bluuebunny/crossref_metadata_2025 huggingface dataset:
Observations of elemental carbon and absorption during ACE‐Asia and implications for aerosol radiative properties and climate forcing
Authors: Chuang P. Y. , Duvall R. M. , Bae M. S. , Jefferson A. , Schauer J. J. , Yang H. , Yu J. Z. , Kim J.
Published: September 2003

Measurements of elemental carbon (EC) during the Asian Pacific Regional Aerosol Characterization Experiment (ACE‐Asia) show that significant amounts of EC were found in the coarse particle phase during yellow sand events. Coagulation during long‐range transport is consistent with this observation. The daily averaged specific mass absorption efficiencies of EC were calculated, yielding values of 12.6 ± 2.6 and 14.8 ± 2.3 m2/g for PM10 (particulate matter <10 μm diameter) and PM1, respectively. On a limited number of days, the absorption efficiency for the coarse particles only (PM10 − PM1) was determined to be 5.7 ± 1.6 m2/g during dust days and 2.0 ± 1.0 m2/g for nondust days. These measurements suggest that fine particulate EC was internally mixed and that the dust was possibly somewhat absorbing. Specific mass absorption efficiency was observed to be inversely related to EC mass concentration, a result that does not appear to reflect only air mass aging effects. We speculate that if this observation holds on a global scale, it would reduce the effectiveness of a strategy for mitigating climate change by reducing EC emissions. Model simulations of idealized nonspherical dust radiative properties predict that scattering is strongly (by nearly a factor of 3) dependent on geometry, while absorption is a very weak function of geometry. The net change in shortwave absorption by polluted dust layers due to coagulation of EC with dust is predicted by model calculations to range between −42% and +58%, depending on the assumption about the initial mixing state of the EC and the dust optical properties, with the observations supporting values in the range of −10 to −40%.
Sr/Ca ratios and oxygen isotopes from sclerosponges: Temperature history of the Caribbean mixed layer and thermocline during the Little Ice Age
Authors: Haase‐Schramm Alexandra , Böhm Florian , Eisenhauer Anton , Dullo Wolf‐Christian , Joachimski Michael M. , Hansen Bent , Reitner Joachim
Published: September 2003

We investigate aragonitic skeletons of the Caribbean sclerosponge Ceratoporella nicholsoni from Jamaica, 20 m below sea level (mbsl), and Pedro Bank, 125 mbsl. We use δ18O and Sr/Ca ratios as temperature proxies to reconstruct the Caribbean mixed layer and thermocline temperature history since 1400 A.D. with a decadal time resolution. Our age models are based on U/Th dating and locating of the radiocarbon bomb spike. The modern temperature difference between the two sites is used to tentatively calibrate the C. nicholsoni Sr/Ca thermometer. The resulting calibration points to a temperature sensitivity of Sr/Ca in C. nicholsoni aragonite of about −0.1 mmol/mol/K. Our Sr/Ca records reveal a pronounced warming from the early 19th to the late 20th century, both at 20 and 125 mbsl. Two temperature minima in the shallow water record during the late 17th and early 19th century correspond to the Maunder and Dalton sunspot minima, respectively. Another major cooling occurred in the late 16th century and is not correlatable with a sunspot minimum. The temperature contrast between the two sites decreased from the 14th century to a minimum in the late 17th century and subsequently increased to modern values in the early 19th century. This is interpreted as a long‐term deepening and subsequent shoaling of the Caribbean thermocline. The major trends of the Sr/Ca records are reproduced in both specimens but hardly reflected in the δ18O records.
Late Jurassic to Early Cretaceous black shale formation and paleoenvironment in high northern latitudes: Examples from the Norwegian‐Greenland Seaway
Authors: Langrock Uwe , Stein Ruediger , Lipinski Marcus , Brumsack Hans‐Juergen
Published: September 2003

The Late Jurassic to Early Cretaceous (Volgian‐Ryazanian) was a period of a second‐order sea‐level low stand, and it provided excellent conditions for the formation of shallow marine black shales in the Norwegian‐Greenland Seaway (NGS). IKU Petroleum Research drilling cores taken offshore along the Norwegian shelf were investigated with geochemical and microscopic approaches to (1) determine the composition of the organic matter, (2) characterize the depositional environments, and (3) discuss the mechanisms which may have controlled production, accumulation, and preservation of the organic matter. The black shale sequences show a wide range of organic carbon contents (0.5–7.0 wt %) and consist of thermally immature organic matter of type II to II/III kerogen. Rock‐Eval pyrolysis revealed fair to very good petroleum source rock potential, suggesting a deposition in restricted shallow marine basins. Well‐developed lamination and the formation of autochthonous pyrite framboids further indicate suboxic to anoxic bottom water conditions. In combination with very low sedimentation rates it seems likely that preservation was the principal control on organic matter accumulation. However, a decrease of organic carbon preservation and an increase of refractory organic matter from the Volgian to the Hauterivian are superimposed on short‐term variations (probably reflecting Milankovitch cycles). Various parameters indicate that black shale formation in the NGS was gradually terminated by increased oxidative conditions in the course of a sea‐level rise.
Uniform asymptotic solution for the radiation from a magnetic source on a large dielectric coated circular cylinder: Nonparaxial region
Authors: Thors B. , Rojas R. G.
Published: September 2003

