bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological properties of P2X3‐receptors present in neurones of the rat dorsal root ganglia
Authors: Rae M. G. , Rowan E. G. , Kennedy C. 
Published: January 2005

The electrophysiological actions of several agonists which may differentiate between P2X1‐ and P2X3‐receptors were studied under concentration and voltage‐clamp conditions in dissociated neurones of 1–4 day old rat dorsal root ganglia.
β,γ‐Methylene‐D‐ATP (β,γ‐me‐D‐ATP) (1–300 μM), diadenosine 5′,5′′′‐P1,P5‐pentaphosphate (AP5A) (100 nM–300 μM), diadenosine 5′,5′′′‐P1,P4‐tetraphosphate (AP4A) (300 nM–300 μM) and uridine 5′‐triphosphate (UTP) (1 μM–1 mM) all activated concentration‐dependent inward currents with a latency to onset of a few ms.
The concentration‐response curves for β,γ‐me‐D‐ATP and AP5A and ATP had similar maximum values, while that for AP4A had a lower maximum. The concentration‐response curve to UTP was shallow and did not reach a maximum. β,γ‐Methylene‐L‐ATP was virtually inactive. The rank order of agonist potency was ATP>AP5A∼amp;AP4A>β,γ‐me‐D‐ATP>UTP>>β,γ‐methylene‐L‐ATP.
The inward currents were inhibited by the P2‐receptor antagonists suramin (100 μM) and pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) (10 μM). PPADS also inhibited responses to ATP (800 nM) and α,β‐methylene ATP (2 μM) in a concentration‐dependent manner.
This study shows that β,γ‐me‐D‐ATP, AP5A, AP4A and UTP all act via a suramin‐ and PPADS‐sensitive P2X‐receptor to evoke rapid, transient inward currents in dissociated neurones of rat dorsal root ganglia. The very low activity of β,γ‐methylene‐L‐ATP suggests that the agonists were acting at the P2X3‐subtype to produce these effects.
Effect of the selective 5‐HT1A receptor antagonist WAY 100635 on the inhibition of e.p.s.ps produced by 5‐HT in the CA1 region of rat hippocampal slices
Authors: Maria Pugliese Anna , Passani M Beatrice , Corradetti Renato 
Published: January 2005

The actions of N‐(2‐(‐4(2‐methoxyphenyl)‐1‐piperazinyl)ethyl)‐N‐(2‐pyridinyl) cyclohexane carboxamide (WAY 100635), a novel and selective 5‐hydroxytryptamine1A (5‐HT1A) antagonist, on excitatory postsynaptic potentials (e.p.s.ps) were investigated by use of intracellular recordings in pyramidal cells of the CA1 region of rat hippocampal slices.
WAY 100635 (10 nM) did not affect any of the investigated parameters of cell excitability such as membrane potential, total input resistance (Rin), firing threshold, action potential amplitude, action potential frequency adaptation, and slow afterhyperpolarization (sAHP) which follows repetitive firing of action potentials. WAY 100635 did not have any effect on either the slope or the amplitude of e.p.s.ps evoked by stimulation of the CA1 stratum radiatum.
Bath application of either 5‐hydroxytryptamine (5‐HT, 10–30 μM) or 5‐carboxamidotryptamine (5‐CT, 300 nM) hyperpolarized the membrane potential (ΔVm=−4.1±0.9 and −6.0±0.9 mV, respectively), and reduced Rin (−25±8% and −18±1%, respectively). 5‐HT blocked the action potential frequency adaptation and significantly reduced the amplitude of the sAHP that follows repetitive firing of action potentials.
5‐HT significantly decreased the amplitude of evoked e.p.s.ps (−14±6%). This effect was greater in the presence of the GABAA receptor antagonist bicuculline (10 μM, −45±12%) and was mimicked by 5‐CT (−49±5%). Both AMPA and NMDA components of e.p.s.ps were significantly reduced in amplitude by 5–HT (−38±8%, n=6, and −29±12%, n=3, respectively; P<0.05).
WAY 100635 fully antagonized the hyperpolarization, the reduction of Rin, and the decrease in amplitude of e.p.s.ps elicited by 5‐HT, while it did not affect the action of 5‐HT on the action potential frequency adaptation. In the presence of WAY 100635, 5‐HT elicited a depolarization which was blocked by 10–30 μM RS 23597‐190, a selective 5‐HT4 receptor antagonist.
