bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of bradykinin receptor antagonists on antigen‐induced respiratory distress, airway hyperresponsiveness and eosinophilia in guinea‐pigs
Authors: Farmer Stephen G. , Wilkins Deidre E. , Meeker Sonya A. , Seeds Esther A.M. , Page Clive P. 
Published: July 2012

We examined effects of bradykinin (BK) receptor antagonists on airway hyperresponsiveness and eosinophilia in sensitized guinea‐pigs that had been administered single, as well as repeated (chronic) challenges with inhaled ovalbumin. In addition, the effects of BK antagonists on antigen‐induced respiratory distress during the chronic study were noted.
At 24 h following single antigen challenge, guinea‐pigs exhibited airway hyperresponsiveness to the bronchoconstrictor effect of i.v. histamine, characterized by a left shift in the dose‐response curve. In addition, responses to the maximum dose of histamine that could be used were significantly increased in hyperresponsive guinea‐pigs. The percentages of bronchoalveolar fluid, eosinophil and neutrophils also increased.
A BK B1 receptor antagonist, desArg9‐[Leu8]‐BK, significantly inhibited airway hyperresponsiveness induced by single antigen challenge. A B2 receptor antagonist, d‐Arg‐[Hyp3, Thi5,8,d‐Phe7]‐BK (NPC 349) had a small, but statistically significant inhibitory effect on responsiveness to the highest histamine dose in challenged animals. DesArg9‐[Leu8]‐BK significantly inhibited the neutrophilia, whereas NPC 349 inhibited infiltration by both cell types.
Chronic antigen challenge also caused airway hyperresponsiveness to i.v. acetylcholine (ACh), distinguished by an increase in the slope of the dose‐response curve. Thus, the magnitude of the bronchoconstrictor responses to the maximum dose of ACh that could be used was significantly increased. No change in sensitivity to ACh was evident. Marked eosinophilia was also noted in the trachea, bronchi and lung parenchyma.
Airway hyperresponsiveness and eosinophilia, induced by chronic antigen challenge, were markedly inhibited by the B2 antagonists, d‐Arg‐[Hyp3,d‐Phe7]‐BK (NPC 567) or d‐Arg‐[Hyp3,Thi5d‐Tic7,Tic8]‐BK (NPC 16731). NPC 16731 also abolished antigen‐induced cyanosis, and delayed the onset of dyspnoea, doubling the time taken for animals to exhibit respiratory distress.
The ability of BK receptor antagonists to inhibit antigen‐induced airway hyperresponsiveness, in addition to eosinophilia, indicates an important role for endogenous kinins. Moreover, the abrogation of eosinophil infiltration suggests that BK has a significant function in maintaining allergic inflammation of the airways.
In vitro effect of oestradiol on thymidine uptake in pulmonary vascular smooth muscle cell: role of the endothelium
Authors: Farhat Michel Y. , Vargas Roberto , Dingaan Brenda , Ramwell Peter W. 
Published: July 2012

The effect of different concentrations of oestradiol‐17β (3–300 nm) on [3H]‐thymidine uptake was studied in segments from canine pulmonary artery, and cultures of rat pulmonary vascular smooth muscle cells (VSMC).
Incubation with oestradiol‐17β for 24 h, potentiated in a concentration‐dependent manner [3H]‐thymidine uptake in VSMC cultures.
Oestradiol‐17β potentiated thymidine uptake by pulmonary arterial segments but only when the endothelium had been removed. Autoradiography showed dense incorporation of radioactive thymidine in the vascular smooth muscle cells of the media.
The non‐steroidal oestrogen, stilboestrol (300 nm), also significantly potentiated [3H]‐thymidine uptake, in both VSMC cultures and pulmonary artery segments. Testosterone was ineffective at a similar concentration.
Pre‐incubation of the pulmonary VSMC with the anti‐oestrogen tamoxifen (1 μm) antagonized the potentiating effect of oestradiol‐17β on [3H]‐thymidine incorporation. The effect of tamoxifen was less pronounced in pulmonary arterial segments.
These data suggest that oestrogen may promote proliferation of pulmonary VSMC. Endothelial injury or dysfunction may be an important factor in the expression of the oestrogenic effect.
We speculate that plasma oestrogen may be a contributing factor to the proliferative lesion observed in certain forms of pulmonary vascular injury in women.
Novel signal transduction pathway mediating endothelium‐dependent β‐adrenoceptor vasorelaxation in rat thoracic aorta
Authors: Gray David W. , Marshall Ian 
Published: July 2012

