bluuebunny/crossref_metadata_2025_split huggingface dataset:
Locomotor activation and dopamine release produced by nicotine and isoarecolone in rats
Authors: Whiteaker P. , Garcha H.S. , Wonnacott S. , Stolerman I.P. 
Published: July 2012

Isoarecolone was approximately 250 times less potent than nicotine as an inhibitor of [3H]‐nicotine binding to rat brain membranes. Isoarecolone failed to inhibit the binding of the nicotinic ligand [125I]‐α‐bungarotoxin or of the muscarinic ligand [3H]‐QNB.
Nicotine (0.01–30 μm) evoked the release of [3H]‐dopamine from striatal and frontal cortex synaptosomes, with EC50 values of approximately 0.5 μM in each case. This release was largely mecamylamine‐sensitive.
Isoarecolone (1–200 μm) evoked predominantly mecamylamine‐sensitive dopamine release from both striatal and cortical synaptosomes, with a potency at least 20 times less than that of nicotine. The maximum effect of isoarecolone was less than that of nicotine, particularly in the frontal cortex preparation.
In control rats treated chronically with saline, neither nicotine nor isoarecolone had clear effects on locomotor activity at the doses tested. Chronic treatment with nicotine clearly sensitized rats to the locomotor activating effect of nicotine; there was only weak cross‐sensitization to isoarecolone. The maximum effect of isoarecolone was seen at a dose about 40 times larger than that of nicotine.
The low potency and efficacy of isoarecolone in facilitating sensitized locomotor activity resembled its lower potency and efficacy, compared with nicotine, in evoking dopamine release in vitro. The agonist profile of the nicotinic receptor population mediating dopamine release may determine the pharmacological characteristics of consequent locomotor behaviour.
Characterization of the thromboxane (TP‐) receptor subtype involved in proliferation in cultured vascular smooth muscle cells of rat
Authors: Ko Feng‐Nien , Yu Sheu‐Meei , Kang Ya‐Fei , Teng Che‐Ming 
Published: July 2012

, Jen‐Ai Rd., 1st Section, Taipei, Taiwan
The effects of the thromboxane A2 (TxA2)‐mimetic, U‐46619, on the proliferation of vascular smooth muscle cells (VSMCs) were examined in a clonal smooth muscle cell line, A10, which was derived from foetal rat aorta
[3H]‐U‐46619 bound to A10 cells of passages 18–20 (pl8‐20) with two classes of sites. The high affinity site showed a Bmax of 3.0 ±1.8 fmol mg−1 protein with a KD value 1.0 ±0.1 nM, while the low affinity site showed a Bmaxx of 43.0 ±6.0 fmol mg protein and KD value of 129.0 ±7.9 nM. However, [3H]‐U‐46619 bound to A10 cells from passages 28–30 (p28‐30) at a single class of site with a Bmax 111.0 ±9.0 fmol mg−1 protein and a Ku value of 175.4 ±22.0 nM
Cinnamophilin and SQ29548 inhibited specific [3H]‐U‐46619 binding to pl8‐20 A10 cells in a concentration‐dependent manner with Ki values of 390.0 ±3.2 and 4.6 ±1.0 nM, respectively at a high affinity site, and 2.6 ±0.2 μm and 310.0 ±6.4 nM, respectively at the low affinity site
U‐46619 produced isometric contractions of rat aorta in a concentration‐dependent manner with an EC50 7.0 ±1.2 nM. Cinnamophilin and SQ29548 antagonized U‐46619‐induced aortic contractions with pA2 values 6.3 ±0.1 and 8.2 ±0.2, respectively
U‐46619 increased [3H]‐thymidine incorporation into DNA of pi8‐20 and p28‐30 A10 cells in a concentration‐dependent manner with EC50 values 362.7 ±27.0 and 302.5 ±20.1 nM, respectively. The U‐46619‐induced increase of [3H]‐thymidine incorporation into DNA of p28‐30 A10 cells was potentiated by PDGF (1 ng ml−1) and FCS (1%) and was inhibited by cinnamophilin (10 μm) and SQ29548 (1 μm) with estimated pKB values 5.4 ±1.2 and 6.3 ±0.9, respectively
Cell cycle analysis revealed that U‐46619‐increased cell cycle progression was primarily due to a rapid transition from the DNA synthetic (S) to the G2/mitotic (M) phase. Moreover, U‐46619 also increased protein synthesis and cell numbers in VSMC. All these effects of U‐46619 were inhibited by cinnamophilin and SQ29548
U‐46619 caused phosphoinositide breakdown and increased the intracellular Ca2+ concentration in VSMC, effects which were blocked by cinnamophilin and SQ29548
These data indicate there are two U‐46619 binding sites in A10 VSMC. The high affinity site is correlated to U‐46619‐induced vasoconstriction while the low affinity site is correlated to U‐46619‐mediated VSMC proliferation. These data also reveal that U‐46619 stimulates the cell cycle progression in VSMC primarily through a rapid transition from S to G2/M. Since cinnamophilin inhibits TP‐receptor‐mediated VSMC proliferation, it may thus hold promising potential for the prevention of atherosclerosis or vascular diseases.
Effects of nicorandil on the recovery of reflex potentials after spinal cord ischaemia in cats
Authors: Suzuki Toshio , Sekikawa Toshihiko , Nemoto Tetsuharu , Moriya Hideshige , Nakaya Haruaki 
Published: July 2012

