bluuebunny/crossref_metadata_2025_split huggingface dataset:
The involvement of potassium channels in the action of ciclazindol in rat portal vein
Authors: Noack Th. , Edwards G. , Deitmer P. , Greengrass P. , Morita T. , Andersson P.‐O. , Criddle D. , Wyllie M. G. , Weston A.H. 
Published: July 2012

In whole portal veins, ciclazindol (0.3–10 μm) increased the amplitude and duration, but decreased the frequency of spontaneous contractions. Glibenclamide (0.3–10 μm) produced a small increase in contraction amplitude and duration with a small reduction in contraction frequency.
In whole portal veins, ciclazindol (1–10 μm) antagonized the relaxant effects of BRL 38227 in a non‐competitive manner. Under identical conditions, the effects of glibenclamide (0.3–10 μm) appeared to be competitive.
In whole portal veins loaded with 42K, ciclazindol itself (up to 3 μm) had no detectable effect on basal 42K exchange. However, the increase in 42K efflux produced by BRL 38227 (5 μm) was antagonized by ciclazindol (3 μm). Similar effects were produced by glibenclamide (up to 3 μm).
In freshly‐isolated portal vein cells examined by the whole‐cell voltage‐clamp technique, ciclazindol (1–100 μm) inhibited the slowly‐activating and inactivating transient outward current (ITO) which could be generated at potentials more positive than −30 mV. In addition ciclazindol (1–10 μm) inhibited the non‐inactivating K‐current (IKCO) induced by BRL 38227 (10 μm).
In freshly‐isolated portal vein cells under current‐clamp conditions, the hyperpolarization produced by BRL 38227 (10 μm) was reversed by ciclazindol (1–10 μm).
In porcine brain membrane fragments, glibenclamide (0.65 nm) displaced 50% of the binding of [3H]‐glibenclamide whereas ciclazindol (up to 10 μm) had no effect.
It is concluded that ciclazindol is a K‐channel blocker. Its action is not selective for the channel(s) which carry IKCO but also extends to those which carry ITO. Its inability to displace [3H]‐glibenclamide from porcine brain fragments may indicate that antagonism of BRL 38227 by ciclazindol in smooth muscle is exerted at a site different from that of glibenclamide.
Manifestations of acute opiate withdrawal contracture in rabbit jejunum after μ‐, κ‐ and δ‐receptor agonist exposure
Authors: Valeri Pacifico , Morrone Luigi A. , Romanelli Luca 
Published: July 2012

Following a 5 min in vitro exposure to morphine (1.3 × 10−7 m), U‐50,488H (2.5 × 10−8 m) and deltorphin (1.6 × 10−8 − 6.5 × 10−9 m), the rabbit isolated jejunum exhibited a precipitated contracture after the addition of naloxone (2.75 × 10−7 m).
The precipitated responses to U‐50,488H and deltorphin but not to morphine were reproducible in the same tissue.
The precipitated contractures were blocked completely by tetrodotoxin (3 × 10−7 m), partially by atropine (1.5 × 10−7 m) and not affected by hexamethonium (1.4 × 10−5 m).
Naloxone administration (2.75 × 10−7 m) before the agonist prevented the development of the adaptive response to morphine and U‐50,488H but not to deltorphin.
The selective antagonists norbinaltorphimine (2.7 × 10−8 − 2.7 × 10−9 m) and naltrindole (1.1 × 10−7 m) prevented the adaptive response development only to the respective agonists.
The opioid agonists partially inhibited the spontaneous activity of the tissue. This study has shown that independent activation of μ‐, κ‐ and δ‐opioid receptors can induce dependence in this isolated tissue. Rabbit jejunum is a suitable tissue for studying the acute effects of opioids on the adaptative processes determined by their administration.
Mechanism of the vasodilator action of calcitonin gene‐related peptide in conscious rats
Authors: Abdelrahman Aly , Wang Yong‐Xiang , Chang Sylvia Diana , Pang Catherine C.Y. 
Published: July 2012