An accurate uniform asymptotic technique to calculate the radiated field from a magnetic current moment situated on the surface of a circular cylinder coated with a thin dielectric layer has been developed. Using the Watson transform, a slowly convergent radially propagating series representation for the fields is converted into a rapidly convergent circumferentially propagating series representation. An asymptotic shadow region solution is then obtained by employing the method of steepest descent. By modifying the shadow region solution in an appropriate manner, a uniform lit region solution is obtained that reduces to the geometrical optics solution in the deep‐lit region. The asymptotic solution is valid for large cylinders away from the paraxial region and can be used to calculate the radiation pattern and the scattering from waveguide‐fed apertures. Numerical results are compared to an eigenfunction solution, and a very good accuracy is achieved within the expected region of validity.
Simulation studies of GPS radio occultation measurements
Authors: Beyerle G. , Gorbunov M. E. , Ao C. O.
Published: September 2003

The atmospheric propagation of GPS signals under multipath conditions and their detection are simulated. Using the multiple phase screen method, C/A‐code modulated L1 signals are propagated through a spherically symmetric refractivity field derived from a high‐resolution radio sonde observation. The propagated signals are tracked by a GPS receiver implemented in software and converted to refractivity profiles by the canonical transform technique and the Abel inversion. Ignoring noise and assuming an ideal receiver tracking behavior, the true refractivity profile is reproduced to better than 0.1% at altitudes above 2 km. The nonideal case is simulated by adding between 14 and 24 dB of Gaussian white noise to the signal and tracking the signal with a receiver operating at 50 and 200 Hz sampling frequency using two different carrier phase detectors. In the upper troposphere and stratosphere the fractional refractivity retrieval error is below 0.3% for 50 Hz sampling and below 0.15% for 200 Hz sampling. In the midtroposphere down to altitudes of about 2 km, phase‐locked loop tracking induces negative fractional refractivity biases on the order of −1 to −2% at 50 Hz sampling frequency. Modifications to the receiver tracking algorithm significantly improve the retrieval results. In particular, replacing the carrier loop's two‐quadrant phase extractor with a four‐quadrant discriminator reduces the refractivity biases by a factor of 5; increasing the sampling frequency from 50 to 200 Hz gains another factor of 2.
A simple formulation for the eddy‐diffusivity parameterization of cloud‐topped boundary layers
Authors: Cheinet S. , Teixeira J.
Published: September 2003

A new formulation for the eddy‐diffusivity parameterization of the cloudy boundary layer is presented. The new aspects of the scheme are: (i) two prognostic turbulent kinetic energies (TKE), for the clear and cloudy air; (ii) in each region, the mixing length is formulated in terms of the TKE and a time scale. Additionally a statistical cloud scheme is used. The model is evaluated in a decoupling stratocumulus case and in a cumulus case, using a single‐column mode. The model realistically simulates the overall cloud properties. The in‐cloud mixing length formulation qualitatively matches the typical eddy size (as diagnosed from large eddy simulations). Consistent interactions between the sub‐cloud and the cloud layers are achieved through a realistic in‐cloud mixing. In the cumulus case, the conditionally unstable layer is maintained. These results show that boundary layer clouds and associated mixing can be represented consistently in the context of the eddy‐diffusivity approach.
Modeling ocean heat content changes during the last millennium
Authors: Crowley Thomas J. , Baum Steven K. , Kim Kwang‐Yul , Hegerl Gabriele C. , Hyde William T.
Published: September 2003

Observational studies show a significant increase in ocean heat content over the last half century. Herein we estimate heat content changes during the last millennium with a climate model whose forcing terms have been best‐fit to surface proxy data. The model simulates the observed late 20th century ocean heat content increase and a comparable Little Ice Age minimum. When glacial advances are factored in, these results imply a sea level fall after the Middle Ages that is consistent with some geologic data. The present ocean heat content increase can be traced back to the mid‐19th century, with a near‐linear rate of change during the 20th century.
Entrainment laws and a bulk mixed layer model of rotating convection derived from large‐eddy simulations
Authors: Wang Dailin
Published: September 2003

Entrainment of rotating convection is investigated using a large‐eddy simulation (LES) model. The model is forced with a uniform destablizing surface buoyancy flux, which varies by about an order of magnitude. The initial mixed layer depth varies from 0 to 3000 m and the background stratification varies over two orders of magnitude. The vertical component of the Earth's rotation rate at 30, 45, and 60°N are used. The corresponding flux Rossby number varies about three orders of magnitude. An empirical formula for the ratio of entrainment buoyancy flux to the surface buoyancy flux as a function of the Rossby number is derived. A bulk mixed‐layer model for rotating convection is formulated based on the entrainment formula. It is suggested this formula can also be used to tune other 1‐D models used in ocean general circulation models to account for the effect of Earth's rotation on convection.
Effects of surface heat flux‐induced sea surface temperature changes on tropical cyclone intensity
Authors: Shen Weixing , Ginis Isaac
Published: September 2003

It is known that in deep and open oceans, the effect of sea surface sensible and evaporative heat fluxes on the tropical cyclone‐induced sea surface cooling is small compared to that caused by turbulent mixing and cold water entrainment into the upper ocean mixed‐layer. This study shows that tropical cyclone‐induced surface heat fluxes dominate the surface cooling in near‐coastal shallow ocean regions with limited or no underlying cold water. The thermal response of the ocean to the surface heat fluxes is nearly one dimensional through very quick vertical mixing in the ocean mixed layer. The flux‐induced sea surface cooling may lead to appreciable reduction of storm intensity if the storm moves slowly. It is therefore important to account this negative feedback of ocean coupling in near‐coastal regions for more skillful forecasting of landfalling tropical cyclones.
Seismicity and neotectonics of West Antarctica
Authors: Winberry J. Paul , Anandakrishnan Sridhar
Published: September 2003