The pathophysiological significance of ATP‐sensitive K+ (KATP) channels in the central nervous system is not fully understood. In this study the effects of nicorandil (a hybrid vasodilator having a dual mechanism of action as a K+ channel opener and a nitrate) on the recovery of the spinal cord reflex potentials after spinal cord ischaemia were examined and compared with those of pinacidil and nitroprusside in anaesthetized spinal cats
Spinal cord ischaemia was produced by occlusion of the thoracic aorta and the bilateral internal mammary arteries for 10 min. Regional blood flow in the spinal cord was continuously measured with a laser‐Doppler flow meter. The monosynaptic (MSR) and polysynaptic reflex (PSR) potentials, elicited by electrical stimulation of the tibial nerve, were recorded from the lumbo‐sacral ventral root. The recovery process of spinal reflex potentials was reproducible when the occlusion was repeated twice at an interval of 120 min
Pretreatment with nicorandil (30–100 μg kg−1) accelerated the recovery of PSR potentials after spinal cord ischaemia. Such an accelerating effect on the recovery of PSR potentials was also shared by pinacidil (100 μg kg−1), another K+ channel opener. In addition, the accelerating effect of nicorandil (100 μg kg−1) on the recovery of PSR potentials was abolished by co‐administration of glibenclamide (3 mg kg−1), a sulphonylurea KATP channel blocker. Nitroprusside (8 μg kg−1 min−1) retarded rather than improved the recovery of PSR potentials after spinal cord ischaemia. AH of these drugs failed to improve the spinal cord blood flow during ischaemia and reperfusion
These results suggest that nicorandil promotes the recovery of polysynaptic reflex potentials after spinal cord ischaemia by opening the KATP channels of neurones rather than by increasing local blood flow. K+ channel openers may exert a salutary effect on the functional recovery of the ischaemic spinal cord.
Characterization of the effect of SR48692 on inositol monophosphate, cyclic GMP and cyclic AMP responses linked to neurotensin receptor activation in neuronal and non‐neuronal cells
Authors: Oury‐Donat F. , Thurneyssen O. , Gonalons N. , Forgez P. , Gully D. , Fur G. Le , Soubrie P. 
Published: July 2012

