bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversal by NPY, PYY and 3–36 molecular forms of NPY and PYY of intracisternal CRF‐induced inhibition of gastric acid secretion in rats
Authors: Gué M. , Junien J.L. , Reeve J.R. , Rivier J. , Grandt D. , Taché Y. 
Published: July 2012

The Y receptor subtype involved in the antagonism by neuropeptide Y (NPY) of intracisternal corticotropin‐releasing factor (CRF)‐induced inhibition of gastric acid secretion was studied in urethaneanaesthetized rats by use of peptides with various selectivity for Y1, Y2 and Y3 subtypes: NPY, a Y1, Y2 and Y3 agonist, peptide YY (PYY), a Y1 and Y2 agonist, [Leu31, Pro34]‐NPY, a Y1 and Y3 agonist, NPY(3–36) and PYY(3–36), highly selective Y2 agonists and NPY(13–36) a weak Y2 and Y3 agonist. Peptides were injected intracisternally 10 min before intracisternal injection of CRF (10 μg) and gastric acid secretion was measured by the flushed technique for 1 h before and 2 h after pentagastrin(10 μg kg−1 h−1, i.v.) infusion which started 10 min after CRF injection.
Intracisternal injection of CRF (10 μg) inhibited by 56% gastric acid secretion stimulated by pentagastrin. Intracisternal injection of NPY and PYY (0.1‐0.5 μg) did not influence the acid response to pentagastrin but blocked CRF‐induced inhibition of pentagastrin‐stimulated acid secretion. NPY(3–36) (0.5 μg) and PYY(3–36) (0.25 and 0.5 μg) also completely blocked the inhibitory action of CRF on pentagastrin‐stimulated acid secretion.
[Leu31, Pro34]‐NPY (0.5‐5 μm) and NPY(13–36) (0.5‐5 μm) injected intracistemally did not modify gastric acid secretion induced by pentagastrin or CRF inhibitory action.
The sigma antagonist, BMY 14802 (1 mg kg−1, s.c.) did not influence the acid response to pentagastrin but prevented the antagonism by PYY(3–36) (0.5 μm) of the CRF antisecretory effect.
These results show that both PYY and NPY and the 3–36 forms of PYY and NPY are equipotent in blocking central CRF‐induced inhibition of pentagastrin‐stimulated gastric acid secretion. The structure‐activity profile suggests a mediation through Y2 receptor subtype and the involvement of sigma binding sites.
Coupling of metabotropic glutamate receptors to phosphoinositide mobilisation and inhibition of cyclic AMP generation in the guinea‐pig cerebellum
Authors: Neil Karen E. , Kendall David A. , Alexander Stephen P.H. 
Published: July 2012

The effects of metabotropic glutamate receptor (mGluR) agonists on cyclic nucleotide and phosphoinositide turnover were investigated in adult guinea‐pig cerebellar slices by use of radioactive precursors.
L‐Glutamate, 1‐aminocyclopentane‐1S,3R‐dicarboxylate (1S,3R‐ACPD) and RS‐3,5‐dihydroxyphe‐nylglycine (DHPG) evoked concentration‐dependent increases in the accumulation of [3H]‐inositol phosphates with pEC50 values of 2.98±0.02, 4.45±0.06 and 4.47±0.07, respectively. Maximal responses to these agents were 43±8, 52±12 and 84±11% of the response to 1 mM histamine, respectively.
The phosphoinositide response to 1S,3R‐ACPD was antagonized in the presence of (+)‐α‐methyl‐4‐carboxyphenylglycine, with a calculated pKi value of 3.55±0.03.
Forskolin‐stimulated accumulation of [3H]‐cyclic AMP was not significantly altered in the presence of 10 μm DCG‐IV or 300 μm 1S,3R‐ACPD. Similarly, 300 μm 1S,3R‐ACPD failed to alter isoprenaline‐ (1 μm) or 2‐chloroadenosine (2‐CA, 30 μm)‐stimulated accumulation of [3H]‐cyclic AMP.
Forskolin‐stimulated accumulation of [3H]‐cyclic AMP was concentration‐dependently inhibited in the presence of L‐glutamate and L‐serine‐O‐phosphate (L‐SOP) with pIC50 values of 2.91±0.17 and 2.86±0.04 with maximal inhibitions of 47±2 and 92±3%, respectively. L‐2‐Amino‐4‐phosphonobutyrate (L‐AP4) inhibited the forskolin response without saturating, evoking an inhibition of 71±7% at 3 mM.
2‐CA‐evoked accumulation of [3H]‐cyclic AMP was also inhibited by L‐glutamate and L‐SOP with pIC50 values of 2.71±0.03 and 2.72±0.08 and maximal inhibitions of 51±5 and 99±0%, respectively. L‐AP4 inhibited the 2‐CA response without saturating, evoking an inhibition of 68±1% at 3 mM.
Isoprenaline‐evoked accumulation of [3H]‐cyclic AMP was inhibited by L‐glutamate and L‐SOP with pIC50 values of 3.21±0.01 and 2.96±0.08 and maximal inhibitions of 88±2 and 93±3%, respectively.
These results suggest that the guinea‐pig cerebellum expresses Group I and Group III mGluRs coupled to phosphoinositide turnover and inhibition of cyclic AMP generation, respectively.
The role of the endocardium in the facilitatory effect of bradykinin on electrically‐induced release of noradrenaline in rat cardiac ventricle
Authors: Vaz‐da‐Silva M. , Magina S. , Domingues‐Costa A. , Moura D. , Guimarães S. 
Published: July 2012

