bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of 18β‐glycyrrhetinic acid on electromechanical coupling in the guinea‐pig renal pelvis and ureter
Authors: Santicioli Paolo , Maggi Carlo Alberto 
Published: January 2005

We have tested the effect of the gap junction inhibitor, 18β‐glycyrrhetinic acid (18βGA) on electromechanical coupling in the guinea‐pig renal pelvis and ureter by the sucrose gap technique.
In the ureter 18βGA (3–30 μM) produced a concentration‐dependent inhibition of the spike component of the action potential (AP) and reduced contraction evoked by electrical stimulation.
Neurokinin A (NKA) produced a slow depolarization with superimposed APs and phasic contractions of the ureter. 18βGA (30 μM) markedly inhibited the depolarization and APs evoked by NKA. However the contractile response was more sustained in the presence than in the absence of 18βGA. At 100 μM, 18βGA inhibited the mechanical responses to NKA.
KCl (80 mM) produced APs and phasic contractions followed by sustained depolarization and tonic contraction. At 30 μM 18βGA markedly inhibited the KCl‐evoked APs and phasic contractions without affecting the sustained responses. At 100 μM 18βGA inhibited the tonic contraction to KCl.
In the renal pelvis 18βGA (30 μM) inhibited the amplitude of pacemaker potentials and accompanying contractions and induced the appearance of low‐amplitude APs not associated with contraction.
We conclude that, up to 30 μM, the action of 18βGA is consistent with an inhibition of cell‐to‐cell electrical coupling via gap junctions. The single‐unit character of smooth muscles in the guinea‐pig upper urinary tract is partly converted to a multi‐unit pattern. At high concentrations 18βGA possesses non specific effects which limit its usefulness as a tool for studying the role of gap junctions in smooth muscles.

British Journal of Pharmacology (2000) 129, 163–169; doi:10.1038/sj.bjp.0703004
Modulation of airway smooth muscle tone by protease activated receptor‐1,‐2,‐3 and ‐4 in trachea isolated from influenza A virus‐infected mice
Authors: Lan Rommel S , Stewart Geoff A , Henry Peter J 
Published: January 2005

Relaxant and contractile effects of the tethered ligand domain sequences of murine PAR‐1, PAR‐2, PAR‐3 and PAR‐4, and of the proteases thrombin and trypsin were examined in mouse isolated tracheal preparations. The epithelium‐ and cyclo‐oxygenase‐dependence of these effects and the potential modulatory effects of respiratory tract viral infection were also investigated.
In carbachol‐contracted preparations, trypsin, thrombin, and the tethered ligand domain sequences of murine PAR‐1 (SFFLRN‐NH2), PAR‐2 (SLIGRL‐NH2) and PAR‐4 (GYPGKF‐NH2), but not PAR‐3 (SFNGGP‐NH2), induced transient, relaxant responses that were abolished by the cyclo‐oxygenase inhibitor indomethacin.
Repeated administration of SFFLRN‐NH2, SLIGRL‐NH2 or GYPGKF‐NH2 (30 μM) was associated with markedly diminished relaxation responses (homologous desensitization), although there was no evidence of cross‐desensitization between these peptides.
The tethered ligand domain sequences for PAR‐1 and PAR‐4 induced a rapid, transient contractile response that preceded the relaxant response. Contractions were not inhibited by indomethacin and were not induced by either thrombin or trypsin.
Influenza A virus infection did not significantly affect the responses induced by either the proteases or peptides. Furthermore, epithelial disruption caused by mechanical rubbing had no significant effect on responses to these PAR activators in preparations from either virus‐ or sham‐infected mice.
In summary, the proteases trypsin and thrombin, and peptide activators of PAR‐1, PAR‐2 and PAR‐4 induced relaxant responses of mouse isolated tracheal smooth muscle preparations, which were mediated by a prostanoid, probably PGE2. Interestingly, PAR‐mediated relaxations were not significantly diminished following acute damage to the epithelium caused by mechanical rubbing and/or the respiratory tract viral pathogen, influenza A.