The aim of this study was to investigate whether the hypotensive effect of rat α‐calcitonin gene‐related peptide (αCGRP) in conscious rats is mediated by endothelium‐derived nitric oxide (NO) or the opening of adenosine 5′‐triphosphate (ATP)‐sensitive potassium (KATP) channels.
Dose‐mean arterial pressure (MAP)‐response curves of αCGRP were examined in the presence of vehicle, phenylephrine, KATP channel antagonist glibenclamide or NO synthase inhibitors, NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐nitro‐d‐arginine methyl ester (d‐NAME). Dose‐MAP‐response curves for sodium nitroprusside were also constructed in the presence and absence of l‐NAME and d‐NAME.
αCGRP and nitroprusside produced dose‐dependent reductions in MAP which were potentiated by phenylephrine. Both l‐NAME and d‐NAME attenuated the depressor response to αCGRP but not nitroprusside.
Dose‐MAP‐response curves for pinacidil, a KATP‐channel activator, were also examined in the presence of glibenclamide or vehicle. Glibenclamide attenuated pinacidil‐ but not αCGRP‐induced reductions in MAP.
It is concluded that the hypotensive effects of αCGRP are partially mediated via endothelium‐derived NO but not via the opening of KATP channels.
Studies on curare‐like action of 2,2′,2″‐tripyridine in the mouse phrenic nerve‐diaphragm
Authors: Lin‐Shiau S.Y. , Hsu K.S. , Fu W.M. 
Published: July 2012

The curare‐like action of 2,2′,2″‐tripyridine (a synthetic by‐product of the herbicide, paraquat) was studied in mouse phrenic nerve‐diaphragm preparation. The inhibition by 2,2′,2″‐tripyridine of nerve‐evoked twitches was dependent on the concentration, ranging from 1 to 100 μm, which had no significant effect on the twitch amplitudes evoked by direct muscle stimulation.
The twitch inhibition by 2,2′,2″‐tripyridine was reversible and could be antagonized by anticholinesterase agents such as neostigmine, physostigmine as well as ecothiophate.
Pretreatment with either 0.7 μm (+)‐tubocurarine or 2.2 μm succinylcholine shifted the concentration‐inhibition curve of 2,2′,2″‐tripyridine to the left.
2,2′2″‐Tripyridine inhibited not only acetylcholine‐induced contracture of the denervated mouse diaphragm but also that of the chick biventer cervicis muscle. Like (+)‐tubocurarine, 2,2′,2″‐tripyridine protected the twitches from the inhibition by α‐bungarotoxin and also specifically inhibited the binding of [125I]‐α‐bungarotoxin to the mouse diaphragm. All of these findings indicate that 2,2′,2″‐tripyridine possesses curare‐like action and inhibits the muscle contractions through binding to postsynaptic acetylcholine receptors.
The postsynaptic inhibition exhibited by 2,2′,2″‐tripyridine was also implicated in the tetanic fade, a decrease in the amplitude of miniature endplate potential (m.e.p.p.) and endplate potential (e.p.p.).
The clinical implication of these findings is that 2,2′,2″‐tripyridine may be involved in the cause of respiratory failure in paraquat‐intoxicated workers since 2,2′,2″‐tripyridine is a by‐product of paraquat synthesis.
The effect of pertussis toxin on β‐adrenoceptor responses in isolated cardiac myocytes from noradrenaline‐treated guinea‐pigs and patients with cardiac failure
Authors: Brown L.A. , Harding S.E. 
Published: July 2012

