bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory effects of capsaicin on acetylcholine‐evoked responses in rat phaeochromocytoma cells
Authors: Nakazawa Ken , Inoue Kaori , Koizumi Schuichi , Ikeda Makoto , Inoue Kazuhide 
Published: July 2012

The effects of capsaicin on cellular responses evoked by acetylcholine (ACh) and those by adenosine 5′‐triphosphate (ATP) were investigated in rat phaeochromocytoma PC12 cells.
Capsaicin (1 to 30 μm) suppressed dopamine release and the intracellular Ca2+ increase evoked by 100 μm ACh. The concentration‐dependence of the ACh‐evoked release of dopamine was not shifted but the maximal response was reduced by capsaicin. Dopamine release evoked by 80 mm KC1 was also suppressed by capsaicin (3 and 30 μm), but the extent of suppression was smaller than that of the ACh‐evoked release.
Under whole‐cell voltage‐clamp, capsaicin (1 to 30 μm) reversibly inhibited the inward current activated by ACh (30 to 300 μm). The inhibition exhibited dependence on the concentration of ACh, and the current activated by a higher concentration of ACh was less inhibited. Voltage‐dependence of block by capsaicin was not observed when it was tested either by applying a ramp pulse during the current activation by ACh or by eliciting the current in cells held at various potentials.
High concentrations of capsaicin (30 to 100 μm) enhanced the inward current as well as dopamine release evoked by 30 μm ATP.
The results suggest that low concentrations of capsaicin selectively antagonize responses mediated by nicotinic receptor‐channels without affecting those mediated by purinoceptor‐coupled channels. As the antagonism by capsaicin of the ACh‐evoked responses was observed at concentrations as low as 1 μm, the influence on nicotinic receptors should be taken into account when this compound is used as a pharmacological tool to deplete neuropeptides.
Induction of nitric oxide synthase activity in phagocytic cells inhibited by tricyclodecan‐9‐yl‐xanthogenate (D609)
Authors: Tschaikowsky Klaus , Meisner Michael , Schönhuber Frank , Rügheimer Erich 
Published: July 2012

The synthesis of nitric oxide (NO) by immune‐stimulated murine phagocytic cells (J774) and the modulation of this synthesis by tricyclodecan‐9‐yl‐xanthogenate (D609), a specific inhibitor of phosphatidylcholine‐specific phospholipase C (PC‐PLC), was investigated. D609 dose‐dependently suppressed production of NO, as measured by the release of nitrite and nitrate, in response to lipopolysac‐charide (LPS) and interferon‐γ (IFN‐γ) in intact cultured cells with an IC50 of approximately 20 μg ml−1. D609 at 40 μg ml−1 completely abrogated immune‐stimulated nitrite production.
The inhibitory effects of D609 on nitrite production were time‐dependent and restricted to the first 18 h post‐stimulation. D609 did not inhibit nitrite production in the cytosol of immune‐stimulated phagocytes.
These findings indicate that the xanthogenate, D609, is a potent inhibitor of the induction of NO‐synthase activity in immune‐stimulated phagocytes. Furthermore, since D609 has been demonstrated to inhibit PC‐PLC specifically, our findings suggest that the activation of this enzyme by LPS and IFN‐γ is a proximal step in the signal transduction of inducible NO‐synthase in phagocytic cells.
The effect of hyperglycaemia on function of rat isolated mesenteric resistance artery
Authors: Taylor Paul D. , Poston Lucilla 
Published: July 2012