The present investigation was undertaken to study the role of bradykinin in noradrenaline release from the ventricle of the rat induced by electrical stimulation. Slices of the left ventricle of adult Wistar rats with or without endocardium were previously loaded with 0.2 μm [3H]‐noradrenaline and washed out before electrical stimulation was applied.
Bradykinin (0.1–100 nM) concentration‐dependently increased tritium release evoked by electrical stimulation (EC50 = 3.5 (1.2–10.2) nM; n= 12). The angiotensin converting enzyme inhibitor, captopril (1 μm), which per se had no effect on tritium release, caused a marked enhancement of the bradykinin facilitatory effect, shifting the concentration‐response curve of bradykinin to the left by about one log unit. The compound Hoe 140, a selective inhibitor of B2‐bradykinin receptors, competitively antagonized the effect of bradykinin, indicating the involvement of these receptors in the action of bradykinin.
In endocardium‐free ventricle, bradykinin had no effect either in the absence or in the presence of captopril.
These results show that: (1) bradykinin is able to facilitate noradrenaline release evoked by electrical stimulation of the rat ventricle through activation of B2‐bradykinin receptors located on endocardial cells; (2) this action of bradykinin which is markedly potentiated by the inhibition of the angiotensin‐converting enzyme seems to be exerted through the release of some factor which is formed in the endocardium and diffuses into the myocardium where it acts.
Preservation of endothelium‐dependent relaxation in cholesterol‐fed and streptozotocin‐induced diabetic mice by the chronic administration of cholestyramine
Authors: Kamata Katsuo , Sugiura Makoto , Kojima Satoshi , Kasuya Yutaka 
Published: July 2012

Experiments were designed to investigate the effects of the low density lipoprotein (LDL)‐lowering drugs cholestyramine on serum LDL levels and endothelium‐dependent relaxation to acetylcholine (ACh) in cholesterol‐fed or streptozotocin (STZ)‐induced diabetic mice.
In aortic rings from control mice, ACh or A23187 caused concentration‐dependent relaxation. The relaxations caused by ACh or A23187 were significantly attenuated in aortic rings from cholesterol‐fed and STZ‐diabetic mice. The attenuated vasodilatation in both cholesterol‐fed and diabetic mice was returned to normal by chronic administration of cholestyramine. The endothelium‐independent relaxations of aortic rings induced by sodium nitroprusside (SNP) were not significantly different between control, cholesterol‐fed and STZ‐induced diabetic mice.
The increased LDL levels in cholesterol‐fed and diabetic mice were returned to normal by the chronic administration of cholestyramine. Chronic administration of cholestyramine had no effects on serum glucose levels.
These results suggest that attenuated endothelium‐dependent vasodilatations in both cholesterol‐fed and STZ‐diabetic mice are improved by the chronic administration of cholestyramine, and these effects are, at least in part, due to lowering serum LDL levels.
Impairment of stress adaptive behaviours in rats by the CCKA receptor antagonist, devazepide
Authors: Hernando Fernando , Fuentes José A. , Ruiz‐Gayo Mariano 
Published: July 2012

