bluuebunny/crossref_metadata_2025_split huggingface dataset:
Substance P‐induced inflammatory responses in guinea‐pig skin: The effect of specific NK1 receptor antagonists and the role of endogenous mediators
Authors: Walsh Desmond T. , Weg Vivian B. , Williams Timothy J. , Nourshargh Sussan 
Published: July 2012

1 The sensory neuropeptide substance P (SP), when released from sensory nerves, has been implicated in the development of neurogenic inflammation. In the present study, using an in vivo model system, we have characterized and investigated the mechanisms underlying SP‐induced leukocyte accumulation and oedema formation in the guinea‐pig.2 Intradermaly injected SP (i.d., 10−13‐10−9mol per site), induced a dose‐ and time‐dependent accumulation of 111In‐neutrophils, 111In‐eosinophils and oedema formation as measured by the local accumulation of i.v. injected l25I‐albumin. The leukocyte accumulation evoked by SP was significant at 10−10 and 10−9mol per site, whereas oedema formation was significant at the lowest dose tested (10−13mol per site).3 The NK1 receptor antagonists, CP‐96,345 (1 mgkg−1, i.v.) and RP‐67,580 (10 μg per site, i.d.), significantly attenuated the oedema formation induced by the lower doses of SP. Oedema formation and leukocyte accumulation induced by 10−9mol per site SP were unaffected by either antagonist.4 SP‐elicited responses were not significantly affected by the platelet activating factor (PAF) receptor antagonist, UK‐74,505 (2.5 mgkg−1, i.v.) or the H1 histamine receptor antagonist, chlorpheniramine (10−8mol per site, i.d.). However, the 111In‐eosinophil accumulation, but not the 111In‐neutrophil accumulation or oedema formation, induced by SP was significantly inhibited by the specific 5lipoxygenase (5‐LO) inhibitor, ZM‐230,487 (10−8 mol per site, i.d.).5 The accumulation of both 111In‐neutrophils and 111In‐eosinophils induced by SP was abolished in guinea‐pigs treated i.v. with an anti‐CD 18 monoclonal antibody 6.5E F(ab′)2 (2.5 mgkg−1). The oedema response was unaffected in these animals.6 These results suggest that SP‐induced inflammatory events may be mediated via two mechanisms involving NK1 receptor‐dependent and independent pathways. Oedema formation induced by the lower doses of SP may be mediated via the direct activation of NK1 receptors whilst, at higher doses, oedema formation and leukocyte accumulation may be mediated via the release of secondary mediators, possibly mast cell derived, with 5‐LO products playing an important role in the leukocyte infiltration. The leukocyte accumulation, but not the oedema induced by SP, is dependent on the expression of the CD 18 antigen on leukocytes.
Study of the in vivo and in vitro cardiovascular effects of (+)‐glaucine and N‐carbethoxysecoglaucine in rats
Authors: Orallo Francisco , Alzueta Alejandro Fdez , Campos‐Toimil Manuel , Calleja José Ma 
Published: July 2012

