bluuebunny/crossref_metadata_2025 huggingface dataset:
A major role for the Rho‐associated coiled coil forming protein kinase in G‐protein‐mediated Ca2+ sensitization through inhibition of myosin phosphatase in rabbit trachea
Authors: Iizuka Kunihiko , Yoshii Akihiro , Samizo Koichi , Tsukagoshi Hideo , Ishizuka Tamotsu , Dobashi Kunio , Nakazawa Tsugio , Mori Masatomo
Published: January 2005

G protein‐mediated Ca2+ sensitization of airway smooth muscle contraction was investigated with respect to the relative importance of Rho‐associated coiled coil forming protein kinase (ROCK) and protein kinase C (PKC). We examined the effects of Y‐27632, a ROCK inhibitor, and GF 109203X, a PKC inhibitor, on guanosine 5′‐O‐(3‐thiotriphosphate) (GTPγS)‐induced contraction in α‐toxin‐ or β‐escin‐permeabilized rabbit trachea.

Although pre‐treatment with Y‐27632 dose‐dependently inhibited GTPγS (10 μM)‐induced Ca2+ sensitization of α‐toxin‐permeabilized trachea, a Y‐27632‐insensitive component (approximately 16% of the maximum contraction) was retained during the early phase of the GTPγS response in the presence of Y‐27632 (100 μM).

GF 109203X (5 μM) abolished 1 μM 4β‐phorbol 12, 13‐dibutyrate (PDBu)‐induced, but only partially inhibited the GTPγS‐induced Ca2+ sensitization. A combination of Y‐27632 (100 μM) and GF 109203X (5 μM) totally abolished the GTPγS response.

GTPγS caused only a small contraction in the absence of Ca2+. Wortmannin (30 μM), a myosin light chain kinase (MLCK) inhibitor, completely inhibited Ca2+‐induced contraction. ATP‐triggered contraction of the strip which had been treated with calyculin A (1 μM), a phosphatase inhibitor, in rigor solutions was markedly slowed by worthmannin (30 μM), but not by Y‐27632 (100 μM), in the presence of GTPγS and Ca2+.

GTPγS, but not PDBu, contracted the β‐escin‐permeabilized trachea in the absence of Ca2+, but the presence of Ca2+‐independent MLCK.

We conclude that ROCK plays a primary role in G‐protein‐mediated Ca2+ sensitization, which requires MLCK activity, with minor contribution of PKC to the early phase of contraction, and PDBu utilizes conventional PKC(s) in airway smooth muscle.

British Journal of Pharmacology (1999) 128, 925–933; doi:10.1038/sj.bjp.0702864
Direction‐independent block of bi‐directional Na+/Ca2+ exchange current by KB‐R7943 in guinea‐pig cardiac myocytes
Authors: Kimura Junko , Watano Tomokazu , Kawahara Masanori , Sakai Eiichi , Yatabe Junichi
Published: January 2005

We investigated the inhibitory effect of KB‐R7943 on ‘bi‐directional’ Na+/Ca2+ exchange current (iNCX) with the reversal potential of iNCX (ENCX) in the middle of the ramp voltage pulse employed.

Bi‐directional iNCX was recorded with ‘full’ ramp pulses given every 10 s from the holding potential of −60 mV over the voltage range between 30 and −150 mV under the ionic conditions of 140 mM [Na]o, 20 mM [Na]i, 1 mM [Ca]o and 433 nM [Ca]i with calculated ENCX at −50 mV.

KB‐R7943 (0.1–100 μM) concentration‐dependently inhibited the current, which reversed near the calculated ENCX, indicating that the blocked current was iNCX.

The inhibition levels were not significantly different between outward and inward iNCX measured at 0 and −120 mV, respectively. IC50 of KB‐R7943 was approximately 1 μM for both directions of iNCX.

Under the bi‐directional ionic conditions, only an outward or inward iNCX was induced by positive or negative ‘half’ ramp pulses, respectively, from the holding potential of −60 mV. KB‐R7943 inhibited both direction of iNCX and the concentration‐inhibition relations were superimposable to the ones obtained by ‘full’ ramp pulses.

These results indicate that KB‐R7943 inhibits iNCX direction‐independently under bi‐directional conditions. This conclusion is different from that of our previous results obtained from iNCX under uni‐directional ionic conditions, where KB‐R7943 inhibited iNCX direction‐dependently. The difference could be attributed to slow dissociation of the drug from the exchanger.

British Journal of Pharmacology (1999) 128, 969–974; doi:10.1038/sj.bjp.0702869
The Pseudomonas aeruginosa quorum‐sensing signal molecule, N‐(3‐oxododecanoyl)‐L‐homoserine lactone, inhibits porcine arterial smooth muscle contraction
Authors: Lawrence R N , Dunn W R , Bycroft B , Camara M , Chhabra S R , Williams P , Wilson V G
Published: January 2005

The Pseudomonas aeruginosa quorum sensing molecule N‐(3‐oxododecanoyl)‐L‐homoserine lactone (OdDHL) has been shown to suppress cytokine production in macrophages. We have examined the effect of OdDHL and related compounds on constrictor tone of porcine blood vessels. OdDHL (1–30 μM) caused a concentration‐dependent inhibition of U46619‐induced contractions of the coronary artery through a largely endothelium‐independent mechanism, but was markedly less effective in the pulmonary artery. Quantitively similar effects to those produced by OdDHL were observed with N‐(3‐oxododecanoyl)‐L‐homocysteine thiolactone, a thiolactone derivative, while N‐3‐oxododecanamide, a lactone‐free acyl analogue, possessed 1/3rd the potency as a vasorelaxant. Neither N‐butanoyl‐L‐homoserine lactone nor L‐homoserine lactone (up to 30 μM) were active. Our findings indicate that OdDHL inhibits vasoconstrictor tone of both pulmonary and coronary blood vessels from the pig. The vasorelaxant action of OdDHL appears to be primarily determined by the N‐acyl chain length, with a minor contribution by the homoserine lactone moiety.