Newly discovered earthquakes in West Antarctica provide the first documentation of seismicity in the region. The data presented here indicate that the ice sheet does not suppress seismicity as has been previously proposed. However, the observed earthquake pattern suggests the West Antarctic rift system is no longer actively extending.
Electrophysiological effects of activating the peptidergic primary afferent innervation of rat mesenteric arteries
Authors: Dunn W R , Hardy T A , Brock J A
Published: September 2003

Intracellular recording was used to investigate the electrophysiological effects of activating peptidergic primary afferent axons with capsaicin in the smooth muscle of rat mesenteric arteries in vitro. In addition, continuous amperometry was used to monitor the effects of capsaicin on noradrenaline release from the sympathetic nerves.

Capsaicin (1 μM) produced a hyperpolarization (−11±2 mV) and a reduction in the time constant of decay of excitatory junction potentials (e.j.p.'s) evoked by electrical stimulation of the perivascular sympathetic nerves. These effects of capsaicin were mimicked by calcitonin gene‐related peptide (CGRP; 1 and 10 nM) but not by substance P (50 nM), which produced a small hyperpolarization (maximum −3±1 mV) but did not change excitatory junction potential (e.j.p.) time course.

The hyperpolarization produced by capsaicin and CGRP was blocked by glibenclamide (10 μM) but was not changed by the CGRP antagonist, CGRP8–37 (0.5 μM). Mechanical denudation of the endothelium also did not reduce the effect of capsaicin on membrane potential.

Capsaicin (1 μM) increased the amplitude of e.j.p.'s. This effect was not mimicked by CGRP or substance P nor blocked by glibenclamide or CGRP8–37.

All effects of capsaicin desensitized.

Capsaicin (1 μM) had no effect on noradrenaline‐induced oxidation currents evoked by electrical stimulation, indicating that noradrenaline release was unchanged.

These results suggest that CGRP released from primary afferent axons hyperpolarizes vascular smooth muscle by activating glibenclamide‐sensitive K+ channels. The findings also indicate that an unknown factor released by the primary afferent axons increases e.j.p. amplitude.

British Journal of Pharmacology (2003) 140, 231–238. doi:10.1038/sj.bjp.0705417
Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats
Authors: Padley James R , Li Qun , Pilowsky Paul M , Goodchild Ann K
Published: September 2003

The nature of the cardiorespiratory effects mediated by cannabinoids in the hindbrain is poorly understood. In the present study we investigated whether cannabinoid receptor activation in the rostral ventrolateral medulla oblongata (RVLM) affects cardiovascular and/or respiratory function.

Initially, we looked for evidence of CB1 receptor gene expression in rostral and caudal sections of the rat ventrolateral medulla (VLM) using reverse transcription–polymerase chain reaction. Second, the potent cannabinoid receptor agonists WIN55,212‐2 (0.05, 0.5 or 5 pmol per 50 nl) and HU‐210 (0.5 pmol per 50 nl) or the CB1 receptor antagonist/inverse agonist AM281 (1 pmol per 100 nl) were microinjected into the RVLM of urethane‐anaesthetised, immobilised and mechanically ventilated male Sprague–Dawley rats (n=22). Changes in splanchnic nerve activity (sSNA), phrenic nerve activity (PNA), mean arterial pressure (MAP) and heart rate (HR) in response to cannabinoid administration were recorded.

The CB1 receptor gene was expressed throughout the VLM. Unilateral microinjection of WIN55,212‐2 into the RVLM evoked short‐latency, dose‐dependent increases in sSNA (0.5 pmol; 175±8%, n=5) and MAP (0.5 pmol; 26±3%, n=8) and abolished PNA (0.5 pmol; duration of apnoea: 5.4±0.4 s, n=8), with little change in HR (P<0.005). HU‐210, structurally related to Δ9‐tetrahydrocannabinol (THC), evoked similar effects when microinjected into the RVLM (n=4). Surprisingly, prior microinjection of AM281 produced agonist‐like effects, as well as significantly attenuated the response to subsequent injection of WIN55,212‐2 (0.5 pmol, n=4).

The present study reveals CB1 receptor gene expression in the rat VLM and demonstrates sympathoexcitation, hypertension and respiratory inhibition in response to RVLM‐administered cannabinoids. These findings suggest a novel link between CB1 receptors in this region of the hindbrain and the central cardiorespiratory effects of cannabinoids. The extent to which these central effects contribute to the cardiovascular and respiratory outcomes of cannabis use remains to be investigated.

British Journal of Pharmacology (2003) 140, 384–394. doi:10.1038/sj.bjp.0705422
Benzydamine inhibits monocyte migration and MAPK activation induced by chemotactic agonists
Authors: Riboldi Elena , Frascaroli Giada , Transidico Pietro , Luini Walter , Bernasconi Sergio , Mancini Francesca , Guglielmotti Angelo , Milanese Claudio , Pinza Mario , Sozzani Silvano , Mantovani Alberto
Published: September 2003

The present study was aimed to investigate the effect of benzydamine, an anti‐inflammatory drug devoid of activity on arachidonic acid metabolism, on monocyte chemotaxis and to define the possible biochemical correlates of activity.

