bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bidirectional modulatory effect of orphanin FQ on morphine‐induced analgesia: antagonism in brain and potentiation in spinal cord of the rat
Authors: Tian Jin‐Hua , Xu Wei , Fang Yuan , Mogil Jeffrey S. , Grisel Judith E. , Grandy David K. , Han Ji‐Sheng 
Published: August 2006

The present study was designed to investigate further the effects of the newly discovered orphanin FQ (OFQ)‐the endogenous ligand for the orphan opioid receptor (called, e.g., ORL1 and LC132)‐on pain modulation in the rat. We used the tail‐flick assay as a nociceptive index.
When injected into a cerebral ventricle, OFQ (4 fmol‐10 nmol) has no effect on basal tail‐flick latency by itself at any dose, but dose‐dependently antagonizes systemic morphine analgesia (400 fmol‐50 nmol).
Injected intrathecally, OFQ (3 and 10 nmol) displayed an analgesic effect without producing motor dysfunction, and potentiated morphine analgesia (1 and 10 nmol).
The anti‐opioid effect of OFQ in rat brain and the high level of expression of LC132/ORL1 receptor in the locus coeruleus indicated a possible role of OFQ in the precipitation of opiate withdrawal symptoms. However, no such precipitation was observed by OFQ in morphine‐dependent rats.
Inhibition of glycine currents by dextromethorphan in neurones dissociated from the guinea‐pig nucleus tractus solitarii
Authors: Takahama Kazuo , Fukushima Hidenao , Isohama Yoichiro , Kai Hirofumi , Miyata Takeshi 
Published: August 2006

The effect of dextromethorphan (DM) on the current induced by glycine in acutely dissociated nucleus tractus solitarii (NTS) neurones of guinea‐pigs was studied by use of the whole‐cell patch clamp technique. The effect of DM on γ‐aminobutyric acid (GABA)‐induced currents (Igaba) was also examined.
DM inhibited 30 μm glycine‐induced current (IGly), without affecting the current caused by 30 μm GABA. The action of DM was concentration‐dependent, with a maximum effect at 100 μm, and reversible. The half‐maximum inhibitory concentration (IC50) of DM was 3.3 μm, about 85 times higher than that of strychnine.
DM 3 μm shifted the concentration‐response curve for glycine to the right without affecting the maximum value. DM 10 μm shifted the curve even more to the right, although it was not a parallel shift. Strychnine at a concentration of 0.1 μm shifted the curve for glycine in a nearly parallel fashion.
The effect of 10 μm DM was slightly weak voltage‐dependency, but the lower concentration of DM, 3 μm, inhibited IGly equally at −50 mV and + 50 mV. The effect of 3 μm DM on IGly showed no use‐dependence. Blockade by strychnine 0.1 μm showed no voltage‐or use‐dependence.
The results indicate that DM inhibits IGly in single neurones of NTS, and further suggest that DM at a low concentration may act on the glycine receptor‐ionophore complex, but not on the Cl− channel of the complex. However, a relatively high concentration of DM may at least partly affect the Cl− channel of the complex.
Characteristics of L‐type calcium channel blockade by lacidipine in guinea‐pig ventricular myocytes
Authors: Cerbai Elisabetta , Giotti Alberto , Mugelli Alessandro 
Published: August 2006