Our data demonstrate that WAY 100635 is devoid of direct effects on CA1 pyramidal cell excitability and on evoked e.p.s.ps, while it fully antagonizes the effects of 5‐HT on excitatory synaptic transmission and on hyperpolarization, without affecting the 5‐HT4 receptor‐mediated response. Since WAY 100635 selectively antagonizes 5‐HT1A receptor‐mediated actions of 5‐HT, our data also demonstrate that the inhibitory action of 5‐HT on excitatory synaptic transmission in CA1 is mediated by 5‐HT1A receptors.
Inhibition of nitrergic neurotransmission in the bovine retractor penis muscle by an oxidant stress: effects of superoxide dismutase mimetics
Authors: Mok Josephine S L , Paisley Karen , Martin William 
Published: January 2005

A number of superoxide dismutase (SOD) mimetics were examined both biochemically for their ability to inhibit the superoxide‐catalyzed reduction of cytochrome c and nitro blue tetrazolium, and functionally for their ability to mimic authentic Cu/Zn SOD in restoring nitrergic neurotransmission in bovine retractor penis (BRP) muscle following its inhibition by oxidant stress.
The SOD mimetics investigated were CuSO4, MnCl2, CuDIPS (copper [II][diisopropylsalicylate]2), MnTBAP (manganese [III] tetrakis 4‐benzoic acid porphyrin), MnTMPyP (manganese [III] tetrakis 1‐methyl‐4‐pyridyl porphyrin pentachloride), tiron (4,5‐dihydroxy‐1,3‐benzene disulphonic acid), PTIYO (4‐phenyl,2,2,5,5,‐tetramethyl‐3‐imidazolin‐1‐yloxy‐3‐oxide) and tempol (4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐N‐oxyl).
The rank order of potency in inhibiting the reduction of cytochrome c was: CuSO4MnCl2CuDIPSMnTMPyP>MnTBAP>tempoltiron>PTIYO.
The requirement for EDTA (0.1 mM) prevented assessment of the activity of CuSO4, MnCl2 and CuDIPS in the assay involving inhibition of reduction of nitro blue tetrazolium. However, the rank order of potency for those agents which could be examined (MnTMPyP>MnTBAP>tirontempol>PTIYO) was essentially similar to that seen in the cytochrome c assay.
Inhibition of endogenous Cu/Zn SOD with diethyldithiocarbamate (DETCA, 3 mM, 120 min) in BRP muscle strips, followed by addition of the superoxide anion generator, LY 83583 (1 μM), resulted in almost complete abolition of nitrergic relaxation (4 Hz, 10 s).
Authentic Cu/Zn SOD (1–300 u ml−1), CuSO4 (0.1–300 μM), MnCl2 (0.1–100 μM) and MnTMPyP (10–300 μM) each restored nitrergic transmission by around 50%. However, CuDIPS (0.1–30 μM), MnTBAP (0.1–100 μM), tempol (10 μM–3 mM), PTIYO (1–300 μM) and tiron (10 μM–10 mM) all failed to restore nitrergic transmission.
The ability of MnTMPyP to restore nitrergic neurotransmission may therefore provide a lead in the development of SOD mimetics as therapeutic agents in the treatment of neuropathies associated with oxidant stress.
Different actions of CCK on pancreatic and gastric growth in the rat: effect of CCKA receptor blockade
Authors: Varga Gábor , Kisfalvi Krisztina , Pelosini Iva , D'Amato Massimo , Scarpignato Carmelo 
Published: January 2005

It is now well established that cholecystokinin (CCK) has a major physiological role in the regulation of pancreatic secretion and gastro‐intestinal (GI) motility. Both these actions are mediated by stimulation of CCKA‐receptors located on pancreatic acini and GI smooth muscle cells. While chronic administration of CCK‐like peptides invariably causes pancreatic hypertrophy and hyperplasia, their action on gastric growth remains controversial.
In the present investigation the action of exogenous and endogenous CCK on both pancreatic and gastric growth was studied in the same animal. In addition, the ability of dexloxiglumide, a new potent and selective CCKA‐receptor antagonist, to counteract CCK‐mediated effects was evaluated.