British Journal of Pharmacology (1999) 128, 845–848; doi:10.1038/sj.bjp.0702870
Mechanisms underlying the impairment of endothelium‐dependent relaxation in the pulmonary artery of monocrotaline‐induced pulmonary hypertensive rats
Authors: Nakazawa Hiroshi , Hori Masatoshi , Ozaki Hiroshi , Karaki Hideaki
Published: January 2005

It has been reported that endothelium‐dependent relaxation is impaired in pulmonary hypertensive vessels. The underlying mechanisms for this phenomenon, however, have not yet been identified. In this study, the mechanisms responsible for decreased endothelium‐dependent relaxation in the pulmonary artery isolated from monocrotaline (MCT)‐induced pulmonary hypertensive rat (MCT rat) were examined. MCT (60 mg kg−1), or its vehicle was administered by a single subcutaneous injection to 6‐week‐old male Sprague Dawley rats.

Endothelium‐dependent relaxation induced by carbachol or ionomycin in the MCT rat artery was significantly smaller than that in vehicle‐treated rat (control rat) artery. Cyclic GMP levels, measured by enzyme‐immunoassay, under resting or stimulation with carbachol or ionomycin were also smaller in the MCT rat artery. However, sodium nitroprusside‐induced cyclic GMP accumulation in the endothelium‐denuded artery was similar in control and MCT rats. These results suggest that MCT treatment decreases endothelial nitric oxide (NO) production.

Resting endothelial Ca2+ levels ([Ca2+]i) in the fura‐PE3‐loaded MCT rat artery, were not different from those in the control rat. However, the increase in endothelial [Ca2+]i elicited by carbachol was attenuated in the MCT rat.

In quantitative RT–PCR analysis, the expression of mRNA encoding endothelial NO synthase was rather increased in the MCT rat artery, suggesting an up‐regulation of eNOS expression.

These results provide evidence that impaired NO‐mediated arterial relaxation in the MCT rat is due to dissociation between eNOS expression and NO production. This dissociation may be derived from an inhibition of receptor‐mediated Ca2+ metabolism and also from the apparent decrease in Ca2+ sensitivity of eNOS.

British Journal of Pharmacology (1999) 128, 1098–1104; doi:10.1038/sj.bjp.0702878
Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis‐associated properties in A431 cells overexpressing epidermal growth factor receptor
Authors: Huang Y ‐T , Hwang J ‐J , Lee P ‐P , Ke F ‐C , Huang J ‐H , Huang C ‐J , Kandaswami C , Middleton E , Lee M ‐T
Published: January 2005

Flavonoids display a wide range of pharmacological properties including anti‐inflammatory. Anti‐mutagenic, anti‐carcinogenic and anti‐cancer effects. Here, we evaluated the effects of eight flavonoids on the tumour cell proliferation, cellular protein phosphorylation, and matrix metalloproteinase (MMPs) secretion.

Of the flavonoids examined, luteolin (Lu) and quercetin (Qu) were the two most potent agents, and significantly inhibited A431 cell proliferation with IC50 values of 19 and 21 μM, respectively.

The epidermal growth factor (EGF) (10 nM) promoted growth of A431 cells (+25±4.6%) and mediated epidermal growth factor receptor (EGFR) tyrosine kinase activity and autophosphorylation of EGFR were inhibited by Lu and Qu. At concentration of 20 μM, both Lu and Qu markedly decreased the levels of phosphorylation of A431 cellular proteins, including EGFR.

A431 cells treated with Lu or Qu exhibited protuberant cytoplasmic blebs and progressive shrinkage morphology. Lu and Qu also time‐dependently induced the appearance of a ladder pattern of DNA fragmentation, and this effect was abolished by EGF treatment.

The addition of EGF only marginally diminished the inhibitory effect of luteolin and quercetin on the growth rate of A431 cells, treatment of cellular proteins with EGF and luteolin or quercetin greatly reduced protein phosphorylation, indicating Lu and Qu may act effectively to inhibit a wide range of protein kinases, including EGFR tyrosine kinase.

EGF increased the levels of matrix metalloproteinase‐2 (MMP‐2) and matrix metalloproteinase‐9 (MMP‐9), while Lu and Qu appeared to suppress the secretion of these two MMPs in A431 cells.

Examination of the relationship between the chemical structure and inhibitory effects of eight flavonoids reveal that the double bond between C2 and C3 in ring C and the OH groups on C3′ and C4′ in ring B are critical for the biological activities.

This study demonstrates that the inhibitory effects of Lu and Qu, and the stimulatory effects of EGF, on tumour cell proliferation, cellular protein phosphorylation, and MMP secretion may be mediated at least partly through EGFR. This study supports the idea that Lu and Qu may have potential as anti‐cancer and anti‐metastasis agents.

British Journal of Pharmacology (1999) 128, 999–1010; doi:10.1038/sj.bjp.0702879
In vitro mechanism of action on insulin release of S‐22068, a new putative antidiabetic compound
Authors: Le Brigand Laurence , Virsolvy Anne , Manechez Dominique , Godfroid Jean‐Jacques , Guardiola‐Lemaître Beatrice , Gribble Fiona M , Ashcroft Frances M , Bataille Dominique
Published: January 2005

The MIN6 cell line derived from in vivo immortalized insulin‐secreting pancreatic β cells was used to study the insulin‐releasing capacity and the cellular mode of action of S‐22068, a newly synthesized imidazoline compound known for its antidiabetic effect in vivo.

S‐22068, was able to release insulin from MIN6 cells in a dose‐dependent manner with a half‐maximal stimulation at 100 μM. Its efficacy (8 fold over the basal value), which did not differ whatever the glucose concentration (stimulatory or not), was intermediate between that of sulphonylurea and that of efaroxan.

Similarly to sulphonylureas and classical imidazolines, S‐22068 blocked KATP channels and, in turn, opened nifedipine‐sensitive voltage‐dependent Ca2+ channels, triggering Ca2+ entry.

Similarly to other imidazolines, S‐22068 induced a closure of cloned KATP channels injected to Xenopus oocytes by interacting with the pore‐forming Kir6.2 moiety.

S‐22068 did not interact with the sulphonylurea binding site nor with the non‐I1 and non‐I2 imidazoline site evidenced in the β cells that is recognized by the imidazoline compounds efaroxan, phentolamine and RX821002.

We conclude that S‐22068 is a novel imidazoline compound which stimulates insulin release via interaction with an original site present on the Kir6.2 moiety of the β cell KATP channels.

