bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence that nitric oxide acts as an inhibitory neurotransmitter supplying taenia from the guinea‐pig caecum
Authors: Shuttleworth C W R , Sweeney K M , Sanders K M 
Published: January 2005

Nitric oxide synthase‐containing nerve fibres are abundant within taenia of the guinea‐pig caecum, but there is little previous evidence supporting a direct role for nitric oxide (NO) in responses to enteric inhibitory nerve stimulation. In this study we have attempted to identify an NO‐dependent component of inhibitory transmission in isolated taenia coli.
Isometric tension was recorded in the presence of atropine and guanethidine (both 1 μM). Tone was raised with histamine (1 μM), and intrinsic inhibitory neurons stimulated using either a nicotinic agonist (1,1‐dimethyl‐4‐phenylpiperazinium iodide; DMPP) or electrical field stimulation (EFS).
DMPP (1–100 μM) produced concentration‐dependent biphasic relaxations, comprising an initial peak relaxation followed by a sustained relaxation. Responses to DMPP were antagonized by tetrodotoxin (1 μM) or apamin (0.3 μM) and abolished by hexamethonium (300 μM). L‐nitro‐arginine (L‐NOARG; 100 μM) and oxyhaemoglobin (2%) both significantly reduced sustained relaxations produced by DMPP.
EFS (5 Hz, 30 s) also produced biphasic relaxations. Both L‐NOARG and an inhibitor of soluble guanylate cyclase (ODQ, 1–10 μM) reduced the sustained component of EFS responses.
Two NO donors, sodium nitroprusside (SNP) and diethylenetriamine‐nitric oxide adduct (DENO), produced concentration‐dependent relaxations. Responses to SNP and DENO were antagonized by ODQ (1 μM) and by apamin (0.3 μM).
These results suggest that NO contributes directly to a component of inhibitory transmission in guinea‐pig taenia coli. The actions of NO appear to be mediated via cyclic GMP synthesis, and may involve activation of small conductance calcium activated K+ channels. A role for NO is most evident during sustained relaxations evoked by longer stimulus trains or chemical stimulation of intrinsic neurons.

British Journal of Pharmacology (1999) 127, 1495–1501; doi:10.1038/sj.bjp.0702674
Evaluation of α1‐adrenoceptors in the rabbit iris: pharmacological characterization and expression of mRNA
Authors: Nakamura Seigo , Taniguchi Takanobu , Suzuki Fumiko , Akagi Yoshio , Muramatsu Ikunobu 
Published: January 2005

Subtypes of α1‐adrenoceptor in rabbit iris have been examined in functional, binding and molecular biological experiments.
In functional studies, exogenous and endogenous noradrenaline produced contractions of the iris dilator muscle. The contractile responses to noradrenaline were competitively antagonized by a range of α1‐adrenoceptor antagonists (pA2 values): prazosin (8.1), WB4101 (8.2), BMY7378 (5.9), YM617 (9.5), JTH‐601 (8.8), HV723 (7.8) and KMD‐3213 (9.8). The same order of inhibitory potency was seen in the adrenergic responses to electrical stimulation. This affinity profile corresponds well to that of the putative α1L‐adrenoceptor, which has been proposed in lower urinary tract tissues.
In binding studies on rabbit iris membrane however, prazosin, KMD‐3213 and WB4101 displayed high affinity (pKd or pKi: 9.6, 10.3, 9.6, respectively), and BMY7378 displayed low affinity (pKi: 6.9). These results show that the binding sites typically correspond to α1A‐adrenoceptor subtype in character, and we could not detect the significant amount of α1L‐adrenoceptor subtype.
The expression of the three distinct mRNAs that encode proteins of α1a‐, α1b‐ and α1d‐adrenoceptors was studied using reverse transcription‐polymerase chain reaction (RT–PCR). RT–PCR demonstrated the strongest expression of the α1a‐adrenoceptor, weak expression of the α1b‐ adrenoceptor and undetectable expression of the α1d‐adrenoceptor.
The present study suggests that α1A‐adrenoceptor is a major subtype detectable in binding and RT–PCR studies in rabbit iris, but that the adrenergic contractions of iris dilator muscle are mediated via activation of α1‐adrenoceptor subtype having low affinity for prazosin and WB4101.