The amphibian peptide caerulein (1 μg kg−1 intraperitoneally three times daily) was used as a CCK agonist, while camostate (200 mg kg−1 intragastrically once daily), a synthetic protease inhibitor, was used to release endogenous CCK. They were administered to rats for seven days with or without dexloxiglumide (25 mg kg−1 subcutaneously 15 min before the stimulus). On the eighth day, animals were killed, the pancreas and stomach excised, weighed, homogenized and their protein and DNA content measured.
Both exogenous and endogenous CCK increased the weight of the pancreas as well as the total pancreatic protein and DNA content. Dexloxiglumide, which alone did not affect pancreatic size and composition, was able to counteract both caerulein‐ and camostate‐induced pancreatic changes. Neither stimuli affected gastric growth in respect of weight and composition of the oxyntic gland area and the antrum.
These results show different effects of CCK on pancreatic and gastric growth. The CCK‐induced pancreatic hypertrophy and hyperplasia are blocked by the potent and specific CCKA‐receptor antagonist, dexloxiglumide. This compound therefore represents a useful tool to investigate CCK‐receptor interactions in peripheral organs.
Pharmacological characterization of a nonpeptide bradykinin B2 receptor antagonist, FR165649, and agonist, FR190997
Authors: Asano Masayuki , Hatori Chie , Sawai Hiroe , Johki Shigeru , Inamura Noriaki , Kayakiri Hiroshi , Satoh Shigeki , Abe Yoshito , Inoue Takayuki , Sawada Yuki , Mizutani Tsuyoshi , Oku Teruo , Nakahara Kunio 
Published: January 2005

The nonpeptide bradykinin (BK) B2 receptor antagonist, FR165649 (8‐[2,6‐dichloro‐3‐[N‐[(E)‐4‐(N‐ methylcarbamoyl)cinnamidoacetyl] ‐N‐methylamino] benzyloxy] ‐2 ‐ methylquinoline), and agonist, FR190997 (8‐[2,6‐dichloro‐3‐[N‐[(E)‐4‐(N‐methylcarbamoyl) cinnamidoacetyl]‐N‐methylamino]benzyloxy]‐2‐methyl‐4‐(2‐pyridylmethoxy)quinoline) have been identified. These compounds have a common chemical structure, and the 2‐pyridylmethoxy group is the only structural difference between them.
Both FR165649 and FR190997 displaced [3H]‐BK binding to B2 receptors in guinea‐pig ileum membranes, with an IC50 of 4.7×10−10 M and 1.5×10−9 M, respectively. They also displaced [3H]‐BK binding to B2 receptors in human lung fibroblast IMR‐90 cells, with an IC50 of 1.6×10−9 M and 9.8×10−10 M, respectively.
In guinea‐pig isolated ileum‐preparations, FR165649 had no agonistic effect on contraction and caused parallel rightward shifts of the concentration‐response curves to BK on contraction. Analysis of the data produced a nominal pA2 value of 9.2±0.1 (n=5) and a slope of 1.4±0.1 (n=5). On the other hand, FR190997 induced concentration‐dependent contraction of guinea‐pig ilea with a pD2 of 7.9±0.2 and the contraction was inhibited by a specific peptide bradykinin B2 receptor antagonist, Hoe 140 (D‐Arg‐[Hyp3, Thi5, D‐Tic7, Oic8]BK) in a non‐competitive manner.
In IMR‐90 cells, FR165649 had no agonistic effect on phosphatidyl inositol (PI) hydrolysis and caused parallel rightward shifts (approximately 200 fold shift at 10−7 M) of the concentration‐response curves to BK on PI hydrolysis. FR190997 induced concentration‐dependent PI hydrolysis in IMR‐90 cells with a pD2 of 8.4±0.1, and this effect was inhibited by Hoe 140.
These results indicate that FR165649 and FR190997 are, respectively, a potent bradykinin B2 receptor antagonist and agonist, and that the agonistic activity depends on the small part of the nonpeptide ligand. FR165649 and FR190997 may be useful tools for studying the relationship between ligands and receptors.