The Ca2+‐antagonistic properties of lacidipine were investigated in patch‐clamp guinea‐pig ventricular myocytes.
In basal conditions, 0.1 μm lacidipine reduced the action potential duration, associated with a decrease in the L‐type calcium current (Ica,L) to 66 ± 4% of the control value, without a change in the current‐voltage relationship. Sodium current and background potassium currents were not affected. All the effects reached a steady state within 2 min.
The Ca2+‐antagonistic effect of lacidipine was voltage‐dependent: a marked negative shift (about 20 mV) of the steady‐state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) prepulses.
The onset of and recovery from the voltage‐dependent effect caused by 0.1 μm lacidipine were significantly slower when compared to those of equiactive concentrations of nimodipine (0.5 μm) and nisoldipine (0.1 μm). ICa,L measured after prepulses at —40 mV lasting 500 ms or less was unchanged (95 ± 5% of maximum current value) while it was reduced to 49±10% by nimodipine and 43 ± 9% by nisoldipine (P <0.05 vs lacidipine for both).
Similarly, the recovery from block in the presence of lacidipine was slower than with nimodipine and nisoldipine. After a prepulse of 1 s at —80 mV, ICa,L recovered up to 54 ± 2% of the maximum current value in the presence of lacidipine, and up to 91 ±3% and 93 ± 5% in the presence of nimodipine and nisoldipine, respectively (P<0.05 vs lacidipine).
Blockade of ICa,L by lacidipine was use‐dependent. After ten 200 ms long pulses (1 Hz) from −80 mV, ICa,L was reduced to 55 ± 7% of the current measured at the first pulse. In the presence of nimodipine and nisoldipine, ICa,L elicited by the tenth pulse amounted to 93 ± 3% and 80 ± 6% of the first pulse value, respectively (P <0.05 vs lacidipine). Lacidipine did not cause use‐dependent blockade of Ica,L in cells stimulated with 10 ms long pulses.
These results demonstrate that lacidipine selectively inhibits ICa,L in isolated cardiomyocytes and suggest that this effect occurs mainly through binding to the inactivated Ca2+ channels.
Involvement of a glibenclamide‐sensitive mechanism in the nitrergic neurotransmission of the pig intravesical ureter
Authors: Hernández Medardo , Prieto Dolores , Orensanz Luis M. , Barahona María Victoria , Jiménez‐cidre Miguel , Rivera Luis , García‐sacristán Albino , Simonsen Ulf 
Published: August 2006

The present study was designed to investigate whether potassium (K+) channels are involved in the relaxations to nitric oxide (NO) of pig intravesical ureteral preparations suspended in organ baths for isometric tension recordings. In ureteral strips treated with guanethidine (10−5 m) and atropine (10−7 m) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO was either released from nitrergic nerves by electrical field stimulation (EFS, 0.5–10 Hz, 1 ms duration, 20 s trains), or exogenously‐applied as an acidified solution of sodium nitrite (NaNO2, 10−6‐10−3 m).
Incubation with an inhibitor of guanylate cyclase activation by NO, methylene blue (10−5 m) did not change the basal tension of intravesical ureteral strips but inhibited the relaxation induced by EFS or exogenous NO on ureteral preparations contracted with the thromboxane analogue U46619 (10−7 m).
Incubation with charybdotoxin (3 × 10−8 m) and apamin (5 × 10−7 m), which are inhibitors of large and small conductance calcium (Ca2+)‐activated K+ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Treatment with charybdotoxin or apamin plus methylene blue (10−5 m) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition evoked by methylene blue alone. The combined addition of charybdotoxin plus apamin did not change the relaxations to EFS or exogenously added NO of the porcine intravesical ureter.
Cromakalim (10−8‐3 × 10−6 m), an opener of ATP‐sensitive K+ channels, evoked a dose‐dependent relaxation with a pD2of 7.3 + 0.2 and maximum relaxant effect of a 71.8 + 4.2% of the contraction induced by U46619 in the pig intravesical ureter. The blocker of ATP‐sensitive K+ channels, glibenclamide (10−6 m), inhibited markedly the relaxations to cromakalim.
Glibenclamide (10−6 m) had no effect on the basal tone of ureteral preparations but significantly reduced the relaxations induced by both EFS and exogenous NO. Combined treatment with methylene blue (10−5 m) and glibenclamide (10−6 m) did not exert an effect greater than that of methylene blue alone on either EFS‐or NO‐evoked relaxations of the pig ureter.
The present results suggest that NO acts as an inhibitory neurotransmitter in the pig intravesical ureter and relaxes smooth muscle through a guanylate cyclase‐dependent mechanism which seems to favour the opening of glibenclamide‐sensitive K+ channels.
Involvement of adrenoceptors in the ovarian vascular pedicle in the regulation of counter current transfer of steroid hormones to the arterial blood supplying the oviduct and uterus of pigs
Authors: Stefańczyk‐Krzymowska S , Grzegorzewski W , Skipor J , Wasowska B , Krzymowski T 
Published: August 2006