British Journal of Pharmacology (1999) 127, 1367–1374; doi:10.1038/sj.bjp.0702675
Expression of immediate early genes, GATA‐4, and Nkx‐2.5 in adrenergic‐induced cardiac hypertrophy and during regression in adult mice
Authors: Saadane Nacéra , Alpert Lesley , Chalifour Lorraine E 
Published: January 2005

Adrenoreceptor agonists induce a hypertrophic phenotype in vitro and in vivo. To investigate the molecular remodeling in chronic cardiac hypertrophy we infused adult male mice with vehicle, isoproterenol, phenylephrine or both agonists for 3, 7 or 14 days.
All drugs increased cardiac mass. After minipump removal cardiac mass regressed to control levels within 7 days after PE and ISO treatment whereas ISO+PE treated hearts were incompletely regressed.
ANF and β‐MHC, but not α‐MHC, expression were increased by agonists at all time points. GATA‐4, Nkx‐2.5, Egr‐1, c‐jun and c‐fos expression were increased after 3, 7 and 14 days of treatment. Expression was greatest after ISO+PE>>ISO>PE>vehicle infusion suggesting a synergistic effect of adrenoreceptor stimulation and indicating a greater effect of β‐ than α‐adrenergic action in vivo.
After PE or ISO drug withdrawal the HW/BW was normal and Egr‐1, c‐jun, c‐fos and GATA‐4, but not Nkx2.5, expression dropped to control levels. HW/BW regression was incomplete after ISO+PE and elevated levels of Egr‐1, c‐jun and Nkx2.5 expression remained.
A hydralazine‐mediated reduction in blood pressure had no effect on the agonist‐induced cardiac hypertrophy or gene expression.
In conclusion, we found that continued agonist stimulation, and not blood pressure, is responsible for the maintained increase in gene expression. Further, we found the decrease in gene expression in the regression after drug withdrawal was gene specific.

British Journal of Pharmacology (1999) 127, 1165–1176; doi:10.1038/sj.bjp.0702676
Protection by imidazol(ine) drugs and agmatine of glutamate‐induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor
Authors: Olmos Gabriel , DeGregorio‐Rocasolano Nuria , Regalado M Paz , Gasull Teresa , Boronat M Assumpció , Trullas Ramón , Villarroel Alvaro , Lerma Juan , García‐Sevilla Jesús A 
Published: January 2005

This study was designed to assess the potential neuroprotective effect of several imidazol(ine) drugs and agmatine on glutamate‐induced necrosis and on apoptosis induced by low extracellular K+in cultured cerebellar granule cells.Exposure (30 min) of energy deprived cells toL‐glutamate (1–100 μM) caused a concentration‐dependent neurotoxicity, as determined 24 h later by a decrease in the ability of the cells to metabolize 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide (MTT) into a reduced formazan product.L‐glutamate‐induced neurotoxicity (EC50=5 μM) was blocked by the specific NMDA receptor antagonist MK‐801 (dizocilpine).Imidazol(ine) drugs and agmatine fully prevented neurotoxicity induced by 20 μM(EC100)L‐glutamate with the rank order (EC50in μM): antazoline (13)>cirazoline (44)>LSL 61122 [2‐styryl‐2‐imidazoline] (54)>LSL 60101 [2‐(2‐benzofuranyl) imidazole] (75)>idazoxan (90)>LSL 60129 [2‐(1,4‐benzodioxan‐6‐yl)‐4,5‐dihydroimidazole] (101)>RX821002 (2‐methoxy idazoxan) (106)>agmatine (196). No neuroprotective effect of these drugs was observed in a model of apoptotic neuronal cell death (reduction of extracellular K+) which does not involve stimulation of NMDA receptors.Imidazol(ine) drugs and agmatine fully inhibited [3H]‐(+)‐MK‐801 binding to the phencyclidine site of NMDA receptors in rat brain. The profile of drug potency protecting againstL‐glutamate neurotoxicity correlated well (r=0.90) with the potency of the same compounds competing against [3H]‐(+)‐MK‐801 binding.In HEK‐293 cells transfected to express the NR1‐1a and NR2C subunits of the NMDA receptor, antazoline and agmatine produced a voltage‐ and concentration‐dependent block of glutamate‐induced currents. Analysis of the voltage dependence of the block was consistent with the presence of a binding site for antazoline located within the NMDA channel pore with an IC50of 10–12 μMat 0 mV.It is concluded that imidazol(ine) drugs and agmatine are neuroprotective against glutamate‐induced necrotic neuronal cell deathin vitroand that this effect is mediated through NMDA receptor blockade by interacting with a site located within the NMDA channel pore.British Journal of Pharmacology(1999)127, 1317–1326; doi:10.1038/sj.bjp.0702679
Presynaptic inhibition preferentially reduces the NMDA receptor‐mediated component of transmission in rat midbrain dopamine neurons
Authors: Wu Yan‐Na , Shen Ke‐Zhong , Johnson Steven W 
Published: January 2005