British Journal of Pharmacology (1999) 128, 1021–1026; doi:10.1038/sj.bjp.0702883
Nociceptin and the ORL‐1 ligand [Phe1ψ (CH2‐NH)Gly2]nociceptin(1‐13)NH2 exert anti‐opioid effects in the Freund's adjuvant‐induced arthritic rat model of chronic pain
Authors: Bertorelli Rosalia , Corradini Laura , Rafiq Kamran , Tupper Joanna , Calò Girolamo , Ongini Ennio
Published: January 2005

Stimulation of the opioid receptor‐like1 (ORL‐1) receptor by nociceptin (NC) produces hyperalgesia and reverses the antinociceptive effects induced by opioids. Most studies concerning the central effects of NC were conducted using acute pain models. The role NC may play in chronic inflammation remains unelucidated.

The present study was undertaken to assess the action of NC in the Freund's adjuvant‐induced monoarthritic rat model. The effects of drugs known to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and the ORL‐1 ligand, [Phe1ψ(CH2‐NH)Gly2]NC(1‐13)NH2 ([F/G]NC(1‐13)NH2), were also studied alone or in association with morphine.

NC (1–30 nmol, i.c.v.) was inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (−4.5±0.9 vs −0.7±0.8 s of vehicle‐treated animals). [F/G]NC(1‐13)NH2 (0.01–10 nmol, i.c.v.) induced hyperalgesia in the arthritic paw (−3.3±0.6 vs −0.3±0.5 s of vehicle‐treated animals; 10 nmol).

Both NC (0.01–10 nmol, i.c.v.) and [F/G]NC(1‐13)NH2 (0.01–1 nmol, i.c.v), 30 min after morphine (3 mg kg−1, s.c.) induced an immediate and short‐lived reversal of morphine effects (2.6±0.3 vs 10.4±1.0 and 1.2±1.5 vs 9.3±1.1 s of morphine alone, respectively), therefore displaying anti‐opioid activity.

In the Freund's adjuvant‐induced rat model of arthritis, both NC and [F/G]NC(1‐13)NH2 act as anti‐opioid peptides. Furthermore, NCNH2 and [F/G]NC(1‐13)NH2 induce hyperalgesia when given alone. Further investigations and the identification of a centrally acting ORL‐1 antagonist are necessary to better understand the role of NC in pain mechanisms.

British Journal of Pharmacology (1999) 128, 1252–1258; doi:10.1038/sj.bjp.0702884
Reduction of myocardial infarct size with sCR1sLex, an alternatively glycosylated form of human soluble complement receptor type 1 (sCR1), possessing sialyl Lewis x
Authors: Zacharowski Kai , Otto Mike , Hafner Gerd , Marsh Henry C , Thiemermann Christoph
Published: January 2005

This study investigated the effects of soluble complement receptor type 1 (sCR1) or sCR1sLex, agents which function as a complement inhibitor or as a combined complement inhibitor and selectin adhesion molecule antagonist, respectively, on the infarct size and cardiac troponin T (cTnT) release caused by regional myocardial ischaemia and reperfusion in the rat.

Eighty‐two, male Wistar rats were subjected to 30 min occlusion of the left anterior descending coronary artery (LAD) followed by 2 h of reperfusion. Haemodynamic parameters were continuously recorded and at the end of the experiments infarct size (with p‐nitro‐blue tetrazolium) and cTnT release were determined.

Infusion of sCR1 (1, 5 or 15 mg kg−1, each n=7) or sCR1sLex (1, 5 or 15 mg kg−1, n=7, 13 or 13, respectively) 5 min prior to LAD‐reperfusion caused a reduction in infarct size from 59±2% (PBS–control, n=12) to 46±6%, 25±9% and 37±6% or 42±6%, 35±6% and 35±4%, respectively.

Infusion of sCR1 (15 mg kg−1, n=5) or sCR1sLex (15 mg kg−1, n=5) also reduces the myocardial TnT release from 80±20 ng ml−1 (control) to 13±7 or 4±1 ng ml−1, respectively.

Thus, sCR1 or sCRsLex significantly reduce infarct size and cardiac TnT release caused by 30 min of regional myocardial ischaemia and 2 h of reperfusion in the rat. The mechanisms of the cardioprotective effects of sCR1 or sCR1sLex are not entirely clear, but may be due complement inhibition and/or prevention of the adhesion and activation of neutrophils.

British Journal of Pharmacology (1999) 128, 945–952; doi:10.1038/sj.bjp.0702889
The involvement of protein kinase C in nitric oxide‐induced damage to rat isolated colonic mucosal cells
Authors: Tepperman B L , Chang Q , Soper B D
Published: January 2005

The role of protein kinase C (PKC) in colonic cellular injury in response to high concentrations of nitric oxide (NO) released from the donor, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP) was investigated.

Addition of SNAP (0.1–1000 μM) to the cellular suspension resulted in a dose‐dependent increase in the extent of damage to isolated colonic mucosal cells as assessed by Trypan blue dye uptake and release of the lysosmal enzyme, N‐acetyl‐β‐glucosaminidase. SNAP treatment also resulted in an increase in cellular total PKC activity. These increases were reduced or eliminated by pretreatment of the cells with the PKC antagonists staurosporine or GF 109203X or the NO scavenger, phenyl‐4,4,5,5,‐tetramethylimidazoline‐1‐oxyl 3‐oxide (PTIO).

PKC‐α, PKC‐δ, PKC‐ε and PKC‐ζ were detected in colonic cellular lysates by immunoblotting. However, only PKC‐ε protein was increased in response to SNAP treatment. Furthermore, SNAP treatment resulted in activation of PKC‐ε by causing translocation of the enzyme from the cytosolic to membrane fraction of the cell. This effect was eliminated if cells were preincubated with the NO scavenger, PTIO.

The extent of cellular damage in response to addition of SNAP to the incubation medium was enhanced by coincubation with the PKC activator, phorbol 12‐myristate 13‐acetate (PMA; 1 and 10 μM).

PKC activity and the extent of cell damage in response to SNAP were reduced by preincubation of the cells with the peroxyl scavenger, ebselen (0.01–10 μM).

These data suggest that the PKC‐ε isoform of the enzyme mediates NO‐induced damage to colonic mucosal cells. This response may occur, at least in part, due to peroxynitrite formation.

British Journal of Pharmacology (1999) 128, 1268–1274; doi:10.1038/sj.bjp.0702891
Contrasting EEG profiles elicited by antipsychotic agents in the prefrontal cortex of the conscious rat: antagonism of the effects of clozapine by modafinil
Authors: Sebban C , Tesolin‐Decros B , Millan M J , Spedding M
Published: January 2005

Power spectra (0–30 Hz) were recorded from transcortical electrodes implanted in prefrontal and sensorimotor cortex in conscious rats. For each animal, the spectra in the presence of a drug were divided by the spectra in the presence of vehicle to give a drug‐related differential display of the power spectra, the profile of EEG effects.

