bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential inhibitory mechanism of cyclic AMP on TNF‐α and IL‐12 synthesis by macrophages exposed to microbial stimuli
Authors: Procópio Daniela O , Teixeira Mauro M , Camargo Maristela M , Travassos Luiz R , Ferguson Michael A J , Almeida Igor C , Gazzinelli Ricardo T
Published: January 2005

Microbial stimuli such as bacterial lipopolysaccharide (LPS) or glycosylphosphatidylinositol‐mucins derived from Trypanosoma cruzi trypomastigotes (tGPI‐mucins) are effective stimulators of the synthesis of cytokines by macrophages. Here, we evaluated the ability of cyclic AMP mimetic or elevating agents to modulate TNF‐α and IL‐12 synthesis by murine inflammatory macrophages.

Cholera Toxin (ChTx) inhibited tGPI‐mucins (2.5 nM) or LPS (100 ng ml−1) induced TNF‐α and IL‐12(p40) synthesis in a concentration‐dependent manner. Similarly, the cyclic AMP mimetics, 8‐bromo cyclic AMP or dibutyryl cyclic AMP, or prostaglandin (PG) E2 inhibited the synthesis of both cytokines by macrophages exposed to microbial stimuli.

The protein kinase A inhibitor H‐89 partially reversed the inhibitory effects of dibutyryl cyclic AMP and PGE2 on both IL‐12(p40) and TNF‐α synthesis.

Pretreatment of macrophages with dibutyryl cyclic AMP or ChTx augmented the synthesis of IL‐10 triggered by microbial products. Elevation of cyclic AMP inhibited the synthesis of TNF‐α, but not IL‐12(p40), by inflammatory macrophages from IL‐10 knockout mice.

Kinetic studies showed that synthesis of both TNF‐α and IL‐10 peaked at 8 h and IL‐12 at 24 h after stimulation with microbial stimuli.

Together, our findings favour the hypothesis that the cyclic AMP inhibitory activity on IL‐12(p40) but not on TNF‐α synthesis is dependent on de novo protein synthesis, most likely involving IL‐10, by macrophages stimulated with microbial products. Accordingly, dibutyryl cyclic AMP inhibited IL‐12(p40) synthesis only when added before or at the same time of the stimuli. In contrast, the effect of this cyclic AMP analogue on TNF‐α synthesis was protracted and observed even 2 h after the addition of the stimuli.

British Journal of Pharmacology (1999) 127, 1195–1205; doi:10.1038/sj.bjp.0702624
Inhibition of GTPase activity of Gi proteins and decreased agonist affinity at M2 muscarinic acetylcholine receptors by spermine and methoctramine
Authors: Daeffler Laurent , Chahdi Ahmed , Gies Jean‐Pierre , Landry Yves
Published: January 2005

The effects of spermine and methoctramine, a selective M2 muscarinic receptor antagonist, were studied on the high‐affinity GTPase activity of G proteins, and on ligand binding to M2 muscarinic receptors in pig heart sarcolemma.

The spontaneous GTP hydrolysis by pig heart sarcolemma and its stimulation by mastoparan or carbachol were prevented by pertussis toxin and inhibited by methoctramine (IC50s: 21, 13 and 0.005 μM, respectively), and spermine (IC50s: 967, 278 and 11 μM). Spermine and methoctramine also inhibited spontaneous GTP hydrolysis by rat peritoneal mast cell membranes which do not respond to carbachol.

The neutral muscarinic antagonists, AF‐DX 116 and atropine, did not modify the inhibitory effect of high concentrations of methoctramine, indicating that this effect was not related to the antagonist binding site of muscarinic receptors. We suggest that methoctramine behaves as a receptor antagonist at nanomolar concentrations and interacts with G proteins at micromolar concentrations.

Spermine did not modify the binding of the tritiated muscarinic antagonist [3H]‐NMS, but decreased the binding of the agonist [3H]‐Oxo‐M. Spermine elicited a rightward shift of the carbachol/[3H]‐NMS binding isotherm with a decrease in the proportion of sites with high‐affinity for carbachol, suggesting that polyamines uncouple Gi proteins from receptors.

The inhibition of GTPase activity by polyamines, preventing the re‐association of α and βγ subunits of Gi proteins, might sustain the regulatory effect of Gi subunits on downstream effectors. The level of intracellular polyamines might be important for the control of the transduction of extracellular signals through Gi protein‐coupled receptors.

British Journal of Pharmacology (1999) 127, 1021–1029; doi:10.1038/sj.bjp.0702625
IL‐2 and IL‐4 counteract budesonide inhibition of GM‐CSF and IL‐10, but not of IL‐8, IL‐12 or TNF‐α production by human mononuclear blood cells
Authors: Larsson Susanne , Löfdahl Claes‐Göran , Linden Margareta
Published: January 2005

The combination of interleukin‐2 (IL‐2) and IL‐4 reduces the inhibitory effects of glucocorticoids on granulocytemacrophage colonystimulating factor (GM‐CSF) production, in agreement with the hypothesis that this combination causes glucocorticoid resistance. Whether a general cytokine resistance to glucocorticoids is induced by IL‐2 and IL‐4 has not been reported.

Mononuclear blood cells from healthy individuals were pretreated with IL‐2, IL‐4, or IL‐2+ IL‐4 (31.3–500 U ml−1) for 48 h, prior to lipopolysaccharide (LPS; 10 ng ml−1; 20 h) and budesonide addition. Cytokine levels in the supernatants were analysed using specific immunoassays. DNA content was analysed to estimate cell numbers.

GM‐CSF production was totally inhibited by budesonide at 10−8 M in vehicle treated cultures, while IL‐10 was inhibited to 33.4±4.3% of control. IL‐2, IL‐4, or IL‐2+IL‐4 reduced the inhibitory effects of budesonide on GM‐CSF to similar levels (23.7±6.7, 31.6±8.5 and 35.1±4.3% of control, respectively). IL‐2, IL‐4, or IL‐2+IL‐4 also reduced the inhibitory effects of budesonide on IL‐10 production (46.5±6.6, 55.9±7.3%, and 68.3±9.9% of control, respectively). In contrast, IL‐8, IL‐12 and TNF‐α production did not become resistant to budesonide.