We used patch pipettes to record whole‐cell currents from single dopamine neurons in slices of rat midbrain. Pharmacological methods were used to isolate EPSCs evoked by focal electrical stimulation.
Baclofen was significantly more potent for inhibiting NMDA receptor‐mediated EPSCs (IC50=0.24 μM) compared with inhibition of EPSCs mediated by AMPA receptors (IC50=1.72 μM). The increased potency of baclofen for inhibiting the NMDA component persisted in superfusate that contained zero Mg2+ and when postsynaptic K+ conductances were reduced by Cs+ and QX‐314. Effects of baclofen on EPSCs were blocked by the GABAB receptor antagonist CGP‐35348.
Adenosine was 20 fold more potent for reducing the NMDA component of transmission (IC50=31 μM) compared with inhibition of AMPA receptor‐mediated EPSCs (IC50=654 μM). Effects of adenosine on EPSCs were blocked by the A1 receptor antagonist DPCPX.
Both baclofen and adenosine significantly increased the ratio of EPSCs in paired‐pulse studies, suggesting presynaptic sites of action. Although adenosine (1 mM) did not reduce currents evoked by exogenous NMDA (10 μM), baclofen (1 μM) reduced NMDA currents by 29%. Neither baclofen nor adenosine altered currents evoked by exogenous AMPA (1 μM).
We conclude that adenosine acts at presynaptic A1 receptors to cause a preferential reduction in the NMDA component of synaptic transmission. In contrast, baclofen preferentially reduces NMDA EPSCs by acting at both pre‐ and postsynaptic GABAB receptors. By regulating NMDA receptor function, A1 and GABAB receptors may play important roles in regulating the excitability of dopamine neurons.

British Journal of Pharmacology (1999) 127, 1422–1430; doi:10.1038/sj.bjp.0702680
Pharmacological characterization of nicotine‐induced acetylcholine release in the rat hippocampus in vivo: evidence for a permissive dopamine synapse
Authors: Reid Richard T , Lloyd G Kenneth , Rao Tadimeti S 
Published: January 2005