Noradrenaline sensitivity and acetylcholine‐induced relaxation were investigated in mesenteric resistance arteries from female Wistar rats (220–250 g) following exposure to isotonic supraphysiological glucose solutions (20 and 45 mm, in physiological buffer, 2h incubation).
Arteries incubated in 20 mm glucose demonstrated enhanced noradrenaline sensitivity compared with those in physiological buffer.
Profoundly impaired endothelium‐dependent relaxation to acetylcholine was observed in arteries incubated in 20 and 45 mm glucose.
Indomethacin (10 μm) normalized noradrenaline sensitivity in 20 mm glucose, but unmasked an enhanced maximum response in 20 and 45 mm glucose relative to controls.
Addition of L‐arginine (0.1 μm) prevented the abnormality of acetylcholine‐induced relaxation in the 20 mm glucose medium and significantly improved relaxation in 45 mm glucose.
The aldose reductase inhibitor, ponalrestat (10−5 m, ZENECA Pharmaceuticals), prevented impaired acetylcholine‐mediated relaxation in 20 mm glucose and significantly improved relaxation in 45 mm glucose.
Indomethacin (10 μm) improved maximum relaxation but did not alter impaired sensitivity to acetylcholine in the high glucose media (20 and 45 μm).
Superoxide dismutase (SOD, 150 u ml−1) also prevented impaired acetylcholine‐induced relaxation in 20 mm glucose but not in 45 mm glucose.
Endothelium‐independent relaxation to sodium nitroprusside (SNP, 10−9‐10−5mM) was normal in 20 mm glucose but was slightly, although significantly impaired by 45 mm glucose.
Enhanced responsiveness of rat isolated mesenteric resistance arteries to noradrenaline caused by elevated glucose would appear to be mediated through abnormal cyclo‐oxygenase activity and the reduced tonic release of nitric oxide.
Hyperglycaemia may lead to abnormal endothelium‐dependent relaxation in these arteries through several mechanisms which include a role for increased free radical production, polyol pathway activation and altered L‐arginine metabolism.
The effect of non‐steroidal anti‐inflammatory drugs on the accumulation and release of interleukin‐1‐like activity by peritoneal macrophages from the mouse
Authors: Bahl A.K. , Dale M.M. , Foreman J.C. 
Published: July 2012

The non‐steroidal anti‐inflammatory drugs (NSAIDs) indomethacin, 10 and 100 μm, piroxicam, 100 μm, and sodium meclofenamate, 1 and 100 μm, potentiated the lipopolysaccharide (LPS)‐stimulated release of interleukin‐1 (IL‐1)‐like activity from mouse peritoneal macrophages. Aspirin up to 100 μm was without effect. The drugs did not themselves stimulate the release of IL‐1‐like activity at the concentrations used.
LPS, 1 μg ml−1, stimulated prostaglandin E2 production by mouse peritoneal macrophages and this was totally inhibited by aspirin, 100 μm, indomethacin, 1 μm, piroxicam, 10 μm and sodium meclofenamate, 0.1 μm.
The potentiation of LPS‐stimulated release of IL‐1‐like activity produced by indomethacin, 100 μm, piroxicam, 100 μm, or sodium meclofenamate, 10 μm, was inhibited by prostaglandin E2, (PGE2) 10 ng ml−1.
Aspirin, 100 μm, indomethacin, 100nM to 10 μm, piroxicam, 1 to 100 μm, and sodium meclofenamate, 10 nm, all potentiated cell‐associated IL‐1‐like activity in LPS‐ stimulated macrophages. The drugs had no effect on cell‐associated IL‐1‐like activity by themselves.
Exogenous PGE2, 2 to 30 ng ml−1, inhibited the cell‐accumulation of IL‐1‐like activity stimulated by LPS in the presence of indomethacin, 1 μm, or sodium meclofenamate, 0.1 μm.
The 5‐lipoxygenase inhibitors BWA4C, 0.01 to 10 μm, and L‐651,392, 0.01 to 10 μm, had no effect on LPS‐stimulated released or cell‐associated IL‐1‐like activity. Over the same concentration‐ranges, neither of the 5‐lipoxygenase inhibitors affected released or cell‐associated IL‐1‐like activity in LPS‐stimulated mouse macrophages in the presence of indomethacin, 1 μm.
The synthetic diacylglycerol, DiC8, 10 to 200 μm, did not itself increase released or cell‐associated IL‐1‐like activity but in the presence of the diacylglycerol kinase inhibitor, R59022, 10 μm, DiC8 increased released and cell‐associated IL‐1‐like activity. The activity of DiC8 on released and cell‐associated IL‐1‐like activity was not increased by indomethacin, 100 μm.
NSAIDs increase LPS‐induced cell‐associated IL‐1‐like activity in mouse macrophages by inhibiting the formation of cyclo‐oxygenase products such as PGE2 but at higher concentrations the NSAIDs potentiate LPS‐induced release of IL‐1‐like activity by a mechanism independent of cyclo‐oxygenase inhibition. The potentiation of the release of IL‐1‐like activity appears not to be related to an effect of NSAIDs on either 5‐lipoxygenase or diacylglycerol metabolism.
The effects of clozapine on behavioural responses to the selective ‘D1‐like’ dopamine receptor agonist, A 68930, and to the selective ‘D2‐like’ agonist, RU 24213
Authors: Daly Siobhan A. , Waddington John L. 
Published: July 2012