The profiles of a range of antipsychotic agents of different classes were compared. Haloperidol (0.5 mg kg−1 and 1 mg kg−1 s.c., peak 8–12 Hz), chlorpromazine (0.5 mg kg−1, i.p., peak 8 Hz), levomepromazine (1 mg kg−1, i.p., peak 8 Hz), quetiapine (2.5 mg kg−1, s.c., peak 9–12 Hz), sertindole (2.5 mg kg−1, s.c., peak 6–14 Hz), risperidone (0.5 and 1 mg kg−1 i.p., peak 9 Hz), clozapine (0.1, 0.2, 0.3 and 5 mg kg−1, s.c., peak 8 Hz) and MDL100907 (0.01 mg kg−1 s.c. peak 2 Hz) synchronized the EEG, increasing the power spectra between 2 and 30 Hz, although there were marked differences between the individual profile of EEG effects for each drug.

In contrast, the benzamides, sulpiride (7.5 and 15 mg kg−1 i.p.), and amisulpiride (1 and 15 mg kg−1 i.p.) caused marked asynchronous changes in the EEG. Raclopride (2.5 mg kg−1 i.p.), caused an initial peak at 9 Hz, but the effects of raclopride desynchronized over a 3 h time period.

Modafinil and apomorphine, administered alone, decreased the power spectra at frequencies higher than 4 Hz. Modafinil (62.4 mg kg−1, i.p.) selectively antagonized the effects of clozapine, but did not antagonize the effects of raclopride.

Different pharmacological classes of antipsychotic show synchronization or desynchronization of the EEG in the prefrontal cortex, with the benzamides showing a distinctive spectrum. There appears to be a specific interaction between modafinil and clozapine. Thus, modulation of prefrontal cortical function, perhaps by thalamic gating, may be important for antipsychotic activity.

British Journal of Pharmacology (1999) 128, 1055–1063; doi:10.1038/sj.bjp.0702893
Voltage‐dependent block of normal and mutant muscle sodium channels by 4‐Chloro‐m‐Cresol
Authors: Haeseler G , Leuwer M , Kavan J , Würz A , Dengler R , Piepenbrock S
Published: January 2005

The effects of 4‐Chloro‐m‐Cresol (4‐CmC) were examined on heterologously expressed wild type (WT), Paramyotonia Congenita (R1448H) and Hyperkalemic Periodic Paralysis (M1360V) mutant α‐subunits of human muscle sodium channels.

Block of rested sodium channels caused by 4‐CmC was concentration‐dependent with an ECR50 of 0.40 mM in WT, 0.45 mM in R1448H and 0.49 mM in M1360V.

Inactivation significantly promoted 4‐CmC‐induced sodium channel block in all clones indicated by 4‐CmC‐induced shifts of steady‐state availability curves, reflecting a higher proportion of channel block at depolarized membrane potentials. Channel block was almost complete (>90%) at concentrations close to the ECR50 (0.5 mM) on application of an inactivating prepulse before the test pulse.

4‐CmC accelerated the current decay following depolarization and prolonged recovery from inactivation in all clones. Of these, R1448H, the mutant which displayed severely impaired inactivation in the controls, responded to 4‐CmC with the most pronounced acceleration of inactivation. Control experiments revealed enhanced recovery from inactivation in the mutants, which was restored to normal in 0.1 mM 4‐CmC.

4‐CmC induced no additional frequency‐dependent block.

Our results clearly demonstrate that 4‐CmC is as effective as lidocaine (Fan et al., 1996) in blocking muscle sodium channels. Low concentrations of the compound (ECR50) were able to restore pathologically accelerated recovery from inactivation and impaired inactivation in the mutants to the WT value.

British Journal of Pharmacology (1999) 128, 1259–1267; doi:10.1038/sj.bjp.0702896
Nociceptin (1–7) antagonizes nociceptin‐induced hyperalgesia in mice
Authors: Sakurada Tsukasa , Sakurada Shinobu , Katsuyama Sou , Sakurada Chikai , Tan‐No Koichi , Terenius Lars
Published: January 2005

Nociceptin and its N‐terminal fragment, nociceptin (1–7), were administered intrathecally (i.t.) into conscious mice. Nociceptin (3.0 fmol) produced a significant reduction in the nociceptive thermal threshold (hyperalgesia) measured as the tail‐flick and paw‐withdrawal responses. Nociceptin (1–7), injected i.t., at 150–1200 fmol had no significant effect. However, when nociceptin (1–7) (150–1200 fmol) was injected simultaneously with nociceptin (3.0 fmol), nociceptin‐induced hyperalgesia was significantly reduced. Analgesia induced by a high dose (1200 pmol) of nociceptin was not antagonized by co‐administration of nociceptin (1–7) (1200 fmol). These results suggest that N‐terminal fragments of nociceptin formed endogenously could modulate the hyperalgesic action of nociceptin in the spinal cord.

British Journal of Pharmacology (1999) 128, 941–944; doi:10.1038/sj.bjp.0702898
Pharmacological similarities between native brain and heterologously expressed α4β2 nicotinic receptors
Authors: Shafaee Navid , Houng McCann , Truong Anthony , Viseshakul Nareerat , Figl Antonio , Sandhu Sumandeep , Forsayeth John R , Dwoskin Linda P , Crooks Peter A , Cohen Bruce N
Published: January 2005

We studied the pharmacological properties of native rat brain and heterologously expressed rat α4β2 nicotinic receptors immunoprecipitated onto a fixed substrate with the anti‐α4 antibody mAb 299.

Immunodepletion with the anti‐β2 antibody mAb 270 showed that 89% of the mAb‐299‐precipitated rat brain receptors contained β2.

The association and dissociation rate constants for 30 pM ±[3H]‐epibatidine binding to α4β2 receptors expressed in oocytes were 0.02±0.01 and 0.03±0.01 min−1 (±standard error, degrees of freedom=7–8) at 20–23°C.