Benzydamine inhibited monocyte chemotaxis in response to three classes of chemoattractants: the prototypic CC‐chemokine CCL2 (MCP‐1), the microbial product fMLP and the complement cascade component C5a. The effect was dose‐dependent with IC50's of 100, 50 and 45 μM for MCP‐1/CCL2, fMLP and C5a, respectively. At the dose of 100 μM, the effect resulted in a 50±10% inhibition of MCP‐1/CCL2‐induced chemotaxis and 53±6 and 54±5% inhibitions of chemotaxis in response of fMLP and C5a, respectively (n=3).

Receptor expression as well as calcium fluxes in response to chemoattractants were not affected by benzydamine.

Benzydamine strongly inhibited chemoattractant‐induced activation of the mitogen‐activated protein kinase (MAPK) ERK1/2, and of its upstream activator kinase MEK1/2. ERK1/12 activation in response to chemoattractants was 89–98% inhibited by a 100 μM concentration of benzydamine with an IC50 of 30 μM.

Under the same experimental conditions, pretreatment with 100 μM benzydamine caused a 75–89% inhibition of p38 activation (IC50 25 μM).

These results indicate that the anti‐inflammatory activity of benzydamine is exerted at multiple levels, including monocyte migration to chemotactic factors associated to a blockage of ERK and p38 MAPK pathways.

British Journal of Pharmacology (2003) 140, 377–383. doi:10.1038/sj.bjp.0705428
Resolution of the oedema associated with allergic pulmonary inflammation in rats assessed noninvasively by magnetic resonance imaging
Authors: Tigani Bruno , Cannet Catherine , Zurbrügg Stefen , Schaeublin Elisabeth , Mazzoni Lazzaro , Fozard John R , Beckmann Nicolau
Published: September 2003

Magnetic resonance imaging (MRI) was used to study noninvasively the effects of compounds to resolve inflammation induced by ovalbumin (OVA) challenge in the lungs of actively sensitised rats.

Marked oedematous signals were detected between 24 and 96 h following OVA in vehicle‐treated animals. When administered 24 h after OVA, budesonide, a glucocorticosteroid, or 4‐(8‐benzo[1,2,5]oxadiazol‐5‐yl‐[1,7]naphthyridin‐6‐yl)‐benzoic acid (NVP‐ABE171), a selective phosphodiesterase 4 inhibitor, increased the rate of resolution of established oedematous signals detected by MRI. The effect was evident 3 h after drug administration and the signals were nearly fully resolved at 96 h postchallenge.

The drug‐induced rapid resolution of MRI signals was not accompanied by changes in parameters of inflammation in the bronchoalveolar lavage fluid, but was associated with perivascular oedema detected histologically.

In conclusion, the effects of anti‐inflammatory drugs on a component of allergic inflammation can be monitored by following with MRI the rate of resolution of the associated oedematous signals.

British Journal of Pharmacology (2003) 140, 239–246. doi:10.1038/sj.bjp.0705429
NANC inhibitory neurotransmission in mouse isolated stomach: involvement of nitric oxide, ATP and vasoactive intestinal polypeptide
Authors: Mulè Flavia , Serio Rosa
Published: September 2003

The neurotransmitters involved in NANC relaxation and their possible interactions were investigated in mouse isolated stomach, recording the motor responses as changes of endoluminal pressure from whole organ.

Field stimulation produced tetrodotoxin‐sensitive, frequency‐dependent, biphasic responses: rapid transient relaxation followed by a delayed inhibitory component.

The inhibitor of the synthesis of nitric oxide (NO), L‐NAME, abolished the rapid relaxation and significantly reduced the slow relaxation. Apamin, blocker of Ca2+‐dependent K+ channels, or ADPβS, which desensitises P2y purinoceptors, reduced the slow relaxation to 2–8 Hz, without affecting that to 16–32 Hz or the fast relaxation. α‐Chymotrypsin or vasoactive intestinal polypeptide 6–28 (VIP6–28), antagonist of VIP receptors, failed to affect the fast component or the delayed relaxation to 2–4 Hz, but antagonised the slow component to 8–32 Hz.

Relaxation to sodium nitroprusside was not affected by L‐NAME, apamin or ADPβS, but was reduced by α‐chymotrypsin or VIP6–28. Relaxation to VIP was abolished by α‐chymotrypsin, antagonised by VIP6–28, but was not affected by L‐NAME, apamin or ADPβS. Relaxation to ATP was abolished by apamin, antagonised by ADPβS, but was not affected by L‐NAME or α‐chymotrypsin.

The present results suggest that NO is responsible for the rapid relaxation and partly for the slow relaxation. ATP is involved in the slow relaxation evoked by low frequencies of stimulation. VIP is responsible for the slow relaxation evoked by high frequencies of stimulation. The different neurotransmitters appear to work in parallel, although NO could serve also as a neuromodulator that facilitates release of VIP.

British Journal of Pharmacology (2003) 140, 431–437. doi:10.1038/sj.bjp.0705431
Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats
Authors: Todorovic Slobodan M , Rastogi A J , Jevtovic‐Todorovic Vesna
Published: September 2003

Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage‐ and ligand‐gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception.

We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage‐gated Na+ channel blockers, phenytoin and carbamazepine, and voltage‐gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose‐dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively.

Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia.

Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide.