Cholecystokinin (CCK) is released during stress both in limbic and hypothalamic areas suggesting that CCK could participate in modulating neuroendocrine as well as behavioural responses to stress.
In this study we have examined the effect of CCK receptor antagonists on the retention of the immobility response to a forced‐swim stress in rats. In this test, rats are forced to swim during 15 min (conditioning period) and 24 h later, the duration of immobility is measured during a period of 5 min (re‐test period). During the conditioning period rats display a period of vigorous activity, followed by progressive inactivity. During the re‐test period rats remain 70–80% of the time in an immobile posture.
The CCKA receptor antagonist, devazepide (MK‐329) but not the CCKB receptor antagonist, L‐365,260, administered s.c. immediately before the conditioning period, decreased the duration of acquired immobility during the re‐test period. The effect of devazepide was prevented by cholecystokinin octapeptide (CCK‐8; 40 μg kg−1, s.c.) as well as by the selective glucocorticosteroid GII receptor agonist, dexamethasone (30 μg kg−1, s.c.).
Neither corticosterone nor ACTH plasma levels measured both after the re‐test period and after the conditioning period were modified by devazepide treatment.
The results suggest a role for CCK in the behavioural adaptation to stress and indicate a relationship between CCK systems and glucocorticoids in the neuronal mechanisms involved in the acquisition of adaptive behaviours to stress.
Stimulation of sodium pump by vasoactive intestinal peptide in guinea‐pig isolated trachea: potential contribution to mechanisms underlying relaxation of smooth muscle
Authors: Morrison Keith J. , Vanhoutte Paul M. 
Published: July 2012

Relaxation of airway smooth muscle induced by vasoactive intestinal peptide (VIP) is mediated by adenosine 3′:5′ cyclic monophosphate (cyclic AMP). An interaction between the synthesis of cyclic AMP and enzymic activity of the plasmalemmal sodium pump (Na+‐K+‐ATPase) exists in certain isolated cell systems. This study sought to determine the contribution of Na+‐K+‐ATPase activity to relaxation of airway smooth muscle evoked by VIP.
All experiments were performed on isolated strips of guinea‐pig trachea from which the epithelium had been removed. VIP was a more potent relaxant in tissues that were contracted with carbachol than those contracted with an equi‐effective depolarizing concentration of K+.
Ouabain (0.1 μm‐10 μm) induced contraction of tracheal strips. Contraction to ouabain (5 μm) was abolished following incubation of tissues with K+‐free, or Ca2+‐free (+EGTA, 0.1 mM) physiological solutions. The contractile response to ouabain (5 μm) was not influenced significantly by exposure of the tissues to atropine (1 μm), phentolamine (5 μm) and diphenhydramine (1 μm) for 60 min.
Tissues were incubated with ouabain (5 μm; 60 min) or K+‐free physiological solution (60 min) to inhibit Na+‐K+‐ATPase activity. These procedures reduced relaxation induced by VIP, peptide histidine isoleucine, forskolin, isoprenaline and sodium nitroprusside.
Relaxation to VIP was impaired significantly following exposure of tissues to a low Na+ solution (30 min) or amiloride (500 μm; 30 min).
Ouabain‐sensitive uptake of 86Rb was measured in tracheal strips (devoid of epithelium and cartilage) as an index of Na+‐K+‐ATPase activity. VIP (1 μm; 2 min) caused a 4.7 fold stimulation of ouabain‐sensitive uptake of 86Rb. This effect was impaired significantly by low Na+ solution.
The results suggest that (i) relaxation of tracheal smooth muscle to VIP is sensitive to procedures that inhibit activity of Na+‐K+‐ATPase and invoke a role for altered sodium pump function in the mechanisms that underlie cyclic AMP‐dependent relaxation; and (ii) VIP stimulates ouabain‐sensitive uptake of 86Rb in airway smooth muscle in a Na+‐dependent manner.
Measurement of lipocortin 1 levels in murine peripheral blood leukocytes by flow cytometry: modulation by glucocorticoids and inflammation
Authors: Perretti Mauro , Flower Roderick J. 
Published: July 2012

Lipocortin 1 (LC1) immunoreactivity in murine peripheral blood leukocytes was quantified by use of a flow cytometric technique associated with a permeabilisation protocol with saponin. Using specific antisera raised against the whole protein or against its N‐terminus peptide, cell‐associated LC1‐like immunoreactivity was easily detected in circulating neutrophils and monocytes, whereas very low levels were found in lymphocytes. Of the total protein measured 17.6% and 36% were associated with the external plasma membrane in neutrophils and monocytes, as assessed in the absence of cell permeabilisation, whereas no signal was detected on lymphocyte plasma membrane.
Treatment of mice with dexamethasone (Dex; 0.5‐5 μg per mouse corresponding to ∼ 0.015‐1.5 mg kg−1) increased LC1 levels in neutrophils and monocytes. The 2–3 fold increase in LC1 levels was time‐dependent with a peak at 2 h. Treatment of mice with the steroid antagonist, RU486 (two doses of 20 mg kg−1 orally) decreased LC1‐like immunoreactivity in all three types of circulating leukocytes by ≥50%.
Extravasation of blood neutrophils into inflamed tissue sites resulted in a consistent reduction (≥50%) in LC1 levels compared with circulating neutrophils. A high LC1‐like immunoreactivity was also measured in resident macrophages, of which approximately one third was membrane‐associated. Induction of an acute inflammatory response in the murine peritoneal cavity did not modify total LC1 levels measured in macrophages, but reduced membrane‐associated LC1 to a significant extent, i.e. up to 70%.
In conclusion, flow cytometric analysis is a rapid and convenient method for detecting and measuring LC1 in murine leukocytes. We confirmed that LC1 protein expression is controlled by exogenous and endogenous glucocorticoids. Amongst other factor(s) influencing protein concentrations, extravasation was found to be associated with a reduced LC1 expression in the emigrated cells.
Reciprocal inhibition of nitric oxide and prostacyclin synthesis in human saphenous vein
Authors: Barker J.E. , Bakhle Y.S. , Anderson J. , Treasure T. , Piper P.J. 
Published: July 2012