The Hill coefficients for ±[3H]epibatidine binding to the native brain, α4β2 receptors expressed in oocytes, and α4β2 receptors expressed in CV‐1 cells (using recombinant adenovirus) were 0.69–0.70 suggesting a heterogeneous receptor population. Fits of the ±[3H]‐epibatidine concentration‐binding data to a two‐site model gave KD s of 8–30 and 560–1,200 pM. The high‐affinity sites comprised 73–74% of the native brain and oocyte α4β2 receptor population, 85% of the CV‐1 α4β2 receptor population.

The expression of rat α4β2 receptors in CV‐1 cells using vaccinia viral infection‐transfection resulted in a more homogeneous receptor population (Hill coefficient of 1.0±0.2). Fits of the ±[3H]‐epibatidine binding data to a single‐site model gave a KD of 40±3 pM.

DHβE (IC50=260–470 nM) and the novel nicotine analogue NDNI (IC50=7–10 μM) inhibited 30 pM±[3H]‐epibatidine binding to the native brain and heterologously expressed α4β2 receptors equally well.

The results show that α4β2‐containing nicotinic receptors in the rat brain and heterologously expressed rat α4β2 receptors have similar affinities for ±[3H]‐epibatidine, DHβE, and NDNI.

British Journal of Pharmacology (1999) 128, 1291–1299; doi:10.1038/sj.bjp.0702900
Efficient functional coupling of the human D3 dopamine receptor to Go subtype of G proteins in SH‐SY5Y cells
Authors: Zaworski Phillip G , Alberts Glen L , Pregenzer Jeffrey F , Im Wha Bin , Slightom Jerry L , Gill Gurnam S
Published: January 2005

The D3 dopamine receptor presumably activates Gi/Go subtypes of G‐proteins, like the structurally analogous D2 receptor, but its signalling targets have not been clearly established due to weak functional signals from cloned receptors as heterologously expressed in mostly non‐neuronal cell lines.

In this study, recombinant human D3 receptors expressed in a human neuroblastoma cell line, SH‐SY5Y, produced much greater signals than those expressed in a human embryonic kidney cell line, HEK293. Quinpirole, a prototypic agonist, markedly inhibited forskolin‐stimulated cyclic AMP production and Ca2+‐channel (N‐type) currents in SH‐SY5Y cells, and enhanced GTPγ35S binding in isolated membranes, nearly ten times greater than that observed in HEK293 cell membranes.

GTPγ35S‐bound Gα subunits from quinpirole‐activated and solubilized membranes were monitored upon immobilization with various Gα‐specific antibodies. Gαo subunits (not Gαi) were highly labelled with GTPγ35S in SH‐SY5Y, but not in HEK293 cell membranes, despite their abundance in the both cell types, as shown with reverse transcription‐polymerase chain reaction and Western blots. N‐type Ca2+ channels and adenylyl cyclase V (D3‐specific effector), on the other hand, exist only in SH‐SY5Y cells.

More efficient coupling of the D3 receptor to Go subtypes in SH‐SY5Y than HEK293 cells may be attributed, at least in part, to the two D3 neuronal effectors only present in SH‐SY5Y cells (N‐type Ca2+‐channels and adenylyl cyclase V). The abundance of Go subtypes in the both cell lines seems to indicate their availability not a limiting factor.

British Journal of Pharmacology (1999) 128, 1181–1188; doi:10.1038/sj.bjp.0702905
Roles of atypical protein kinase C in lysophosphatidic acid‐induced type II adenylyl cyclase activation in RAW 264.7 macrophages
Authors: Lin Wan‐Wan , Chang Sheng‐Ho , Wang Seu‐Mei
Published: January 2005

Lysophosphatidic acid (LPA) has been widely studied as a naturally occurring and multifunctional phospholipid messenger in diverse tissue and cell types and shown to inhibit adenylyl cyclase (AC) by a G protein‐mediated mechanism.

In type II AC‐expressing mouse RAW 264.7 macrophages, we showed that LPA at 3–50 μM increased cyclic AMP formation in a concentration‐dependent manner, the effect being additive with that of forskolin or cholera toxin, and synergistic with that of prostaglandin E1 (PGE1) or isoproterenol.

The potentiation effect of LPA was unaffected by the removal of serum or pertussis toxin treatment.

Both colchicine and cytochalasin B potentiated the cyclic AMP response to PGE1, the effect being additive to that of LPA.

On studying the regulation of type II AC by protein kinase C (PKC), phorbol 12‐myristate‐13 acetate (PMA) potentiated the PGE1‐elicited cyclic AMP response, this effect being non‐additive to that of LPA, suggesting that PKC activation was the common mechanism involved in AC potentiation by LPA and PMA.

PKC inhibitor Ro 31‐8220, but not Go 6976, significantly inhibited the LPA‐induced cyclic AMP potentiation.

The potentiation effect of LPA was unaffected by long‐term treatment with PMA, which resulted in the down‐regulation of PKCα, βI, βII and PKCδ, but not PKCε, μ, λ and ζ.

By in situ kinase assay, we found a marked increase in atypical PKC activity after LPA treatment.

Taken together, we conclude that LPA can elicit a unique signalling cascade in RAW 264.7 macrophages and increase type II AC activity via the activation of atypical PKC.

British Journal of Pharmacology (1999) 128, 1189–1198; doi:10.1038/sj.bjp.0702906
Identification of the G‐protein‐coupled ORL1 receptor in the mouse spinal cord by [35S]‐GTPγS binding and immunohistochemistry
Authors: Narita Minoru , Mizoguchi Hirokazu , Oji David E , Narita Michiko , Dun Nae J , Hwang Bang H , Nagase Hiroshi , Tseng Leon F
Published: January 2005

Although the ORL1 receptor is clearly located within the spinal cord, the functional signalling mechanism of the ORL1 receptor in the spinal cord has not been clearly documented. The present study was then to investigate the guanine nucleotide binding protein (G‐protein) activation mediated through by the ORL1 receptor in the mouse spinal cord, measuring the modulation of guanosine‐5′‐o‐(3‐[35S]‐thio) triphosphate ([35S]‐GTPγS) binding by the putative endogenous ligand nociceptin, also referred as orphanin FQ. We also studied the anatomical distribution of nociceptin‐like immunoreactivity and nociceptin‐stimulated [35S]‐GTPγS autoradiography in the spinal cord.

Immunohistochemical staining of mouse spinal cord sections revealed a dense plexus of nociceptin‐like immunoreactive fibres in the superficial layers of the dorsal horn throughout the entire length of the spinal cord. In addition, networks of fibres were seen projecting from the lateral border of the dorsal horn to the lateral grey matter and around the central canal.