Isoprenaline (3 × 10−8−10−5 m), salbutamol (3 × 10−7−10−4 m) and forskolin (3 × 10−9−3 × 10−7 m) relaxed rat isolated thoracic aortic rings contracted with noradrenaline (10−7 m). Removal of the endothelium from the aortic rings abolished the effect of acetylcholine (10−6 m) and completely prevented the vascular relaxation induced by isoprenaline, salbutamol or forskolin.
The isoprenaline concentration‐relaxation curve was shifted in parallel to the right about 10 fold by propranolol (3 × 10−7 m) with no change in the maximum response, showing that the relaxation was mediated by a β‐adrenoceptor.
The inhibitor of nitric oxide synthesis, NG‐nitro‐l‐arginine (l‐NOARG; 10−5 m), shifted the isoprenaline relaxation curve to the right and reduced the maximum response.
Isoprenaline (10−6 m) relaxed noradrenaline‐induced tone by approximately 95% and at the same time increased levels of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) 4 fold and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) 12 fold in the aortic rings. Sodium nitroprusside (3 × 10−8 m) relaxed noradrenaline‐evoked tone by 82% without changing levels of cyclic AMP but raised cyclic GMP 19 fold.
Forskolin (10−7 m) relaxed noradrenaline‐induced tone by approximately 41% and, like isoprenaline, increased levels of cyclic AMP (2.5 fold) and cyclic GMP (12 fold) in the aortic rings.
Removal of the endothelium abolished the relaxant effects of isoprenaline (10−6 m) and also the associated accumulation of cyclic AMP and cyclic GMP.
l‐NOARG (10−5 m) inhibited the relaxant responses and accumulation of cyclic GMP induced by isoprenaline (10−6 m) and forskolin (10−7 m) without affecting the associated cyclic AMP accumulation.
It is concluded that, in the rat aorta, isoprenaline acts through a β‐adrenoceptor on the endothelium to raise cyclic AMP and that this may, directly or indirectly, release nitric oxide to evoke vascular relaxation via the increase in cyclic GMP. The importance of this novel transduction pathway for cardiovascular regulation remains to be determined.
Effects of the PAF antagonists BN50726 and BN50739 on arrhythmogenesis and extent of necrosis during myocardial ischaemia/reperfusion in rabbits
Authors: Chakrabarty Sisiresh , Fluck David S. , Flores Nicholas A. , Sheridan Desmond J. 
Published: July 2012

The effects of two novel platelet activating factor (PAF) antagonists BN50726 and BN50739 on arrhythmias, haemodynamics and extent of necrosis during myocardial ischaemia and reperfusion were investigated in anaesthetized rabbits subjected to coronary artery ligation.
BN50739 reduced heart rate prior to coronary artery occlusion (P < 0.005) but had no other significant haemodynamic effects at this time. BN50739 and BN50726 did not significantly alter heart rate or blood pressure during 30 min of ischaemia or 30 min of reperfusion, compared to control hearts.
BN50739 and BN50726 had no effect on the incidence of arrhythmias during ischaemia. BN50726 significantly reduced the incidence of reperfusion ventricular fibrillation compared to controls (0% v 40%, P < 0.05), and improved survival (80% v 39%, P < 0.05). Similar trends were observed with BN50739.
BN50726 reduced the extent of necrosis compared to control hearts (18 ± 2% v 30 ± 3%, P <0.01). A similar trend was observed with BN50739.
These results demonstrate that PAF antagonism with BN50726 attenuates reperfusion‐induced arrhythmias and preserves myocardium in the early phase of ischaemia, independently of haemodynamic effects.
Chronic antihypertensive treatment with captopril plus hydrochlorothiazide improves aortic distensibility in the spontaneously hypertensive rat
Authors: Chillon Jean‐Marc , Capdeville‐Atkinson Christine , Lartaud Isabelle , Guillou Joel , Mertès Paul‐Michel , Atkinson Jeffrey 
Published: July 2012