Angiotensin II (AII) causes contraction of isolated rings of human saphenous vein, responses that are attenuated by the presence of functional endothelium. In this study, we have investigated the mechanisms controlling the release by AII of two endothelial‐derived vasorelaxants, prostacyclin (PGI2) and nitric oxide (NO).
Myotropic and biochemical changes were measured in response to AII. The biochemical responses measured were the output of PGI2 (as 6‐oxo‐PGF1α) and of NO (as cyclic GMP). Inhibitors of cyclo‐oxygenase (COX; piroxicam) or NO synthase (NOS; L‐NAME), were added to the system to determine the influence of endogenous prostaglandins and NO on both myotropic and biochemical responses. Furthermore, to mimic the effects of endogenous, PGI2 or NO, exogenous forms of these relaxants were added, during inhibition of their endogenous release.
Contractions of the rings of saphenous vein in response to AII (1–100 nM) were unaffected by treatment with either piroxicam (5 μm) or L‐NAME (200 μm) individually. However, when these two inhibitors were used together, there was an increase in the contractions in response to AII.
Biochemical analyses revealed that during stimulation by AII, levels of PGI2 and NO were enhanced when synthesis of the other vasodilator was inhibited, suggesting that endogenous NO inhibits PGI2 synthesis and endogenous, PGI2 or another vasorelaxant PG can inhibit NO synthesis.
Exogenous PGI2 (as iloprost) or NO (from glyceryl trinitrate) inhibited the increased output of endogenous NO or PGI2 respectively.
These results demonstrate the presence, in human saphenous vein, of a mechanism which ensures that levels of vasodilatation are maintained through a compensatory increase in one relaxant agonist when output of the other is decreased. If present in vivo such a mechanism would be important in maintaining saphenous vein graft patency as both PGI2 and NO are not only vasodilators, but inhibit platelet aggregation and myoinitimal hyperplasia, processes implicated in degeneration of graft function.
Effect of calmodulin antagonists on calmodulin‐induced biphasic modulation of Ca2+‐induced Ca2+ release
Authors: Ikemoto Takaaki , Lino Masamitsu , Endo Makoto 
Published: July 2012

Calmodulin (CaM) has a biphasic effect on Ca2+‐induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR): potentiation and inhibition at low (pCa > 6.0) and high (pCa 5) Ca2+ concentrations, respectively. To characterize the mode of action of CaM, we studied the effect of CaM antagonists on the CICR in skinned muscle fibres of the rabbit. Ca2+ release was measured by microfluorometry with Fura‐2.
A CaM antagonist, trifluoperazine (TFP), potentiated the CICR in a dose‐dependent manner (10–300 μm) at pCa 6, where a simple reversal of the CaM effect would be inhibition of the CICR. Furthermore, 100 μm TFP sensitized the CICR to Ca2+. A similar effect was produced by other CaM antagonists that were tested: chlorpromazine, W‐7, mastoparan, and peptide fragment of CaM‐binding residues of CaM‐dependent protein kinase II.
The biphasic effect of CaM on the CICR was observed even in the presence of high concentrations of CaM antagonists or CaM‐binding peptides.
From these results we suggest that CaM has a unique mode of action on the CICR which is quite different from the effect of CaM on known enzymes.
Antithrombotic actions of the thrombin inhibitor, argatroban, in a canine model of coronary cyclic flow: comparison with heparin
Authors: Duval N. , Lunven C. , O'Brien D.P. , Grosset A. , O'Connor S.E. , Berry C.N. 
Published: July 2012

