant‐induced adhesion of PMN to the EC monolayer induced a rapid rise in EC cytosolic free Ca2+, similar to that obtained by direct stimulation of EC with histamine, indicating an active response of EC to PMN activation and adhesion.
In summary, continuous recording of transendothelial electrical resistance in the in vitro model described permits rapid and sensitive analysis of leukocyte activation‐induced effects on EC barrier function. The kinetics and specificity of the EC and PMN responses to chemoattractant stimulation suggest that activated PMN, via adhesion‐dependent events, have a direct effect on EC junctional integrity independent of whether transmigration occurs or not.

British Journal of Pharmacology (1998) 125, 1109–1114; doi:10.1038/sj.bjp.0702186
The antihypertensive profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential homeostatic compensatory mechanisms in renal hypertensive rats
Authors: Anderson Ian K , Drew Geoffrey M 
Published: January 2005

The cardiovascular profile of the angiotensin AT1 receptor antagonist, GR138950, and the influence of potential compensatory homeostatic mechanisms on this profile, were investigated in renal artery ligated hypertensive (RALH) rats.
GR138950 caused a marked reduction in blood pressure associated with immediate tachycardia in conscious RALH rats. The antihypertensive action of GR138950 appeared biphasic; an immediate fall in blood pressure, which plateaued within 1 h, and which was followed by a further slow decline that reached maximum between 5–7 h after administration.
The tachycardia caused by GR138950 was attenuated by atenolol and was abolished by combined pretreatment with atenolol and atropine methyl nitrate. However, the antihypertensive profile of GR138950 was unchanged by these pretreatments.
The resting blood pressure and the antihypertensive effect of GR138950, in RALH rats, were unaffected by the vasopressin V1 receptor antagonist, [β‐mercapto‐β,β‐cyclopentamethylene propionyl1‐O‐Me‐Tyr2,Arg8]‐vasopressin. Thus, vasopressinergic mechanisms are not involved in either maintaining blood pressure in RALH rats, or in compensating for the fall in blood pressure caused by GR138950.
In anaesthetized RALH rats, GR138950 caused a marked fall in blood pressure that was accompanied by an increase in heart rate along with sustained increases in renal and splanchnic sympathetic nerve activity.
In summary, the biphasic fall in blood pressure evoked by GR138950 in RALH rats can not be explained on the basis of changes in autonomic control of the heart, alteration of vasopressin‐mediated vasoconstrictor mechanisms or overall suppression of central sympathetic outflow. Rather, increased vasoconstrictor tone might serve to oppose the initial fall in blood pressure.

British Journal of Pharmacology (1998) 125, 1236–1246; doi:10.1038/sj.bjp.0702187
Characterization of a prostanoid EP3‐receptor in guinea‐pig aorta: partial agonist action of the non‐prostanoid ONO‐AP‐324
Authors: Jones Robert L , Qian Yue‐ming , Chan Kam‐ming , Yim Anthony P C 
Published: January 2005

Contraction of guinea‐pig isolated aorta induced by the prostaglandin E analogue sulprostone (1–400 nm) has a lower maximum response (40%) than that of phenylephrine or U‐46619 (TP‐receptor agonist). A prostanoid EP3‐receptor subtype is involved based on agonist potency ranking: equi‐effective molar ratios (EMR) are sulprostone (EC50∼23 nm) 1.0, SC‐46275 0.11, misoprostol 2.2, gemeprost 3.3, PGE2 5.4, 17‐phenyl PGE2 6.0, GR‐63799 8.9. GR‐63799, which contains a bulky ester group, is relatively more potent on neuronal EP3 preparations than on the aorta.
ONO‐AP‐324, a relative of the non‐prostanoid prostacyclin mimetic series, behaves as an EP3 partial agonist on the aorta, inhibiting sulprostone responses but acting synergistically (in a similar manner to sulprostone) with phenylephrine; it may be a useful pharmacological tool for studying EP3‐receptors.
Sulprostone contractions are markedly suppressed in zero‐Ca2+ bathing fluid containing either 2 mm EDTA or 50 μm EGTA, and by Cd2+ (500 μm), but are usually unaffected by nifedipine (0.3 μm) and verapamil (4.44 μm). Influx of Ca2+, but not through L‐type Ca2+‐channels, appears to be the major contractile mechanism.
The guinea‐pig aorta is a valuable addition to the vascular EP3 preparations available and may increase our knowledge of the mechanisms whereby Gi‐coupled receptors mediate vasoconstriction (c.f. 5‐HT1B/D‐ and α2‐receptors). The possibility of certain EP3 agonists distinguishing EP3‐receptor isoforms is discussed.