Thus, glucocorticoid resistance induced by IL‐2 and IL‐4 is not general at the cytokine production level. While the glucocorticoid sensitivity of GM‐CSF and IL‐10 production decreased, the sensitivity of IL‐8, IL‐12 or TNF‐α production was unchanged. Also, the mixture of IL‐2 and IL‐4 is not crucial for induction of glucocorticoid resistance of GM‐CSF production.

British Journal of Pharmacology (1999) 127, 980–986; doi:10.1038/sj.bjp.0702631
Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro
Authors: Vaughan Christopher W , McGregor Iain S , Christie MacDonald J
Published: January 2005

The rostral ventromedial medulla (RVM) is thought to play a crucial role in the antinociceptive actions of cannabinoids. This study examined the actions of the cannabinoid receptor agonist, WIN55,212‐2, on membrane properties and GABAergic synaptic transmission in RVM neurons using whole cell patch clamp recordings in brain slices.

WIN55,212‐2 (3 μM) had no effect on membrane K+ conductance of primary or secondary RVM neurons. Primary neurons responded to the κ‐opioid receptor agonist U69,593 (300 nM–1 μM). Secondary neurons responded to the μ,δ‐opioid receptor agonist met‐enkephalin (10 μM).

WIN55,212‐2 reduced the amplitude of electrically evoked (GABAergic) inhibitory postsynaptic currents (IPSCs) in all neurons (58%, pEC50=6.2±0.1). The inhibition was reversed by the CB1 receptor selective antagonist, SR141716 (3 μM). WIN55,212‐2 also produced relative facilitation of the second IPSC to paired evoked IPSCs.

WIN55,212‐2 and met‐enkephalin reduced the rate of spontaneous miniature IPSCs in all cells (44 and 53%), but had no effect on their amplitude distributions or kinetics.

These results suggest that the antinociceptive actions of cannabinoids within RVM are primarily due to presynaptic inhibition of GABAergic neurotransmission. The neuronal substrates of cannabinoid actions in RVM therefore differ from those of opioids, which have both pre‐ and postsynaptic inhibitory actions.

British Journal of Pharmacology (1999) 127, 935–940; doi:10.1038/sj.bjp.0702636
Mechanisms of noradrenaline‐induced vasorelaxation in isolated femoral arteries of the neonatal rat
Authors: Nishina H , Ozaki T , Hanson M A , Poston L
Published: January 2005

Isolated arteries from the femoral circulation of Wistar rats mounted on a small vessel myograph demonstrated age related tension development to noradrenaline (NA, 1×10−8–5×10−5 M) day 20 greater than day 10 (P < 0.005); day 100 greater than day 20 (P < 0.001) and depolarizing potassium (125 mM) buffer day 20 greater than day 10 (P < 0.001). NA evoked dilatation in femoral arteries from neonatal rats (10 days) when added to unstimulated vessels or to those preconstricted with the thromboxane mimetic, U46619. Relaxation to NA was inhibited by L‐NAME (0.1 mM) (P < 0.001), endothelial removal (P < 0.001) and the α2‐adrenoceptor antagonist, yohimbine (0.1 μM) (P < 0.001). α1‐ or β‐adrenoceptor antagonism was without effect. Relaxation was evoked in femoral arteries of the 10‐day‐old rats by the α2‐adrenoceptor agonist UK14304 (1×10−8–5×10−5 M). This relaxation was also abolished by L‐NAME (0.1 mM) (P < 0.001) or endothelial removal (P < 0.001). α2‐adrenoceptor‐mediated vasorelaxation was the predominant response to NA stimulation in femoral arteries of the neonatal rat. These responses were endothelium‐dependent and were NO‐mediated.

British Journal of Pharmacology (1999) 127, 809–812; doi:10.1038/sj.bjp.0702641
Separation of M‐like current and ERG current in NG108‐15 cells
Authors: Meves Hans , Schwarz Jürgen R , Wulfsen Iris
Published: January 2005

Differentiated NG108‐15 neuroblastoma×glioma hybrid cells were whole‐cell voltage‐clamped. Hyperpolarizing pulses, superimposed on a depolarized holding potential (−30 or −20 mV), elicited deactivation currents which consisted of two components, distinguishable by fitting with two exponential functions.

Linopirdine [DuP 996, 3,3‐bis(4‐pyridinylmethyl)‐1‐phenylindolin‐2‐one), a neurotransmitter‐release enhancer known as potent and selective blocker of the M‐current of rat sympathetic neurons, in concentrations of 5 or 10 μM selectively inhibited the fast component (IC50=14.7 μM). The slow component was less sensitive to linopirdine (IC50>20 μM).

The class III antiarrhythmics [(4‐methylsulphonyl)amido]benzenesulphonamide (WAY‐123.398) and 1‐[2‐(6‐methyl‐2‐pyrydinil)ethyl]‐4‐(4‐methylsulphonylaminobenzoyl) piperidine (E‐4031), selective inhibitors of the inwardly rectifying ERG (ether‐à‐go‐go‐related gene) potassium channel, inhibited predominantly the slow component (IC50=38 nM for E‐4031). The time constant of the WAY‐123.398‐sensitive current resembled the time constant of the slow component in size and voltage dependence.

Inwardly rectifying ERG currents, recorded in K+‐rich bath at strongly negative pulse potentials, resembled the slow component of the deactivation current in their low sensitivity to linopirdine (28% inhibition at 50 μM).

The size of the slow component varied greatly between cells. Accordingly, varied the effect of WAY‐123.398 on deactivation current and holding current.

RNA transcripts for the following members of the ether‐à‐go‐go gene (EAG) K+ channel family were found in differentiated NG108‐15 cells: ERG1, ERG2, EAG1, EAG‐like (ELK)1, ELK2; ERG3 was only present in non‐differentiated cells. In addition, RNA transcripts for KCNQ2 and KCNQ3 were found in differentiated and non‐differentiated cells.

We conclude that the fast component of the deactivation current is M‐like current and the slow component is deactivating ERG current. The molecular correlates are probably KCNQ2/KCNQ3 and ERG1/ERG2, respectively.