Neurotensin stimulated inositol monophosphate (IP1) formation in both human colonic carcinoma HT29 cells and in mouse neuroblastoma N1E115 cells with EC50 values of 3.5 ± 0.5 nM (n = 4) and 0.46±0.02 nM (n = 3), respectively. Neurotensin also stimulated cyclic GMP production with an EC50 of 0.47±1.2 nM and inhibited cyclic AMP accumulation induced by forskolin (0.5 μm) with an IC50 of 1.33 + 1.5 nM (n = 3) on the N1E115 cell line
The competitive antagonism by the non‐peptide neurotensin receptor antagonist, SR48692 of neurotensin‐induced IP1 formation revealed pA2 values of 8.7 ±0.2 (n = 3) for HT29 and 10.1 ±0.2 (n = 3) for N1E115 cells. SR48692 also antagonized the cyclic GMP and cyclic AMP responses induced by neurotensin in the N1E115 cell line with pA2 values of 10.7±0.7 (n = 3) and 9.8±0.3 (n = 3), respectively
In CHO cells transfected with the rat neurotensin receptor, neurotensin stimulated IP1 and cyclic AMP formation with EC50 values of 3.0±0.5 nM (n = 3) and 72.2 ±20.7 nM (n = 3), respectively. Both effects were antagonized by SR48692, giving pA2 values of 8.4 ±0.1 (n = 3) for IP1 and 7.2 ±0.4 (n = 3) for cyclic AMP responses
Radioligand binding experiments, performed with [125I]‐neurotensin (0.2 nM), yielded IC50 values of 15.3 nM (n = 2) and 20.4 nM (n = 2) for SR48692 versus neurotensin receptor binding sites labelled in HT29 and N1E115 cells, respectively
In conclusion, SR48692 appears to be a potent, species‐independent antagonist of the signal transduction events triggered by neurotensin receptor activation in both neuronal and non‐neuronal cell systems.
In vitro and in vivo profile of SB 206553, a potent 5‐HT2C/5‐HT2B receptor antagonist with anxiolytic‐like properties
Authors: Kennett G.A. , Wood M.D. , Bright F. , Cilia J. , Piper D.C. , Gager T. , Thomas D. , Baxter G.S. , Forbes I.T. , Ham P. , Blackburn T.P. 
Published: July 2012

SB 206553 (5‐methyl‐1‐(3‐pyridylcarbamoyl)‐1,2,3,5‐tetrahydropyrrolo[2,3‐f]indole) displays a high affinity (pK1 7.9) for the cloned human 5‐HT2C receptor expressed in HEK 293 cells and the 5‐HT2B receptor (pA2 8.9) as measured in the rat stomach fundus preparation. SB 206553 has low affinity for cloned human 5‐HT2A receptors expressed in HEK 293 cells (pK1 5.8) and (pK1 <6) for a wide variety of other neurotransmitter receptors.
SB 206553 appears to be a surmountable antagonist of 5‐HT‐stimulated phosphoinositide hydrolysis in HEK 293 cells expressing the human 5‐HT2C receptor (pKB 9.0).
The compound potently (ID50 5.5 mg kg−1, p.o., 0.27 mg kg−1, i.v.) inhibited the hypolocomotor response to m‐chlorophenylpiperazine (mCPP), a putative model of 5‐HT2C/5‐HT2B receptor function in vivo.
At similar doses (2–20 mg kg−1, p.o.) SB 206553 increased total interaction scores in a rat social interaction test and increased punished responding in a rat Geller‐Seifter conflict test. These effects are consistent with the possession of anxiolytic properties.
SB 206553 also increased suppressed responding in a marmoset conflict model of anxiety at somewhat higher doses (15 and 20 mg kg−1, p.o.) but also reduced unsuppressed responding.
These results suggest that SB 206553 is a potent mixed 5‐HT2C/5‐HT2B receptor antagonist with selectivity over the 5‐HT2A and all other sites studied and possesses anxiolytic‐like properties.
Cocaine‐induced microvascular vasoconstriction but differential systemic haemodynamic responses in Yucatan versus Yorkshire varieties of swine
Authors: Miao Lin , Núñez Boris D. , Susulic Vojken , Wheeler Suzanne , Carrozza Joseph P. , Ross James N. , Morgan James P. 
Published: July 2012

Systemic and coronary haemodynamics were measured in 6 Yorkshire swine and 6 Yucatan miniature swine under isoflurane anaesthesia to investigate the influence of cocaine following its intravenous administration at 1, 3 and 7 mg kg−1.
Cocaine in Yorkshire swine decreased mean arterial pressure and rate pressure product (systolic pressure × heart rate), suggesting a cardiac depressant effect, whereas cocaine in Yucatan miniature swine increased these parameters, consistent with a hyperadrenergic state.
Cocaine in both Yorkshire swine and Yucatan miniature swine decreased coronary blood flow and coronary flow reserve, and increased coronary vascular resistance.
A modest generalized epicardial coronary artery constriction was observed by angiography, without evidence of focal spasm.
Our results confirm a marked vasoconstrictor effect of cocaine on the coronary arterial circulation, predominantly distal to the epicardial coronary arteries, but also indicate important differences in the systemic cardiovascular responses to the drug between two closely related strains of animals within the same species. Due to the similarities between the swine and human coronary arterial vasculature, we suggest that vasoconstriction in the coronary microcirculation may produce cardiac toxicity in man.
Influence of monovalent cations on the binding of a charged and an uncharged (‘carbo’‐)muscarinic antagonist to muscarinic receptors
Authors: Hou X. , Wehrle J. , Menge W. , Ciccarelli E. , Wess J. , Mutschler E. , Lambrecht G. , Timmerman H. , Waelbroeck M. 
Published: July 2012