The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in a canine model of coronary cyclic flow having some of the characteristics of acute unstable angina. Heparin was studied as a reference anticoagulant.
Localized endothelial damage was induced in the circumflex coronary artery of anaesthetized open‐chest foxhounds and a critical stenosis was applied by use of a Lexan constrictor placed around the artery at the site of endothelial damage. An electro‐magnetic flow probe was placed distal to the lesion, and cyclic flow variations (CFVs) were observed, as thrombi formed at the site of the arterial lesion and were dislodged. Test compounds were administered by i.v. infusion commencing 1 h after the appearance of CFVs, and maintained for 1 h. On termination of the treatments, coronary flow was observed for a further 60 min. A series of blood samples were taken at predetermined times throughout each experiment in order to determine the coagulation parameters, thrombin time (TT) activated partial thromboplastin time (aPTT) and for the determination of fibrinopeptide A (FpA) levels before, during and post‐treatment.
Argatroban and heparin showed antithrombotic effects in this model. Argatroban dose‐dependently increased the minimum coronary flow at the nadir of the CFVs from 5.4 ± 1.7 to 9.1 ± 2.1 ml min−1 (30 μg kg−1 min−1, P = 0.041) and from 2.9 ± 0.9 to 16.3 ± 4.5 ml min−1 (100 μg kg−1 min−1, P = 0.023, n = 8 dogs at each dose level). Heparin (5 and 15 iu kg−1 min−1) also increased minimum flow, but the increase was not statistically significant at the 5% level, although the P value in animals treated with 15 iu kg−1 min−1 (P = 0.0521, n = 6 dogs) fell just outside this limit. Although neither compound significantly decreased the overall CFV frequency, argatroban (100 μg kg−1 min−1) significantly (P < 0.01) decreased the number of large amplitude CFVs (minimum coronary flow < 10 ml min−1) by 63%, and heparin (15 iu kg−1 min−1) caused a 50% decrease in this parameter (P < 0.05).
The thrombin times were increased by a factor greater than 10 during antithrombotic treatment, irrespective of the compound or doses used. Heparin treatment induced 17 and > 30 fold increases in aPTT at 5 and 15 iu kg−1 min−1 respectively. However, argatroban produced only 2 and 3 fold increases in aPTT at 30 and 100 μg kg−1 min−1, despite significant antithrombotic effects. FpA levels were reduced in the presence of both argatroban and heparin.
These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in a canine model of coronary cyclic flow.
Characterization of the anatomical structures involved in the contractile response of the rat lung periphery
Authors: Salerno Francesco G. , Kurosawa Hajime , Eidelman David H. , Ludwig Mara S. 
Published: July 2012

When lung parenchymal strips are challenged with different smooth muscle agonists, the tensile and viscoelastic properties change. It is not clear, however, which of the different anatomical elements present in the parenchymal strip, i.e., small vessel, small airway or alveolar wall, contribute to the response.
Parenchymal lung strips from Sprague Dawley rats were suspended in an organ bath filled with Krebs solution (37°C, pH = 7.4) bubbled with 95%O2/5%CO2. Resting tension (T) was set at 1.1 g and sinusoidal oscillations of 2.5% resting length (Lo) at a frequency of 1 Hz were applied. Following 1 h of stress adaptation, measurements of length (L) and T were recorded under baseline conditions and after challenge with a variety of pharmacological agents, i.e., acetylcholine (ACh), noradrenaline (NA) and angiotensin II (AII). Elastance (E) and resistance (R) were calculated by fitting changes in T, L and ΔL/Δt to the equation of motion. Hysteresivity (η, the ratio of the energy dissipated to that conserved) was obtained from the equation η = (R/E)2πf.
In order to determine whether small airways or small vessels accounted for the responses to the different pharmacologic agents, further studies were carried out in lung explants. Excised lungs from Sprague Dawley rats were inflated with agarose. Transverse slices of lung (0.5–1.0 mm thick) were cultured overnight. By use of an inverted microscope and video camera, airway and vascular lumen area were measured with an image analysis system.
NA, ACh and AII constricted the parenchymal strips. Airways constricted after all agonists, vessels constricted only after AII. Atropine (Atr) pre‐incubation decreased the explanted airway and vessel response to AII, but no difference was found in the parenchymal strip response.
Preincubation with the arginine analogue Nω‐nitro‐L‐arginine (L‐NOARG) did not modify the response to ACh but mildly increased the oscillatory response to NA after co‐preincubation with propranolol (Prop).
These results suggest that during ACh and NA challenge, small vessels do not contribute substantially to the parenchymal strip response. The discrepancy between results in airways, vessels and strips when Atr was administered prior to AII implicates a direct contractile response in the parenchymal strip.