In vitro [35S]‐GTPγS autoradiography showed high levels of nociceptin‐stimulated [35S]‐GTPγS binding in the superficial layers of the mouse dorsal horn and around the central canal, corresponding to the areas where nociceptin‐like immunoreactive fibres were concentrated.

In [35S]‐GTPγS membrane assay, nociceptin increased [35S]‐GTPγS binding of mouse spinal cord membranes in a concentration‐dependent and saturable manner, affording maximal stimulation of 64.1±2.4%. This effect was markedly inhibited by the specific ORL1 receptor antagonist [Phe1Ψ (CH2‐NH) Gly2] nociceptin (1–13) NH2. None of the μ‐, δ‐, and κ‐opioid and other G‐protein‐coupled receptor antagonists had a significant effect on basal or nociceptin‐stimulated [35S]‐GTPγS binding.

These findings suggest that nociceptin‐containing fibres terminate in the superficial layers of the dorsal horn and the central canal and that nociceptin released in these areas may selectively stimulate the ORL1 receptor to activate G‐protein. Furthermore, the unique pattern of G‐protein activation in the present study provide additional evidence that nociceptin is distinct from the μ‐, δ‐ or κ‐opioid system.

British Journal of Pharmacology (1999) 128, 1300–1306; doi:10.1038/sj.bjp.0702907
Characterization of the in vitro effects of 5‐hydroxytryptamine (5‐HT) on identified neurones of the rat dorsal motor nucleus of the vagus (DMV)
Authors: Browning Kirsteen N , Travagli R Alberto
Published: January 2005

Whole cell patch clamp techniques were used on thin brainstem slices to investigate the effects of 5‐hydroxytryptamine (5‐HT) on gastrointestinal‐projecting dorsal motor nucleus of the vagus (DMV) neurones. Neurones were identified as projecting to the stomach (n=122) or intestine (n=84) if they contained the fluorescent tracer Dil after it had been applied to the gastric fundus, corpus or antrum/pylorus or to the duodenum or caecum.

A higher proportion of intestinal neurones (69%) than gastric neurones (47%) responded to 5‐HT with a concentration‐dependent inward current which was antagonized fully by the 5‐HT2A receptor antagonist ketanserin (1 μM).

Stimulation of the nucleus tractus solitarius (NTS) induced inhibitory synaptic currents that were reduced in amplitude by application of the 5‐HT1A receptor agonist 8‐OHDPAT (1 μM) or the 5‐HT1A/1B receptor agonist TFMPP (1 μM) in 61% and 52% of gastric‐ and intestinal‐projecting neurones, respectively. 5‐HT also significantly reduced the frequency but not the amplitude of spontaneous inhibitory currents.

These data show that 5‐HT excites directly a larger proportion of intestinal projecting neurones than gastric‐projecting neurones, as well as inhibiting synaptic transmission from the NTS to the DMV. These data imply that the response to DMV neurones to 5‐HT may be determined and classified by their specific projections.

British Journal of Pharmacology (1999) 128, 1307–1315; doi:10.1038/sj.bjp.0702908
Effect of the nonpeptide neurotrophic compound SR 57746A on the phenotypic survival of purified mouse motoneurons
Authors: Duong F H T , Warter J M , Poindron P , Passilly P
Published: January 2005

Neurotrophic factors have been used for the treatment of several neurodegenerative diseases. However, their use is limited by their inability to cross the blood‐brain barrier, their short half life and their side effects. SR 57746A is a new orally active compound that exhibits in vivo and in vitro neurotrophic effects in several experimental models.

We show here that SR 57746A (1 μM) increases the phenotypic survival of embryonic purified mouse motoneurons in vitro to the same extent as brain‐derived neurotrophic factor (100 ng ml−1), and increases the outgrowth and number of their neurites. It acts in a dose‐dependent manner up to 1 μM which is the optimal concentration. Above this concentration, its neurotrophic effect decreases.

Genistein (10 μM), a protein tyrosine kinase inhibitor, also increases the phenotypic survival and differentiation of mouse motoneurons. It does not act in a synergistic or additive manner with SR 57746A. However, at concentrations equal or superior to 25 μM, it decreases the survival of motoneurons. This suggests that the neurotrophic effect of genistein is due to a favourable alteration of equilibrium between phosphorylated and dephosphorylated states of proteins involved in survival and differentiation of motoneurons.

Like genistein, SR 57746A should be used at a critical concentration (1 μM) to exert its optimal effects. Since SR 57746A does not act synergistically with genistein, it is likely that its mechanism of action involves a pathway similar to that affected by this tyrosine kinase inhibitor.

At the present time, SR 57746A is the only orally active compound and the only synthetic compound shown to be active on motoneurons in vitro. It should thus be considered as a good candidate for the treatment of motoneuron diseases.

British Journal of Pharmacology (1999) 128, 1385–1392; doi:10.1038/sj.bjp.0702910
Investigation of the subtypes of α1‐adrenoceptor mediating contractions of rat vas deferens
Authors: Honner Valerie , Docherty J R
Published: January 2005

The subtypes of α1‐adrenoceptor mediating contractions of rat vas deferens to endogenous and exogenous noradrenaline and to the exogenous agonists methoxamine, phenylephrine and A61603 have been examined.

The effects of antagonists on the shape of concentration‐response curves, both tonic and phasic, to the four agonists were analysed. Prazosin produced parallel shifts in all cases. Particularly for RS 17053 against noradrenaline, there was some evidence for a resistant component of the agonist response. High concentrations of RS 17053 (1–10 μM) virtually abolished tonic contractions but phasic contractions were resistant.

A series of nine antagonists (the above and WB4101, benoxathian, phentolamine, BMY 7378, HV 723, spiperone) were investigated against contractions to noradrenaline. The correlation with the potency of the series of α1‐adrenoceptor antagonists against contractions to noradrenaline was significant only for the α1A‐adrenoceptor ligand binding site (r=0.88, n=9, P<0.01).

In epididymal portions (nifedipine 10 μM), the isometric contraction to a single electrical pulse is α1‐adrenoceptor mediated. The correlation with ligand binding sites for 11 antagonists (the above plus ARC 239 and (+)‐niguldipine) was significant only for the α1D‐adrenoceptor subtype (r=0.65, n=11, P<0.05).