The effect of the buffer concentration on binding of [3H]‐N‐methylscopolamine to muscarinic receptors M2 was tested in rat heart. Tracer binding was of low affinity in a 20 mM imidazole buffer (pKD 8.3), inhibited by an increase from 10 to 100 mM of the sodium phosphate buffer concentration (pKD 9.92 to 9.22), slightly inhibited by an increase of the Tris/HCl buffer concentration from 20 to 100 mM (pKD 9.70 to 9.47) and unaffected by an increase of the histidine/HCl buffer concentration from 20 to 100 mM (pKD 9.90 to 9.82). We chose the last buffer to analyse the effect of ions on antagonists binding to cardiac M2 receptors and to transiently expressed wild‐type and (Y533→F) mutant m3 muscarinic receptors in COS‐7 cells.
Equilibrium [3H]‐N‐methylscopolamine binding to cardiac M2 receptors was inhibited, apparently competitively, by monovalent salts (LiCl≥NaCl≥KCl). In contrast, binding of the uncharged 3,3‐dimethylbutan‐l‐ol ester of diphenylglycolic acid (BS‐6181) was facilitated by addition of monovalent salts (LiCl≥NaCl≥KCl) to the binding buffer. This cation binding pattern is consistent with interaction with a large, negative field strength binding site, such as, for instance, a carboxylic acid.
In the presence of 100 mM NaCl, [3H]‐N‐methylscopolamine had a similar affinity for the wild‐type m3 receptor (pKD 9.85) and for a (Y533→F) mutant m3 receptor (pKD 9.68). However, in the absence of added salts, the tracer had a significantly lower affinity for the mutated (pKD 10.19) as compared to the wild‐type (pKD 10.70) m3 receptor. BS‐6181 had a significantly lower affinity for the (Y533→F) mutant m3 muscarinic receptor, as compared to the wild‐type m3 receptor, both in the absence (pKD 6.19‐6.72) in the presence (pKD 6.48‐7.40) of 100 mM NaCl. The effects of NaCl on binding of the uncharged ester and of [3H]‐N‐methylscopolamine to the m3 receptor were decreased by the mutation.
Taken together, these results support the hypothesis that monovalent cations from the buffer may interact with the cation binding site of the receptors (an aspartate residue in the third transmembrane helix of muscarinic receptors). Buffer cations may inhibit competitively the binding of (charged) muscarinic ligands having a tertiary amine or ammonium group, while facilitating the receptor recognition by uncharged, isosteric ‘carbo‐analogues’. Mutation of the (Y533→F) of the m3 receptor decreased the affinity of the receptor for positive charges, including the sodium ion.
KW‐4679‐induced inhibition of tachykininergic contraction in the guinea‐pig bronchi by prejunctional inhibition of peripheral sensory nerves
Authors: Ikemura Toshihide , Okarmura Kyoko , Sasaki Yasuo , Ishi Hidee , Ohmori Kenji 
Published: July 2012