1 The cardiovascular and vasorelaxant effects of (+)‐glaucine and of a semisynthetic derivative (N‐carbethoxysecoglaucine) were studied in rats.2 N‐carbethoxysecoglaucine did not modify either systolic arterial pressure or heart rate values in conscious (25 mg kg−1, p.o.) and anaesthetized normotensive rats (5 mg kg−1, i.v.). Furthermore, this compound showed no activity in the experiments carried out on rat isolated aorta [contractility and 45Ca2+ influx assays (5 μm)] and did not modify the rate and force of contraction in rat isolated atria (5 μm).3 In conscious normotensive rats, oral administration of (+)‐glaucine (25 mg kg−1) did not modify either systolic arterial pressure or heart rate.4 In anaesthetized normotensive rats, (+)‐glaucine (5 mg kg−1, i.v.) produced a remarkable fall in mean arterial pressure (MAP) accompanied by a significant decrease in heart rate. In the same preparation, (+)‐glaucine (5 mg kg−1, i.v.) did not modify the cardiovascular effects induced by noradrenaline (NA) (5 μg kg−1) and 5‐hydroxytryptamine (5‐HT) (300 μg kg−1) but markedly inhibited those induced by nicotine (200 μg kg−1).5 In isolated intact aorta of rat, (+)‐glaucine (0.15‐5 μm) competitively inhibited the contractions induced by NA (with a pA2 value of 7.14) and non‐competitively those induced by 5‐HT (in normal Krebs solution) and Ca2+ (in depolarizing Ca2+‐free high‐K+ 50 mM solution), with depression of the maximal response and with pD2′ values of 5.56 and 5.26, respectively.6 In experiments in Ca2+‐free medium, (+)‐glaucine (3 μm) inhibited the contractions induced by NA and had no effect on either 5‐HT‐ or caffeine‐induced contractions.7 Furthermore, in the experiments with radioactive Ca2+, (+)‐glaucine (3 μm) did not modify the basal uptake of 45Ca2+ but strongly inhibited the influx of 45Ca2+ induced by NA, 5‐HT and K+.8 (+)‐Glaucine (5 μm) had no effect on rate and force of contraction in rat isolated atria.9 These results indicate that: (a) the cardiovascular effects (hypotension and bradycardia) of (+)‐glaucine in anaesthetized normotensive rats (5 mg kg−1) may be due, at least in part, to a ganglioplexic effect; (b) the vasorelaxant action of (+)‐glaucine (0.15‐5 μm) in rat isolated aorta can be attributed to an α1adrenoceptor blocking property (which may explain its inhibition of noradrenaline‐induced 45Ca2+ influx and contractions in normal Krebs solution and noradrenaline‐induced contractions in Ca2+‐free medium) and to a Ca2+‐antagonist activity (which may be responsible, at least in part, for the inhibition of 45Ca2+ uptake induced by NA, 5‐HT and K+ and the contractions induced by both NA and 5‐HT in normal Krebs solution and by Ca2+ in Ca2+‐free high‐K+ medium) and (c) there is no correlation between the mechanisms of action observed for (+)‐glaucine in vivo and in vitro, which suggests that the vasorelaxant activity of this alkaloid does not contribute to its hypotensive activity.
Inhibitory effects of SR 58611A on canine colonic motility: evidence for a role of β3‐adrenoceptors
Authors: De Ponti Fabrizio , Cosentino Marco , Costa Angela , Girani Marco , Gibelli Graziano , D'Angelo Luigi , Frigo Gianmario , Crema Antonio 
Published: July 2012

1 In order to clarify whether atypical or β‐adrenoceptors can modulate canine colonic motility in vivo, we studied the effects of SR 58611A (a selective agonist for atypical β‐adrenoceptors) alone and after pretreatment with β‐adrenoceptor antagonists on colonic motility in the conscious dog. The gastrocolonic response (postprandial increase in motility) was monitored by means of electrodes and strain‐gauge force transducers chronically implanted along the distal colon. In some experiments, heart rate was also measured. The possible role of β3‐adrenoceptors in mediating the effects of SR 58611A was also tested in vitro in circular muscle strips taken from the canine distal colon.2 Intravenous infusion of SR 58611 A, ritodrine or isoprenaline at doses inducing the same degree of tachycardia inhibited the gastrocolonic response to a different extent, with SR 58611A and ritodrine being more effective than isoprenaline.3 In a dose‐response study, SR 58611A was more potent in inhibiting colonic motility than in inducing tachycardia: the ED35 values for inhibition of colonic motility and induction of tachycardia were 23 and 156 μg kg−1, i.v., respectively.4 The inhibitory effect of SR 58611A 100 μg kg−1, i.v., on the gastrocolonic response was reversed by alprenolol (non‐selective β‐adrenoceptor antagonist), but resistant to CGP 20712A (β1‐adrenoceptor antagonist) or ICI 118551 (β2‐adrenoceptor antagonist).5 In vitro, SR 58611A concentration‐dependently relaxed circular muscle strips, an effect that was competitively antagonized by alprenolol with a pA2 value of 7.1, but resistant to CGP 20712A (100 nM), ICI 118551 (100 nM) or tetrodotoxin (1 μm).6 The present study provides strong functional evidence for a role of atypical or β3‐adrenoceptors in the modulation of canine colonic motility both in vivo and in vitro by an inhibitory effect most likely at the smooth muscle level.
Effect of inhibition of nitric oxide synthesis on the uptake of LDL and fibrinogen by arterial walls and other organs of the rat
Authors: Cardona‐Sanclemente L.E. , Born G.V.R. 
Published: July 2012