British Journal of Pharmacology (1999) 127, 1213–1223; doi:10.1038/sj.bjp.0702642
Rundown of somatodendritic N‐methyl‐D‐aspartate (NMDA) receptor channels in rat hippocampal neurones: evidence for a role of the small GTPase RhoA
Authors: Nörenberg Wolfgang , Hofmann Fred , Illes Peter , Aktories Klaus , Meyer Dieter K
Published: January 2005

Actin filament (F‐actin) depolymerization leads to the use‐dependent rundown of N‐methyl‐D‐aspartate (NMDA) receptor activity in rat hippocampal neurones. Depolymerization is promoted by Ca2+ which enters the cells via NMDA receptor channels. The ras homologue (Rho) GTPases (RhoA, Rac1 and Cdc42) promote actin polymerization and thus control the actin cytoskeleton. We have investigated, by means of the whole‐cell patch clamp technique, whether the actin fibres which interact with NMDA receptors are controlled by Rho GTPases.

In the presence of intracellular ATP which attenuates rundown, the C3 toxin from Clostridium (C.) botulinum was used to inactivate RhoA. Indeed, it enhanced the use‐dependent rundown of NMDA‐evoked inward currents to a level similar to that obtained in the absence of ATP.

Lethal toxin from Clostridium sordellii which inactivates Rac1 and Cdc42 lacked this effect.

We suggest that the function of somatodendritic NMDA receptor channels in rat hippocampal neurones can be modulated by RhoA via its action on F‐actin.

British Journal of Pharmacology (1999) 127, 1060–1063; doi:10.1038/sj.bjp.0702643
Pharmacological characterization of endothelin receptor subtypes in the guinea‐pig prostate gland
Authors: Lau Winnie A K , Cox Sandra L , Pennefather Jocelyn N , Mitchelson Fred J
Published: January 2005

Experiments have been conducted to investigate the actions of endothelins on the guinea‐pig prostate gland.

Saturation experiments with [125I]‐endothelin‐1 (2–800 pM) in guinea‐pig prostatic homogenates indicated the presence of high affinity binding sites with an equilibrium dissociation constant (KD) of 230±50 pM, a maximum number of binding sites (Bmax) of 52±16 fmol mg−1 protein or 269±61 fmol g−1 tissue and a Hill coefficient (nH) of 1.01±0.03 (n=3). Competition experiments revealed that binding of [125I]‐endothelin‐1 (20 pM) was inhibited with the following order of potency: endothelin‐1 >>BQ‐788 (N‐cis‐2,6‐dimethylpiperidinocarbonyl‐L‐γ‐methyl‐Leu‐D‐Trp[1‐CO2CH3‐D‐Nle‐ONa])>BQ‐123 (cyclo‐D‐Asp‐L‐Pro‐D‐Val‐Leu‐D‐Trp) sarafotoxin S6c.

At concentrations with negligible influence on smooth muscle tone, endothelin‐1, endothelin‐2 and sarafotoxin S6b (1 nM–0.1 μM) produced concentration‐dependent potentiation of the contractions evoked by electrical field stimulation with trains of 20 pulses at 10 Hz every 50 s, 0.5 ms pulse width and a dial setting of 60 V. In contrast, the endothelin ETB receptor‐preferring agonist endothelin‐3 (1 nM–1 μM) was much less potent, and the endothelin ETB receptor‐selective agonists sarafotoxin S6c and BQ‐3020 (Ac‐[Ala11,15]‐endothelin‐1 (6–21)), up to 1 μM, were without effect.

The endothelin ETA receptor antagonist BQ‐123 (1 μM) markedly inhibited the potentiation induced by endothelin‐1, endothelin‐2 and sarafotoxin S6b while the endothelin ETB receptor antagonist BQ‐788 (1 μM) was less effective.

While our binding data indicates the presence of ETA and ETB binding sites in the guinea‐pig prostate, the endothelin‐induced facilitation of neurotransmission to the prostatic smooth muscle is mediated largely via activation of endothelin receptors of the ETA subtype.

British Journal of Pharmacology (1999) 127, 1091–1098; doi:10.1038/sj.bjp.0702644
Functional characterization and m‐RNA expression of 5‐HT receptors mediating contraction in human umbilical artery
Authors: Lovren Fina , Li Xiao‐Fang , Lytton Jonathan , Triggle Chris
Published: January 2005

5‐HT1‐like and 5‐HT2 receptors have both been described to mediate contractions to 5‐HT in the human umbilical artery (HUA). However, the nature of the 5‐HT receptor subtypes is unknown.

In isometric force studies with ring preparations of HUA α‐methyl‐5‐hydroxytryptamine (α‐Me‐5‐HT) and 5‐hydroxytryptamine (5‐HT) contracted HUA with pED50 values of 8.04 and 7.74, respectively. In the presence of a subthreshold concentration of another vasoconstrictor sumatriptan and 5‐nonyloxytryptamine elicited concentration‐dependent contractions with pEC50 values of 7.21 and 7.67, respectively.

In the presence of the selective 5‐HT1B/D receptor antagonist GR127935, contractile responses elicited by sumatriptan and 5‐nonyloxytryptamine were competitively antagonized (pKB 9.01 and 9.02, respectively). In the experiments with 5‐HT, GR127935 appeared to be non‐competitive with shallow Schild plot slopes. The data were fitted with two linear regression lines and the calculated pKB of the high affinity component (8.90) was comparable to that expected for GR127935 at the 5‐HT1B/1D receptor.

Several 5‐HT2 selective receptor antagonists (spiperone, cyproheptadine, pirenperone) competitively inhibited responses to 5‐HT. The selective 5‐HT2A antagonist ketanserin against sumatriptan and 5‐nonyloxytryptamine behaved as a weak antagonist while against 5‐HT demonstrated a competitive antagonism (pKB 8.56).

Using specific primers for human 5‐HT1B, 5‐HT1D and 5‐HT2A receptor genes, the reverse transcriptase‐polymerase chain reaction revealed mRNA expression of 5‐HT1B and 5‐HT2A receptors in the HUA.

The results suggest that the HUA has a functional population of 5‐HT1B and 5‐HT2A receptor subtypes which are involved in the contractile response to 5‐HT. Contractions mediated by 5‐HT1B receptors can be ‘uncovered’ by exposure to other vasoactive agents.