Interaction between superoxide anion and nitric oxide in the regulation of vascular endothelial function
Authors: Laight David W , Kaw Amar V , Carrier Martin J , Änggård Erik E 
Published: January 2005

Nitric oxide (NO)‐mediated, endothelium‐dependent vasodilator function in rat aortic smooth muscle was investigated in an in vitro model of endogenous vascular superoxide anion stress, generated by pretreatment with the Cu/Zn superoxide dismutase (SOD, EC 1.15.1.1) inhibitor, diethyldithiocarbamate (DETCA).
Contraction to noradrenaline (NA, 1 nM–1 μM) in endothelium‐intact vessels was augmented after a 30 min pretreatment with DETCA (10 mM) followed by 30 min washout. This effect was abolished by NG‐nitro‐L‐arginine methyl ester (L‐NAME, 0.3 mM) and removal of the endothelium and partially reversed by exogenous Cu/Zn SOD (200 u ml−1).
Endothelium‐ and basal NO‐dependent vasorelaxation to the phosphodiesterase (PDE) type V inhibitor ONO‐1505 (4‐[2‐(2‐hydroxyethoxy)ethylamino]‐2‐(1H‐imidazol‐1‐yl)‐6‐methoxyquinazoline methanesulphonate) (0.1–10 μM) was inhibited after DETCA (10 mM) pretreatment. In addition, the ability of L‐NAME (0.3 mM) to enhance established contractile tone was effectively absent.
In contrast, DETCA pretreatment did not significantly affect vasorelaxation to acetylcholine (ACh, 1 nM–3 μM) or S‐nitroso‐N‐acetyl penicillamine (SNAP, 0.03–30 μM). However, L‐NAME (0.3 mM) unmasked an inhibitory effect of DETCA pretreatment on vasorelaxation to SNAP in endothelium‐intact vessels while markedly potentiating vasorelaxation to SNAP in control tissue.
L‐NAME (0.3 mM)‐ and exogenous catalase (200 u ml−1)‐sensitive vasorelaxation to exogenous Cu/Zn SOD (200 u ml−1) was greater after DETCA (10 mM) pretreatment in endothelium‐intact aortic rings. This difference was abolished by catalase (200 u ml−1).
In conclusion, tissue Cu/Zn SOD inhibition elicited a selective lesion in basal endothelial function in rat isolated aortic smooth muscle, consistent with the inactivation of basal NO by superoxide anion. The resulting leftward shift in nitrovasodilator reactivity, due to the loss of the tonic depression by basal NO, is likely to mask the inhibitory effect of superoxide anion on agonist‐stimulated endothelial function and nitrovasodilator‐derived NO, thereby accounting for the differential pattern of endothelial dysfunction after DETCA pretreatment.
Bladder distension and activation of the efferent function of sensory fibres: similarities with the effect of capsaicin
Authors: Lecci A , Giuliani S , Tramontana M , Santicioli P , Criscuoli M , Dion S , Maggi C A 
Published: January 2005

The effects of the tachykinin NK2 receptor antagonist MEN 11420 (100 nmol kg−1, i.v.) and isoprenaline (400 nmol kg−1, i.v.) were compared in a model of distension‐induced bladder activity in isovolumetric conditions. MEN 11420 induced a relaxation of the basal tone of the urinary bladder that was dependent on the volume of the viscus: the effect was absent at low volumes (0.2 and 0.5 ml) and it was maximal at high volumes of distension (1 and 2 ml), approaching about 60% of the isoprenaline‐induced relaxation. The relaxant effect of isoprenaline was always evident at all volumes of distension.
Tetrodotoxin (1–100 μM, intravesically applied) abolished distension‐evoked micturition contractions, but did not prevent the relaxant effect of MEN 11420‐ or isoprenaline on the bladder tone.
The cyclo‐oxygenase inhibitor S‐ketoprofen (0.5 μmol kg−1, i.v.) produced a marked decrease of the bladder tone and a concomitant reduction of bladder motility at 1 ml volume of distension. At 2 ml of distension, S‐ketoprofen still decreased the minimal pressure but had no significant effect on other parameters of vesical motility. In S‐ketoprofen‐pretreated rats, the relaxant effect of MEN 11420 was significant at 2 but not at 1 ml of distension, and that of isoprenaline was reduced by 50% at both 1 and 2 ml.