1 The effects of administering 3 mg ml−1 NG‐nitro‐L‐arginine methyl ester (L‐NAME), an inhibitor of nitric oxide (NO), on the uptake of low density lipoprotein (LDL), fibrinogen and blood pressure were determined in conscious, unrestrained, cannulated normotensive and spontaneously hypertensive (SHR) Wistar rats.2 The uptake of LDL and fibrinogen, labelled respectively with 125I or 131I via the adduct tyramine cellobiose ([125I]TC‐LDL and [131I]TC‐fibrinogen), were compared in aortic walls, heart, skeletal muscle, lung, liver, kidney and adrenal during the final 24 h of 6 days' administration of L‐NAME in the drinking water.3 In control normotensive rats, the systolic blood pressure did not change significantly over 6 days, while administration of L‐NAME in normotensive rats increased the blood pressure progressively and significantly to about 170 mmHg over the same period.4 In normotensive rats L‐NAME increased significantly the uptake of both LDL and fibrinogen by aortic walls and heart, but not by muscle, lung, liver, kidney and adrenal.5 The blood pressure in SHR was about 170 mmHg before administration of L‐NAME and did not increase significantly after 6 days of treatment. In these rats the uptake of LDL or of fibrinogen was increased only in the heart but not in aortic walls nor in any of the other organs.6 In normotensive rats the increase in blood pressure caused by inhibition of NO generation was associated with increases in the uptake of the atherogenic plasma proteins LDL and fibrinogen by the wall of the aorta and by the heart but not by the skeletal muscle, lung, liver, kidney and adrenal. The slightly higher blood pressure of SHR treated with L‐NAME was not associated with increased uptake of LDL or fibrinogen by aorta nor by any organ except heart. Thus, while in normotensive rats the increase in blood pressure caused by inhibition of NO generation was associated with increase in the uptake of atherogenic plasma proteins LDL and fibrinogen by the wall of the aorta and by the heart, in SHR which showed uptakes similar to the normotensive animals, the non‐significant increase in blood pressure induced by inhibition of NO generation was not associated with increased uptake of LDL or fibrinogen in any organ except the heart.7 These results are consistent with effects, demonstrated earlier, of infusing the pressor agents noradrenaline, adrenaline and angiotensin II, which produce increases in uptake of LDL and fibrinogen by aortic wall, whereas this is not so in spontaneously hypertensive rats.
Electrophysiological effects of Ro 22–9194, a new antiarrhythmic agent, on guinea‐pig ventricular cells
Authors: Maruyama Kazuyasu , Kodama Itsuo , Anno Takafumi , Suzuki Ryouko , Toyama Junji 
Published: July 2012

Cardiac effects of Ro 22–9194 were examined in papillary muscles and single ventricular myocytes isolated from guinea‐pigs and compared with those of moricizine.
In papillary muscles, both Ro 22–9194 (≥ μm) and moricizine (≥ μm) caused a significant dose‐dependent decrease in the maximum upstroke velocity (V̇max) and a shortening of the action potential duration.
In the presence of either drug, trains of stimuli at rates ≥ 0.2 Hz led to an exponential decline in V̇max. This use‐dependent block was enhanced at higher stimulation frequencies. A time constant (τR) for V̇max recovery from the use‐dependent block was 9.3 s for Ro 22–9194 and 26.4 s for moricizine.
The curves relating membrane potential and V̇max in single myocytes were shifted by Ro 22–9194 (30 μm) or by moricizine (3 μm) in a hyperpolarizing direction by 8.4 mV and 8.0 mV respectively.
In myocytes treated with Ro 22–9194 (30 μm), a 10 ms conditioning clamp to 0 mV caused a significant decrease in V̇max of the subsequent test action potential; further prolongation of the clamp pulse duration resulted in a modest enhancement of the V̇max inhibition. In the presence of moricizine (3 μm), a similar conditioning clamp > 200 ms caused a significant V̇max reduction; the longer the clamp pulse duration, the greater the V̇max reduction.
Ro 22–9194 ≥ 30 μm caused a slight decrease of calcium inward current (ICa) of myocytes without affecting the delayed rectifier potassium current (IK).
These findings suggest that the primary electrophysiological effect of Ro 22–9194 as an antiarrhythmic agent is, like moricizine, a use‐ and voltage‐dependent inhibition of sodium channels. From the onset and offset kinetics of the use‐dependent block, Ro 22–9194 belongs to the intermediate kinetic Class I drugs, while moricizine is a slow kinetic drug. From the state‐dependence of sodium channel block, Ro 22–9194 may belong to activated channel blockers, while moricizine belongs to inactivated channel blockers.
Production of antinociception by peripheral administration of [Lys7]dermorphin, a naturally occurring peptide with high affinity for μ‐opioid receptors
Authors: Negri Lucia , Lattanzi Roberta , Melchiorri Pietro 
Published: July 2012