British Journal of Pharmacology (1998) 125, 1288–1296; doi:10.1038/sj.bjp.0702189
In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum
Authors: Croci Tiziano , Manara Luciano , Aureggi Giulio , Guagnini Fabio , Rinaldi‐Carmona Murielle , Maffrand Jean‐Pierre , Le Fur Gérard , Mukenge Sylvain , Ferla Gianfranco 
Published: January 2005

We investigated the effect of the cannabinoid agonist (+)WIN‐55212‐2 on human ileum longitudinal smooth muscle preparations, either electrically stimulated or contracted by carbachol. Electrical field stimulation mostly activated cholinergic neurons, since atropine and tetrodotoxin (TTX), alone or co‐incubated, reduced twitch responses to a similar degree (85%). (+)WIN‐55212‐2 concentration‐dependently inhibited twitch responses (IC50 73 nm), but had no additive effect with atropine or TTX. The cannabinoid CB1 receptor antagonist SR 141716 (pA2 8.2), but not the CB2 receptor antagonist, SR 144528, competitively antagonized twitch inhibition by (+)WIN‐55212‐2. Atropine but not (+)WIN‐55212‐2 or TTX prevented carbachol‐induced tonic contraction.  These results provide functional evidence of the existence of prejunctional cannabinoid CB1‐receptors in the human ileum longitudinal smooth muscle. Agonist activation of these receptors prevents responses to electrical field stimulation, presumably by inhibiting acetylcholine release. SR 141716 is a potent and competitive antagonist of cannabinoid CB1 receptors naturally expressed in the human gut.British Journal of Pharmacology (1998) 125, 1393–1395; doi:10.1038/sj.bjp.0702190
Role of cyclo‐oxygenase‐2 induction in interleukin‐1β induced attenuation of cultured human airway smooth muscle cell cyclic AMP generation in response to isoprenaline
Authors: Pang Linhua , Holland Elaine , Knox Alan J 
Published: January 2005

Airway smooth muscle (ASM) in human asthma shows reduced relaxation and cyclic AMP generation in response to β‐adrenoceptor agonists. IL‐β attenuates cyclic AMP generation but the underlying mechanism is unclear. We have reported that IL‐1β induces cyclo‐oxygenase‐2 (COX‐2) in human ASM cells and results in a marked increase in prostanoid generation with PGE2 and PGI2 as the major products.
We investigated the role of COX‐2 induction and prostanoid release (measured as PGE2) in IL‐1β induced attenuation of cyclic AMP generation in response to the β‐adrenoceptor agonist isoprenaline (ISO).
Pre‐treatment of human ASM cells with IL‐1β significantly attenuated cyclic AMP generation in response to high concentrations of ISO (1.0–10.0 μm) in a time‐ and concentration‐dependent manner. The effect was accompanied by a high concentration of PGE2 release. The non‐selective COX inhibitor indomethacin (Ind), the selective COX‐2 inhibitor NS‐398, the protein synthesis inhibitors cycloheximide (CHX) and actinomycin D and the steroid dexamethasone (Dex) all abolished the PGE2 release and prevented the attenuated cyclic AMP generation.
COX substrate arachidonic acid time‐ and concentration‐dependently mimicked IL‐1β induced attenuation and the effect was prevented by the non‐selective COX inhibitors Ind and flurbiprofen, but not by NS‐398, CHX and Dex.
In contrast to IL‐1β, TNFα and IFNγ, which are ineffective in inducing COX‐2 and releasing PGE2 from human ASM cells, did not affect the cyclic AMP formation.
Our study demonstrates that COX‐2 induction and the consequent release of prostanoids plays a crucial role in IL‐1β induced attenuation of human ASM cell cyclic AMP response to ISO.