British Journal of Pharmacology (1999) 127, 1247–1255; doi:10.1038/sj.bjp.0702647
Regulation of epidermal homeostasis through P2Y2receptors
Authors: Dixon C Jane , Bowler Wayne B , Littlewood‐Evans Amanda , Dillon Jane P , Bilbe Graeme , Sharpe Graham R , Gallagher James A
Published: January 2005

Previous studies have indicated a role for extracellular ATP in the regulation of epidermal homeostasis. Here we have investigated the expression of P2Y2receptors by human keratinocytes, the cells which comprise the epidermis.

Reverse transcriptase‐polymerase chain reaction (RT–PCR) revealed expression of mRNA for the G‐protein‐coupled, P2Y2receptor in primary cultured human keratinocytes.

In situhybridization studies of skin sections revealed that P2Y2receptor transcripts were expressed in the native tissue. These studies demonstrated a striking pattern of localization of P2Y2receptor transcripts to the basal layer of the epidermis, the site of cell proliferation.

Increases in intracellular free Ca2+concentration ([Ca2+]i) in keratinocytes stimulated with ATP or UTP demonstrated the presence of functional P2Y receptors.

In proliferation studies based on the incorporation of bromodeoxyuridine (BrdU), ATP, UTP and ATPγS were found to stimulate the proliferation of keratinocytes.

Using a real‐time firefly luciferase and luciferin assay we have shown that under static conditions cultured human keratinocytes release ATP.

These findings indicate that P2Y2receptors play a major role in epidermal homeostasis, and may provide novel targets for therapy of proliferative disorders of the epidermis, including psoriasis.

British Journal of Pharmacology(1999)127, 1680–1686; doi:10.1038/sj.bjp.0702653
Induction of eotaxin expression and release from human airway smooth muscle cells by IL‐1β and TNFα: effects of IL‐10 and corticosteroids
Authors: Chung K Fan , Patel Hema J , Fadlon Emma J , Rousell Jonathan , Haddad El‐Bdaoui , Jose Peter J , Mitchell Jane , Belvisi Maria
Published: January 2005

Eotaxin is a novel C‐C chemokine with selective chemoattractant activity for eosinophils. We determined whether eotaxin could be produced by human airway smooth muscle (HASM) cells in culture and examined its regulation by interleukin‐10 (IL‐10) and the corticosteroid, dexamethasone.

Stimulation of the cells with interleukin‐1β (IL‐1β) or tumour necrosis factor (TNFα) each at 10 ng ml−1 induced the release of eotaxin protein with maximal accumulation by 24 h. Interferon‐γ (IFNγ) alone at 10 ng ml−1 had no effect and there was no synergy between these cytokines on the release of eotaxin.

Reverse phase high performance liquid chromatographic (HPLC) analysis of supernatents from cells treated with TNFα (10 ng ml−1 for 96 h showed immunoreactivity to eotaxin which eluted with the expected retention time of 34.5–35 min.

Both IL‐1β and TNFα‐induced release of eotaxin was not inhibited by dexamethasone (1 μM), however IL‐10 (10 ng ml−1) had a significant inhibitory effect. Dexamethasone and IL‐10 did not inhibit the induction of eotaxin mRNA induced by IL‐1β or TNFα.

Thus, human airway smooth muscle cells can release eotaxin and could be an important source of chemokine production during airway inflammatory events.

British Journal of Pharmacology (1999) 127, 1145–1150; doi:10.1038/sj.bjp.0702660
Pharmacological characterization of Ca2+ entry channels in endothelin‐1‐induced contraction of rat aorta using LOE 908 and SK&F 96365
Authors: Zhang Xiao‐Feng , Iwamuro Yasushi , Enoki Taijiro , Okazawa Makoto , Lee Ken , Komuro Taro , Minowa Tetsuya , Okamoto Yasuo , Hasegawa Hiroshi , Furutani Hidekatsu , Miwa Soichi , Masaki Tomoh
Published: January 2005

We have recently shown that endothelin‐1 (ET‐1) activates two types of Ca2+‐permeable nonselective cation channels (designated NSCC‐1 and NSCC‐2) and store‐operated Ca2+ channel (SOCC). These channels can be pharmacologically discriminated using Ca2+ channel blockers such as SK&F 96365 and LOE 908. Here we characterized Ca2+ entry channels involved in ET‐1‐induced contractions of rat thoracic aortic rings and increases in the intracellular free Ca2+ concentration ([Ca2+]i) of single smooth muscle cells using these blockers.

LOE 908 or a blocker of voltage‐operated Ca2+ channel nifedipine had no effect on the contractions and increases in [Ca2+]i induced by thapsigargin or ionomycin, whereas SK&F 96365 abolished them.

The contractions and increases in [Ca2+]i induced by ET‐1 depended on extracellular Ca2+ but were resistant to nifedipine. The responses to lower concentrations (0.1 nM) of ET‐1 were abolished by either SK&F 96365 or LOE 908. The responses to higher concentrations (1 nM) were abolished by SK&F 96365, but were partially resistant to LOE 908.

SK&F 96365 inhibited the LOE 908‐resistant contractions induced by higher concentrations of ET‐1 with IC50 values similar to those for contractions induced by thapsigargin or ionomycin.

These results show that the contractions and increases in [Ca2+]i of rat aortic smooth muscles at lower concentrations of ET‐1 involve only one Ca2+ entry channel which is sensitive to SK&F 96365 and LOE 908 (NSCC‐2), whereas those at higher concentrations of ET‐1 involve another Ca2+ entry channel which is sensitive to SK&F 96365 but resistant to LOE 908 (SOCC) in addition to the former channel.

British Journal of Pharmacology (1999) 127, 1388–1398; doi:10.1038/sj.bjp.0702661
Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness
Authors: Imig John D , Falck John R , Inscho Edward W
Published: January 2005

Previous studies have demonstrated an important role for the cytochrome P450 (CYT‐P450) pathway in afferent arteriole autoregulatory responses but the involvement of specific pathways remains unknown. Experiments were performed to determine the role of CYT‐P450 epoxygenase and hydroxylase pathways in pressure mediated preglomerular autoregulatory responses.

