bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of angiostatic steroids and dexamethasone on angiogenesis and cytokine levels in rat sponge implants
Authors: Hori Yozo , Hu De‐En , Yasui Kiyoshi , Smither Rachel L. , Gresham G. Austin , Fan Tai‐Ping D. 
Published: July 2012

. Subcutaneous implantation of sterile polyether sponges elicited a reproducible neovascular response in rats, as determined by blood flow measurement with a 133Xe clearance technique and confirmed histologically. This model was used to monitor the levels of two cytokines during angiogenesis and to compare the activities of angiostatic steroids and anti‐inflammatory steroids.
. Initial experiments followed the neovascular development over a 20‐day period. Daily local injection of hydrocortisone caused a dose‐dependent (0.5, 5 and 50 μg per sponge) inhibition of the basal sponge‐induced angiogenesis. However, daily systemic treatment of hydrocortisone (2, 10 and 50 mg kg−1, s.c.) was less effective at inhibiting angiogenesis, and this inhibition was not sustained by day 20 after sponge implantation.
. To investigate the involvement of cytokines during the course of angiogenesis, we measured the endogenous levels of tumour necrosis factor‐α (TNF‐α) and interleukin 6 (IL‐6) in sponge implants. Levels of IL‐6 and TNF‐α peaked at day 7 and day 11 after implantation, respectively. These cytokine levels subsided through the completion of angiogenesis by day 20.
. Subsequent experiments were carried out over a 14‐day period. Among the three angiostatic steroids tested, U‐24067 (6α‐fluoro‐17,21‐dihydroxy‐16α‐methylpregna‐4,9(11)‐diene‐3,20‐dione‐21‐acetate) showed a dose‐dependent inhibition (0.5, 5 and 50 μg per sponge per day) of sponge‐induced angiogenesis. Tetrahydro‐S was also effective at 5 μg doses, but medroxyprogesterone failed to affect the angiogenic response. None of these steroids caused atrophies of the spleen and thymus.
. Daily local injection of dexamethasone (0.5 μg per sponge) inhibited the basal sponge‐induced angiogenesis almost completely. Although higher doses of dexamethasone (5 and 50 μg per sponge) did not produce further inhibition of angiogenesis, they caused severe spleen and thymus weight losses, indicative of immunosuppression.
. At the daily dose of 5 μg per sponge, dexamethasone inhibited angiogenesis and produced a marked reduction in the levels of TNF‐α and IL‐6 at day 14. In contrast, hydrocortisone, U‐24067 and tetrahydro‐S did not influence the levels of TNF‐α and IL‐6.
. We concluded that the anti‐angiogenic activity of angiostatic steroids and anti‐inflammatory steroids in the rat sponge model is independent of their ability to reduce the production of TNF‐α and IL‐6. The differential effects of angiostatic and anti‐inflammatory steroids suggest that U‐24067 and its derivatives may have therapeutic potential in the management of angiogenic diseases such as rheumatoid arthritis.
Effects of theophylline and rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of human eosinophils from normal and atopic subjects
Authors: Tenor Hermann , Hatzelmann Armin , Church Martin K. , Schudt Christian , Shute Janis K. 
Published: July 2012

. The effects of the non‐selective phosphodiesterase (PDE) inhibitor theophylline and the selective PDE4 inhibitor rolipram on leukotriene C4 (LTC4) synthesis and chemotaxis of complement 5a (C5a)‐and platelet‐activating factor (PAF)‐stimulated human eosinophils obtained from normal and atopic donors were investigated.
. Eosinophils were purified from peripheral venous blood of normal and atopic subjects by an immunomagnetic procedure to a purity > 99%. Eosinophils were stimulated with PAF (0.1 μm) or C5a (0.1 μm) for 15 min and LTC4 was measured by radioimmunoassay (RIA). Eosinophil chemotaxis in response to PAF and C5a was assessed with 48‐well microchambers (Boyden).