British Journal of Pharmacology (2000) 129, 63–70; doi:10.1038/sj.bjp.0703007
Regulation of β1‐ and β3‐adrenergic agonist‐stimulated lipolytic response in hyperthyroid and hypothyroid rat white adipocytes
Authors: Germack Renée , Starzec Anna , Perret Gérard Y 
Published: January 2005

This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to β‐adrenoceptor (β‐AR) stimulation. The β1‐ and β3‐AR mRNAs and proteins were measured by Northern and saturation analyses, respectively. Glycerol production and adenyl cyclase (AC) activity induced by various non‐selective and selective β1/β3‐AR agonists and drugs which act distal to the receptor in the signalling cascade were measured in cells from untreated, tri‐iodothyronine (T3)‐treated and thyroidectomized rats.
The β3‐AR density was enhanced (72%) by T3‐treatment and reduced (50%) by introduction of a hypothyroid state while β1‐AR number remained unaffected. The β1‐ and β3‐AR density was correlated with the specific mRNA level in all thyroid status.
The lipolytic responses to isoprenaline, noradrenaline (β1/β3/β3‐AR agonists) and BRL 37344 (β3‐AR agonist) were potentiated by 48, 58 and 48%, respectively in hyperthyroidism and reduced by about 80% in hypothyroidism.
T3‐treatment increased the maximal lipolytic response to the partial β3‐AR (CGP 12177) and β1‐AR (xamoterol) agonists by 234 and 260%, respectively, increasing their efficacy (intrinsic activity: 0.95 versus 0.43 and 1.02 versus 0.42). The maximal AC response to these agonists was increased by 84 and 58%, respectively, without changing their efficacy.
In the hypothyroid state, the maximal lipolytic and AC responses were decreased with CGP (0.17±0.03 versus 0.41±0.08 μmol glycerol/106 adipocytes; 0.048±0.005 versus 0.114±0.006 pmol cyclic AMP min−1 mg−1) but not changed with xamoterol.
The changes in lipolytic responses to postreceptor‐acting agents (forskolin, enprofylline and dibutenyl cyclic AMP, (Bu)2cAMP) suggest the modifications on receptor coupling and phosphodiesterase levels in both thyroid states.
Thyroid status affects lipolysis by modifying β3‐AR density and postreceptor events without changes in the β1‐AR functionality.

British Journal of Pharmacology (2000) 129, 448–456; doi:10.1038/sj.bjp.0703008
Vascular endothelial growth factor attenuates trauma‐induced injury in rats
Authors: Campbell Barry , Chuhran Craig , Lefer Allan M 
Published: January 2005

Endothelial dysfunction and loss of nitric oxide (NO) is an integral part of the initiation and maintenance of the inflammatory process such as that occurring in traumatic shock, and is considered responsible for much of the trauma induced microvascular injury.
We investigated the effects of a vascular endothelial growth factor (VEGF) in a rat model of traumatic shock. Pentobarbital‐anaesthetized rats subjected to Noble‐Collip drum trauma developed a shock state characterized by marked hypotension and a 93% mortality rate with a mean survival time of 108±10 min in 14 rats. Accompanying these effects was a significant degree of endothelial dysfunction and a markedly elevated intestinal myeloperoxidase (MPO) activity.
Treatment with 125 μg kg−1 VEGF administered intravenously 18 h pre‐trauma, increased survival rate to 67% (P<0.01), and prolonged survival time to 252±24 min in 12 rats (P<0.01). VEGF also significantly preserved the endothelium‐dependent relaxation to ACh indicating a preservation of endothelium‐derived NO.
Our results indicate that endothelial dysfunction with its accompanying loss of NO plays an important role in tissue injury associated with trauma, and that preservation of NO is beneficial in traumatic shock. The mechanisms of the protective effect of VEGF in trauma involves preservation of eNOS function and diminished neutrophil accumulation resulting in reduced neutrophil‐mediated tissue injury.