Adult male spontaneously hypertensive rats (SHR) were given captopril plus hydrochlorothiazide mixed in the diet for 10 weeks. Calculated daily doses were 44 mg kg−1 per day for captopril, and 22 mg kg−1 per day for hydrochlorothiazide. Separate groups received captopril or hydrochlorothiazide alone, at similar doses, or no treatment. A final group of WKY normotensive rats received no drug.
Systolic arterial blood pressure, measured at regular intervals throughout the 10 weeks' period was lowered but not normalized, in groups receiving either captopril plus hydrochlorothiazide, or captopril alone, but not in the group receiving hydrochlorothiazide alone.
Following pentobarbitone anaesthesia, systolic arterial blood pressure, measured in the femoral artery, was found to be lower in all treated groups, but the greatest effect was observed in SHR previously treated with captopril plus hydrochlorothiazide. Aortic pulse wave velocity was also lower in treated SHR, and once again the greatest decrease was observed in the group previously treated with captopril plus hydrochlorothiazide.
Following pithing, systolic arterial blood pressures were similar in all SHR groups. Aortic pulse wave velocity was lower in pithed rats previously treated with captopril and hydrochlorothiazide.
In conclusion, antihypertensive treatment of SHR produces falls in blood pressure and pulse wave velocity, an indicator of aortic distensibility. Results in pithed rats suggest that treatment with the combination of captopril plus hydrochlorothiazide may increase aortic distensibility independently of blood pressure.
An investigation of some S‐nitrosothiols, and of hydroxy‐arginine, on the mouse anococcygeus
Authors: Gibson A. , Babbedge R. , Brave S.R. , Hart S.L. , Hobbs A.J. , Tucker J.F. , Wallace P. , Moore P.K. 
Published: July 2012

The effect of five S‐nitrosothiols, and of the stereoisomers of NG‐hydroxy‐arginine (HOARG), were investigated on the mouse anococcygeus.
All five S‐nitrosothiols produced concentration‐related (0.1–100 μm) relaxations of carbachol (50 μm)‐induced tone; the order of potency was S‐nitroso‐l‐cysteine (CYSNO) > S‐nitroso‐N‐acetyl‐d,l‐penicillamine (SNAP) > S‐nitrosoglutathione (GSNO) > S‐nitrosocoenzyme A (CoASNO) > S‐nitroso‐N‐acetyl‐l‐cysteine (NACNO). The relaxations were unaffected by the nitric oxide synthase (NOS) inhibitor, l‐NG‐nitro‐arginine (10 μm) (l‐NOARG).
Cold‐storage of the tissue for 72 h resulted in loss of sympathetic and non‐adrenergic, non‐cholinergic (NANC) nerve function. NOS activity in the tissue was reduced by 97%. Despite this, relaxations induced by the S‐nitrosothiols were unaffected.
Haemoglobin (50 μm) attenuated relaxations induced by NO and the S‐nitrosothiols, although responses to 3‐isobutyl‐1‐methyl‐xanthine were unaffected. N‐methyl‐hydroxylamine (2 Mm) which has been shown previously to produce selective inhibition of NANC and nitrovasodilator responses in this tissue, also reduced responses to all S‐nitrosothiols.
Hydroquinone (100 μm) greatly reduced relaxations to CYSNO (by 88%) but had no effect on those to SNAP, GSNO, CoASNO or NACNO. Since hydroquinone does not reduce responses to NANC stimulation, CYSNO is unlikely to be the NANC transmitter.
l‐HOARG by itself (up to 100 μm) had no significant effect on carbachol‐induced tone or on NANC (10 Hz; 10 s train every 100 s) relaxations. However, it produced reversal of the inhibitory effects of l‐NOARG (10 μm), being only slightly less potent than l‐arginine. d‐HOARG was without effect. l‐HOARG had no effect on relaxations induced by 1.5 μm NO.
The results show that S‐nitrosothiols are potent relaxants of the mouse anococcygeus; they act directly on the smooth muscle with a mechanism similar to NO and other nitrovasodilators. In addition, the results are consistent with l‐HOARG being an intermediate in the biosynthesis of NO from l‐arginine, although there is no evidence for it acting to stabilize NO extracellularly.
Contribution of NO and cytochrome P450 to the vasodilator effect of bradykinin in the rat kidney
Authors: Fulton D. , McGiff J.C. , Quilley J. 
Published: July 2012