. Under these conditions substantial amounts of LTC4 (about 300–1000 pg per 106 cells) were only detectable in the presence of indomethacin (0.1–10 μm). To explain this finding it was hypothesized that indomethacin reversed the inhibition of LTC4 synthesis by endogenously synthesized prostaglandins, in particular prostaglandin E2 (PGE2). In fact, eosinophils release 23 pg PGE2 per 106 cells following PAF stimulation; this PGE2 synthesis was completely inhibited by indomethacin and readdition of PGE2 inhibited eosinophil LTC4 synthesis (IC50 = 3 nM). The following experiments were performed in the presence of 10 μm indomethacin.
. Theophylline (IC50∼50 μm) and rolipram (IC50∼ 0.03‐0.2 μm) suppressed PAF‐ and C5a‐stimulated LTC4 synthesis. This PDE inhibitor‐induced suppression of LTC4 generation is mediated by activation of protein kinase A, since it was reversed by the protein kinase A inhibitor Rp‐8‐Br‐cyclic AMPS. In addition, exogenous arachidonic acid concentration‐dependently (0.3 μm‐3 μm) reversed the inhibition of LTC4 synthesis by the PDE inhibitors, indicating that theophylline and rolipram suppress the mobilization of arachidonic acid. The β‐adrenoceptor agonist salbutamol inhibited eosinophil LTC4 synthesis (IC50 = 0.08 μm). The combination of salbutamol with theophylline (10 μm) or rolipram (3 nM) appeared to be additive.
. Theophylline (IC50∼40 μm), rolipram (IC50∼0.02 μm [C5a], ∼0.6 μm [PAF]) and PGE2 (IC50∼3 nM) inhibited C5a‐ and PAF‐stimulated eosinophil chemotaxis. The combination of PGE2 with theophylline resulted in an additive effect.
. Both C5a‐ and PAF‐stimulated eosinophil chemotaxis and LTC4 generation were significantly elevated in eosinophils from atopic individuals compared to normal subjects. However, eosinophils from normal and atopic individuals were not different with respect to their total cyclic AMP‐PDE and PDE4 isoenzyme activities as well as the potencies of theophylline and rolipram to suppress LTC4 generation and chemotaxis.
Effects of protein tyrosine kinase inhibitors on cytokine‐induced adhesion molecule expression by human umbilical vein endothelial cells
Authors: May Michael J. , Wheeler‐Jones Caroline P.D. , Pearson Jeremy D. 
Published: July 2012

. Endothelial cells can be stimulated by the pro‐inflammatory cytokines interleukin (IL)‐1α and tumour necrosis factor (TNF)α to express the leukocyte adhesion molecules E‐selectin, vascular cell adhesion molecule (VCAM)‐1 and intercellular adhesion molecule (ICAM)‐1 but the intracellular signalling mechanisms leading to this expression are incompletely understood. We have investigated the role of protein tyrosine kinases (PTK) in adhesion molecule expression by cytokine‐activated human umbilical vein endothelial cells (HUVEC) using the PTK inhibitors genistein and herbimycin A, and the protein tyrosine phosphatase (PTP) inhibitor sodium orthovanadate.
. Maximal E‐selectin expression induced by incubation of HUVEC for 4 h with IL‐1α (100 u ml−1) and TNFα (100 u ml−1) was dose‐dependently inhibited by genistein and herbimycin A. Although similar effects were seen on phorbol 12‐myristate, 13‐acetate (PMA)‐induced expression, this was not due to inhibition of protein kinase C (PKC) activity as the selective inhibitors of PKC, bisindolylmaleimide (BIM), Ro31‐7549 or Ro31‐8220 did not affect IL‐1α‐ or TNFα‐induced E‐selectin expression at concentrations which maximally inhibited PMA‐induced expression.
. Genistein inhibited VCAM‐1 expression induced by incubation of HUVEC for 24 h with TNFα or IL‐1α whereas it did not affect ICAM‐1 expression induced by 24 h incubation with either of these cytokines. Herbimycin A inhibited both VCAM‐1 and ICAM‐1 expression induced by TNFα.