On Day 10 of the oestrous cycle in pigs, after laparotomy noradrenaline (NA), methoxamine (α1‐adrenomimetic, M), Prazosin (α1‐adrenolytic, Pr) in total doses of 4 μmol, and saline were infused (10 min) into the superficial layer of mesovarium on both sides of the ovarian pedicle vasculature, close to the ovary.
Blood flow in the ovarian artery, heart rate and progesterone (P4) and androstenedione (A4) secretion from the ovary and their concentrations in the ovarian venous effluent, as well as the concentrations of P4 and A4 in the blood supplying the oviduct and the uterus, were determined.
A significant increase of P4 and A4 secretion after NA and M infusion and increased concentrations of P4 and A4 in the ovarian venous effluent were found, but these changes did not influence the counter current transfer of hormones from the venous effluent into arterial blood supplying the oviduct and the uterus.
Infusion of Pr caused a significant decrease of P4 and A4 secretion and their concentrations in the ovarian venous effluent and significantly increased A4 concentration in the blood supplying the oviduct and uterus.
The results indicate that stimulation of α1‐adrenoceptors in the area of ovarian vasculature did not influence, whereas block of α1‐adrenoceptors affected, the local concentration of steroid hormones in the blood supplying the oviduct and the part of the uterus proximal to the ovary, despite the changes in the concentrations of steroid hormones in the ovarian effluent.

British Journal of Pharmacology (1997) 120, 763–768; doi:10.1038/sj.bjp.0700953
1‐(3‐(9H‐Carbazol‐9‐yl)‐1‐propyl)‐4‐(2‐methoxyphenyl)‐4‐piperidinol, a novel subtype selective inhibitor of the mouse type II GABA‐transporter
Authors: Thomsen Christian , Sørensen Per Olaf , Egebjerg Jan 
Published: August 2006

The selectivity of new derivatives of the γ‐aminobutyric acid (GABA)‐uptake inhibitor, tiagabine was characterized at the four cloned mouse GABA transporters (mGAT1 through mGAT4) by measuring [3H]‐GABA uptake into stably transfected baby hamster kidney cells. While tiagabine is a highly selective inhibitor of mGAT1 (Ki=0.11±0.02 μm), these derivatives exhibited low potencies at mGAT1 but differential activities at mGAT2, mGAT3 and mGAT4. In particular, 1‐(3‐(9H‐carbazol‐9‐yl)‐1‐propyl)‐4‐(2‐methoxyphenyl)‐4‐piperidinol (NNC 05‐2090) was a potent inhibitor of mGAT2 (Ki=1.4±0.3 μm) showing at least 10 fold selectivity over mGAT1, mGAT3 and mGAT4. NNC 05‐2090 is the first subtype selective inhibitor of mGAT2 and may represent a novel useful tool for investigating the physiological roles of GAT2 in the brain and periphery.British Journal of Pharmacology (1997) 120, 983–985; doi:10.1038/sj.bjp.0700957
Role of α2‐adrenoceptors in the regulation of intestinal water transport
Authors: Liu Lu , Coupar Ian M 
Published: August 2006