Inhibition of nitric oxide generation with Nw‐nitro‐l‐arginine (nitroarginine) reduced vasodilator responses to bradykinin and acetylcholine and enhanced those to nitroprusside in the rat isolated perfused kidney, preconstricted with phenylephrine.
Inhibition of cyclo‐oxygenase with indomethacin, decreased the vasodilator responses to bradykinin by ∼25% without affecting those to acetylcholine or nitroprusside.
BW755c, a dual inhibitor of cyclo‐oxygenase and lipoxygenase, reduced renal vasodilator responses to bradykinin, comparable to the effect of indomethacin suggesting an effect related to inhibition of cyclo‐oxygenase rather than lipoxygenase.
ETYA, an inhibitor of all arachidonic acid metabolic pathways, markedly reduced vasodilator responses to bradykinin but was without effect on the renal vasodilatation induced by acetylcholine or nitroprusside.
Clotrimazole and 7‐ethoxyresorufin, inhibitors of cytochrome P450, greatly attenuated vasodilator responses to bradykinin without affecting those to acetylcholine or nitroprusside.
These data suggest that the renal vasodilator response to bradykinin is subserved by arachidonic acid metabolites as well as nitric oxide, the former accounting for up to 70% of the vasodilator effect of bradykinin.
The pharmacology of recombinant GABAA receptors containing bovine α1, β1, γ2L sub‐units stably transfected into mouse fibroblast L‐cells
Authors: Home A.L. , Hadingham K.L. , Macaulay A.J. , Whiting P. , Kemp J.A. 
Published: July 2012

Responses to γ‐aminobutyric acid (GABA) were evoked in mouse fibroblast L‐cells stably transfected with bovine, α1, β1, γ2L sub‐units of the GABAA receptor. Expression was stimulated via a steroid‐inducible promoter system.
In near symmetrical intracellular and extracellular chloride concentrations, GABA evoked inward currents at negative holding potentials that reversed at + 5 mV and displayed slight outward rectification. Concentration‐response curves were fitted well by the logistic equation. GABA had a pEC50 = 5.1 ± 0.1 and the curves had a slope of 1.9 ± 0.1
Responses to GABA were antagonized by bicuculline, picrotoxin and penicillin. The action of bicuculline was competitive (pA2 = 6.4) whilst the block by picrotoxin was uncompetitive and strongly agonist‐dependent.
Benzodiazepine receptor agonists potentiated responses to 3 μm GABA. The rank order of potency was FG 8205 > flunitrazepam > Zolpidem > C1218872. FG 8205 and C1218872 produced markedly lower maximal potentiations with efficacies 0.4 and 0.6 × that of flunitrazepam, respectively. The potencies of Zolpidem and C1218872 observed are in agreement with the BZ1 type pharmacology of this sub‐unit combination. The potentiation of GABA by flunitrazepam was antagonized by flumazenil with a Ki of 3.8 nm.
GABA responses were potentiated in the presence of pentobarbitone and alphaxalone. The response was also noticeably broadened by these compounds due to a decrease in the response decay rate. Concentrations of pentobarbitone of 100 μm and above evoked an inward current in the absence of GABA. Alphaxalone up to 10 μm did not evoke a direct response.
This expression system produced functional receptors that behaved in a fashion analogous to those found endogenously in other preparations. Thus, this system appears to provide a useful and versatile preparation for the analysis of sub‐unit regulation of GABAA receptor pharmacology.
S‐nitroso‐glutathione inhibits platelet activation in vitro and in vivo
Authors: Radomski Marek W. , Rees Daryl D. , Dutra Alberto , Moncada Salvador 
Published: July 2012