The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25–30 times by peripheral administration.
The dose‐response curves of [Lys7]dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg−1, s.c.) or with the μ1‐selective antagonist, naloxonazine (10 mg kg−1, i.v. 24 h before peptide injection).
The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw.
High central and peripheral doses of [Lys7]dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment.
In rats and mice, central or peripheral administration of [Lys7]dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine.
Upon naloxone precipitation of the withdrawal syndrome, [Lys7]dermorphin‐dependent mice made fewer jumps and lost less weight than the morphine‐dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]dermorphin‐dependent mice.
In conclusion, [Lys7]dermorphin seems to be a unique opioid peptide having a high penetration into the blood‐brain barrier despite its low lipid solubility. This peptide causes fewer side‐effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.
The receptor occupation and plasma concentration of NKY‐722, a water‐soluble dihydropyridine‐type calcium antagonist, in spontaneously hypertensive rats
Authors: Uchida S. , Yamada S. , Ohkura T. , Heshikiri M. , Yoshimi A. , Shirahase H. , Kimura R. 
Published: July 2012

The occupation in vivo by NKY‐722 of 1,4‐dihydropyridine (DHP) calcium antagonist receptors in myocardium, aorta and cerebral cortex was investigated. At 1 and 3 h after oral administration of NKY‐722 (3 mg kg−1) in spontaneously hypertensive rats (SHR), there was a significant (44 and 41%, respectively) decrease in the number of myocardial (+)‐[3H]‐PN 200‐110 binding sites (Bmax) compared to control values. A greater reduction of Bmax values was observed at 1 (86%), 3 (88%), 6 (63%) and 12 (46%) h later by a higher dose (10 mg kg−1) of this drug. The occupation of myocardial 1,4‐DHP calcium antagonist receptors after oral administration of NKY‐722 correlated significantly with its plasma concentration. There was a significant decrease in cerebral cortical (+)‐[3H]‐PN 200‐110 binding (Bmax) at 1 and 3 h after oral administration of NKY‐722 (10 mg kg−1).
Oral administration of nicardipine (10 mg kg−1) in SHR caused a significant reduction of Bmax values for (+)‐[3H]‐PN 200‐110 binding in myocardium at 1 and 3 h later and in cerebral cortex at 1 h later.
The in vivo specific binding of (+)‐[3H]‐PN 200‐110 in particulate fractions of aorta of SHR was significantly (79 and 83%, respectively) reduced at 1 and 6 h after oral administration of NKY‐722 (3 mg kg−1), while myocardial (+)‐[3H]‐PN 200‐110 binding was decreased by 52% only at 1 h later. Also, nicardipine administration reduced in vivo (+)‐[3H]‐PN 200‐110 binding in aorta at 1 and 6 h later and in myocardium at 1 h later. On the other hand, the administration of both NKY‐722 and nicardipine had no significant effect on in vivo (+)‐[3H]‐PN 200‐110 binding in cerebreal cortex.
It is concluded that NKY‐722 may exert more selective and sustained occupation in vivo of 1,4‐DHP calcium antagonist receptors in vascular tissues of SHR than in myocardial and brain tissues.
The effect of chlormethiazole on neuronal damage in a model of transient focal ischaemia
Authors: Sydserff S.G. , Cross A.J. , West K.J. , Green A.R. 
Published: July 2012

The effect of chlormethiazole has been studied in a transient middle cerebral artery (MCA) occlusion model of cerebral ischaemia in the rat. The MCA was occluded for 1 h by use of an intraluminal suture technique, with reperfusion for 24 h following removal of the occluding filament. Neuronal damage was determined by measurement of the area of necrosis following Cresyl Violet staining of sections taken through the ischaemic region.
In the initial experiment, occlusion of the MCA produced a large volume of ischaemic damage in both cortex and striatum, characterized by necrosis and pyknosis (total volume of damage, 287 ± 13 mm3; n = 9). Rats injected with chlormethiazole (1000 μmol kg−1, i.p.) 60 min before occlusion had a reduced volume of damage in both regions (104 ± 11 mm3; n = 9; P < 0.001).
In a subsequent study systemic physiological parameters (heart rate, blood pressure, blood pH, blood gases and rectal temperature) were measured throughout the ischaemic period.
Chlormethiazole (10000 μmol kg−1) pretreatment produced little change in systemic physiology and the neuroprotective effect of the drug when given 60 min prior to the MCA occlusion was confirmed. Chlormethiazole was also neuroprotective when given 10 min following the start of reperfusion (control group: 244 ± 52 mm3, n = 10; chlormethiazole pretreatment group: 102 ± 23 mm3, n − 10; P < 0.001; chlormethiazole post‐ischaemia group: 122 ± 16mm3; P<0.001, n= 10).
It is concluded that chlormethiazole is an effective neuroprotective agent in this model of transient focal ischaemia. The observation that chlormethiazole is protective when given after reperfusion indicates that the effect of the drug is unlikely to be due to an alteration of intra‐ischaemic cerebral blood flow, but is more probably a direct effect on the development of ischaemic damage.
Enhancement by 5‐hydroxytryptamine and analogues of desensitization of neuronal and muscle nicotinic receptors expressed in Xenopus oocytes
Authors: Cross K.M.L. , Foreman R.C. , Chad J.E. 
Published: July 2012