Sensory mechanisms play an important role in the vagal regulation of tracheobronchial smooth muscle tone. We examined the effect of KW‐4679, an anti‐allergic drug, on guinea‐pig tachykinin‐mediated contractile responses induced by electrical field stimulation (EFS) in guinea‐pig bronchial muscles.
EFS (8 Hz, 0.5 ms, 15 V, for 15 s) evoked biphasic contractile responses in the guinea‐pig isolated main bronchus in the presence of 5 μm indomethacin. The contractions consisted of a fast phase of an atropine‐sensitive transient contraction and a slow phase of a sustained contraction which was inhibited by a combination of the tachykinin NK1 receptor antagonist, (±)‐CP‐96,345 (1 μm) and the NK2 receptor antagonist, SR 48969 (0.1 μm).
KW‐4679 preferentially inhibited the slow phase in a concentration‐dependent manner by 43.2±7.7% at 10 μm, whereas the drug had no effect on the fast phase at concentrations up to 10 μm. KW‐4679, at a concentration of 100 μm, inhibited not only the slow phase by 49.2±11.4%, but also the fast phase by 36.8±8.4%.
KW‐4679 (10 μm and 100 μm) did not affect the substance P‐induced or neurokinin A‐induced contraction. Against the acetylcholine‐induced contractile responses, 100 μm KW‐4679 had a marked effect producing a 10.2 fold shift to the right in the curve.
The inhibitory effect of KW‐4679 (10 μm) on the slow phase contraction was not influenced by treatment with naloxone (100 nM), propranolol (1 μm), thioperamide (1 μm) saclofen (50 μm), yohimbine (1 μm), methiothepin (1 μm) or methysergide (1 μm).
The inhibitory effect of KW‐4679 (10 μm) on the slow phase contraction was not influenced by treatment with intermediate or large conductance Ca2+‐activated K+ channel blockers (charybdotoxin (10 nM) or iberiotoxin (10 nM)), but suppressed by treatment with small conductance Ca2+‐activated K+ channel blockers, apamin (500 nM) or scyllatoxin (300 nM). Apamin or scyllatoxin per se did not influence the slow phase contractions.
The results suggest that KW‐4679 preferentially inhibits the release of tachykinins from the bronchial sensory nerves through activation of small conductance Ca2+‐activated K+ channels.
Second messenger cascade specificity and pharmacological selectivity of the human P2Y1‐purinoceptor
Authors: Schachter Joel B. , Li Qing , Boyer José L. , Nicholas Robert A. , Harden T. Kendall 
Published: July 2012

. The coding sequence of the P2Y1‐purinoceptor was cloned from a human genomic library.
. The open reading frame encodes a protein of 373 amino acids that is 83% identical to the previously cloned chick and turkey P2Y1‐purinoceptor and is ≥95% homologous to the recently cloned rat, mouse, and bovine P2Y1‐purinoceptors.
. The human P2Y1‐purinoceptor was stably expressed in 1321N1 human astrocytoma cells using a retroviral vector. Although the P2Y1‐purinoceptor agonist, 2MeSATP, had no effect on inositol phosphate accumulation in 1321N1 cells infected with the control virus, this agonist markedly stimulated inositol phosphate accumulation in cells infected with the P2Y1‐purinoceptor virus. No effect of 2MeSATP on cyclic AMP accumulation was observed in P2Y1‐receptor‐expressing 1321N1 cells.
. The pharmacological selectivity of 18 purinoceptor agonists was established for the expressed human P2Y1‐purinoceptor. 2MeSATP was more potent than ATP but less potent than 2MeSADP. ADP also was more potent than ATP. A similar maximal effect was observed with most agonists tested. However, α,β‐MeATP had no effect and 3′‐NH2‐3′‐deoxyATP and A2P4 were partial agonists. The order of potency of agonists for activation of the turkey P2Y1‐purinoceptor, also stably expressed in 1321N1 cells, was identical to that observed for the human P2Y1‐purinoceptor.
. C6 glioma cells express a P2Y‐purinoceptor that inhibits adenylyl cyclase but does not activate phospholipase C. Expression of the human P2Y1‐purinoceptor in C6 cells conferred 2MeSATP‐stimulated inositol lipid hydrolysis to these cells. The phospholipase C‐activating human P2Y1‐purinoceptor could be delineated from the endogenous P2Y‐purinoceptor of C6 glioma cells by use of the P2‐purinoceptor antagonist, PPADS, which blocks the P2Y1‐purinoceptor but does not block the endogenous P2Y‐ purinoceptor of C6 cells. P2‐purinoceptor agonists also exhibited differential selectivities for activation of these two P2Y‐purinoceptors.
Dual regulation of cerebrovascular tone by UTP: P2U receptor‐mediated contraction and endothelium‐dependent relaxation
Authors: Miyagi Yasushi , Kobayashi Sei , Nishimura Junji , Fukui Masashi , Kanaide Hideo 
Published: July 2012