A decreased responsiveness to the positive inotropic effects of β‐adrenoceptor agonists is a characteristic of human heart failure. We have investigated the involvement of inhibitory guanine nucleotide binding proteins (G‐proteins) in this process using pertussis toxin treatment of isolated cardiac myocytes.
Myocytes isolated from failing human myocardium had a reduced maximum contractile response to isoprenaline relative to that for maximally stimulating concentrations of calcium, giving an isoprenaline/calcium ratio of 0.71 ± 0.06 (n = 7 patients). This was significantly lower than in myocytes from non‐failing myocardium, where the isoprenaline/calcium ratio was 1.16 ± 0.07 (n = 6, P < 0.001). Responses to high calcium were unchanged.
Myocytes were treated with pertussis toxin for 3–5 h at 35°C. Successful inactivation of inhibitory G‐proteins by pertussis toxin treatment was indicated by a loss of responsiveness to 10 μm adenosine (in the presence of submaximal isoprenaline).
Following pertussis toxin treatment of the myocytes from failing human heart the isoprenaline/calcium ratio increased to 1.43 ± 0.27 (n = 7, P < 0.05). Pertussis toxin treatment had no effect upon the maximum calcium contraction. The isoprenaline/calcium ratio in myocytes from non‐failing human ventricle was not affected by the toxin treatment (n = 3). These observations support the hypothesis that increased inhibitory G‐protein levels or activities contribute to β‐adrenoceptor desensitization in human heart failure.
β‐Adrenoceptor desensitization in human heart failure is thought to be secondary to raised noradrenaline levels in these patients. Experiments were repeated on myocytes isolated from hearts of guinea‐pigs which had been chronically infused with noradrenaline. The isoprenaline/calcium ratio of these myocytes was reduced below that of myocytes from sham‐operated animals (0.65 ± 0.04, n = 6 compared with 0.88 ± 0.02, n = 7, P < 0.001).
Pertussis toxin treatment (2 h at 35°C) increased the isoprenaline/calcium ratio to 1.02 ± 0.02 (n ≅ 6, P < 0.01) in myocytes from noradrenaline‐treated guinea‐pigs. This effect of pertussis toxin treatment was not seen in myocytes from sham‐operated guinea‐pig hearts.
Incubation at 35°C for similar periods in the absence of pertussis toxin also restored the isoprenaline/calcium ratio towards normal in the myocytes from both failing human and noradrenaline‐treated guinea‐pig hearts, although the effect was significantly smaller than that produced by the toxin. Myocytes kept at room temperature (22°C) showed no such evidence of resensitization over periods up to 6 h.
These observations are consistent with the hypothesis that raised catecholamine levels result in increased inhibitory G‐protein levels and functional β‐adrenoceptor desensitization in heart failure.
FR 113680: a novel tripeptide substance P antagonist with NK1 receptor selectivity
Authors: Morimoto Hiroshi , Murai Masako , Maeda Yasue , Hagiwara Daijiro , Miyake Hiroshi , Matsuo Masaaki , Fujii Takashi 
Published: July 2012

We have discovered a novel tripeptide substance P (SP) antagonist, FR 113680 [Nα‐[Nα‐(Nα‐acetyl‐l‐threonyl)‐N′‐formyl‐d‐tryptophyl]‐N‐methyl‐N‐phenylmethyl‐l‐phenylalaninamide]. In binding experiments, FR 113680 inhibited [3H]‐SP binding to guinea‐pig lung membranes (NK1) in a competitive manner but had not effect on [3H]‐SP binding to rat cerebral cortical membranes (NK1), [3H]‐neurokinin A ([3H]‐NKA) binding to rat duodenum smooth muscle membranes (NK2) and [3H]‐eledoisin (Ele) binding to rat cerebral cortical membranes (NK3).
In bioassay experiments, FR 113680 dose‐dependently inhibited SP‐induced guinea‐pig ileum contraction (NK1), but did not inhibit either NKA‐induced rat vas deferens contraction (NK2) or neurokinin B (NKB)‐induced contraction of rat portal vein (NK3). According to Schild plot analysis, the inhibitory effect of FR 113680 on SP‐induced guinea‐pig ileum contraction is competitive and the pA2 value is 7.53.
The inactivity of FR 113680 on NK1 receptors in rat compared to guinea‐pig may represent species‐specific forms of the NK1 receptor.
These findings suggest that FR 113680 interacts selectively with the NK1 neurokinin receptor.
Modulation of vascular tone by endothelin‐1: role of preload, endothelial integrity and concentration of endothelin‐1
Authors: Mehta J.L. , Lawson D.L. , Yang B.C. , Mehta P. , Nichols W.W. 
Published: July 2012