. Basal expression of E‐selectin, VCAM‐1 and ICAM‐1 was dose‐dependently enhanced by sodium orthovanadate. In contrast, vanadate differentially affected TNFα‐induced expression of these molecules with maximal E‐selectin and ICAM‐1 expression being slightly enhanced and VCAM‐1 expression dose‐dependently reduced.
. We also studied the effects of PTK and PTP inhibitors on adhesion of the human pre‐myeloid cell line U937 to TNFα‐stimulated HUVEC. Adhesion of U937 cells to HUVEC pretreated for 4 or 24 h with TNFα was dose‐dependently inhibited by genistein and herbimycin A but unaffected by daidzein. Adhesion of U937 cells after 4 h was partially inhibited by blocking antibodies against both E‐selectin and VCAM‐1 but after 24 h was only inhibited by anti‐VCAM‐1.
. Sodium orthovanadate had no effect on TNFα‐induced U937 adhesion but dose‐dependently enhanced adhesion to unstimulated HUVEC. Vanadate‐induced adhesion was inhibited by an antibody against VCAM‐1.
. These results demonstrate that PTK‐mediated phosphorylation events are important for the regulation of adhesion molecule expression by human endothelial cells, and additionally show that PTK inhibitors differentially affect upregulation of different adhesion molecules, implicating divergent regulatory pathways for cytokine‐induced adhesion molecule expression.
Cardiac and gastric effects of histamine H2 receptor antagonists: no evidence for a correlation between lipophilicity and receptor affinity
Authors: Coruzzi G. , Adami M. , Pozzoli C. , Giorgi F. , Bertaccini G. 
Published: July 2012

. A series of histamine H2 receptor antagonists with different lipophilicity were tested in cardiac and gastric assays in order to reveal possible differences in receptor affinity. Lipophilicity of the compounds was expressed as CLOG P (theoretically‐determined logarithm of octanol:water partition coefficient) and log k' (logarithm of capacity factor, experimentally‐determined by reverse‐phase high performance liquid chromatography).
. Aminopotentidine (APT) and iodoaminopotentidine (I‐APT), which are both lipophilic compounds, behaved as insurmountable antagonists of histamine responses in rat isolated gastric fundus (pKB = 6.20 ± 0.16 and 6.89 ± 0.19, respectively) and guinea‐pig isolated papillary muscle (pKB = 6.34 ± 0.37 and 6.81 ± 0.26, respectively). They were approximately as effective as ranitidine (RAN) in reducing histamine‐induced acid secretion in the anaesthetized rat, ID50 values being 0.018 ± 0.02, 0.020 ± 0.03 and 0.036 ± 0.01 μmol kg−1 i.v. for APT, I‐APT and RAN, respectively. Both APT and I‐APT had a significantly longer duration of action than RAN.
. The hydrophilic compound, SK&F 92857, was inactive up to 10 μm in modifying histamine‐induced acid secretion in the isolated rat stomach. In the papillary muscle, low concentrations (0.1‐1 μm) of this compound produced a competitive antagonism of the histamine responses (pA2 value = 7.38 ± 0.11), while a higher concentration (10 μm) significantly reduced the maximal response to histamine.
. RAN competitively antagonized histamine effects with a comparable affinity in cardiac and gastric preparations (pA2 values were 6.42 ± 0.09 and 6.78 ± 0.38 in heart and stomach, respectively).
. Results obtained in this study clearly showed that the discrepancies between gastric and cardiac effects observed for some H2 antagonists are not explained solely by differences in lipophilicity of compounds. Moreover, the significant correlation found between CLOG P and log k' parameter, which takes into account, besides their lipophilicity, the ionization of the molecules, suggests that ionization has a similar influence for all the molecules on the partition between the lipophilic and aqueous phase.
Influence of aminoguanidine and the endothelin antagonist, SB 209670, on the regional haemodynamic effects of endotoxaemia in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , March J.E. , Bennett T. 