Our data strongly suggest that cellular targets like voltage‐gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage‐gated Na+ and Ca2+ channels may be useful analgesics.

British Journal of Pharmacology (2003) 140, 255–260. doi:10.1038/sj.bjp.0705434
Inhibition of guinea‐pig and human sensory nerve activity and the cough reflex in guinea‐pigs by cannabinoid (CB2) receptor activation
Authors: Patel Hema J , Birrell Mark A , Crispino Natascia , Hele David J , Venkatesan Priya , Barnes Peter J , Yacoub Magdi H , Belvisi Maria G
Published: September 2003

There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C‐fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve‐mediated responses.

We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea‐pig and human vagus nerve preparations, and the cough reflex in conscious guinea‐pigs.

The non‐selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea‐pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin‐evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528.

Using a guinea‐pig in vivo model of cough, JWH 133 (10 mg kg−1, i.p., 20 min) significantly reduced citric acid‐induced cough in conscious guinea pigs compared to those treated with the vehicle control.

These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea‐pig and human vagus nerve, and the cough reflex in guinea‐pigs, suggesting that the development of CB2 agonists, devoid of CB1‐mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

British Journal of Pharmacology (2003) 140, 261–268. doi:10.1038/sj.bjp.0705435
Possible involvement of IGF‐1 receptor and IGF‐binding protein in insulin‐induced enhancement of noradrenaline response in diabetic rat aorta
Authors: Kobayashi Tsuneo , Kaneda Akihito , Kamata Katsuo
Published: September 2003

We investigated the mechanisms underlying the changes in vascular contractile responsiveness induced by chronic treatment with insulin in controls and established streptozotocin (STZ)‐induced diabetic rats.

The aortic contractile response to noradrenaline (NA) showed no significant difference between controls and diabetics, but it was significantly greater in insulin‐treated diabetic rats than in the other groups. To investigate the mechanism, we examined the changes in NA‐induced contractility following treatment with insulin and insulin‐like growth factor‐1 (IGF‐1) in organ‐cultured control and diabetic aortas.

The contractile response to NA in organ‐cultured diabetic rat aortas treated with insulin (500 ng ml−1, 16 h) or IGF‐1 (20 ng ml−1, 16 h) was significantly greater than the corresponding values for (a) diabetic rat aortas cultured in serum‐free medium, and (b) control aortas incubated with insulin or IGF‐1. Incubating control aortas with insulin or IGF‐1 had no significant effect on the contraction induced by NA.

The expressions of the IGF‐1 receptor mRNA and protein were increased in STZ‐induced diabetic aortas and further increased in insulin‐treated diabetics. The mRNA expressions of IGF‐binding protein (IGFBP)‐2 and IGFBP‐3 were normal in diabetic aortas. In contrast, those of IGFBP‐4 and IGFBP‐5 were significantly decreased in diabetic aortas, and not restored by insulin treatment.

These results suggest that the insulin deficiency and chronic hyperinsulinemia in diabetes upregulate the IGF‐1 receptor and downregulate IGFBP‐4 and IGFBP‐5 in the aorta. This may be a major cause of the increased vascular contractility induced by insulin administration and by hyperinsulinemia in established diabetes, resulting in hypertension.

British Journal of Pharmacology (2003) 140, 285–294. doi:10.1038/sj.bjp.0705438
Molecular mechanisms of ligand–receptor interactions in transmembrane domain V of the α2A‐adrenoceptor
Authors: Peltonen Juha M , Nyrönen Tommi , Wurster Siegfried , Pihlavisto Marjo , Hoffrén Anna‐Marja , Marjamäki Anne , Xhaard Henri , Kanerva Liisa , Savola Juha‐Matti , Johnson Mark S , Scheinin Mika
Published: September 2003

The structural determinants of catechol hydroxyl interactions with adrenergic receptors were examined using 12 α2‐adrenergic agonists and a panel of mutated human α2A‐adrenoceptors. The α2ASer201 mutant had a Cys → Ser201 (position 5.43) amino‐acid substitution, and α2ASer201Cys200 and α2ASer201Cys204 had Ser → Cys200 (5.42) and Ser → Cys204 (5.46) substitutions, respectively, in addition to the Cys → Ser201 substitution.

Automated docking methods were used to predict the receptor interactions of the ligands. Radioligand‐binding assays and functional [35S]GTPγS‐binding assays were performed using transfected Chinese hamster ovary cells to experimentally corroborate the predicted binding modes.

The hydroxyl groups of phenethylamines were found to have different effects on ligand affinity towards the activated and resting forms of the wild‐type α2A‐adrenoceptor. Substitution of Ser200 or Ser204 with cysteine caused a deterioration in the capability of catecholamines to activate the α2A‐adrenoceptor. The findings indicate that (i) Cys201 plays a significant role in the binding of catecholamine ligands and UK14,304 (for the latter, by a hydrophobic interaction), but Cys201 is not essential for receptor activation; (ii) Ser200 interacts with the meta‐hydroxyl group of phenethylamine ligands, affecting both catecholamine binding and receptor activation; while (iii) substituting Ser204 with a cysteine interferes both with the binding of catecholamine ligands and with receptor activation, due to an interaction between Ser204 and the para‐hydroxyl group of the catecholic ring.