Ruthenium red (10 μmol kg−1, i.v.) had no effect at a low volume of distension (0.2 ml) or at highest volume (2 ml) but decreased the basal tone and the frequency of bladder contractions at 1 ml of distension. In ruthenium red‐pretreated rats, MEN 11420 failed to decrease bladder tone at 1 ml, whereas at 2 ml the effect of MEN 11420 was not different from that observed in controls (43 vs 60% of isoprenaline‐induced relaxation, respectively).
At both 1 and 2 ml of distension, capsaicin pretreatment (164 μmol kg−1, s.c. 5 days before) reduced the frequency of micturition contractions but had no effect on the bladder tone. Capsaicin pretreatment prevented the relaxant effect of MEN 11420 on the bladder tone both at 1 and at 2 ml of distension.
It is concluded that the release of tachykinins from capsaicin‐sensitive afferent nerves induced by bladder distension is resistant to tetrodotoxin and to prostaglandin synthesis inhibition. Tachykinins modulate the vesical tone by acting through NK2 receptors.
Effects of tachykinin NK1 receptor antagonists on vagal hyperreactivity and neuronal M2 muscarinic receptor function in antigen challenged guinea‐pigs
Authors: Costello Richard W , Fryer Allison D , Belmonte Kristen E , Jacoby David B 
Published: January 2005

The role of tachykinin NK1 receptors in the recruitment of eosinophils to airway nerves, loss of inhibitory neuronal M2 muscarinic receptor function and the development of vagal hyperreactivity was tested in antigen‐challenged guinea‐pigs.
In anaesthetized guinea‐pigs, the muscarinic agonist, pilocarpine (1–100 μg kg−1, i.v), inhibited vagally induced bronchoconstriction, in control, but not in antigen‐challenged guinea‐pigs 24 h after antigen challenge. This indicates normal function of neuronal M2 muscarinic receptors in controls and loss of neuronal M2 receptor function in challenged guinea‐pigs. Pretreatment of sensitized guinea‐pigs with the NK1 receptor antagonists CP99994 (4 mg kg−1, i.p.), SR140333 (1 mg kg−1, s.c.) or CP96345 (15 mg kg−1, i.p.) before antigen challenge, prevented M2 receptor dysfunction.
Neither administration of the NK1 antagonists after antigen challenge, nor pretreatment with an NK2 receptor antagonist, MEN10376 (5 μmol kg−1, i.p.), before antigen challenge, prevented M2 receptor dysfunction.
Electrical stimulation of the vagus nerves caused a frequency‐dependent (2–15 Hz, 10 V, 0.2 ms for 5 s) bronchoconstriction that was significantly increased following antigen challenge. Pretreatment with the NK1 receptor antagonists CP99994 or SR140333 before challenge prevented this increase.
Histamine (1–20 nmol kg−1, i.v.) caused a dose‐dependent bronchoconstriction, which was vagally mediated, and was significantly increased in antigen challenged guinea‐pigs compared to controls. Pretreatment of sensitized animals with CP99994 before challenge prevented the increase in histamine‐induced reactivity.
Bronchoalveolar lavage and histological studies showed that after antigen challenge significant numbers of eosinophils accumulated in the airways and around airway nerves. This eosinophilia was not altered by pretreatment with the NK1 receptor antagonist CP99994.
These data indicate that pretreatment of antigen‐sensitized guinea‐pigs with NK1, but not with NK2 receptor antagonists before antigen challenge prevented the development of hyperreactivity by protecting neuronal M2 receptor function. NK1 receptor antagonists do not inhibit eosinophil accumulation around airway nerves.
Dual effects of dichloroacetate on cardiac ischaemic preconditioning in the rat isolated perfused heart
Authors: Randall Michael D , Keon Claudia A , Greenhaff Paul L , Constantin‐Teodosiu Dumitru 
Published: January 2005

Ischaemic cardiac preconditioning represents an important cardioprotective mechanism which limits myocardial ischaemic damage. The aim of this investigation was to assess the impact of dichloroacetate (DCA), a pyruvate dehydrogenase complex activator, on preconditioning.