In this study, the mechanism of nicotine‐induced hippocampal acetylcholine (ACh) release in awake, freely moving rats was examined using in vivo microdialysis.
Systemic administration of nicotine (0.4 mg kg−1, s.c.) increased the levels of ACh in hippocampal dialysates.
The nicotine‐induced hippocampal ACh release was sensitive to the pretreatment of neuronal nicotinic acetylcholine receptor (nAChR) antagonists mecamylamine (3.0 mg kg−1, s.c.) and dihydro‐β‐erythrodine (DHβE; 4.0 mg kg−1, s.c.) as well as systemic administration of the dopamine (DA) D1 receptor antagonist SCH‐23390 (R‐(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐benzazepine; 0.3 mg kg−1, s.c.).
Local perfusion of mecamylamine (100 μM), DHβE (100 μM) or SCH‐23390 (10 μM) through microdialysis probe did not increase basal hippocampal ACh release.
Hippocampal ACh release elicited by systemic administration of nicotine (0.4 mg kg−1, s.c.) was antagonized by local perfusion of SCH‐23390 (10 μM), but not by MEC (100 μM) or DHβE (100 μM).
Direct perfusion of nicotine (1 mM, but not 0.1 mM) increased hippocampal ACh levels; however, this effect was relatively insensitive to blockade by co‐perfusion of either mecamylamine (100 μM) or SCH‐23390 (10 μM).
These results suggest that nicotine‐induced hippocampal ACh release occurs by two distinct mechanisms: (1) activation of nAChRs outside the hippocampus leading to DA release and subsequent ACh release involving a permissive DA synapse, and (2) direct action of nicotine within the hippocampus leading to ACh release via non‐DA‐ergic mechanism.

British Journal of Pharmacology (1999) 127, 1486–1494; doi:10.1038/sj.bjp.0702683
Alternative splicing generates two isoforms of the β3‐adrenoceptor which are differentially expressed in mouse tissues
Authors: Evans B A , Papaioannou M , Hamilton S , Summers R J 
Published: January 2005

The β3‐adrenoceptor (AR) differs from the β1‐AR and β2‐ARs in having introns within and downstream of the coding block. This study demonstrates two splice variants of the mouse β3‐AR which differ within the coding region.
Reverse transcription/polymerase chain reaction with intron‐spanning primers was used to demonstrate the splice variant of the mouse β3‐adrenoceptor. The novel β3b‐AR has 17 amino acids encoded by exon 2 (SSLLREPRHLYTCLGYP) which differ from the 13 in the known β3a‐AR (RFDGYEGARPFPT).
β3b‐AR mRNA is differentially expressed in mouse tissues, with levels relative to β3a‐AR mRNA highest in hypothalamus, cortex and white adipose tissue, and lower in ileum smooth muscle and brown adipose tissue.

British Journal of Pharmacology (1999) 127, 1525–1531; doi:10.1038/sj.bjp.0702688
IL‐12 as a therapeutic target for pharmacological modulation in immune‐mediated and inflammatory diseases: regulation of T helper 1/T helper 2 responses
Authors: Haskó György , Szabó Csaba 
Published: January 2005

Interleukin‐12 (IL‐12) is a pivotal cytokine in driving the immune system towards a T helper (Th)1 type response and preventing a Th2 type immune profile. Therefore, IL‐12 is indispensable in the defense against certain, mainly intracellular pathogens, but overproduction of this cytokine is crucially involved in the etiology of several inflammatory and autoimmune diseases.
Hence, IL‐12 is an ideal target for pharmacological intervention in the therapy of autoimmune and inflammatory diseases.
The production of IL‐12 and a resultant Th1 type immune response can be suppressed with several pharmacological approaches including modulation of intracellular cyclic AMP levels, glucocorticoids and nuclear factor‐κB inhibition. IL‐12 responsiveness may be inhibited using anti‐IL‐12 antibodies, soluble IL‐12 receptors or the IL‐12 p40 homodimer.
Exploitation of these approaches may provide novel means for the experimental therapy of a variety of pathophysiological states.

British Journal of Pharmacology (1999) 127, 1295–1304; doi:10.1038/sj.bjp.0702689
Differential blockade of rat α3β4 and α7 neuronal nicotinic receptors by ω‐conotoxin MVIIC, ω‐conotoxin GVIA and diltiazem
Authors: Herrero Carlos J , García‐Palomero Esther , Pintado Antonio J , García Antonio G , Montiel Carmen 
Published: January 2005