Afferent arteriolar diameter was measured as renal perfusion pressure was increased from 80–160 mmHg. Afferent arteriolar diameter averaged 19±2 μm at a renal perfusion pressure of 80 mmHg and decreased by 15±2% when pressure was increased to 160 mmHg.

Inhibition of the epoxygenase pathway with 6‐(2‐proparglyloxyphenyl)hexanoic acid (PPOH), enhanced the microvascular response to increasing renal perfusion pressure. In the presence of 50 μM PPOH, afferent arteriolar diameter decreased by 29±4% when pressure was increased from 80–160 mmHg.

Likewise, the sulphonimide derivative of PPOH, N‐methylsulphonyl‐6‐(2‐proparglyloxyphenyl) hexanamide (MS‐PPOH, 50 μM), enhanced the afferent arteriolar response to increasing renal perfusion pressure.

In contrast, the selective CYT‐P450 hydroxylase inhibitor, N‐methylsulphonyl‐12,12‐dibromododec‐11‐enamide (DDMS) attenuated the vascular response to increasing renal perfusion pressure. In the pressure of 25 μM DDMS, afferent arteriolar diameter decreased by 4±2% when pressure was increased from 80–160 mmHg.

These results suggest that CYT‐P450 metabolites of the epoxygenase pathway alter afferent arteriolar responsiveness and thereby modify the ability of the preglomerular vasculature to autoregulate renal blood flow. Additionally, these results provide further support to the concept that a metabolite of the hydroxylase pathway is an integral component of the afferent arteriolar response to elevations in perfusion pressure.

British Journal of Pharmacology (1999) 127, 1399–1405; doi:10.1038/sj.bjp.0702662
Involvement of ATP‐sensitive potassium channels in a model of a delayed vascular hyporeactivity induced by lipopolysaccharide in rats
Authors: Sorrentino Raffaella , Di Villa Bianca Roberta d'Emmanuele , Lippolis Laura , Sorrentino Ludovico , Autore Giuseppina , Pinto Aldo
Published: January 2005

We have investigated the role of ATP‐sensitive potassium (KATP) channels in an experimental model of a delayed phase of vascular hyporeactivity induced by lipopolysaccharide (LPS) in rats.

After 24 h, from LPS treatment, in anaesthetized rats the bolus injection of phenylephrine (PE) produced an increase in mean arterial pressure (MAP) significantly (P<0.05) reduced in LPS‐treated rats compared to the vehicle‐treated rats. This reduction was prevented by pre‐treatment of rats with glibenclamide (GLB), a selective inhibitor of KATP channels.

GLB administration did not affect the MAP in vehicle‐treated rats but produced an increase of MAP in rats treated with LPS.

Cromakalim (CRK), a selective KATP channel opener, produced a reduction of MAP that was significantly (P<0.05) higher in LPS‐ than in vehicle‐treated rats. In contrast, the hypotension induced by glyceryl trinitrate (GTN) in LPS‐treated rats was not distinguishable from that produced in vehicle‐treated rats.

Experiments in vitro were conducted on aorta rings collected from rats treated with vehicle or LPS 24 h before sacrifice. The concentration‐dependent curve to PE was statistically (P<0.005) reduced in aorta rings collected from LPS‐ compared to vehicle‐treated rats. This difference was totally abolished by tetraethylammonium (TEA), a non‐selective inhibitor of K+ channels.

CRK produced a relaxation of PE precontracted aorta rings higher in rings from LPS‐ than in vehicle‐treated rats. GLB inhibited CRK‐induced relaxation in both tissues, abolishing the observed differences.

In conclusion, our results indicate an involvement of KATP channels to the hyporesponsiveness of vascular tissue after 24 h from a single injection of LPS in rats. We can presume an increase in the activity of KATP channels on vascular smooth muscle cells but we cannot exclude an increase of KATP channel number probably due to the gene expression activation.

British Journal of Pharmacology (1999) 127, 1447–1453; doi:10.1038/sj.bjp.0702666
Evidence for two different P2X‐receptors mediating vasoconstriction of Ap5A and Ap6A in the isolated perfused rat kidney
Authors: Van Der Giet Markus , Cinkilic Okan , Jankowski Joachim , Tepel Martin , Zidek Walter , Schlüter Hartmut
Published: January 2005

The activation of various P2‐receptor subtypes in rat renal vasculature by P1, P5‐diadenosine pentaphosphate (Ap5A) and P1, P6‐diadenosine hexaphosphate (Ap6A) were studied by measuring their effects on perfusion pressure during continuous perfusion in a rat isolated perfused kidney.

Permanent perfusion with Ap5A and Ap6A elicited both a transient and sustained vasoconstriction with both vasoconstrictions to be different: the transient vasoconstriction can be elicited with concentrations 10 nM, whereas the sustained vasoconstriction is observed with concentrations 1 nM.

Ap5A and Ap6A act via the same receptors as α,β‐methylene ATP (α,β‐meATP).

The rank order of potency for transient vasconstriction was α,β‐meATP=Ap5A>Ap6A>β,γ‐meATP, and for sustained vasoconstriction α,β‐meATP=Ap5A>β,γ‐meATP Ap6A.

Suramin, a non‐selective P2‐receptor antagonist, and pyridoxal‐phosphate‐6‐azophenyl‐2;4‐disulphonic acid (PPADS) a highly selective P2X‐receptor antagonist antagonized both the transient and the sustained vasoconstriction.

Taken together the results of the agonist profile of Ap5A and Ap6A and comparing its findings to literature it can be demonstrated that the transient but not the sustained vasoconstriction is mediated via the P2X1‐receptor which is present in rat renal vasculature.

It is demonstrated that the agonist profile of the sustained vasoconstriction induced by Ap5A and Ap6A does not fit to any currently known P2X‐ or P2Y‐receptor subtype.

We conclude a yet unidentified P2X‐receptor or chimeric P2X‐receptor may contribute to the effects on rat renal vasculature produced by Ap5A and Ap6A and which may play an important role in glomerular perfusion pressure and blood pressure control.