British Journal of Pharmacology (1998) 125, 1320–1328; doi:10.1038/sj.bjp.0702193
Expression of cyclooxygenase‐2 in foetal rat hepatocytes stimulated with lipopolysaccharide and pro‐inflammatory cytokines
Authors: Martín‐Sanz Paloma , Callejas Nuria A , Casado Marta , Díaz‐Guerra María J M , Boscá Lisardo 
Published: January 2005

Cyclooxygenase‐2 (COX‐2) is involved in the biosynthesis of prostanoids in the course of inflammatory reactions. This isoenzyme is regulated at the transcription level and many cells express COX‐2 upon challenge with lipopolysaccharide (LPS) or pro‐inflammatory cytokines.
Since hepatocytes respond to LPS and pro‐inflammatory stimuli, we investigated the expression of COX‐2 in foetal and adult hepatocytes upon challenge with these substances.
COX‐2 was expressed in foetal hepatocytes incubated with LPS, tumour necrosis factor‐α and interleukin‐1β. This response rapidly decreased after birth and was absent in hepatocytes from animals aged 2 days or more and treated under identical conditions. The expression of COX‐2 was determined at the mRNA, protein and enzyme activity levels using Northern and Western blot, and following the synthesis of prostaglandin E2, respectively. The use of NS 398, a specific pharmacological inhibitor of COX‐2, confirmed the expression of this isoenzyme in activated foetal hepatocytes.
Synergism in COX‐2 expression was observed between LPS, tumour necrosis factor‐α and interleukin‐1β. Interleukin‐6 and permeant analogues of cyclic AMP failed to induce COX‐2 or to synergize with LPS. Also, transforming growth factor‐β inhibited the LPS‐ and pro‐inflammatory cytokines‐dependent expression of COX‐2.
These results indicate that foetal hepatocytes are competent to express COX‐2 upon challenge with pro‐inflammatory stimuli, a process lost completely in hepatocytes isolated from animals aged 2 days.

British Journal of Pharmacology (1998) 125, 1313–1319; doi:10.1038/sj.bjp.0702196
Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea‐pig isolated bronchus
Authors: Harrison S. , Reddy S. , Page C. P. , Spina D. 
Published: January 2005

We have investigated the contractile property of cyclosporin A and FK506 in guinea‐pig isolated bronchus.
Cyclosporin A (10 μm) failed to significantly attenuate the excitatory non‐adrenergic non‐cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)‐1 and (NK)‐2 receptor antagonists, N‐acetyl‐l‐tryptophan 3,5‐bis (trifluoromethyl)‐benzyl and SR48968, respectively.
Cyclosporin A and FK506 caused a concentration‐dependent contraction in guinea‐pig isolated bronchus, which was significantly attenuated by NK‐1 and NK‐2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 μm) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506.
The N‐type calcium channel blocker, ω‐Conotoxin (ωCTX: 10 nm), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, ω‐CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A.
In bronchial preparations desensitized by repeated application of capsaicin (1 μm), the contractile responses to both cyclosporin A (100 μm) and FK506 (100 μm), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 μm) were not altered. Furthermore, repeated application of cyclosporin A (100 μm) significantly inhibited the contractile response to capsaicin (1 μm).
The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea‐pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N‐type calcium channels.

British Journal of Pharmacology (1998) 125, 1405–1412; doi:10.1038/sj.bjp.0702198