Rat α3β4 or α7 neuronal nicotinic acetylcholine receptors (AChRs) were expressed in Xenopus laevis oocytes, and the effects of various toxins and non‐toxin Ca2+ channel blockers studied. Nicotinic AChR currents were elicited by 1 s pulses of dimethylphenylpiperazinium (DMPP, 100 μM) applied at regular intervals.
The N/P/Q‐type Ca2+ channel blocker ω‐conotoxin MVIIC inhibited α3β4 currents with an IC50 of 1.3 μM; the blockade was non‐competitive and reversible. The α7 currents were unaffected.
At 1 μM, ω‐conotoxin GVIA (N‐type Ca2+ channel blocker) inhibited by 24 and 20% α3β4 and α7 currents, respectively. At 1 μM, ω‐agatoxin IVA (a P/Q‐type Ca2+ channel blocker) did not affect α7 currents and inhibited α3β4 currents by only 15%.
L‐type Ca2+ channel blockers furnidipine, verapamil and, particularly, diltiazem exhibited a preferential blocking activity on α3β4 nicotinic AChRs.
The mechanism of α3β4 currents blockade by ω‐conotoxins and diltiazem differed in the following aspects: (i) the onset and reversal of the blockade was faster for toxins; (ii) the blockade by the peptides was voltage‐dependent, while that exerted by diltiazem was not; (iii) diltiazem promoted the inactivation of the current while ω‐toxins did not.
These data show that, at concentrations currently employed as Ca2+ channel blockers, some of these compounds also inhibit certain subtypes of nicotinic AChR currents. Our data calls for caution when interpreting many of the results obtained in neurons and other cell types, where nicotinic receptor and Ca2+ channels coexist.

British Journal of Pharmacology (1999) 127, 1375–1387; doi:10.1038/sj.bjp.0702692
Characterization of the muscarinic receptor in isolated uterus of sham operated and ovariectomized rats
Authors: Choppin A , Stepan G J , Loury D N , Watson N , Eglen R M 
Published: January 2005

The pharmacological characteristics of muscarinic receptors in rat isolated uterus were studied in ovariectomized (ov.) and sham operated (sh.) animals.
Competition radioligand binding studies, using uterine membranes and [3H]‐NMS, were undertaken with several muscarinic receptor antagonists. Most of the antagonists indicated a one‐site fit with apparent affinity estimates (pKi) unchanged by ovariectomy. The selective M2 antagonist, tripitramine revealed high (representing 33±8 and 38±2%) and low (67±8 and 62±2%) affinity binding sites in both sh. and ov. rat uterus, respectively. These sites likely represented muscarinic M2 and M3 receptors and the proportions were not significantly different in the two conditions.
Carbachol induced concentration‐dependent contractions which were surmountably antagonized by several muscarinic receptor antagonists (pKB, sh.; ov.): zamifenacin (9.19; 9.18), p‐F‐HHSiD (8.50; 9.06), tripitramine (7.23; 7.54), himbacine (7.21; 7.41), methoctramine (6.79; 7.49), pirenzepine (6.48; 7.21), AF DX 116 (6.26; 6.61), MTx 3 (<7.00; <7.00) and PD 102807 (<7.00; <7.00).
The apparent affinity values obtained in functional studies using the uteri from both sh. and ov. animals correlated most closely with values reported at human recombinant muscarinic M3 receptors. This suggests that the muscarinic M3 receptor mediates contraction under both conditions.
Radioligand binding experiments indicate the presence of M2 receptors, in addition to M3 receptors, which probably explains the discrepancies between functional and binding affinities. These data further suggest that the pharmacological profile and proportions of the two populations of muscarinic receptors are unaffected by ovariectomy.