British Journal of Pharmacology (2003) 140, 347–358. doi:10.1038/sj.bjp.0705439
Pre‐conditioning protection in the brain
Authors: Stone T W
Published: September 2003

British Journal of Pharmacology (2003) 140, 229–230. doi:10.1038/sj.bjp.0705441
Brief, repeated, oxygen‐glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptors
Authors: Pugliese Anna Maria , Latini Serena , Corradetti Renato , Pedata Felicita
Published: September 2003

Ischemic preconditioning in the brain consists of reducing the sensitivity of neuronal tissue to further, more severe, ischemic insults. We recorded field epsps (fepsps) extracellularly from hippocampal slices to develop a model of in vitro ischemic preconditioning and to evaluate the role of A1, A2A and A3 adenosine receptors in this phenomenon.

The application of an ischemic insult, obtained by glucose and oxygen deprivation for 7 min, produced an irreversible depression of synaptic transmission. Ischemic preconditioning was induced by four ischemic insults (2 min each) separated by 13 min of normoxic conditions. After 30 min, an ischemic insult of 7 min was applied. This protocol substantially protected the tissue from the irreversible depression of synaptic activity.

The selective adenosine A1 receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 100 nM), completely prevented the protective effect of preconditioning. The selective adenosine A2A receptor antagonist 4‐(2‐[7‐amino‐2‐(2‐furyl)[1,2,4]triazolo[2,3‐a][1,3,5]triazin‐5‐ylamino]ethyl)phenol (ZM 241385, 100 nM) did not modify the magnitude of fepsp recovery compared to control slices. The selective A3 adenosine receptor antagonists, 3‐propyl‐6‐ethyl‐5[ethyl(thio)carbonyl]‐2‐phenyl‐4‐propyl‐3‐pyridinecarboxylate (MRS 1523, 100 nM) significantly improved the recovery of fepsps after 7 min of ischemia.

Our results show that in vitro ischemic preconditioning allows CA1 hippocampal neurons to become resistant to prolonged exposure to ischemia. Adenosine, by stimulating A1 receptors, plays a crucial role in eliciting the cell mechanisms underlying preconditioning; A2A receptors are not involved in this phenomenon, whereas A3 receptor activation is harmful to ischemic preconditioning.

British Journal of Pharmacology (2003) 140, 305–314. doi:10.1038/sj.bjp.0705442
Protein kinase C‐mediated Ca2+ entry in HEK 293 cells transiently expressing human TRPV4
Authors: Xu Feng , Satoh Eisaku , Iijima Toshihiko
Published: September 2003

We investigated whether protein kinase C (PKC) activation stimulates Ca2+ entry in HEK 293 cells transfected with human TRPV4 cDNA and loaded with fura‐2.

Phorbol 12‐myristate 13‐acetate (PMA), a PKC‐activating phorbol ester, increased the intracellular Ca2+ concentration ([Ca2+]i) in a dose‐dependent manner, with an EC50 value of 11.7 nM. Exposure to a hypotonic solution (HTS) after PMA further increased [Ca2+]i. Two other PKC‐activating phorbol esters, phorbol 12,13‐didecanoate (PDD) and phorbol 12,13‐dibutyrate, also caused [Ca2+]i to increase.

The inactive isomer 4α‐PMA was less effective and the peak [Ca2+]i increase was significantly smaller than that induced by PMA. In contrast, 4α‐PDD produced a monophasic or biphasic [Ca2+]i increase with a different latency, while 4α‐phorbol had no effect.

The PMA‐induced [Ca2+]i increase was abolished by prior exposure to bisindolylmaleimide (BIM), a PKC‐specific inhibitor, and suppressed by the nonspecific PKC inhibitor 1‐(5‐isoquinolinesulphonyl)‐2‐methylpiperazine. The [Ca2+]i increase induced by 4α‐PMA, 4α‐PDD or HTS was not significantly affected by BIM.

These results suggest that both PKC‐dependent and ‐independent mechanisms are involved in the phorbol ester‐induced activation of TRPV4, and the PKC‐independent pathway is predominant in HTS‐induced Ca2+ entry.

British Journal of Pharmacology (2003) 140, 413–421. doi:10.1038/sj.bjp.0705443
Effects of GABA agonists on body temperature regulation in GABAB(1)−/− mice
Authors: Quéva Christophe , Bremner‐Danielsen Marianne , Edlund Anders , Jonas Ekstrand A , Elg Susanne , Erickson Sven , Johansson Thore , Lehmann Anders , Mattsson Jan P
Published: September 2003

Activation of GABAB receptors evokes hypothermia in wildtype (GABAB(1)+/+) but not in GABAB receptor knockout (GABAB(1)−/−) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABAB receptor agonist γ‐hydroxybutyrate (GHB), and of the GABAA receptor agonist muscimol. In addition, basal body temperature was determined in GABAB(1)+/+, GABAB(1)+/− and GABAB(1)−/− mice.

GABAB(1)−/− mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABAB receptor‐binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature‐sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale.

GABAB(1)−/− mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABAB(2) receptor protein was below the detection limit in brains from GABAB(1)−/− mice, in the absence of changes in mRNA levels.

GABAB receptor‐binding sites were absent in brain membranes from GABAB(1)−/− mice.

GABAB(1)−/− mice were hypothermic by approximately 1°C compared to GABAB(1)+/+ and GABAB(1)+/− mice.