British Journal of Pharmacology (1999) 127, 1463–1469; doi:10.1038/sj.bjp.0702667
Different effect of simvastatin and atorvastatin on key enzymes involved in VLDL synthesis and catabolism in high fat/cholesterol fed rabbits
Authors: Verd Joan C , Peris Cristina , Alegret Marta , Díaz Cristina , Hernández Gonzalo , Vázquez Manuel , Adzet Tomás , Laguna Juan C , Sánchez Rosa M
Published: January 2005

The effects of atorvastatin (3 mg kg−1) and simvastatin (3 mg kg−1) on hepatic enzyme activities involved in very low density lipoprotein metabolism were studied in coconut oil/cholesterol fed rabbits.

Plasma cholesterol and triglyceride levels increased 19 and 4 fold, respectively, after 7 weeks of feeding.

Treatment with statins during the last 4 weeks of feeding abolished the progression of hypercholesterolaemia and reduced plasma triglyceride levels.

3‐Hydroxy‐3‐methyl‐glutaryl Coenzyme A reductase, acyl‐coenzyme A:cholesterol acyltransferase, phosphatidate phosphohydrolase and diacylglycerol acyltransferase activities were not affected by drug treatment. Accordingly, hepatic free cholesterol, cholesteryl ester and triglyceride content were not modified.

Simvastatin treatment caused an increase (72%) in lipoprotein lipase activity without affecting hepatic lipase activity.

Atorvastatin caused a reduction in hepatic phospholipid content and a compensatory increase in CTP:phosphocholine cytidylyl transferase activity.

The results presented in this study suggest that, besides the inhibitory effect on 3‐hydroxy‐3‐methyl‐glutaryl Coenzyme A reductase, simvastatin and atorvastatin may have additional effects that contribute to their triglyceride‐lowering ability.

British Journal of Pharmacology (1999) 127, 1479–1485; doi:10.1038/sj.bjp.0702668
Regulation of platelet function by catecholamines in the cerebral vasculature of the rabbit
Authors: Emerson Michael , Paul William , Page Clive P
Published: January 2005

111In‐labelled platelets were monitored continuously in the cerebral and pulmonary vascular beds of anaesthetized rabbits. Dopamine can, depending upon the concentration, either potentiate or inhibit thrombin‐induced platelet accumulation in the cerebral vasculature of rabbits by unknown mechanisms. The effects of specific adrenergic and dopaminergic receptor antagonists were tested upon dopamine's actions on intracarotid (i.c.) thrombin‐induced (80 u kg−1) platelet accumulation in the cerebral vasculature. The effect of adrenaline on the response to thrombin in this vascular bed was also investigated.

Thrombin‐induced platelet accumulation was significantly (P<0.01) potentiated by dopamine (100 μg kg−1 min−1, i.c.) and this effect was significantly inhibited by infusion of the α‐adrenoceptor antagonist, phentolamine.

A higher dose of dopamine (2 mg kg−1 min−1, i.c.) inhibited thrombin‐induced platelet accumulation. The β‐adrenoceptor antagonist, propranolol, did not significantly alter this inhibitory effect whereas it was abolished by the dopamine D1 selective antagonist, SCH23390.

Adrenaline (when administered i.c. by bolus injection or infusion) had no significant effect on thrombin‐induced accumulation at any of the doses tested.

Potentiation of in vivo platelet accumulation by dopamine therefore seems to occur via α‐adrenergic receptors. However, the inhibitory effect of dopamine appears to be exerted via the activation of dopamine D1 receptors and not via β‐adrenergic receptors. Our findings confirm that dopamine, but not adrenaline, can modify platelet function in the cerebral vasculature and these observations may have implications for current and potential therapeutic uses of dopamine and selective dopaminergic compounds.

British Journal of Pharmacology (1999) 127, 1652–1656; doi:10.1038/sj.bjp.0702671
Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells
Authors: Coldwell Martyn C , Boyfield Izzy , Brown Tony , Hagan Jim J , Middlemiss Derek N
Published: January 2005

The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF‐104557 (4‐[2‐(propylamino)ethyl]‐2‐(3H) indolone), SKF‐97930 (4‐carboxy‐2‐(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry.

All the receptor agonists tested (ropinirole, SKF‐104557, SKF‐97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members.

At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF‐104557, were partial agonists at the hD4 receptor.

Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s.

The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities.

The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF‐104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound.

British Journal of Pharmacology (1999) 127, 1696–1702; doi:10.1038/sj.bjp.0702673
Calcium antagonistic properties of the cyclooxygenase‐2 inhibitor nimesulide in human myometrial myocytes
Authors: Knock Gregory A , Aaronson Philip I
Published: January 2005

The non‐steroidal anti‐inflammatory drug nimesulide is a selective inhibitor of cyclooxygenase‐2 which relaxes spontaneously contracting human myometrium in vivo and is potentially a useful tocolytic drug. Part of the relaxant action of nimesulide may be via block of myometrial Ca2+ channels. Here, we describe the Ca2+ channel blocking properties of nimesulide in freshly dispersed human term‐pregnant myometrial smooth muscle cells (HMSMCs).

Both L‐ and T‐components of the whole cell Ca2+ channel current were inhibited by 100 μM nimesulide (38±3 and 35±1% block, respectively). At physiological pH inside and outside the cell (pHo/pHi=7.4/7.2), this block did not depend on the holding or test potential, although a degree of use‐dependence was observed during high frequency stimulation at a higher concentration of drug (300 μM).

At pHo/pHi=6.8, under which condition the concentration of the non‐ionized form of the drug is increased 3 fold compared to pH 7.4, nimesulide blocked the L‐type current more potently (58±3% inhibition at 100 μM, P<0.01) compared to physiological pH. Nimesulide caused a 7 mV leftward shift in the availability curve of the current at pH 6.8, suggesting that the affinity of the drug for the inactivated channel is approximately 4 fold higher than its affinity for the closed channel. We speculate that acidification and depolarization of the myometrium during the intense and prolonged contractions of labour might increase the potency of nimesulide as a Ca2+ channel antagonist, promoting its action as a tocolytic agent.

British Journal of Pharmacology (1999) 127, 1470–1478; doi:10.1038/sj.bjp.0702685
Differential effects of adenine nucleotide analogues on shape change and aggregation induced by adenosine 5′‐diphosphate (ADP) in human platelets
Authors: Park Hye‐Seong , Hourani Susanna M O
Published: January 2005

Adenosine 5′‐diphosphate (ADP) induces human blood platelets to aggregate and change shape, and it has been suggested that these two responses are mediated by more than one subtype of ADP receptor.