British Journal of Pharmacology (1999) 127, 1551–1558; doi:10.1038/sj.bjp.0702696
Central control of blood pressure by nitrergic mechanisms in organum vasculosum laminae terminalis of rat brain
Authors: Lin M ‐T , Pan S ‐P , Lin J ‐H , Yang Y ‐L 
Published: January 2005

Experiments were carried out to explore the possible role played by the nitric oxide (NO) system in the organum vasculosum laminae terminalis (OVLT) of rat brain in arterial pressure regulation.
Intracerebroventricular (ICV) or intra‐OVLT administration of NO donors such as hydroxylamine, sodium nitro‐prusside or s‐nitro‐acetylpenicillamine caused an up to 55 mmHg decrease in blood pressure (BP) but an increase in NO release (measured by porphyrin/nafion coated carbon fibre electrodes in combination with voltammetry) in the OVLT. In contrast, ICV or intra‐OVLT administration of NG‐nitro‐L‐arginine methyl ester (L‐NAME; a constitutive NO synthase inhibitor) caused an up to 45 mmHg increase in BP but a fall in NO release in the OVLT.
Compared with the BP responses induced by ICV injection of NO donors or NO synthase inhibitors, the OVLT route of injection required a much lower dose of NO donors or NO synthase inhibitors to produce a similar BP effect.
The depressor effects induced by ICV or intra‐OVLT administration of NO donors were attenuated by pretreatment with intra‐OVLT injection of methylene blue (an inhibitor of guanylate cyclase), haemoglobin (a NO scavenger), L‐NAME or spinal transection. On the other hand, the L‐NAME‐induced pressor effects were attenuated by pretreatment with intra‐OVLT injection of L‐arginine or spinal transection.
The data suggest that activation of cyclic GMP‐dependent NO synthase in the OVLT of rat brain causes cyclic GMP‐dependent decreases in arterial pressure via inhibiting the sympathetic efferent activity.

British Journal of Pharmacology (1999) 127, 1511–1517; doi:10.1038/sj.bjp.0702699
KATP channels and ‘border zone’ arrhythmias: role of the repolarization dispersion between normal and ischaemic ventricular regions
Authors: Picard Sandra , Rouet René , Ducouret Pierre , Puddu Paolo Emilio , Flais Frédéric , Criniti Anna , Monti Francesco , Gérard Jean‐Louis 
Published: January 2005

In order to investigate the role of KATP channel activation and repolarization dispersion on the ‘border zone’ arrhythmias induced by ischaemia‐reperfusion, the effects of glibenclamide and bimakalim, agents modifying action potential (AP) duration, were studied in an in vitro model of myocardial ‘border zone’.
The electrophysiological effects of 10 μM glibenclamide and 1 μM bimakalim (n=8 each), respectively KATP channel blocker and activator, were investigated on guinea‐pig ventricular strips submitted partly to normal conditions (normal zone, NZ) and partly to simulated ischaemic then reperfused conditions (altered zone, AZ).
By preventing the ischaemia‐induced AP shortening (P<0.0001), glibenclamide reduced the dispersion of AP duration 90% (APD90) between NZ and AZ (P<0.0001), and concomitantly inhibited the ‘border zone’ arrhythmias induced by an extrastimulus (ES), their absence being significantly related to the lessened APD90 dispersion (χ2=8.28, P<0.01).
Bimakalim, which also reduced the APD90 dispersion (P<0.005) due to differential AP shortening in normal and ischaemic tissues, decreased the incidence of myocardial conduction blocks (25% of preparations versus 83% in control, n=12, P<0.05) and favoured ‘border zone’ spontaneous arrhythmias (75% of preparations versus 25% in control, P<0.05).
During reperfusion, unlike bimakalim, glibenclamide inhibited the ES‐induced arrhythmias and reduced the incidence of the spontaneous ones (12% of preparations versus 92% in control, P<0.05), this latter effect being significantly related (χ2=6.13, P<0.02) to the lessened ischaemia‐induced AP shortening in the presence of glibenclamide (P<0.0001).
These results suggest that KATP blockade may protect the ischaemic‐reperfused myocardium from ‘border zone’ arrhythmias concomitantly with a reduction of APD90 dispersion between normal and ischaemic regions. Conversely, KATP channel activation may modify the incidence of conduction blocks and exacerbate the ischaemia‐induced ‘border zone’ arrhythmias.

British Journal of Pharmacology (1999) 127, 1687–1695; doi:10.1038/sj.bjp.0702704