British Journal of Pharmacology (2000) 129, 71–76; doi:10.1038/sj.bjp.0703010
Evidence that activation of central 5‐HT2B receptors causes renal sympathoexcitation in anaesthetized rats
Authors: Knowles Ian D , Ramage Andrew G 
Published: January 2005

The effects of injections i.c.v. of α‐methyl‐5‐(2‐thienylmethoxy)‐1H‐indole‐3‐ethanamine (BW723C86; 0.02–2 μmol kg−1), a 5‐HT2B receptor agonist, on renal sympathetic and phrenic nerve activity, mean arterial blood pressure and heart rate were investigated in α‐chloralose anaesthetized rats pretreated with a peripherally acting 5‐HT2 receptor antagonist.
BW723C86 i.c.v. caused a dose‐related increase in renal nerve activity reaching a maximum of 67±6%, which at the highest dose was associated with a small and maintained fall in mean arterial blood pressure of 7±3 mmHg. These changes were not associated with any significant changes in heart rate or phrenic nerve activity.
BW723C86‐evoked increases in renal nerve activity and hypotension were attenuated by pretreatment (i.c.v.) with SB204741 (300 nmol kg−1; a 5‐HT2B receptor antagonist) but not by the same dose (i.c.v.) of ketanserin (a 5‐HT2A receptor antagonist) or RS102221 (a 5‐HT2C receptor antagonist). None of these antagonists alone had any effect on the variables being measured.
It is concluded that central 5‐HT2B receptors may play a selective role in the control of sympathetic supply to the kidney, which could be important in the central mechanisms involved in blood volume regulation.

British Journal of Pharmacology (2000) 129, 177–183; doi:10.1038/sj.bjp.0703011
Sustained ethanol inhibition of native AMPA receptors on medial septum/diagonal band (MS/DB) neurons
Authors: Frye Gerald D , Fincher Annette 
Published: January 2005

The direct impact of ethanol on native, non‐NMDA glutamate receptors was examined in acutely isolated MS/DB neurons from rat. The impact of ethanol functional tolerance and physical dependence on non‐NMDA receptor function was also determined.
Non‐NMDA receptors were defined pharmacologically as predominantly the AMPA subtype, because both AMPA‐ or kainate‐activated currents were blocked by GYKI 52466, a selective AMPA receptor antagonist. The relative magnitude of potentiation of AMPA‐activated currents by 10 or 100 μM cyclothiazide was consistent with recombinant AMPA flop‐subtype receptors. Finally, the selective kainate receptor agonist, SYM 8021, induced little current in MS/DB neurons.
AMPA receptor currents when activated by kainate were sensitive to ethanol, showing inhibition of ∼5–50% when 10–300 mM ethanol and kainate were briefly co‐applied (3 s). Ethanol (100 mM) also inhibited both the initial transient peak and sustained currents activated by AMPA. Inhibition was sustained during continuous ethanol superfusions of 5 min, suggesting a lack of acute tolerance to ethanol‐induced AMPA receptor blockade.
Rapid application of 3–3000 μM kainate activated concentration‐dependent currents in MS/DB neurons from Control and Ethanol Dependent animals that were not significantly different. Also, direct ethanol inhibition (300 mM) of kainate‐activated currents was not reduced by ethanol dependence, suggesting a lack of functional tolerance.
These results suggest that native AMPA receptors on MS/DB neurons are inhibited by pharmacologically‐relevant concentrations of ethanol. However, these receptors, unlike NMDA receptors, do not undergo adaptation with sustained ethanol exposure sufficient to induce physical dependence.