In conclusion, tonic contractions of rat vas deferens produced by exogenous agonists are mediated predominantly by α1A‐adrenoceptors, although a second subtype of receptor may additionally be involved in phasic contractions. Nerve‐stimulation evoked α1‐adrenoceptor mediated contractions seem to predominantly involve non‐α1A‐adrenoceptors, and the receptor involved resembles the α1D‐receptor.

British Journal of Pharmacology (1999) 128, 1323–1331; doi:10.1038/sj.bjp.0702913
Perindopril, an angiotensin converting enzyme inhibitor, in pulmonary hypertensive rats: comparative effects on pulmonary vascular structure and function
Authors: Jeffery Trina K , Wanstall Janet C
Published: January 2005

Hypoxic pulmonary hypertension in rats (10% O2, 4 weeks) is characterized by changes in pulmonary vascular structure and function. The effects of the angiotensin converting enzyme inhibitor perindopril (oral gavage, once daily for the 4 weeks of hypoxia) on these changes were examined.

Perindopril (30 mg kg−1 d−1) caused an 18% reduction in pulmonary artery pressure in hypoxic rats.

Structural changes (remodelling) in hypoxic rats included increases in (i) critical closing pressure in isolated perfused lungs (remodelling of arteries <50 μm o.d.) and (ii) medial wall thickness of intralobar pulmonary arteries, assessed histologically (vessels 30–100 and 101–500 μm o.d.). Perindopril 10 and 30 mg kg−1 d−1 attenuated remodelling in vessels 100 μm (lungs and histology), 30 mg kg−1 d−1 was effective in vessels 101–500 μm but neither dose prevented hypertrophy of main pulmonary artery. 3 mg kg−1 d−1 was without effect.

Perindopril (30 mg kg−1 d−1) prevented the exaggerated hypoxic pulmonary vasoconstrictor response seen in perfused lungs from hypoxic rats but did not prevent any of the functional changes (i.e. the increased contractions to 5‐HT, U46619 (thromboxane‐mimetic) and K+ and diminished contractions to angiotensins I and II) seen in isolated intralobar or main pulmonary arteries. Acetylcholine responses were unaltered in hypoxic rats.

We conclude that, in hypoxic rats, altered pulmonary vascular function is largely independent of remodelling. Hence any drug that affects only remodelling is unlikely to restore pulmonary vascular function to normal and, like perindopril, may have only a modest effect on pulmonary artery pressure.

British Journal of Pharmacology (1999) 128, 1407–1418; doi:10.1038/sj.bjp.0702923
Studies on the acute and chronic effects of reboxetine on extracellular noradrenaline and other monoamines in the rat brain
Authors: Sacchetti G , Bernini M , Bianchetti A , Parini S , Invernizzi R W , Samanin R
Published: January 2005

The effect of reboxetine, a novel antidepressant drug that potently and selectively inhibits neuronal noradrenaline (NA) uptake, on brain extracellular monoamines was studied by microdialysis.

Fifteen mg kg−1 i.p. reboxetine raised extracellular NA in the frontal cortex (by 242%) and dorsal hippocampus (by 240%).

Idazoxan (1 mg kg−1 s.c.), given 60 min after 15 mg kg−1 reboxetine, markedly potentiated the effect on extracellular NA in the frontal cortex (by 1580%) and dorsal hippocampus (by 1360%), but had no effect by itself.

Twenty‐four hours after the last injection of a chronic schedule (15 mg kg−1 i.p. once daily for 14 days) reboxetine had no effect on basal extracellular concentrations of NA in the dorsal hippocampus and a challenge dose of reboxetine (15 mg kg−1) raised extracellular NA similarly in rats treated chronically with reboxetine (by 353%) and saline (by 425%).

Ten and 20 μg kg−1 i.p. clonidine dose‐dependently reduced hippocampal extracellular NA similarly in rats given chronic reboxetine (by 32% and 57%) and saline (by 42% and 56%).

Extracellular concentrations of dopamine and 5‐HT in the striatum were similar in rats treated chronically with reboxetine and saline. A challenge dose of reboxetine (15 mg kg−1) had no effect on striatal extracellular dopamine and slightly increased striatal extracellular 5‐HT to a similar extent in rats treated chronically with reboxetine (by 137%) and saline (by 142%).

The results suggest that combining reboxetine with an α2‐adrenoceptor antagonist may facilitate its antidepressant activity. Repeated treatment confirmed that reboxetine is fairly selective for the noradrenergic system but provided no evidence of adaptive changes in that system that could facilitate its effect on extracellular NA.

British Journal of Pharmacology (1999) 128, 1332–1338; doi:10.1038/sj.bjp.0702926
Direct myocardial anti‐ischaemic effect of GTN in both nitrate‐tolerant and nontolerant rats: a cyclic GMP‐independent activation of KATP
Authors: Csont Tamás , Szilvássy Zoltán , Fülöp Ferenc , Nedeianu Saviana , Páli Tibor , Tosaki Árpád , Dux László , Ferdinandy Péter
Published: January 2005

We have recently demonstrated that glyceryl trinitrate (GTN) exerts a direct myocardial anti‐ischaemic effect in both GTN‐tolerant and nontolerant rats. Here we examined if this effect is mediated by GTN‐derived nitric oxide (NO) and involves guanosine 3′5′ cyclic monophosphate (cyclic GMP) and ATP‐sensitive K+ channels (KATP).

Rats were treated with 100 mg kg−1 GTN or vehicle s.c. three times a day for 3 days to induce vascular GTN‐tolerance or nontolerance. Isolated working hearts obtained from either GTN‐tolerant or nontolerant rats were subjected to 10 min coronary occlusion in the presence of 10−7 M GTN or its solvent.

GTN improved myocardial function and reduced lactate dehydrogenase (LDH) release during coronary occlusion in both GTN‐tolerant and nontolerant hearts.

Cardiac NO content significantly increased after GTN administration in both GTN‐tolerant and nontolerant hearts as assessed by electron spin resonance. However, cardiac cyclic GMP content measured by radioimmunoassay was not changed by GTN administration.

When hearts from both GTN‐tolerant and nontolerant rats were subjected to coronary occlusion in the presence of the KATP‐blocker glibenclamide (10−7 M), the drug itself did not affect myocardial function and LDH release, however, it abolished the anti‐ischaemic effect of GTN.

We conclude that GTN opens KATP via a cyclic GMP‐independent mechanism, thereby leading to an anti‐ischaemic effect in the heart in both GTN‐tolerant and nontolerant rats.