The effect of S‐nitroso‐glutathione (GSNO), a stable nitrosothiol, on platelet activation was examined in vitro and in vivo.
The adhesion of human platelets to fibrillar collagen and human endothelial cell monolayers was inhibited by GSNO.
GSNO caused a concentration‐dependent inhibition of collagen‐induced platelet aggregation in vitro and decreased ADP‐induced aggregation in the conscious rat.
Inhibition of platelet aggregation in vitro correlated with the increase in intraplatelet cyclic GMP levels.
The release of NO from GSNO was enhanced by platelet lysate, native glutathione and ascorbate.
The results show that GSNO is a carrier of NO and therefore has pharmacological activity as an inhibitor of platelet activation.
Use of selective antagonists to dissociate the central cardiovascular and behavioural effects of tachykinins on NK1 and NK2 receptors in the rat
Authors: Tschöpe Carsten , Picard Pierre , Culman Juraj , Prat Alexandre , Itoi Keiichi , Regoli Domenico , Unger Thomas , Couture Réjean 
Published: July 2012

The effects of intracerebroventricular (i.c.v.) pretreatment with selective NK1 ((±)‐CP 96,345), NK2a (MEN 10,207; MEN 10,376) and NK2b (R 396) tachykinin receptor antagonists on the cardiovascular and behavioural responses to i.c.v. substance P (SP) and neurokinin A (NKA) were studied in conscious rats.
SP and NKA (25 pmol) induced mean arterial blood pressure and heart rate increases of the same magnitude and duration. The cardiovascular responses to both peptides were accompanied by excessive face washing, sniffing, grooming and wet dog shakes.
The cardiovascular responses to SP but not to NKA were attenuated by pretreatment with a NK1 receptor antagonist, (±)‐CP 96,345. Of the behavioural responses, only face washing was significantly inhibited.
The cardiovascular and behavioural effects of NKA but not of SP were significantly attenuated by pretreatment with the selective NK2b receptor antagonist, R 396.
The selective NK2a receptor antagonists, MEN 10,207 and MEN 10,376, did not affect the cardiovascular and behavioural responses to either SP or NKA.
These results suggest, firstly, that the cardiovascular and behavioural effects of i.c.v. SP are mediated by NK1 receptors; secondly, that NKA injected i.c.v. does not interact with NK1 receptors but with another type of tachykinin receptor which may belong to the NK2b subclass. These findings provide pharmacological evidence for the existence of functionally active NK2 receptors in the rat brain.
(±)‐CP‐96,345, a selective tachykinin NK1 receptor antagonist, has non‐specific actions on neurotransmission
Authors: Wang Zun‐Yi , Håkanson Rolf 
Published: July 2012

The non‐specific effects of the non‐peptide tachykinin receptor antagonist (±)‐CP‐96,345, were assessed in several smooth muscle‐nerve preparations. The preparations were the iris sphincter muscle of the rabbit and the taenia coli, vas deferens and seminal vesicle of the guinea‐pig.
(±)‐CP‐96,345 concentration‐dependently inhibited the elctrically evoked, tachykinin‐mediated contractile responses of the iris sphincter and the taenia coli. The pIC50 values were 5.4 ± 0.2 (mean ± s.e.mean) and 5.7 ± 0.08 respectively.
(±)‐CP‐96,345 also inhibited non‐tachykinin‐mediated contractile responses to electrical stimulation of the iris sphincter, taenia coli, vas deferens and seminal vesicle. The pIC50 values were 4.3 ± 0.02, 4.8 ± 0.03, 4.7 ± 0.02 and 4.4 ± 0.05 respectively. These values differ significantly from the pIC50 values of the inhibition of the tachykinin‐mediated response in the iris sphincter and taenia coli.
(±)‐CP‐96,345 was without effect on carbachol‐ and noradrenaline‐evoked contractions of the iris sphincter but inhibited carbachol‐ and prostaglandin F2α (PGF2α)‐evoked contractions of the taenia coli.
We suggest that (±)‐CP‐96,345, apart from its NK1 receptor blocking activity, induces non‐specific suppression of neurotransmission, exerted at both pre‐ and post‐junctional sites.
The effect of in vivo oestrogen pretreatment on the contractile response of rat isolated detrusor muscle
Authors: Elliott Ruth A. , Castleden C.M. , Miodrag A. 
Published: July 2012