Published: July 2012

. We compared the regional haemodynamic responses to lipopolysaccharide (LPS; 150 μg kg−1 h−1, i.v.) in the presence of saline, aminoguanidine (AG; 45 mg kg−1 bolus, 45 mg kg−1 h−1 infusion), or AG and the non‐selective endothelin receptor antagonist, SB 209670 (600 μg kg−1 h−1), in conscious, chronically instrumented, Long Evans rats (350–450 g; n = 8 in all groups). We used AG because there is evidence that it is a selective inhibitor of inducible nitric oxide synthase (iNOS), although recently it has been claimed AG also inhibits constitutive NOS.
. Infusion of LPS in the presence of saline caused an early, transient hypotension (1–2 h) and a renal vasodilatation, with a secondary, delayed fall in mean arterial blood pressure (MAP), progressive tachycardia, and renal and hindquarters vasodilatation.
. AG alone caused a rapid (within 30 s) transient rise in MAP (Δ 27 ± 3 mmHg), accompanied by tachycardia and regional vasoconstrictions, but no reduction in regional flows, indicating the pressor effect of AG was, probably, largely due to an increase in cardiac output. These effects are not consistent with AG inhibiting constitutive NOS. In the presence of AG, LPS still caused an early, transient fall in MAP accompanied by a renal vasodilatation, but thereafter there was a significant rise in MAP (17 ± 3 mmHg, 3 h after onset of LPS infusion) accompanied by bradycardia and marked mesenteric and hindquarters vasoconstrictions. However, 23 h after the onset of co‐infusion of AG and LPS all variables were not different from baseline, except heart rate and renal vascular conductance, which were increased.
. In the presence of AG and SB 209670, LPS caused progressive hypotension and increases in renal, mesenteric and hindquarters vascular conductances. Hence, SB 209670 prevented the rise in MAP and the regional vasoconstrictions seen with AG and LPS, indicating an involvement of endothelin in these events.
. In the presence of AG and SB 209670, 23 h after the onset of LPS infusion, the AT1‐receptor antagonist, losartan (10 mg kg−1), and the V1‐receptor antagonist, d(CH2)5‐O‐Me‐Tyr‐AVP (10 μg kg−1, 10 μg kg−1 h−1) caused additional incremental falls in MAP and increases in renal, mesenteric and hindquarters vascular conductances. Under these circumstances, MAP was lower and regional vascular conductances higher than in the other experiments following administration of losartan and d(CH2)5‐O‐Me‐Tyr‐AVP. Thus, although the findings are consistent with AG inhibiting iNOS, thereby revealing the pressor and vasoconstrictor actions of endothelin released by LPS, it is clear that LPS activates a very powerful hypotensive/vasodilator mechanism(s) which is resistant to AG, and whose full influence is only unmasked when the actions of endothelin, angiotensin II and vasopressin are inhibited.
Regional differences in the arterial response to vasopressin: role of endothelial nitric oxide
Authors: García‐Villalón Angel Luis , García José Luis , Fernández Nuria , Monge Luis , Gómez Bernardino , Diéguez Godofredo 
Published: July 2012

. The isometric response to arginine‐vasopressin (10−10‐10−7 m) was studied in 2 mm long rabbit arterial segments isolated from several vascular beds (cutaneous, pial, renal, coronary, muscular, mesenteric and pulmonary).
. Vasopressin induced contraction in central ear (cutaneous), basilar (pial), renal, coronary and saphenous (muscular) arteries, but had no effect in mesenteric and pulmonary arteries; the order of potency for the contraction was: ear > basilar > renal > coronary > saphenous arteries.
. Treatment with the blocker of nitric oxide synthesis NG‐nitro‐L‐arginine methyl ester (L‐NAME; 10−6‐10−4 m) increased significantly (P < 0.05) the contraction to vasopressin in ear (148% of control), basilar (150% of control), renal (304% of control), coronary (437% of control) and saphenous (235% of control) arteries. Removal of the endothelium increased significantly (P < 0.05) the contraction to vasopressin in basilar (138% of control), renal (253% of control), coronary (637% of control) and saphenous (662% of control) arteries, but not in ear artery. Mesenteric and pulmonary arteries in the presence of L‐NAME or after endothelium removal did not respond to vasopressin, as occurred in control conditions.