The influence of the sympathetic nervous system on intestinal fluid transport by the jejunum and ileum of the anaesthetized rat was investigated under basal conditions and during active secretion induced by intra‐arterial infusion of vasoactive intestinal peptide (VIP).
Intra‐arterial infusion of noradrenaline (3, 10, 30 nmol min−1, i.a.) and i.v. injection of the selective α2‐adrenoceptor agonist UK 14,304 (1 μmol kg−1, i.v.) increased the rate of basal fluid absorption. The effect of UK 14,304 was blocked by yohimbine (10 μmol kg−1, i.v). However, the selective α1‐adrenoceptor agonist phenylephrine (5 μmol kg−1, i.v.) did not alter either the jejunal or ileal absorption rate.
The α2‐adrenoceptor antagonists yohimbine (0.3, 1.0, 3 and 10 μmol kg−1, i.v.) and rauwolscine (10 μmol kg−1, i.v.) decreased the basal absorption rate, while the α1‐adrenoceptor antagonist prazosin (3 μmol kg−1, i.v.) was without effect. Intracerebroventricular injection of yohimbine (3 μmol kg−1) caused a significant antiabsorptive effect in the jejunum but not ileum.
Peripheral chemical sympathectomy induced by pretreating animals with 6‐hydroxydopamine (150 mg kg−1, i.p., total dose) induced a trend towards impaired absorption in the jejunum and ileum.
The findings provide evidence that the sympathetic nervous system exerts tonic control on intestinal fluid transport and that the effect is mainly through peripheral α2‐adrenoceptors.
The subtype determination of α2‐adrenoceptors in modulating intestinal fluid transport was assessed by determining the effects of α2‐adrenoceptor agents on intestinal fluid secretion induced by i.a. infusion of VIP (0.8 μg min−1).
Intravenous administration of UK 14,304 caused a dose‐dependent reversal of the secretory phase of the VIP‐induced response, but failed to restore fluid transport to the control level of net absorption. EC50 values were 0.17 μmol kg−1 in the jejunum and 0.22 μmol kg−1 in the ileum.
The effect of UK 14,304 was blocked by the selective α2A/D antagonist BRL 44408 and the non‐selective α2 antagonist yohimbine (each 10 μmol kg−1). The selective α2B/C antagonist ARC 239 (10 μmol kg−1) did not affect the antisecretory action of UK 14,304. It is suggested that the α2‐adrenoceptors in the rat intestinal epithelium are the α2D or α2A‐like subtype.

British Journal of Pharmacology (1997) 120, 892–898; doi:10.1038/sj.bjp.0700958
Purinergic facilitation of ATP‐sensitive potassium current in rat ventricular myocytes
Authors: Babenko Andrey P. , Vassort Guy 
Published: August 2006

The effects of different purinergic agonists on the cardiac adenosine 5′‐triphosphate (ATP)‐sensitive potassium current (IK(atp)) appearing during dialysis of rat isolated ventricular myocytes with a low‐ATP (100 μm) internal solution under whole‐cell patch‐clamp conditions, were examined in the presence of a P1 purinoceptor antagonist.
The extracellular application of ATP in the micromolar range induced, besides known inward currents through cationic and chloride channels, the facilitation of IK(atp) once IK(atp) had already been partially activated during the low‐ATP dialysis.
Analogues of ATP, α,β‐methyleneadenosine 5′‐triphosphate (α,βmeATP), 2‐methylthioadenosine triphosphate (2MeSATP), adenosine 5′‐O‐3‐thiotriphosphate (ATPγS) similarly facilitated IK(atp). UTP and ADP were very weak agonists while AMP and adenosine had no detectable effect.
The half‐maximal stimulating concentration (C50) of α,βmeATP, an analogue that did not elicite the interfering inward cationic current was 1.5 μm. Similar apparent C50 (1–2 μm) were observed for ATP and analogues tested with somewhat less maximal effect of ATPγS.
Suramin, a nonselective P2‐purinoceptor antagonist, altered IK(atp) at the relatively high concentration required to inhibit purinoceptors. Pyridoxal‐phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS), a supposedly predominantly P2X‐purinoceptor antagonist, at micromolar concentration inhibited the transient inward current but did not block the facilitation of IK(atp).
Our results demonstrate that ATP and its analogues facilitate IK(atp) in rat ventricular myocytes by stimulation of non‐P1‐, non‐P2X‐purinoceptors.
Differential actions of charybdotoxin on central and daughter branch arteries of the rabbit isolated ear
Authors: Berman Rodney S. , Griffith Tudor M. 
Published: August 2006