The mechanisms of vascular tone regulation by extracellular uridine 5′‐triphosphate (UTP) were investigated in bovine middle cerebral arterial strips. Changes in cytosolic Ca2+ concentration ([Ca2+]i) and force were simultaneously monitored by use of front‐surface fluorometry of fura‐2.
In the arterial strips without endothelium, UTP (0.1 μm‐1 mM) induced contraction in a concentration‐dependent manner. However, when the endothelium was kept intact, cumulative application of UTP (0.1–100 μm) (and only at 1 mM) induced a modest phasic contraction in arterial strips. This endothelium‐dependent reduction of the UTP‐induced contraction was abolished by 100 μm Nω‐nitro‐L‐arginine (L‐NOARG) but not by 10 μm indomethacin. In the presence of intact endothelium, UTP (30 μm) induced a transient relaxation of the strips precontracted with 30 nM U‐46619 (a stable analogue of thromboxane A2), which was completely inhibited by pretreatment with L‐NOARG but not with indomethacin.
In the endothelium‐denuded strips, the contractile response to UTP was abolished by desensitization to either ATPγS or ATP (P2U receptor agonists), but not by desensitization to α, β‐methylene‐ATP (P2X receptor agonist) or to 2‐methylthio‐ATP (P2Y receptor agonist). Desensitization to UTP abolished the contractile response to ATP.
In the endothelium‐denuded artery, a single dose application of UTP induced an initial transient, and subsequently lower but sustained increase in [Ca2+]i and force. In the absence of extracellular Ca2+, UTP induced only the initial transient increases in [Ca2+]i and force, while the sustained increases in [Ca2+]i and force were abolished. UTP (1 mM) had no effect on the basic [Ca2+]i‐ force relationship obtained on cumulative application of extracellular Ca2+ at steady state of 118 mM K+‐depolarization‐induced contraction.
We conclude that in the presence of an intact endothelium, UTP‐induced relaxation of pre‐constricted middle cerebral artery is mainly mediated indirectly, by the production of an endothelium‐derived relaxing factor, but at high doses of UTP, vascular smooth muscle contraction is mediated directly via activation of P2U purinoceptor and [Ca2+]i elevation without Ca2+‐sensitization of the contractile apparatus. UTP may thus exert a dual regulatory effect upon cerebrovascular tone, but in cases where the endothelium is impaired, it may also act as a significant vasoconstrictor.
The involvement of the release of nitric oxide in the pharmacological activity of the new furoxan derivative CHF 2363
Authors: Civelli Maurizio , Giossi Massimo , Caruso Paola , Razzetti Roberta , Bergamaschi Marco , Bongrani Stefano , Gasco Alberto 
Published: July 2012

The mechanism of action and the pharmacological effects of the new furoxan derivative, CHF 2363 (4‐ethoxy‐3‐phenylsulphonylfuroxan), were investigated.
Pre‐incubation of CHF 2363 with human platelet‐rich plasma produced a concentration‐dependent inhibition of the platelet aggregation induced by collagen, adenosine diphosphate (ADP) and platelet activating factor (PAF). The test compound was about 5 times more potent than sodium nitroprusside. 3‐Isobutyl‐1‐methyl‐xanthine (IBMX) potentiated the antiaggregating effect of CHF 2363.
CHF 2363 was a potent inhibitor of rubbed endothelium rabbit aortic ring contraction induced by noradrenaline. Comparison of IC50 values showed that CHF 2363 was as potent as glyceryl trinitrate (GTN).
Increasing concentrations of CHF 2363 elevated platelet guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels. Adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels were unaffected.
Oxyhaemoglobin reduced all the pharmacological actions of the test compound. Moreover, CHF 2363 concentration‐dependently released nitric oxide (NO) in platelet‐rich plasma. The NO release was correlated to its ability to increase platelet cyclic GMP levels.
After exposure of rat aortic strips to supramaximal concentrations of GTN (550 μm), the vasorelaxant activity of CHF 2363 did not change, although that of GTN decreased about 55 fold.
It has been concluded that the new furoxan derivative CHF 2363 exerts a potent antiaggregating and vasorelaxant activity via NO release and increase of cyclic GMP levels. No in vitro cross tolerance between GTN and CHF 2363 was observed.