. The specific antagonist for V1 vasopressin receptors d(CH2)5Tyr(Me)AVP (3 × 10−9‐10−7 m) was more potent (pA2 = 9.3–10.1) than the antagonist for both V1 and V2 vasopressin receptors desGly‐d(CH2)5‐D‐Tyr(Et)ValAVP (10−7‐10−6 m) (pA2 = 7.4–8.4) to block the contraction to vasopressin of ear, basilar, renal and coronary arteries.
. The specific V2 vasopressin agonist [deamino‐Cys1, D‐Arg8]‐ vasopressin (desmopressin) (10−10‐10−7 m) did not produce any effect in any of the arteries studied, with or without endothelium.
. In arteries precontracted with endothelin‐1, vasopressin or desmopressin did not produce relaxation.
. These results suggest: (a) most arterial beds studied (5 of 7) exhibit contraction to vasopressin with different intensity; (b) the vasoconstriction to this peptide is mediated mainly by stimulation of V1 vasopressin receptors, and (c) endothelial nitric oxide may inhibit the vasoconstriction to this peptide, especially in coronary and renal vasculatures.
Modulation by atrial natriuretic factor of receptor‐mediated cyclic AMP‐dependent responses in canine pulmonary artery during heart failure
Authors: Mathew Rajamma , Omar Hatim A. , Fayngersh Raisa , Shen Weiqun , Wang Jie , Gewitz Michael H. , Hintze Thomas H. , Wolin Michael S. 
Published: July 2012

Pacing‐induced congestive heart failure (CHF) in dogs is associated with increased plasma levels of atrial natriuretic factor (ANF) and inhibiton of receptor‐mediated cyclic AMP‐dependent relaxation in isolated pulmonary arteries (PA). Since ANF is known to be negatively coupled to adenylate cyclase, we studied cyclic AMP‐mediated relaxation to isoprenaline (Iso) and arachidonic acid (AA) in PA from control dogs (C), dogs with pacing‐induced CHF (CHF) and dogs with bilateral atrial appendectomy and CHF (ATR APP + CHF).
In CHF, plasma ANF levels increased from a baseline of 80±8 pg ml−1 to 283±64 pg ml−1 (P<0.05), but the ATR APP + CHF group failed to show this increase (67±7 pg ml−1 vs 94±15 pg ml−1, P = NS). Plasma ANF levels, however, did not influence myocardial dysfunction in CHF.
The relaxation of 49±5% to 1 μm Iso in C was reduced to 23±4% in CHF (P<0.05), but relaxation of 49±12% was observed in the ATR APP+CHF group (P = NS vs C). Relaxation responses to 10 μm AA were as follows: 77±5% (C, n = 8), 27±8% (CHF, n = 10, P<0.05 vs C), and 93±5% (ATR APP + CHF, n = 5). The presence of CHF, or the plasma ANF levels, did not affect responses to cyclic GMP‐mediated relaxing agents in PA.
These data indicate that the myocardial performance in CHF is not influenced by plasma ANF levels. However, altered cyclic AMP‐mediated relaxation in PA during CHF is, in part, modulated by circulating ANF levels.
Effect of Hoe 694, a novel Na+‐H+ exchange inhibitor, on intracellular pH regulation in the guinea‐pig ventricular myocyte
Authors: Loh Shih‐Hurng , Sun Bing , Vaughan‐Jones Richard D. 
Published: July 2012

Hoe 694 (3‐methylsulphonyl‐4‐piperidinobenzoyl, guanidine hydrochloride) is a Na+/H+ exchange (NHE) inhibitor exhibiting cardioprotective properties during ischaemia and reperfusion in animal hearts. We have (i) tested the selectivity of Hoe 694 for NHE over other pHi‐regulating mechanisms in the myocardium, and (ii) tested if the functionally important NHE isoform contributing to intracellular pH regulation in heart is NHE‐1, as suggested from molecular biology studies of this protein.
pHi was recorded by fluorescence microscopy with carboxy SNARF‐1, AM‐loaded into single ventricular myocytes of guinea‐pig.