British Journal of Pharmacology (2000) 129, 87–94; doi:10.1038/sj.bjp.0703039
Voltage‐dependent block of native AMPA receptor channels by dicationic compounds
Authors: Tikhonov D B , Samoilova M V , Buldakova S L , Gmiro V E , Magazanik L G 
Published: January 2005

The kinetics of open channel block of GluR2‐containing and GluR2‐lacking AMPA receptors (AMPAR) by dicationic compounds (IEM‐1460, IEM‐1754, and IEM‐1925) have been studied in rat hippocampal neurones using whole‐cell patch clamp recording and concentration‐jump techniques. Neurones were isolated from hippocampal slices by vibrodissociation.
The dicationic compounds were approximately 100–200 times more potent as blockers of GluR2‐lacking AMPAR than as blockers of GluR2‐containing AMPAR. The subunit specificity of channel block is determined by the blocking rate constant of a dicationic compound, whereas differences in unblocking rate constants account for differences in potency.
Hyperpolarization may decrease the block produced by IEM‐1460 and IEM‐1754 block due to the voltage‐dependence of the unblocking rate constants for these compounds. This suggests that dicationic compounds permeate the AMPAR channel at negative membrane potentials. The effect was particularly apparent for GluR2‐lacking AMPAR. These findings indicate that the presence of GluR2‐subunit(s) in AMPAR hinders the binding of the cationic compounds and their permeation through the channel.
The most potent compound tested was IEM‐1925. The presence of a phenylcyclohexyl moiety instead of an adamantane moiety, as in IEM‐1460 and IEM1754, is probably responsible for the higher potency of IEM‐1925. Dicationic compounds are important not only as pharmacological tools, but also as templates for the synthesis of new selective AMPAR blockers which may be potential therapeutic agents.

British Journal of Pharmacology (2000) 129, 265–274; doi:10.1038/sj.bjp.0703043
ADP can induce aggregation of human platelets via both P2Y1 and P2T receptors
Authors: Jarvis G E , Humphries R G , Robertson M J , Leff P 
Published: January 2005

In the present study we have investigated the roles of P2Y1 and P2T receptor subtypes in adenosine 5′‐diphosphate (ADP)‐induced aggregation of human platelets in heparinized platelet rich plasma.
The response to ADP can be characterized as the initial rate or the maximum or final extent of aggregation. The response profile is determined by the concentration of ADP used, being transient at lower and sustained at higher concentrations.
The P2Y1 receptor antagonist, adenosine‐3′‐phosphate‐5′‐phosphate (A3P5P) competitively antagonized the initial rate of aggregation (pKB 5.47) and transformed the response profile to a slowly developing but sustained response. Both maximum and final extents were also inhibited by A3P5P although not in a competitive manner (Schild slope <1).
The P2T receptor antagonist, AR‐C67085, competitively antagonized the final extent of aggregation (pKB 8.54), transforming the response profile to one of rapid, transient aggregation. Its effect on maximum extent (the most widely used index of aggregation) was complex, and further supported the involvement of both receptor subtypes in the aggregation response.
ADP‐induced aggregation is a complex phenomenon, the nature of which is determined by the relative occupancy of the two receptor subtypes. While P2Y1 receptor activation causes a rapid and transient aggregation, the extent of sustained aggregation is determined by the level of P2T receptor occupancy. Hence, detailed analysis of the aggregation response is essential to correctly define the purinergic pharmacology of the platelet and interpretation of results is critically dependent on the response index chosen.

British Journal of Pharmacology (2000) 129, 275–282; doi:10.1038/sj.bjp.0703046
The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1)
Authors: Smart D , Gunthorpe M J , Jerman J C , Nasir S , Gray J , Muir A I , Chambers J K , Randall A D , Davis J B 
Published: January 2005

The endogenous cannabinoid anandamide was identified as an agonist for the recombinant human VR1 (hVR1) by screening a large array of bioactive substances using a FLIPR‐based calcium assay. Further electrophysiological studies showed that anandamide (10 or 100 μM) and capsaicin (1 μM) produced similar inward currents in hVR1 transfected, but not in parental, HEK293 cells. These currents were abolished by capsazepine (1 μM). In the FLIPR anandamide and capsaicin were full agonists at hVR1, with pEC50 values of 5.94±0.06 (n=5) and 7.13±0.11 (n=8) respectively. The response to anandamide was inhibited by capsazepine (pKB of 7.40±0.02, n=6), but not by the cannabinoid receptor antagonists AM630 or AM281. Furthermore, pretreatment with capsaicin desensitized the anandamide‐induced calcium response and vice versa. In conclusion, this study has demonstrated for the first time that anandamide acts as a full agonist at the human VR1.British Journal of Pharmacology (2000) 129, 227–230; doi:10.1038/sj.bjp.0703050
Modulation by bicuculline and penicillin of the block by t‐butyl‐bicyclo‐phosphorothionate (TBPS) of GABAA‐receptor mediated Cl−‐current responses in rat striatal neurones
Authors: Behrends Jan C 
Published: January 2005