British Journal of Pharmacology (1999) 128, 1427–1434; doi:10.1038/sj.bjp.0702929
Therapeutic index for rosiglitazone in dietary obese rats: separation of efficacy and haemodilution
Authors: Pickavance L C , Tadayyon M , Widdowson P S , Buckingham R E , Wilding J P H
Published: January 2005

The blood glucose‐lowering efficacy of rosiglitazone (RSG) and the mechanisms of associated weight gain were determined in dietary obese rats (DIOs). DIO and chow‐fed rats received RSG 0.3–30 mg kg−1 daily for 21 days.

In DIOs, plasma glucose and insulin concentrations were reduced by RSG at dosages of 3 and 10 mg kg−1, respectively. Homeostasis model assessment (HOMA) indicated the threshold for a reduction of insulin resistance was 1 mg kg−1. Neither glucose nor insulin levels were affected by treatment in chow‐fed rats.

RSG 0.3 mg kg−1 lowered free fatty acids (FFAs) in DIOs, whereas for plasma triglycerides (TGs), the threshold was 3 mg kg−1. By contrast, the threshold for reducing packed red cell volume (PCV) and increasing cardiac mass was 10 mg kg−1. Thus, the therapeutic index for RSG in DIOs was >3 and 10.

Energy intake and weight gain increased in treated DIOs (by 20% and 50 g, at 30 mg kg−1) and chow‐fed rats (by 25% and 35 g, at 30 mg kg−1). In DIOs, these increases coincided with falls in plasma leptin (40% lower at 30 mg kg−1) and insulin (43% lower at 30 mg kg−1). By contrast, in chow‐fed rats, weight gain and hyperphagia occurred without changes in either leptin or insulin. However, reductions in FFAs below 0.4–0.3 mM were associated with hyperphagia and weight gain in DIO and chow‐fed rats.

We conclude that increased energy intake and body weight did not attenuate the improved metabolism evoked by RSG in DIO rats, and that insulin action was enhanced at a dose >3 fold below the threshold for causing haemodilution and cardiac hypertrophy in DIO rats.

British Journal of Pharmacology (1999) 128, 1570–1576; doi:10.1038/sj.bjp.0702932
Effect of Gd3+ on bradykinin‐induced catecholamine secretion from bovine adrenal chromaffin cells
Authors: Bales Peter J R , Zerbes Mariann , Powis David A , Marley Philip D
Published: January 2005

The effects of Gd3+ on bradykinin‐ (BK‐) induced catecholamine secretion, 45Ca2+ efflux and cytosolic [Ca2+] were studied using bovine adrenal chromaffin cells.

BK increased secretion in a Ca2+‐dependent manner. From 1–100 μM, Gd3+ progressively inhibited secretion induced by 30 nM BK to near‐basal levels, however from 0.3–3 mM Gd3+ dramatically enhanced BK‐induced secretion to above control levels. Gd3+ also increased basal catecholamine secretion by 2–3 fold at 1 mM. These effects were mimicked by Eu3+ and La3+.

Gd3+ enhanced secretion induced by other agonists that mobilize intracellular Ca2+ stores, but simply blocked the response to K+.

Gd3+ still enhanced basal and BK‐induced secretion in Ca2+‐free solution or in the presence of 30 μM SKF96365, however both effects of Gd3+ were abolished after depleting intracellular Ca2+ stores.

Gd3+ (1 mM) reduced the rate of basal 45Ca2+ efflux by 57%. In Ca2+‐free buffer, BK transiently increased cytosolic [Ca2+] measured with Fura‐2. The [Ca2+] response to BK was substantially prolonged in the presence of Gd3+ (1 mM).

The results suggest that Gd3+ greatly enhances the efficacy of Ca2+ released from intracellular stores in evoking catecholamine secretion, by inhibiting Ca2+ extrusion from the cytosol. This suggests that intracellular Ca2+ stores are fully competent to support secretion in chromaffin cells to levels comparable to those evoked by extracellular Ca2+ entry. Drugs that modify Ca2+ extrusion from the cell, such as lanthanide ions, will be useful in investigating the mechanisms by which intracellular Ca2+‐store mobilization couples to Ca2+‐dependent exocytosis.

British Journal of Pharmacology (1999) 128, 1435–1444; doi:10.1038/sj.bjp.0702933
Pharmacological activation of the ryanodine receptor in Jurkat T‐lymphocytes
Authors: Hohenegger Martin , Berg Ingeborg , Weigl Lukas , Mayr Georg W , Potter Barry V L , Guse Andreas H
Published: January 2005

Recently, we provided evidence for cyclic adenosine 5′‐diphosphate‐ribose, cADP‐ribose, as a second messenger in Jurkat T‐lymphocytes upon stimulation of the T‐cell receptor/CD3‐ complex (Guse et al., 1999). cADP‐ribose mobilizes Ca2+ from an intracellular Ca2+ store which is sensitive to caffeine and gated by the ryanodine receptor/Ca2+ release channel. In the present study we investigated the ability of the trypanocidal drug, suramin, to activate the ryanodine receptor of T‐cells. Since suramin cannot permeate the plasma membrane, it was necessary to microinject the drug into Fura‐2 loaded T‐lymphocytes.

In a dose dependent manner suramin increased the intracellular Ca2+ concentration. The dose‐response curve is very steep and calculates for an EC50 of 7.6±2.9 mM suramin in the injection pipette.

Co‐injection of the selective ryanodine receptor inhibitor ruthenium red completely abolished the suramin induced Ca2+ transient. This finding allows for the conclusion that the IP3‐receptor sensitive Ca2+ pool is not the primary target of the suramin induced Ca2+ transient.

Furthermore, Ins(1,4,6)PS3, an antagonist of the InsP3‐receptor could not suppress the suramin‐induced Ca2+ signal. The suramin induced Ca2+ transients declined very slowly; however, in the presence of Ins(1,4,6)PS3 this decay was accelerated. In addition, suramin did not interact with the cADP‐ribose binding site of the ryanodine receptor of T‐cells.

In conclusion, suramin is found to be an agonist for the T‐cell ryanodine receptor as previously found for the cardiac and skeletal muscle isoform. Therefore, suramin can be designated a universal ryanodine receptor agonist.

British Journal of Pharmacology (1999) 128, 1235–1240; doi:10.1038/sj.bjp.0702935