The influence of the atypical antipsychotic clozapine on D1 dopamine receptor‐mediated function was examined in terms of its effects on behavioural responses to the new isochroman selective D1 agonist, A 68930, and to the selective D2 agonist, RU 24213.
In rat striatal membrane preparations, radioligand binding studies with [3H]‐SCH 23390 and [3H]‐spiperone confirmed clozapine to show weak and non‐selective affinity for both D1 and D2 receptors.
Using a rapid time‐sampling behavioural check list technique, clozapine (4.0–36.0 mg kg−1) exerted only modest antagonism of RU 24213 (15.0 mg kg−1)‐induced sniffing and locomotion, and weakly released some episodes of myoclonic jerking; such antagonism with release of jerking has been shown previously to occur only during concurrent stimulation of D2 receptors and attenuation of D1 function.
Over the same dose‐range, clozapine completely blocked A68930 (0.25 mg kg−1)‐induced intense grooming but failed to influence the vacuous chewing response; this profile was similar to that demonstrated previously for selective D1 antagonists.
On the basis of complete blockade of typical D1 agonist‐induced grooming and weak release of atypical jerking to D2 agonism in the face of modest reduction in typical D2‐stimulated behaviours, clozapine apears to exert some preferential but not selective attenuation of D1 receptor‐mediated function. Clozapine may attenuate activity through a classical D1 receptor at a level beyond the recognition site, for which it has little affinity, or by way of new, putative ‘Dplike’ site(s) that subserve distinct elements of dopaminergic behaviour.
The sensitivity of nicotinic synapses in bullfrog sympathetic ganglia to α‐bungarotoxin and neuronal‐bungarotoxin
Authors: Shen Wei‐Xing , Jobling Phillip , Horn John P. 
Published: July 2012

The sensitivity of nicotinic synapses to α‐bungarotoxin (α‐Bgt) and neuronal‐bungarotoxin (n‐Bgt) was measured in the B and C cell systems of bullfrog paravertebral sympathetic ganglia 9 and 10 by recording extracellular compound postganglionic action potentials from the rami communicantes.
High concentrations (10 μm) of α‐Bgt applied for up to 8 h had no effect upon synaptic transmission in either the B or C cell system. Ganglia pretreated with collagenase were also insensitive to α‐Bgt. In control experiments on isolated sartorius muscle preparations, nerve‐evoked twitches were fully blocked by 30‐100nM α‐Bgt.
Nicotinic transmission in the B and C cell systems was reversibly blocked by 30–300 nm n‐Bgt. Block appeared within 25–45 min of exposure to toxin and reversed fully with a half‐time of 40‐80min. This was indistinguishable from washout times after block by 100 μm (+)‐tubocurarine.
The results demonstrate close parallels between the bungarotoxin sensitivity of neuronal nicotinic receptors mediating ganglionic transmission in functional subclasses of bullfrog sympathetic neurones and the bungarotoxin sensitivity which has been reported for autonomic neurones in avian and mammalian preparations.
Role of K+ channels in the vasodilator response to bradykinin in the rat heart
Authors: Fulton David , McGiff John C. , Quilley John 
Published: July 2012