T‐butyl‐bicyclo‐phosphorothionate (TBPS) is a prototypical representative of the cage‐convulsants which act through a use‐dependent block of the GABAA‐receptor‐ionophore complex. Using current recordings from cultured neurones of rat striatum the manner was investigated in which two antagonists, bicuculline and penicillin, presumably acting at the agonist binding site and in the ionic channel, respectively, modify the rate of block by TBPS.
Penicillin (5 or 10 mM) did not slow the rate of block by TBPS, but produced a significant enhancement of block rate, which, however, was inversely related to the degree of antagonism by penicillin of the GABA‐induced current.
Bicuculline (10 μM) reduced the rate of block by TBPS. However, this effect was 3 fold weaker than its GABA‐antagonistic action. The slowing of block rate and the current antagonism exhibited a biphasic, positive‐negative relationship. Co‐application of bicuculline (100 μM) in a concentration that produced nearly complete antagonism and TBPS (10 μM) resulted in a marked (∼40%) reduction of subsequent GABA response amplitudes compatible with a direct, bicuculline‐induced conformational change in the receptor required for the binding of and block by TBPS.
The lack of protection afforded by the channel blocker penicillin as well as the lack of correlation between bicuculline antagonism of the Cl−‐current and its efficiency in protecting against TBPS block is evidence against an open channel blocking mechanism for TBPS. TBPS does, therefore, not appear to gain access to its binding site via the open pore but through alternative routes regulated from the agonist binding site.

British Journal of Pharmacology (2000) 129, 402–408; doi:10.1038/sj.bjp.0703063
Ontogenic aspects of D1 receptor coupling to G proteins and regulation of rat jejunal Na+, K+ ATPase activity and electrolyte transport
Authors: Vieira‐Coelho M A , Soares‐da‐Silva P 
Published: January 2005

The present study examined the effect of dopamine on rat jejunal electrolyte transport (rheogenic transport and Na+, K+‐ATPase activity) in adult (60‐day old) and young (20‐day old) animals.
In young rats, dopamine, in the presence of phentolamine, produced an increase in jejunal Isc, this being completely abolished by SKF 83566, and not changed by S‐sulpiride. SKF 38393, but not quinerolane, also increased Isc; this effect was abolished by SKF 83566 and ouabain, but not by furosemide. In adult rats, dopamine in the presence of phentolamine (0.2 μM) decreased Isc.
Na+, K+‐ATPase activity in isolated jejunal epithelial cells from adult rats was 2.4 fold that in young rats. In the presence of phentolamine, both dopamine and SKF 38393, but not quinerolane, significantly decreased jejunal Na+, K+‐ATPase activity in young animals but not in adult animals.
Binding [3H]‐Sch 23390 to membranes of jejunal mucosa revealed the presence of a single class of receptors in both young and adult rats, with similar KD and Bmax values.
GTPγS and cholera toxin inhibited jejunal Na+, K+‐ATPase activity in young, but not in adult rats. Co‐incubation of pertussis toxin with dopamine was found to potentiate the inhibitory effects of dopamine upon the enzyme in both young and adult rats.
Regulation of Na+, K+‐ATPase activity by cholera toxin‐sensitive G proteins is absent in adult animals, and such difference may explain the failure of dopamine to inhibit intestinal Na+, K+‐ATPase activity in adult rats.