Injection of baclofen (9.6 mg kg−1) produced a large reduction in body temperature and behavioural effects in GABAB(1)+/+ and in GABAB(1)+/− mice, but GABAB(1)−/− mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg−1). The GABAA receptor agonist muscimol (2 mg kg−1), on the other hand, produced a more pronounced hypothermia in GABAB(1)−/−mice. In GABAB(1)+/+ and GABAB(1)+/− mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABAB(1)−/− mice, muscimol triggered periods of intense jumping and wild running.

It is concluded that hypothermia should be added to the characteristics of the GABAB(1)−/−phenotype. Using this model, GHB was shown to be a selective GABAB receptor agonist. In addition, GABAB(1)−/− mice are hypersensitive to GABAA receptor stimulation, indicating that GABAB tone normally balances GABAA‐mediated effects.

British Journal of Pharmacology (2003) 140, 315–322. doi:10.1038/sj.bjp.0705447
Lack of CB1 receptors increases noradrenaline release in vas deferens without affecting atrial noradrenaline release or cortical acetylcholine release
Authors: Schlicker Eberhard , Redmer Agnes , Werner André , Kathmann Markus
Published: September 2003

We studied whether cannabinoid CB1 receptor gene disruption (to yield CB1−/− mice) affects the electrically evoked tritium overflow from vas deferens and atrial pieces preincubated with [3H]‐noradrenaline (NA) (‘noradrenaline release’) and from cerebral cortex slices preincubated with [3H]‐choline (‘acetylcholine release’).

NA release was higher by 37% in vas deferens from CB1−/− mice than in vas deferens from CB1+/+ mice. The cannabinoid receptor agonist WIN 55,212‐2 inhibited, and the CB1 receptor inverse agonist/antagonist SR 141716, increased NA release in vas deferens from CB1+/+ mice without affecting it in vas deferens from CB1−/− mice.

Atrial NA release did not differ between CB1+/+ and CB1−/− mice nor did WIN 55,212‐2 affect NA release in either strain.

Cortical acetylcholine (Ach) release did not differ between CB1+/+ and CB1−/− mice. WIN 55,212‐2 inhibited, but SR 141716 did not affect, Ach release in the cortex from CB1+/+ mice. Both drugs did not alter Ach release in the cortex from CB1−/− mice.

Tritium content did not differ between CB1+/+ and CB1−/− mice in any preparation.

In conclusion, the increase in NA release associated with CB1 receptor deficiency in the vas deferens, which cannot be ascribed to an alteration of tritium content of the preparations, suggests an endogenous tone at the CB1 receptors of CB1+/+ mice in this tissue. Furthermore, the effect of WIN 55,212‐2 on NA release in the vas deferens and on cortical Ach release involves CB1 receptors, whereas the involvement of non‐CB1–non‐CB2 receptors can be excluded.

British Journal of Pharmacology (2003) 140, 323–328. doi:10.1038/sj.bjp.0705449
MX1013, a dipeptide caspase inhibitor with potent in vivo antiapoptotic activity
Authors: Yang Wu , Guastella John , Huang Jin‐Cheng , Wang Yan , Zhang Li , Xue Dong , Tran Minhtam , Woodward Richard , Kasibhatla Shailaja , Tseng Ben , Drewe John , Cai Sui Xiong
Published: September 2003

Caspases play a critical role in apoptosis, and are considered to be key targets for the design of cytoprotective drugs. As part of our antiapoptotic drug‐discovery effort, we have synthesized and characterized Z‐VD‐fmk, MX1013, as a potent, irreversible dipeptide caspase inhibitor.

MX1013 inhibits caspases 1, 3, 6, 7, 8, and 9, with IC50 values ranging from 5 to 20 nM. MX1013 is selective for caspases, and is a poor inhibitor of noncaspase proteases, such as cathepsin B, calpain I, or Factor Xa (IC50 values >10 μM).

In several cell culture models of apoptosis, including caspase 3 processing, PARP cleavage, and DNA fragmentation, MX1013 is more active than tetrapeptide‐ and tripeptide‐based caspase inhibitors, and blocked apoptosis at concentrations as low as 0.5 μM.

MX1013 is more aqueous soluble than tripeptide‐based caspase inhibitors such as Z‐VAD‐fmk.

At a dose of 1 mg kg−1 i.v., MX1013 prevented liver damage and the lethality caused by Fas death receptor activation in the anti‐Fas mouse‐liver apoptosis model, a widely used model of liver failure.

At a dose of 20 mg kg−1 (i.v. bolus) followed by i.v. infusion for 6 or 12 h, MX1013 reduced cortical damage by approximately 50% in a model of brain ischemia/reperfusion injury.

At a dose of 20 mg kg−1 (i.v. bolus) followed by i.v. infusion for 12 h, MX1013 reduced heart damage by approximately 50% in a model of acute myocardial infarction.

Based on these studies, we conclude that MX1013, a dipeptide pan‐caspase inhibitor, has a good combination of in vitro and in vivo properties. It has the ability to protect cells from a variety of apoptotic insults, and is systemically active in three animal models of apoptosis, including brain ischemia.

British Journal of Pharmacology (2003) 140, 402–412. doi:10.1038/sj.bjp.0705450
Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin‐induced carotid haemodynamic changes in anaesthetised pigs
Authors: Kapoor Kapil , Arulmani Udayasankar , Heiligers Jan P C , Garrelds Ingrid M , Willems Edwin W , Doods Henri , Villalón Carlos M , Saxena Pramod R
Published: September 2003

Calcitonin gene‐related peptide (CGRP), a potent vasodilator released from capsaicin‐sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 μg kg−1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin‐induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone.