The role of K+ channels in the nitric oxide (NO)‐independent coronary vasodilator efffect of bradykinin was examined in the Langendorff heart preparation in which nitroarginine was used to inhibit NO synthesis and elevate perfusion pressure; cyclo‐oxygenase was inhibited with indomethacin.
The K+ channel inhibitors, tetraethylammonium, procaine and charybdotoxin, but not glibenc‐lamide, further increased perfusion pressure suggesting a role for K+ channels, other than ATP‐sensitive K+ channels, in the regulation of coronary vascular tone under the experimental conditions adopted here.
The non‐specific K+ channel inhibitors, tetraethylammonium and procaine, reduced vasodilator responses to bradykinin and cromakalim but not those to nitroprusside in the perfused heart treated with nitroarginine and indomethacin.
Glibenclamide, an inhibitor of ATP‐sensitive K+ channels, reduced vasodilator responses to cromakalim but did not affect those to bradykinin or nitroprusside.
Charybdotoxin, an antagonist of Ca2+‐activated K+ channels, inhibited responses to bradykinin but did not affect those to cromakalim or nitroprusside.
Nifedipine inhibited vasodilator responses to bradykinin and cromakalim without affecting those to nitroprusside.
Inhibition of cytochrome P450 with clotrimazole reduced responses to bradykinin but did not modify those to cromakalim or nitroprusside.
These results suggest that bradykinin utilizes a Ca2+‐activated K+ channel to produce vasodilatation in the rat heart.
Modulatory effect of neuropeptide Y on acetylcholine‐induced oedema and vasoconstriction in isolated perfused lungs of rabbit
Authors: Delaunois Annie , Gustin Pascal , Dessy‐Doize Cécile , Ansay Michel 
Published: July 2012

The modulatory role of neuropeptide Y (NPY) on pulmonary oedema induced by acetylcholine and capsaicin was investigated. The effects of NPY on the haemodynamic response to acetylcholine, phenylephrine and substance P were also investigated.
Isolated, ventilated, exsanguinated lungs of the rabbit were perfused with a constant flow of recirculating blood‐free perfusate. The double/arterial/venous occlusion method was used to partition the total pressure gradient (ΔPt) into four components: the arterial gradient (ΔPa), the pre‐ and post‐capillary gradients (respectively ΔPa' and ΔPv') and the venous pressure gradient (ΔPv). Endothelial permeability was evaluated by measuring the capillary filtration coefficient (Kf,c).
Acetylcholine (10−8 m to 10−4 m) and substance P (SP, 10−10 m to 10−6 m) induced a concentration‐dependent increase in the Kf,c. Capsaicin (10−4m) and 5‐hydroxytryptamine (5‐HT) (10−4m) also increased this parameter. NPY (10−8m) completely inhibited the effects of acetylcholine and capsaicin on the Kf,c, without preventing the effects of substance P and 5‐HT.
Acetylcholine induced concentration‐dependent vasoconstriction in the precapillary segment. The effect was inhibited by NPY and aspirin, an inhibitor of cyclo‐oxygenase, while ketanserin, a 5‐HT2 receptor antagonist, and SR140333, a new NK1 antagonist, had no protective effect. Phenylephrine increased ΔPa at high concentration, an effect also inhibited by NPY and aspirin. Substance P had no significant haemodynamic effect. When injected together with NPY, substance P (10−6m) induced a significant increase in the total pressure gradient.
It was concluded that NPY can protect the lung against acetylcholine‐ and capsaicin‐induced oedema via a prejunctional modulatory effect on the C‐fibres. NPY also inhibits acetylcholine‐evoked precapillary and phenylephrine‐induced arterial vasoconstriction, probably by interfering with cyclo‐oxygenase products synthesis.
Role of Ca+‐dependent K‐channels in the membrane potential and contractility of aorta from spontaneously hypertensive rats
Authors: Silva Eneida G. , Frediani‐Neto Eugenio , Ferreira Alice T. , Paiva Antonio CM. , Paiva Therezinha B. 
Published: July 2012