British Journal of Pharmacology (2000) 129, 573–581; doi:10.1038/sj.bjp.0703065
On the mechanism of d‐amphetamine‐induced changes in glutamate, ascorbic acid and uric acid release in the striatum of freely moving rats
Authors: Miele Maddalena , Mura Maria A , Enrico Paolo , Esposito Giovanni , Serra Pier A , Migheli Rossana , Zangani Danilo , Miele Egidio , Desole Maria S 
Published: January 2005

The effects of systemic, intrastriatal or intranigral administration of d‐amphetamine on glutamate, aspartate, ascorbic acid (AA), uric acid, dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations in dialysates from the striatum of freely‐moving rats were evaluated using microdialysis.
d‐Amphetamine (2 mg kg−1) given subcutaneously (s.c.) increased DA, AA and uric acid and decreased DOPAC+HVA, glutamate and aspartate dialysate concentrations over a 3 h period after d‐amphetamine. 5‐HIAA concentrations were unaffected. Individual changes in glutamate and AA dialysate concentrations were negatively correlated.
d‐Amphetamine (0.2 mM), given intrastriatally, increased DA and decreased DOPAC+HVA and aspartate dialysate concentrations, but failed to change those of glutamate, AA uric acid or 5‐HIAA, over a 2 h period after d‐amphetamine. Haloperidol (0.1 mM), given intrastriatally, increased aspartate concentrations without affecting those of glutamate or AA.
d‐Amphetamine (0.2 mM), given intranigrally, increased AA and uric acid dialysate concentrations and decreased those of glutamate, aspartate and DA; DOPAC+HVA and 5‐HIAA concentrations were unaffected.
These results suggest that d‐amphetamine‐induced increases in AA and uric acid and decreases in glutamate concentrations are triggered at nigral sites. The changes in aspartate levels may be evoked by at least two mechanisms: striatal (mediated by inhibitory dopaminergic receptors) and nigral (activation of amino acid carrier‐mediated uptake).

British Journal of Pharmacology (2000) 129, 582–588; doi:10.1038/sj.bjp.0703066
Gamma‐aminobutyric acid (GABA) transport across human intestinal epithelial (Caco‐2) cell monolayers
Authors: Thwaites David T , Basterfield Laura , McCleave Peter M J , Carter Simon M , Simmons Nicholas L 
Published: January 2005

Transintestinal absorption of gamma‐aminobutyric acid (GABA) via a pH‐dependent mechanism is demonstrated in the model human intestinal epithelial cell line Caco‐2.
Experiments with BCECF [2′,7′,‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein]‐loaded Caco‐2 cells demonstrate that GABA transport across the apical membrane is coupled to proton flow into the cell.
Short‐circuit current (ISC) measurements using Caco‐2 cell monolayers under voltage‐clamped conditions demonstrate that pH‐dependent GABA transport is a rheogenic process even in the absence of extracellular Na+, consistent with H+/GABA symport.
A range of GABA analogues were tested for their abilities to: (a) inhibit pH‐dependent [3H]GABA uptake across the apical membrane; (b) stimulate H+ flow across the apical surface of BCECF‐loaded Caco‐2 cell monolayers; (c) increase inward ISC across voltage‐clamped Caco‐2 cell monolayers.
Nipecotic acid, isonipecotic acid, D,L‐β‐aminobutyric acid, and 3‐amino‐1‐propanesulphonic acid each caused a marked acidification of intracellular pH and an increase in ISC when superfused at the apical surface of Caco‐2 cell monolayers. In contrast L‐α‐amino‐n‐butyric acid failed to induce proton flow or ISC. The ability of these compounds to induce proton or current flow across the apical surface of this intestinal epithelium was closely related to the relative inhibitory effects on [3H]GABA uptake.
These observations demonstrate H+/GABA symport and suggest that this transport mechanism may be accessible as a route for oral absorption of therapeutically‐useful GABA analogues.

British Journal of Pharmacology (2000) 129, 457–464; doi:10.1038/sj.bjp.0703069