The structure‐activity relationships for several analogues of adenine nucleotides in causing aggregation and shape change were measured and compared in washed platelets using an aggregometer. ADP and its analogues 2‐methylthioadenosine 5′‐diphosphate (2‐methylthio‐ADP), adenosine 5′(α,β‐methylene)diphosphonate (AMPCP), SP‐adenosine 5′‐O‐(1‐thiodiphosphate) (AD‐PαS) and adenosine 5′‐O‐(2‐thiodiphosphate) (ADPβS) were used as agonists. Adenosine 5′‐triphosphate (ATP) and its analogues, P1, P5‐diadenosine pentaphosphate (Ap5A), adenosine (5′‐(α,β‐methylene)triphosphonate (AMPCPP), 2‐methylthioadenosine 5′‐triphosphate (2‐methylthio‐ATP) and uridine 5′‐triphosphate (UTP), as well as the trypanocidal drug suramin, were used as antagonists.

In general, the structure‐activity relationships for both responses were similar, but for some analogues differences were observed. ADPαS and ADPβS were much more potent agonists relative to ADP for shape change than for aggregation and indeed ADPαS antagonized ADP‐induced aggregation with an apparent pKB value of 5.5±0.1. 2‐Methylthio‐ATP also had different effects in aggregation and shape change, being a much higher affinity antagonist of aggregation than of shape change with an apparent pKB value of 7.0±0.2 for aggregation and 5.2±0.2 for shape change.

These results support the suggestion that these two responses are mediated by multiple ADP receptors on human platelets, and are consistent with shape change being mediated via one receptor (the P2Y1 receptor) with aggregation requiring the activation of two receptors (the P2Y1 and another P2Y receptor).

British Journal of Pharmacology (1999) 127, 1359–1366; doi:10.1038/sj.bjp.0702690
The ether lipid ET‐18‐OCH3 increases cytosolic Ca2+ concentrations in Madin Darby canine kidney cells
Authors: Jan Chung‐Ren , Wu Sheng‐Nan , Tseng Ching‐Jiunn
Published: January 2005

The effect of the ether lipid 1‐O‐octadecyl‐2‐O‐methyl‐sn‐glycero‐3‐phosphorylcholine (ET‐18‐OCH3) on the intracellular free Ca2+ concentration ([Ca2+]i) in Madin Darby canine kidney (MDCK) cells was studied using fura‐2 as the Ca2+ probe. In Ca2+ medium, ET‐18‐OCH3 induced a significant rise in [Ca2+]i at concentrations between 10–100 μM with a concentration‐dependent delay of 45–175 s. The [Ca2+]i signal was composed of a gradual rise and a sustained plateau.

In Ca2+‐free medium, ET‐18‐OCH3 (10–100 μM) induced a Ca2+ release from internal Ca2+ stores with a concentration‐dependent delay of 45–175 s. This discharge of internal Ca2+ triggered capacitative Ca2+ entry in a concentration‐dependent manner. This capacitative Ca2+ entry was not inhibited by econazole (25 μM), 1‐[β‐[3‐(4‐methoxyphenyl)propoxy]‐4‐methoxyphenethyl]‐1H‐imidazole hydrochloride (SKF96365; 50 μM), nifedipine (10 μM), verapamil (10 μM), diltiazem (10 μM) and cadmium (0.5 μM).

Methyl 2‐(phenylthio)ethyl‐1,4‐dihydro‐2,4,6‐trimethylpyridine‐3,5‐dicarboxylate (PCA‐4248), a platelet‐activating factor (PAF) receptor antagonist, inhibited 25 μM ET‐18‐OCH3‐induced [Ca2+]i rise in a concentration‐dependent manner between 1–20 μM, with 20 μM exerting a complete block.

The [Ca2+]i rise induced by ET‐18‐OCH3 (25 μM) was not altered when the production of inositol 1,4,5‐trisphosphate (IP3) was suppressed by the phospholipase C inhibitor U73122 (2 μM), but was partly inhibited by the phospholipase D inhibitor propranolol (0.1 mM) or the phospholipase A2 inhibitor aristolochic acid (20–40 μM).

In Ca2+‐free medium, pretreatment with 25 μM ET‐18‐OCH3 completely depleted the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin‐sensitive Ca2+ store. In contrast, pretreatment with thapsigargin abolished 0.1 mM ATP‐induced [Ca2+]i rise without altering the ET‐18‐OCH3‐induced [Ca2+]i rise. This suggests that ET‐18‐OCH3 depleted thapsigargin‐sensitive Ca2+ stores and also released Ca2+ from thapsigargin‐insensitive stores. The thapsigargin‐insensitive stores involve mitochondria because the mitochondria uncoupler carbonylcyanide m‐chlorophenylhydrazone (CCCP; 2 μM) induced a release of mitochondrial Ca2+ which was abolished by pretreatment with 25 μM ET‐18‐OCH3.

ET‐18‐OCH3 (25 μM) induced a significant Mn2+ quench of fura‐2 fluorescence at 360 nm excitation wavelength confirming that ET‐18‐OCH3 induced capacitative Ca2+ entry. La3+ (0.1 mM) or Gd3+ (50 μM) abolished the ET‐18‐OCH3‐induced Mn2+ quench and [Ca2+]i rise.

Our data imply that ET‐18‐OCH3 induced a [Ca2+]i rise in MDCK cells by activating PAF receptors leading to an internal Ca2+ release followed by capacitative Ca2+ entry. Phospholipase D and phospholipase A2, but not phospholipase C, might be involved in mediating the capacitative Ca2+ entry. La3+ abolished the ET‐18‐OCH3‐induced [Ca2+]i rise presumably by inhibiting PAF receptors.

British Journal of Pharmacology (1999) 127, 1502–1510; doi:10.1038/sj.bjp.0702691
GABAB, opioid and α2 receptor inhibition of calcium channels in acutely‐dissociated locus coeruleus neurones
Authors: Chieng B , Bekkers J M
Published: January 2005

The effects of GABAB, opioid and α2 receptor activation on different subtypes of calcium channels in acutely‐dissociated rat locus coeruleus (LC) neurones were investigated using whole‐cell patch clamping.