In nominally HCO3−‐free media, recovery of pHi from an intracellular acid load is mediated by NHE, and was inhibited by Hoe 694, amiloride (an NHE inhibitor) or dimethyl amiloride (DMA, a high affinity NHE inhibitor) with potency values of 2.05, 87.3 and 1.96 μm respectively, giving the potency series: Hoe 694 ⋍ DMA > > amiloride. This potency series, and the potency values (corrected for drug competition with extracellular Na+) match those determined previously for cloned NHE‐1 expressed in mutant fibroblasts. In the absence of extracellular Na+ (to inhibit NHE), Hoe 694 had no effect on pHi.
In 5% CO2/HCO3−‐buffered solution containing DMA, pHi recovery from acidosis is mediated by Na+‐HCO3− symport and was unaffected by Hoe 694. The drug also had no effect on pHi recovery from an alkali‐load, a process largely mediated by Cl−‐HCO3− exchange. Finally, the fall of pHi upon adding extracellular Na‐lactate is assisted by H+‐lactate symport, and this too was unaffected by Hoe 694.
We conclude (i) Hoe 694 has no detectable inhibitory potency for pH‐regulating carriers in heart other than NHE. (ii) native NHE functioning during pHi‐regulation in the cardiomyocyte is the NHE‐1 isoform. These data strengthen the case for NHE‐1 being the receptor for mediating the cardioprotective effects of Hoe 694.
Intranasal administration of neuropeptide Y in man: systemic absorption and functional effects
Authors: Lacroix J.S. , Ricchetti A.P. , Morel D. , Mossimann B. , Waeber B. , Grouzmann E. 
Published: July 2012

Exogenous neuropeptide Y (NPY, 10 nmol, 50 nmol and 100 nmol) and its vehicle (NaCl 0.9%) were administered in a double blind, randomized and controlled manner by intranasal spray in 7 healthy volunteers. Variations of plasma NPY concentration over time were measured during 120 min. Forty min after the administration of 50 nmol and 100 nmol of exogenous NPY, plasma NPY increased from 5.5 ± 1.1 pM to 9.8 ± 2.3 pM (P < 0.05) and from 9.06 ± 5.1 pM to 20.8 ± 6.16 pM (P < 0.001), respectively. There was no significant modification of the mean arterial blood pressure and no subjective discomfort was reported.
Nasal airway resistance (NAR) was measured by anterior rhinomanometry and was reduced by 25 ± 3% and 32 ± 5% after the spray of 50 nmol and 100 nmol, respectively, for about 90 min.
Double‐blind, randomized, placebo‐controlled and 3‐way crossover design experiments were performed in 8 healthy volunteers to evaluate the influence of intranasal pretreatment with NPY (20 nmol) and the mixed α1/α2‐adrenoceptor agonist oxymetazoline (20 nmol) on the functional effects of subsequent local irritation evoked by capsaicin (3.3 × 10−4 mol). Subjective evaluation of NAR and local intensity of discomfort were evaluated by means of a visual analogue scale. Nasal secretions were collected and objective NAR was recorded by rhinomanometry.
Subjective NAR, nasal secretions and rhinomanometry recordings were not modified by intranasal application of saline, NPY or oxymetazoline. Subjective nasal obstruction, local discomfort, nasal secretions and NAR increase evoked by capsaicin were markedly reduced by NPY pretreatment (P < 0.05) when compared to saline or oxymetazoline.
It is concluded that intranasal application of exogenous NPY has very low systemic absorption but induced long lasting nasal vasoconstriction without cardiovascular effects. Pretreatment of the nasal mucosa with exogenous NPY reduces both secretagogue and vasodilator responses to subsequent application of capsaicin.