By use of rabbit isolated perfused intact ears and isolated perfused segments of central and first generation daughter branch ear arteries, we investigated the actions of charybdotoxin (ChTX), a blocker of calcium‐activated K+ channels (KCa channels), and Nω‐nitro‐L‐arginine methyl ester (l‐NAME) on pressure‐flow and diameter‐flow relationships.
ChTX (1 nM) induced an upwards shift in the pressure‐flow curve in the rabbit intact isolated ear preconstricted with 5‐hydroxytryptamine (5‐HT; 100 nM) with subsequent administration of L‐NAME (100 μM) inducing a further upwards shift. L‐NAME itself induced an upwards shift in the pressure‐flow curve, but subsequent administration of ChTX was without significant effect.
Microangiographic analysis revealed a tendency of ChTX (1 nM) to decrease vessel diameter in the central ear artery (G0) with little effect on the first two generations of daughter branch arteries (G1 and G2) in the intact ear. Subsequent addition of L‐NAME (100 μM) did not significantly further decrease vessel diameter in G0, but did decrease vessel diameter in G1 and G2. L‐NAME itself showed a tendency to decrease vessel diameter in G0, G1 and G2 vessels with subsequent addition of ChTX being without significant effect.
In an isolated G0 preparation which was preconstricted with 5‐HT (100 nM), ChTX (1 nM) caused an upwards shift in the pressure‐flow curve which was augmented by subsequent addition of L‐NAME (100 μM). L‐NAME (100 μM) itself caused an upwards shift in the pressure‐flow curve but subsequent addition of ChTX (1 nM) had no significant effect.
In comparison, in an isolated G1 preparation which was preconstricted with 5‐HT (100 nM), ChTX (1 nM) had no significant effect on the pressure‐flow curve relative to control, but subsequent addition of L‐NAME (100 μm) caused an upwards shift. L‐NAME (100 μM) itself induced an upwards shift in the pressure‐flow curve with subsequent addition of ChTX (1 nM) being without significant effect.
ChTX (10 pM‐10 nM) caused a concentration‐dependent increase in perfusion pressure in isolated G0 and G1 preparations at fixed flow rates of 2 ml min−1 and 0.5 ml min−1, respectively. These responses were enhanced in the presence of L‐NAME (100 μM) in G1 but not G0 preparations.
We conclude that at 1 nM, ChTX exhibits differential actions on central and daughter branch arteries of the intact ear of the rabbit, which are also apparent in the corresponding arteries when studied in isolation. The action of 1 nM ChTX in G0 vessels may reflect inhibition of either the release or action of nitric oxide as it was blocked in the presence of L‐NAME. At higher concentrations of ChTX, there would appear to be a direct constrictor effect on vascular smooth muscle which is apparent in both G0 and G1 vessels. This observed heterogeneity could reflect different distributions of KCa channels between central and daughter branch arteries at either the endothelial or smooth muscle levels, or both.
The effect of the putative endogenous imidazoline receptor ligand, clonidine‐displacing substance, on insulin secretion from rat and human islets of Langerhans
Authors: Chan Susan L F , Atlas Daphne , James Roger F L , Morgan Noel G 
Published: August 2006