Barium currents through calcium channels could be fractionated into four classes: L‐type (nimodipine‐sensitive), N‐type (ω‐conotoxin GVIA‐sensitive), P/Q‐type (ω‐agatoxin IVA‐sensitive) and R‐type (remaining in the presence of all three blockers). The percentage of each was, respectively, 25±2, 34±1, 28±3 and 12±1% (mean±s.e.mean, n=4).

The GABAB receptor agonist, baclofen, and the opioid receptor agonist, enkephalin, partially inhibited the total barium current in a concentration‐dependent manner with EC50 values of 2 and 0.3 μM, respectively. Maximal inhibition was 17±1% (n=38) for baclofen and 30±2% (n=20) for enkephalin. The α2‐adrenoceptor agonist, UK14304 (10 μM), also inhibited barium current in these neurones (28±2%, n=11). The agonists did not shift the current‐voltage relationship along the voltage axis.

Maximal baclofen inhibition of different calcium channel subtypes was 9±7% (L‐type, n=4), 11±8% (N‐type, n=4), 26±6% (P/Q‐type, n=4), and 6±5% (R‐type, n=5). The corresponding values for enkephalin inhibition were 5±9% (L‐type), 30±11% (N‐type), 37±9% (P/Q‐type), and 17±8% (R‐type).

In the presence of a saturating concentration of enkephalin, baclofen produced additional inhibition of the barium current. In contrast, in the presence of a saturating concentration of enkephalin, UK14304 produced no further inhibition of the barium current.

These results indicate that neuromodulation of calcium channels in LC neurones involves a complex pattern of overlapping and distinct second messenger pathways. Regulation of LC neuronal firing activity by the modulation of calcium channels may be important for LC‐mediated behaviour such as alertness and vigilance.

British Journal of Pharmacology (1999) 127, 1533–1538; doi:10.1038/sj.bjp.0702693
Pacing‐induced delayed protection against arrhythmias is attenuated by aminoguanidine, an inhibitor of nitric oxide synthase
Authors: Kis Adrienn , Végh Agnes , Papp Julius , Parratt James
Published: January 2005

Cardiac pacing, in anaesthetized dogs, protects against ischaemia and reperfusion‐induced ventricular arrhythmias when this is initiated 24 h after the pacing stimulus. Now we have examined whether this delayed cardioprotection afforded by cardiac pacing is mediated through nitric oxide.

Twenty‐two dogs were paced (4×5 min periods at 220 beats min−1) by way of the right ventricle, 24 h prior to a 25 min period of coronary artery occlusion. Nine of these dogs were given the inhibitor of induced nitric oxide synthase, aminoguanidine (50 mg kg−1 i.v.), 0.5 h prior to coronary artery occlusion. Sham‐operated non‐paced dogs with and without aminoguanidine treatment served as controls.

Pacing markedly (P<0.05) reduced arrhythmia severity (ventricular fibrillation, VF, during occlusion 15%; survival from the combined ischaemia‐reperfusion insult 62%) compared to control, sham‐operated, unpaced dogs (VF during occlusion 58%; survival 17%). This protection was attenuated by the administration of aminoguanidine prior to coronary artery occlusion (survival from the combined ischaemia‐reperfusion insult 11%, which was significantly (P<0.05) less than in the paced dogs not given aminoguanidine and similar to the controls). Aminoguanidine had no significant effects on coronary artery occlusion when given to dogs that had not been paced. In the dose used aminoguanadine transiently elevated systemic arterial pressure by a mean of 20 mmHg and reduced heart rate by a mean of 22 beats min−1.

These results suggest that nitric oxide, probably derived from induced nitric oxide synthase, contributes significantly to the delayed cardioprotection afforded by cardiac pacing.

British Journal of Pharmacology (1999) 127, 1545–1550; doi:10.1038/sj.bjp.0702695
Bronchodilator and anti‐inflammatory activities of glaucine: In vitro studies in human airway smooth muscle and polymorphonuclear leukocytes
Authors: Cortijo J , Villagrasa V , Pons R , Berto L , Martí‐Cabrera M , Martinez‐Losa M , Domenech T , Beleta J , Morcillo E J
Published: January 2005

Selective phosphodiesterase 4 (PDE4) inhibitors are of potential interest in the treatment of asthma. We examined the effects of the alkaloid S‐(+)‐glaucine, a PDE4 inhibitor, on human isolated bronchus and granulocyte function.

Glaucine selectively inhibited PDE4 from human bronchus and polymorphonuclear leukocytes (PMN) in a non‐competitive manner (Ki=3.4 μM). Glaucine displaced [3H]‐rolipram from its high‐affinity binding sites in rat brain cortex membranes (IC50∼100 μM).

Glaucine inhibited the spontaneous and histamine‐induced tone in human isolated bronchus (pD2∼4.5). Glaucine (10 μM) did not potentiate the isoprenaline‐induced relaxation but augmented cyclic AMP accumulation by isoprenaline. The glaucine‐induced relaxation was resistant to H‐89, a protein kinase A inhibitor. Glaucine depressed the contractile responses to Ca2+ (pD'2∼3.62) and reduced the sustained rise of [Ca2+]i produced by histamine in cultured human airway smooth muscle cells (−log IC50∼4.3).

Glaucine augmented cyclic AMP levels in human polymorphonuclear leukocytes challenged with N‐formyl‐Met‐Leu‐Phe (FMLP) or isoprenaline, and inhibited FMLP‐induced superoxide generation, elastase release, leukotriene B4 production, [Ca2+]i signal and platelet aggregation as well as opsonized zymosan‐, phorbol myristate acetate‐, and A23187‐induced superoxide release. The inhibitory effect of glaucine on superoxide generation by FMLP was reduced by H‐89.

In conclusion, Ca2+ channel antagonism by glaucine appears mainly responsible for the relaxant effect of glaucine in human isolated bronchus while PDE4 inhibition contributes to the inhibitory effects of glaucine in human granulocytes. The very low PDE4/binding site ratio found for glaucine makes this compound attractive for further structure‐activity studies.

British Journal of Pharmacology (1999) 127, 1641–1651; doi:10.1038/sj.bjp.0702702