Contractile responses to KCl and membrane potentials were determined in aortic rings from spontaneously hypertensive rats (SHR), normotensive Wistar rats (NWR) and Wistar Kyoto rats (WKY) both in the absence and in the presence of the Ca2+‐dependent K‐channel blockers, apamin and tetraethylammonium (TEA).
Compared to NWR, aortic rings from WKY and SHR were less reactive and their Ca2+ uptake after stimulation with K+ was decreased.
Smooth muscle cell membrane potentials were higher in aortae from SHR and WKY than in NWR aortae, whereas SHR had higher K+ and lower Na+ intracellular activities than WKY and NWR, suggesting overactivity of the Na+/K+ pump in the hypertensive animals.
Treatment with apamin caused depolarization of WKY and SHR aortae, and increased their contractile responses to the same level as those of the NWR. Treatment with TEA also caused depolarization of aortae from WKY and SHR, but in the SHR the depolarization induced by TEA was smaller than that produced by apamin and the contractile responses to KCl did not reach the level of those of aortae from NWR.
It is concluded that overactivity of Ca2+‐dependent K‐channels in aortae of WKY and SHR contributes to their higher membrane potentials and lower responsiveness to vasoconstrictor stimuli. In SHR, an overactive Na+/K+ pump is also present, and the contribution of apamin‐sensitive Ca2+‐dependent K‐channels to the membrane potential and reactivity appears to be more relevant than that of TEA‐sensitive channels.
Paired‐pulse depression of the N‐methyl‐D‐aspartate receptor‐mediated synaptic potentials in the amygdala
Authors: Huang Chiung‐Chun , Gean Po‐Wu 
Published: July 2012

An in vitro slice preparation of rat amygdala was used to study the paired‐pulse depression of the N‐methyl‐D‐aspartate (NMDA) receptor‐mediated synaptic potential e.p.s.p.NMDA.
The e.p.s.p.NMDA was isolated pharmacologically by applying a solution containing the non‐NMDA receptor antagonist, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) and the γ‐aminobutyric acidA (GABAA) blocker picrotoxin and increasing the stimulus intensity.
When two stimuli of identical strength were applied in close succession, the second e.p.s.p.NMDA was depressed. This paired‐pulse depression was seen with interstimulus intervals of between 100 ms and 2000 ms; the maximal depression was observed at interval of 200 ms.
Superfusion of phaclofen or 2‐hydroxy‐saclofen inhibited the paired‐pulse depression indicating the involvement of GABAB receptors.
Bath applications of Ba2+ or intracellular injection of Cs+ to block post‐ but not presynaptic GABAB receptors failed to inhibit the paired‐pulse depression (PPD).
Incubation of slices with pertussis toxin prevented the postsynaptic hyperpolarization induced by baclofen. The PPD of e.p.s.p.NMDA, however, was not affected by pertussis toxin treatment.
These results suggest that GABA released by the first stimulus acts on GABAB receptors to suppress the second e.p.s.p.NMDA via mechanisms other than activation of a postsynaptic GABAB receptor‐coupled K+ conductance.
Pharmacological reactivity of human epicardial coronary arteries: characterization of relaxation responses to endothelium‐derived relaxing factor
Authors: Stork Andrew P. , Cocks Thomas M. 
Published: July 2012