The effects of a rat brain extract containing clonidine‐displacing substance (CDS), a putative endogenous imidazoline receptor ligand, on insulin release from rat and human isolated islets of Langerhans were investigated.
CDS was able to potentiate the insulin secretory response of rat islets incubated at 6 mm glucose, in a dose‐dependent manner. The magnitude of this effect was similar to that in response to the well‐characterized imidazoline secretagogue, efaroxan.
CDS, like other imidazoline secretagogues, was also able to reverse the inhibitory action of diazoxide on glucose‐induced insulin release, in both rat and human islets.
These effects of CDS on secretion were reversed by the imidazoline secretagogue antagonists, RX801080 and the newly defined KU14R, providing the first evidence that imidazoline‐mediated actions of CDS can be blocked by specific imidazoline antagonists.
The effects of CDS on insulin secretion were unaffected when the method of preparation involved centri‐filtration through a 3,000 Da cut‐off membrane or when the extract was treated with protease. These results confirm that the active principle is of low molecular weight and is not a peptide.
Overall, the data suggest that CDS behaves as a potent endogenous insulin secretagogue acting at the islet imidazoline receptor.

British Journal of Pharmacology (1997) 120, 926–932; doi:10.1038/sj.bjp.0700964
Effects of FR173657, a non‐peptide B2 antagonist, on kinin‐induced hypotension, visceral and peripheral oedema formation and bronchoconstriction
Authors: Griesbacher Thomas , Legat Franz J 
Published: August 2006

Kinins are believed to play a key role in many inflammatory conditions. Therefore, bradykinin antagonists are being developed for potential therapeutic applications. In the present investigation we describe the pharmacology, in vivo, of (E)‐3‐(6‐ acetamido‐ 3‐pyridyl)‐ N‐[N‐ [2,4‐ dichloro‐ 3‐[(2‐ methyl‐8‐ quinolinyl)oxymethyl]phenyl]‐ N‐methylaminocarbonylmethyl]acrylamide (FR173657), a novel, non‐peptide bradykinin antagonist.
The hypotensive effects of i.v. injections of bradykinin (50 pmol) in captopril‐pre‐treated anaesthetized rats were significantly inhibited by 100 nmol kg−1 FR173657 s.c., and completely abolished by 300 nmol kg−1. The full inhibitory effect developed within 60 min and remained unchanged for at least 4 h. However, the effect was reversible, since 24 h after an injection of 300 nmol kg−1 FR173657 no inhibitory effect could be observed.
The plasma protein extravasation into the pancreas and duodenum induced by an i.v. infusion of bradykinin (11 nmol kg−1 within 20 min) in captopril‐treated anaesthetized rats was completely abolished by FR173657 at doses of 30 nmol kg−1 s.c. and above, given 60 min before bradykinin. FR173657 3 nmol kg−1 was ineffective, while a dose of 10 nmol kg−1 produced an intermediate effect.
The paw oedema induced by the subplantar injection of bradykinin (30 nmol) in anaesthetized rats was inhibited slightly by s.c. injection of FR173657 0.3 μmol kg−1, whereas 1 and 3 μmol kg−1 produced significant inhibition of the bradykinin‐induced oedema. The maximum inhibition amounted to about 50% and could not be increased even when the dose of FR173657 was increased to 30 μmol kg−1. FR173657 did not effect the oedema caused by histamine or 5‐hydroxytryptamine.
Bradykinin (20 nmol kg−1, i.v.) caused increases in pulmonary inflation pressure by 300–600 Pa in anaesthetized, respirated guinea‐pigs. The effect was reduced to 58±9% of the initial value 60 min after the s.c. injection of FR173657 1 μmol kg−1, whereas only 9±7% remained after 10 μmol kg−1. The bronchoconstrictor actions of histamine remained unaffected by FR173657.
In summary, FR173657 is a highly potent and selective bradykinin antagonist. The inhibitory action in vivo lasts for longer than 4 h but is fully reversible. FR173657, or similar compounds, will be a useful tool for the pharmacological investigation of pathophysiological states and may possess a therapeutic potential in diseases involving the endogenous release of kinins.

British Journal of Pharmacology (1997) 120, 933–939; doi:10.1038/sj.bjp.0700966