The action of 5‐hydroxytryptamine (5‐HT) on neuronal and muscle nicotinic acetylcholine receptors (nicotinic AChR) expressed in Xenopus oocytes was studied.
5‐HT enhanced the rate of desensitization of the acetylcholine (ACh) current response in all receptor subtypes investigated (muscle, αβ2γδ and α4β2), acting in a dose‐dependent manner.
5‐HT also reduced the peak current elicited by ACh in a dose‐dependent manner. The IC50 value for the muscle type receptor was 227 ± 0.44 μm, and 166 ± 0.47 μm and 283 ± 0.28 μm for the combinations αβ2γ and α4β2 respectively.
The effect of 5‐HT on the responses to ACh (10 μm) was found to be independent of membrane voltage over the range tested (−80 to −10 mV), and to be readily reversed by washout.
The action of 5‐HT could be mimicked by structurally similar molecules. The homologue tryptamine was less potent than 5‐HT in blocking the ACh current, with an IC50 of 1.0 ± 0.02 mM. Ketanserin, a 5‐HT2 receptor antagonist, was more potent than 5‐HT, the IC50 being 49.0 ± 1.4 μm.
We postulate that a highly conserved portion of the tertiary structure of nicotinic AChRs, which includes some part of the ACh binding site, has affinity for 5‐HT and structural analogues.
Effect of UK‐84149 on voltage‐activated calcium currents of single smooth muscle cells from guinea‐pig and rabbit jejunum and rabbit coronary artery
Authors: Zhang H. , Bolton T.B. 
Published: July 2012

Smooth muscle cells of the longitudinal muscle of the guinea‐pig and the rabbit jejunum and rabbit coronary artery were dispersed by enzyme treatment and recordings of membrane current were made in the standard whole cell voltage‐clamp mode and by perforated patch technique. The effect of UK‐84149 on the voltage‐dependent calcium inward current of single isolated smooth muscle was studied at room temperature.
When inward and outward currents were evoked by stepping to O mV or + 10 mV from − 80 mV every 20 s, UK‐84149 reduced the voltage‐dependent inward current in guinea‐pig jejunum smooth muscle cells with a ID50 of 2.3 μm, and also reduced voltage‐dependent outward current with a ID50 of 7.2 μm. The effect of UK‐84149 was difficult to wash out.
The inactivation of the inward current was studied by holding at various potentials for 10 s before evoking inward current at a test potential of 0 mV. The voltage‐inactivation curve was shifted to the left by 3 μm UK‐84149. The voltage at which current was 50% available (Vh) was changed from − 37 ± 2 mV to − 50 mV ± 2.2 (n = 6, means ± s.e.mean).
When inward current was evoked by stepping to 0 mV from − 80 mV for 50 ms, every 20 s, nicardipine immediately, and verapamil and UK‐84149 slowly, reduced the peak amplitude. Inhibition by the latter two drugs depended on the number of stimulations applied. So, like verapamil, UK‐84149 had a use‐dependent action.
The effect of UK‐84149 on inward current from rabbit jejunum and coronary artery smooth muscle cells was compared with the effect of nicardipine and D600. When inward current was evoked by stepping to 0 mV from − 80 mV every 20 s, UK‐84149 inhibited inward currents from both types of smooth cell with an ID50 of 1.7 μm for jejunum and an ID50 of 3.2 μm for coronary artery. ID50 values of D600 were 8.1μm for jejunum and 3.9 μm for coronary artery. ID50 values of nicardipine were 24 nM for jejunum and 12 nM for coronary artery.
The results of the present studies indicate that UK‐84149 has a calcium‐antagonist action that can explain its inhibitory action on bowel motility. Its bowel selectivity may arise due to its use‐dependent, and persistent, action.