Endothelin‐1 (ET‐1) has been shown to exert both arterial relaxant and constrictor effects. To examine the mechanisms of these divergent effects, rat aortic rings were suspended in an organ bath (baseline preload, 5 g) and exposed to ET‐1 (10−11 to 10−7 m). ET‐1 contracted these rings in a concentration‐dependent fashion.
When aortic rings were contracted with noradrenaline (NA) to 1 g of tension, ET‐1 caused further contraction of these rings. In rings precontracted to 2 to 4 g of tension, low concentrations of ET‐1 (10−11 to 10−9 m) caused a significant relaxation, but high concentrations (≥5× 10−9 m) caused a marked contraction, indicating both relaxant and contractile effects of ET‐1 depending on the preload and ET‐1 concentration.
To determine the mechanism of ET‐1‐induced relaxation, aortic rings were pretreated with the cyclo‐oxygenase inhibitor indomethacin, NG‐monomethyl‐l‐arginine (l‐NMMA) an inihibitor of synthesis of endothelium‐derived relaxing factor (EDRF), or oxyhaemoglobin (Hb) which decreases the activity of EDRF, prior to their exposure to ET‐1. Both indomethacin and l‐NMMA markedly (P < 0.01) attenuated ET‐1‐induced relaxation, whereas Hb totally abolished it. Removal of the endothelium from aortic rings also abolished ET‐1‐mediated relaxation.
The relaxant effect of ET‐1 in NA‐precontracted rings was associated with marked accumulation of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP), whereas ET‐1‐induced contraction of quiescent rings was not.
In manually stretched rings (4 g of tension), ET‐1 caused only concentration‐dependent contraction, but no cyclic GMP accumulation.
Thus, ET‐1 contracts rat aortic rings with intact endothelium and those which are passively stretched. However, stimulation of rat aortic rings with NA to modest tension alters the contractile effect of ET‐1 to a potent relaxant effect. The ET‐1‐mediated relaxation in this setting appears to be endothelium‐dependent and is related to release of both cyclo‐oxygenase products and EDRF.
Opposing roles for 5‐HT1B and 5‐HT3 receptors in the control of 5‐HT release in rat hippocampus in vivo
Authors: Martin Keith F. , Hannon Serina , Phillips Ian , Heal David J. 
Published: July 2012

Intracerebral microdialysis was used to determine whether 5‐hydroxytryptamine (5‐HT) release in the ventral hippocampus of rats anaesthetized with chloral hydrate was modulated by 5‐HT3 receptors.
It was confirmed that 5‐methoxy‐3‐(1,2,3,6‐tetrahydro‐4‐pyridinyl)‐1H‐indole (RU 24969), a selective 5‐HT1B receptor agonist, decreased 5‐HT release in a dose‐ and concentration‐related manner when administered i.p. (1 and 5 mg kg−1) or via the dialysis probe (0.1 and 1 μm) respectively. The effect of RU 24969 infusion (1 μm) was attenuated by concurrent infusion of metitepine (10 μm) into the hippocampus.
When infused into the hippocampus for 15 min, the selective 5‐HT3 receptor agonist, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT; 0.1–10 μm) increased dialysate 5‐HT levels in a concentration‐related manner; an effect which was abolished by concurrent infusion of 3‐tropanyl‐3,5‐dichlorobenzoate (1 μm, MDL 72222), a selective 5‐HT3 antagonist.
MDL 72222 had no effects on hippocampal 5‐HT release when administered via the dialysis probe (1 or 10 μm).
The data show that 5‐HT3 and 5‐HT1B receptors have opposing roles in the control of 5‐HT release in the hippocampus, with 5‐HT3 receptors facilitating and 5‐HT1B receptors inhibiting 5‐HT efflux, respectively. They also indicate that the facilitatory 5‐HT3 receptors are not tonically activated.
Effects of a new pteridine derivative on urinary sodium, potassium and magnesium excretion in conscious saline‐loaded rats
Authors: Netzer T. , Ullrich F. , Priewer H. , Majewski M. , Mutschler E. 
Published: July 2012