Rat isolated hearts were perfused by use of the Langendorff technique, and were subjected to either preconditioning (3×4 or 3×6 min ischaemia) or continuous perfusion, followed by 30 min global ischaemia and 60 min reperfusion. DCA (3 mM) was either given throughout the protocol (pretreatment), during reperfusion only (post‐treatment), or not at all. Throughout reperfusion mechanical performance was assessed as the rate‐pressure product (RPP: left ventricular developed pressure×heart rate).
In non‐preconditioned control hearts, mechanical performance was substantially (P<0.001) depressed on reperfusion (the RPP after 60 min of reperfusion (RPPt=60) was 4,246±974 mmHg beats min−1 compared to baseline value of 21,297±1,728 mmHg beats min−1). Preconditioning with either 3×4 min or 3×6 min cycles caused significant protection, as shown by enhanced recovery (RPPt=60=7,818±1,138, P<0.05, and 11,123±587 mmHg beats min−1, P<0.001, respectively).
Addition of DCA (3 mM) to hearts under baseline conditions significantly (P<0.001) enhanced systolic function with an increased left ventricular developed pressure of 108±5 mmHg compared to 88.3±3.0 mmHg in the controls.
Pretreatment with 3 mM DCA had no effect on recovery of mechanical performance in the non‐preconditioned hearts (RPPt=60=3,640±1,235 mmHg beats min−1) while the beneficial effects of preconditioning were reduced in the preconditioned hearts (3×4 min: RPPt=60=2,919±1,060 mmHg beats min−1; 3×6 min: RPPt=60=8,032±1,367 mmHg beats min−1). Therefore, DCA had increased the threshold for preconditioning.
By contrast, post‐treatment of hearts with 3 mM DCA substantially improved recovery on reperfusion in all groups (RPPt=60=5,827±1,328 (non‐preconditioned), 14,022±3,743 (3×4 min; P<0.01) and 23,219±1,374 (3×6 min; P<0.001) mmHg beats min−1).
The results of the present investigation clearly show that pretreatment with DCA enhances baseline cardiac mechanical performance but increases the threshold for cardiac preconditioning. However, post‐treatment with DCA substantially augments the beneficial effects of preconditioning.
Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin‐resistant, obese JCR:LA‐cp rats
Authors: McKendrick Joyce D , Salas Eduardo , Dubé Gregory P , Murat Jesus , Russell James C , Radomski Marek W 
Published: January 2005

The effects of nitric oxide (NO) on vascular reactivity and platelet function in the obese (cp/cp) and lean (+/?) JCR:LA‐cp rats were investigated.
Phenylephrine (PE; 0.1 nM–10 μM) induced contraction of isolated aortic rings in both genotypes (cp/cp and +/?) of JCR:LA‐cp rats. The sensitivity to contraction with PE was enhanced in cp/cp compared with +/? rings. Rings from both genotypes showed an increased contraction upon removal of the endothelium.
Acetylcholine (ACh; 0.1 nM–10 μM)‐induced endothelium‐dependent relaxation of rings was not significantly different in the two genotypes. Both were inhibited to a similar extent by NG‐nitro‐L‐arginine methyl ester (L‐NAME; 0.01–1 mM) when administered in vitro.
The nitric oxide synthase (NOS) inhibitor (L‐NAME; 0.3, 1 or 3 mg ml−1, p.o.) when administered in vivo increased blood pressure in cp/cp rats but not in +/? rats.
L‐NAME resulted in greater inhibition of ACh‐induced relaxation in cp/cp rings compared with +/? rings.
L‐NAME treatment in vivo caused a decrease in cyclic GMP and NOS activity in rings from cp/cp but not +/? rats.
The NO donor, S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP; 0.1 nM–10 μM)‐induced relaxation of rings from +/? rats, an effect enhanced by the treatment with L‐NAME in vivo.
Oral administration of L‐NAME did not enhance the vasorelaxant effect of SNAP on rings of aorta from cp/cp animals.
Platelet aggregation and NOS activity were similar in both genotypes and were not modified by oral administration of L‐NAME.
These results show that unimpaired generation of NO is crucial for maintenance of vascular tone particularly under conditions of vascular insult exemplified by insulin resistance, obesity and dyslipidemia detected in cp/cp rats.