The effect of oestradiol pretreatment was investigated on the response of rat isolated detrusor muscle to cholinergic, electrical and 5‐hydroxytryptamine (5‐HT) stimulation with and without diethystilboestrol (DES) (2 μm) in the organ bath.
Virgin female Wistar rats were injected subcutaneously for 8 days with oestradiol benzoate 150 μg kg−1. Control rats received no injections or injection only with the vehicle, ethyl oleate.
Detrusor muscle from treated rats showed a decreased sensitivity to acetylcholine (ACh) and carbachol‐induced contractile responses. The dose‐response curves to these agonists showed a 44% reduction in maximum contractile response for ACh (P < 0.001), and a 38% reduction in maximum contractile response for carbachol (P < 0.05). The addition of 2 μm DES to the bathing medium further significantly reduced the maximum contractile response by 56 and 57% of control respectively.
Electrically stimulated detrusor muscle from treated rats showed a significant 49% reduction in the maximum contractile response (P < 0.001). The addition of 2 μm DES to the bathing medium further significantly reduced the maximum contractile response by 66% of control. The tetrodotoxin resistant responses were smaller in pretreated rats, suggesting a reduced sensitivity of the smooth muscle to direct electrical stimulation.
The response to 5‐HT stimulation by detrusor muscle samples from oestradiol‐treated rats showed a non‐significant reduction in maximum contractile response, but the addition of 2 μm DES to the bath chamber resulted in a 67% reduction in the response (P < 0.001).
Oestradiol pretreatment did not affect the potassium dose‐response curve.
Oestradiol pretreatment reduced the rat detrusor muscle sensitivity to the blocking effect of atropine on the response to electrical field stimulation. Pretreatment also reduced the potentiating effect of physostigmine on the same response.
These results suggest that oestradiol pretreatment had a modulating effect on cholinergic responses. The addition of oestrogen to the tissue environment enhances this inhibitory effect.
Effects of neuropeptide Y and agonists selective for neuropeptide Y receptor sub‐types on arterioles of the guinea‐pig small intestine and the rat brain
Authors: Xia J. , Neild T.O. , Kotecha N. 
Published: July 2012

The actions of neuropeptide Y (NPY) and agonists selective for NPY receptor subtypes were examined on arterioles from the guinea‐pig small intestine and the rat pia in order to characterize the receptors mediating the vasoconstrictor and potentiating effects of NPY.
A method was developed for measuring the potentiating effects of NPY in situations where it was not possible to obtain a full concentration‐response relationship for the vasoconstrictor. NPY, 50 nm, had a greater potentiating effect on the guinea‐pig intestinal arterioles than those from the rat pia.
NPY and the Y1‐selective agonist, NPY[Leu31,Pro34], potentiated the constrictor responses to U46619 in both arterioles and responses to noradrenaline in the guinea‐pig arterioles. There was marked desensitization of the potentiating effect, and cross‐desensitization between NPY and NPY[Leu31,Pro34]. Both NPY and NPY[Leu31,Pro34] caused constriction of the rat pial arterioles but not of those from the guinea‐pig intestine.
The Y2‐selective agonist PYY(13–36) caused no potentiation or vasoconstriction and did not affect the potentiation by NPY or NPY[Leu31,Pro34].
The potentiating and vasoconstrictor effects of NPY on these arterioles were mediated by Y1 receptors.