Two recently synthesized pteridine derivatives (RPH 3036; RPH 3038) were tested in conscious saline‐loaded rats and showed natriuretic and antimagnesiuretic properties but hardly reduced potassium excretion.
In the same model a dose‐response curve was performed for RPH 3036. ED50 and Emax values were calculated for the natriuretic (ED50 = 13.4 μmol kg−1; Emax = 1.08 mmol kg−1) and antimagnesiuretic (ED50 = 11.3 μmol kg−1; Emax = − 0.099 mmol kg−1) properties of RPH 3036. There were no significant changes of potassium and calcium excretion.
After a single dose of RPH 3036 (100 μmol kg−1) the time course of electrolyte excretion was analysed over 6 h. RPH 3036 did not show any significant effects on renal potassium and calcium excretion whereas a pronounced decrease (P < 0.01) in renal magnesium excretion was evident during the 6 h. A moderate increase of sodium excretion was observed only after 3, 5 and 6 h.
A selective reduction of magnesium secretion in the late distal tubule and collecting duct was proposed as a possible mechanism of action of RPH 3036. This would explain the fast onset of action as well as the lack of antikaliuretic and anticalciuretic effects. The high selectivity of RPH 3036 makes it potentially valuable for the future investigation of renal magnesium transport.
Evidence that the apparent complexity of receptor antagonism by angiotensin II analogues is due to a reversible and syntopic action
Authors: Liu Y.J. , Shankley N.P. , Welsh N.J. , Black J.W. 
Published: July 2012

The interactions between angiotensin II (AII), two non‐peptide antagonists DuP 753 and IMI, and eight peptide analogues of AII were investigated on the rabbit isolated aorta assay. DuP 753 and IMI behaved as simple competitive antagonists (pKB values 8.4 and 6.8, respectively). To different degrees, all the AII‐peptide analogue interactions failed to meet the basic criteria for simple competition. In addition to rightward shift, the most significant feature was a concentration‐dependent saturable depression of the upper asymptote of the AII concentration‐effect curves.
‘Washout’ and combined dose‐ratio analysis experiments, in which DuP 753 was used as a reference antagonist, indicated that the profile of peptide antagonism was solely due to a reversible and syntopic action at the AII receptor.
By use of an operational model of agonism (Black & Leff, 1983) as a starting point, it was possible to account for the data with a new model which describes reversible receptor occupancy and occupied receptor‐determined, saturable reduction in the efficacy of AII. Model‐fitting gave estimates of pKB values for the peptide analogues and agonist affinity and efficacy parameters for AII.
The model was successfully tested by applying it to qualitatively similar results obtained in a cross‐tissue analysis on guinea‐pig aorta, ileum and stomach.
A ‘molecular’ interpretation of the efficacy changes, based on the concepts of receptor internalisation and expression, is offered.
Involvement of substance P present in primary afferent neurones in modulation of cutaneous blood flow in the instep of rat hind paw
Authors: Yonehara Norifumi , Chen Ji‐Qiang , Imai Yasuo , Inoki Reizo 
Published: July 2012

The participation of small‐diameter afferent fibres in the microcirculatory haemodynamics of cutaneous tissue was examined by studies on the effects of antidromic stimulation of primary afferent neurones on cutaneous blood flow (CBF) and tachykinin release into the subcutaneous space in the instep of the hind paw of rats.
Antidromic stimulation of the sectioned sciatic nerve induced a biphasic flow response, an initial transient decrease followed by an increase, with no alteration in the blood pressure.
Neither phase was affected by pretreatment with phentolamine (0.1 mg kg−1, i.a.), propranolol (0.5 mg kg−1, i.a.), atropine (0.5 mg kg−1, i.a.), methysergide (0.5 mg kg−1, i.a.) or mepyramine (10 mg kg−1, i.a.) plus cimetidine (10 mg kg−1, i.a.), but both were significantly inhibited by pretreatment with capsaicin (50 mg kg−1, s.c).
Spantide (1–2 μmol kg−1, i.a.), a substance P (SP) antagonist, reduced the basal CBF, and also inhibited both phases of the biphasic flow response evoked by antidromic stimulation of the sectioned sciatic nerve.
Intra‐arterial infusion of SP (0.5 μmol kg−1, i.a.) induced a biphasic flow response similar to that elicited by antidromic stimulation of the sectioned sciatic nerve.
Antidromic stimulation of the sectioned sciatic nerve caused a marked increase in SP release into the subcutaneous perfusate of the instep of the rat hind paw, but no detectable increase in neurokinin A release.
We suggest that SP and its receptors are mainly responsible for the vascular response induced by stimulation of the sectioned sciatic nerve, and that small‐diameter afferent fibres containing SP tonically regulate vascular tone in cutaneous microvessels.
Platelet activating factor and systemic anaphylaxis in Nippostrongylus brasiliensis‐sensitized rats: differential effects of PAF antagonists
Authors: Mathison Ronald , Davison J.S. , Befus A. Dean 
Published: July 2012