Human epicardial coronary artery rings, freshly obtained from cardiac transplantation patients, commonly examined for their responses to endothelium‐derived relaxing factor (EDRF)‐releasing agents.
Functional antagonism profoundly influenced relaxation responses in this tissue. Increasing force with concentrations of U46619 above 3 nm (40% of maximum contraction response) resulted in a reduction of the maximum response to four vasorelaxants which relax vascular smooth muscle via different mechanisms: the EDRF‐releasing agents, substance P and bradykinin; the endothelium‐independent nitro‐vasodilator, sodium nitroprusside (SNP); and the β‐adrenoceptor agonist, isoprenaline.
Substance P, histamine, bradykinin and the Ca2+ ionophores ionomycin and A23187 all caused concentration‐ and endothelium‐dependent relaxation in vessels pre‐contracted with the thromboxane A2‐mimetic, U46619 (3 nm) to an active force optimal for relaxation responses. Nifedipine (0.1 μm), added to prevent spontaneous contractions, had no effect on relaxation responses to substance P, bradykinin and histamine.
Substance P was the most potent of the EDRF‐releasing agents examined and all agents except for bradykinin caused near‐maximal relaxation. Bradykinin caused only 46.2% ± 7.3% relaxation. Responses were abolished when the endothelium was removed and, except for histamine, were not significantly affected by indomethacin (3–10 μm, P>0.05). Histamine (0.1–10 μm) caused a concentration‐dependent contraction of arterial rings without endothelium.
The L‐arginine analogues NG‐nitro‐L‐arginine (L‐NOARG, 0.1 μm) and NG‐monomethyl‐L‐arginine (L‐NMMA, 0.1 μm) both caused no further contraction in arteries precontracted with U46619 (3 nm) and were in general, poor inhibitors of responses to EDRF agonists. L‐NMMA, but not L‐NOARG, caused small but significant decreases in the maximum responses to substance P, bradykinin (18.5 ± 6.9% and 27.6 ± 10.9% relaxation with L‐NMMA and L‐NOARG, respectively), histamine and A23187 (P < 0.05). The analogues had no effect on SNP responses.
In conclusion, EDRF release in human isolated coronary artery is only poorly antagonized by the nitric oxide synthase inhibitors L‐NOARG and L‐NMMA. These results indicate that either the nitric oxide transduction pathway present in human coronary artery is different from that in other tissues or that another factor(s) (e.g. endothelium‐derived hyperpolarizing factor) is also released in response to EDRF‐releasing agents and augments the relaxation to nitric oxide.
Antianginal effects of FK409, a new spontaneous NO releaser
Authors: Kita Yasuhiro , Ozaki Reiko , Sakai Shigeru , Sugimoto Toshiko , Hirasawa Yoshimi , Ohtsuka Minoru , Senoh Hachiro , Yoshida Keizo , Maeda Kazuhiro 
Published: July 2012

The aim of this study was to compare antianginal effects of (±)‐(E)‐ethyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐3‐hexeneamide (FK409), a new spontaneous nitric oxide releaser, with those of isosorbide dinitrate (ISDN). We used two types of rat angina model; methacholine‐ and arginine vasopressin (AVP)‐induced coronary vasospasm models.
In the in vitro study, FK409 showed 80 times more potent vasorelaxant effect in dog isolated coronary artery than ISDN (EC50= 16.7 ± 4.8 and 1340 ± 320 nm, respectively).
In the rat methacholine‐induced coronary vasospasm model, FK409 suppressed the elevation of ST segment dose‐dependently and significantly at 0.1 mg kg−1, i.d. On the other hand, ISDN suppressed it significantly at 3.2 mg kg−1, i.d. In addition, the efficacy of 3.2 mg kg−1 ISDN in the model was almost the same as that of 0.1 mg kg−1 FK409.
In the above experiments, FK409 and ISDN decreased mean blood pressure significantly at the maximum dose tested (1.0 mg kg−1, i.d. and 3.2 mg kg−1, i.d., respectively) but did not change heart rate at these doses. Therefore, the hypotensive effect of FK409 was 10 times weaker than the antianginal effect of the compound, while those of ISDN were almost the same.
In the rat AVP‐induced coronary vasospasm model, 32mg kg−1 FK409 significantly inhibited the depression of ST segment 60 min after oral administration. On the other hand, 32 mg kg−1 ISDN did not inhibit it at 60 and 120 min after oral administration.
In conclusion, FK409 inhibits coronary vasospasm more potently in two types of rat angina models than ISDN. In addition, FK409 shows an antianginal effect more selectively that a hypotensive effect, compared with ISDN.