Infusions of capsaicin (0.3, 1, 3 and 10 μg kg−1 min−1, i.c.) did not alter the heart rate, but dose‐dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS.

Capsaicin infusion (10 μg kg−1 min−1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose‐dependently blocked by BIBN4096BS.

Capsaicin infusion (10 μg kg−1 min−1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS.

The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin‐induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.

British Journal of Pharmacology (2003) 140, 329–338. doi:10.1038/sj.bjp.0705451
The ability of neuropeptide Y to mediate responses in the murine cutaneous microvasculature: an analysis of the contribution of Y1 and Y2 receptors
Authors: Chu Duc Quyen , Cox Helen M , Costa Soraia K P , Herzog Herbert , Brain Susan D
Published: September 2003

The ability of neuropeptide Y (NPY) to modulate skin blood flow, oedema formation and neutrophil accumulation was investigated. Experiments were designed to examine the possible contribution of the Y2 receptor, in addition to the Y1 receptor, through use of Y2 receptor knockout mice (Y2−/−) and selective receptor antagonists.

The development of a 99mTc clearance technique for the measurement of microvascular blood flow changes in mouse dorsal skin revealed a dose‐dependent ability of picomole amounts of NPY, and also of the Y1‐preferred agonist Pro34NPY and the Y2‐preferred agonist PYY(3–36) to decrease blood flow.

The Y1 receptor antagonist BIBO3304 blocked responses to the Y1 agonist at the lower doses, but only partially inhibited at the higher doses tested in Y2+/+. In Y2−/− receptor mice, the responses to the Y2 agonist were abolished at the lower doses and partially reduced at the highest dose tested, while those to the Y1 agonist were similar in both Y2+/+ and Y2−/−receptor mice.

In Y2+/+ receptor mice, the simultaneous injection of the Y2 antagonist BIIE0246 with BIBO3304 abolished Y2 agonist‐induced decreases in blood flow over the dose range used (10–100 pmol). When the Y2 receptor antagonist BIIE0246 was given alone, it was not able to significantly affect the PYY(3–36)‐induced response, whereas the Y1 receptor antagonist BIBO3304 partially (P<0.001) inhibited the decrease in blood flow evoked by PYY(3–36) at the highest dose.

NPY did not mediate either oedema formation, even when investigated in the presence of the vasodilator calcitonin gene‐related peptide (CGRP), or neutrophil accumulation in murine skin.

We conclude that the major vasoactive activity of NPY in the cutaneous microvasculature is to act in a potent manner to decrease blood flow via Y1 receptors, with evidence for the additional involvement of postjunctional Y2 receptors. Our results do not provide evidence for a potent proinflammatory activity of NPY in the cutaneous microvasculature.

British Journal of Pharmacology (2003) 140, 422–430. doi:10.1038/sj.bjp.0705452
A model for receptor–peptide binding at the glucagon‐like peptide‐1 (GLP‐1) receptor through the analysis of truncated ligands and receptors
Authors: Al‐Sabah Suleiman , Donnelly Dan
Published: September 2003

The receptor for glucagon‐like peptide‐1 (GLP‐1) can be activated by both its physiological hormone and a peptide discovered in the venom of the Gila Monster, exendin‐4, which shows promise as an antidiabetic agent.

Exendin‐4 displays receptor‐binding properties not observed for GLP‐1. Firstly, exendin‐4 can be truncated by up to eight residues at its N‐terminus without a significant loss of affinity. Secondly, exendin‐4 maintains high affinity for the isolated N‐terminal domain of the receptor, suggesting that exendin‐4 makes additional contacts with this domain of the receptor, which nullify the requirement for ligand–receptor interactions involving the extracellular loops and/or transmembrane helices of the receptor's core domain.

In order to further understand the nature of the receptor–peptide interaction, a variety of full length and truncated peptide analogues were used to quantify the contribution of each distinct region of exendin‐4 and GLP‐1 to receptor affinity.

Our data show that, for both exendin‐4 and GLP‐1, the primary interaction is between the putative helical region of the peptide and the extracellular N‐terminal domain of the receptor.

However, we demonstrate that the contribution to receptor affinity provided by the N‐terminal segment of GLP‐1 is greater than that of exendin‐4, while the C‐terminal nine residue extension of exendin‐4, absent in GLP‐1, forms a compensatory interaction with the N‐terminal domain of the receptor.

We describe a peptide–receptor binding model to account for these data.

British Journal of Pharmacology (2003) 140, 339–346. doi:10.1038/sj.bjp.0705453
Mapping and SNP analysis of bovine candidate genes for meat and carcass quality
Authors: Haegeman A. , Williams J. L. , Law A. , Van Zeveren A. , Peelman L. J.
Published: September 2003

The chromosomal localization of 13 bovine genes was determined using radiation hybrid (RH) mapping. The RH mapping data were in agreement with published data using either linkage, somatic cell hybrids or in situ hybridization. Mutation analysis using single‐stranded conformational polymorphism, restriction fragment length polymorphism (RFLP) and sequencing revealed 13 SNPs in four different genes, namely carboxypeptidase E (CPE), uncoupling protein 2 (UCP2), single‐minded (Drosophila) homologue 1 (SIM1) and methallothionein IIa (MT2A). With the exception of one mutation in CPE, all other mutations are either silent or are situated in an intron. The polymerase chain reaction RFLP was used on unrelated animals from different cattle breeds for determing allelic distribution.