The effects of two platelet‐activating factor (PAF) antagonists, WEB 2086 and BN 52021, in reducing the changes in extravasation (Evans blue technique) and blood flow (radiolabelled microsphere method) to various organs and tissues following anaphylactic shock in the Nippostrongylus brasiliensis‐sensitized rat were investigated.
Both antagonists attenuated anaphylaxis‐induced increases in plasma protein leak in the trachea, stomach and small intestine, although they did not block extravasation in the colon and kidneys.
Anaphylaxis‐induced decreases in blood flow to the adrenals were effectively antagonized by WEB 2086, although this antagonist did not reverse blood flow decreases to any other tissues. BN 52021, on the other hand, did not alter anaphylaxis‐induced decreases in blood flow to the adrenals, but effectively prevented dramatic decreases in blood flow to the large and small bowel and spleen.
Anaphylactic shock produced marked reduction in blood pressure that was partly reversed by WEB 2086, whereas BN 52021 effectively blocked the decreases in cardiac output.
Thus, PAF is responsible for some of the haemodynamic and extravasation of protein changes associated with systemic anaphylaxis in the rat, although the differential inhibition observed with the two antagonists suggests that PAF alters vascular responsiveness through different mechanisms in selected tissues.
The role of CD 18 in IL‐8 induced dermal and synovial inflammation
Authors: Forrest M.J. , Eiermann G.J. , Meurer R. , Walakovits L.A. , MacIntyre D.E. 
Published: July 2012

The intradermal administration of endothelial IL‐8 (IL‐81–77) or monocyte derived IL‐8 (IL‐81–72) to rabbits produced a concentration‐dependent increase in plasma extravasation and an accumulation of polymorphonuclear leukocytes (PMNs) when measured over a 3 h time period. When plasma extravasation and PMN accumulation were measured over a 30 min time period no significant increases in PMN accumulation or plasma extravasation were observed in response to IL‐8 alone. However, under these conditions, the addition of prostaglandin E2 (100 pmol) produced a significant potentiation of IL‐8‐induced plasma extravasation. There was no significant difference between the biological activities of IL‐8177 and IL‐81–72.
Plasma extravasation and PMN accumulation induced by IL‐8 were inhibited in rabbits pretreated with the monoclonal antibody designated IB4 (1 mg kg−1, i.v.) directed against the common β chain (CD 18) of the leukocyte integrins.
The intra‐articular administration to rabbits of IL‐81–77 (1 nmol) resulted 24 h later in the appearance of a mixed population of leukocytes (PMNs and mononuclear cells) in synovial lavage fluid. Biochemical analyses revealed the presence of an increased level of sulphated proteoglycans (sPG) and of the metalloproteinase stromelysin. Pretreatment of rabbits with IB4 (3 mg kg−1, i.v.) inhibited the accumulation of PMNs but had no effect on the mononuclear infiltrate nor on the levels of sPG or stromelysin.
The intradermal or intra‐articular injection of E. coli‐derived endotoxin induced similar inflammatory changes to those observed with IL‐8. The possibility that the biological activities of IL‐8 were attributable to minor contamination with endotoxin is unlikely for two reasons. Firstly, biological effects of endotoxin were observed at levels greater than that contained in the IL‐8 preparation. Secondly, reduction of the endotoxin content of the IL‐8 preparation by a factor of 10 did not produce a concomitant reduction in the observed biological activity of the IL‐8.