bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sumatriptan‐induced saphenous venoconstriction in the anaesthetized dog through 5‐HT1‐like receptor activation
Authors: la Rochelle C. Drieu , O'Connor S.E. 
Published: July 2012

The role of vasoconstrictor 5‐HT1‐like receptors in the control of vascular reactivity in vivo has been relatively little studied, particularly with regards to venous function. Using an anaesthetized dog model, we have investigated the haemodynamic profile of the selective 5‐HT, ‐like agonist, sumatriptan, focussing on the reactivity of the saphenous venous bed. The key feature of our experimental model was the implantation of ultrasonic crystals on the adventitial surface of the lateral saphenous vein to provide direct and continuous measurement of drug‐induced changes in vein diameter. Saphenous vein pressure was measured simultaneously via a proximal branch.
Sumatriptan 1–30 μg kg−1, i.v., produced pronounced dose‐related reductions in saphenous vein diameter which reached ⋍40% at the highest dose tested. Sumatriptan also produced modest increases in mean blood pressure, total peripheral resistance and left ventricular end diastolic pressure but had little or no effect on cardiac output, heart rate, cardiac contractility or saphenous venous pressure. Sumatriptan‐induced reductions in saphenous vein diameter were strongly antagonized by the 5‐HT1‐receptor antagonist, methiothepin (0.3 mg kg−1, i.v.) but were unaffected by the 5‐HT2 antagonist, ketanserin (0.3 mg kg−1, i.v.).
Hence, 5‐HT1‐like receptor stimulation in vivo can result in a powerful local venoconstrictor effect.
Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen‐2)27), hypertensive rats
Authors: Gardiner S.M. , March J.E. , Kemp P.A. , Mullins J.J. , Bennett T. 
Published: July 2012

Hypertensive transgenic (TGR(mRen‐2)27) (abbreviated to TG) rats (n = 6) and their normotensive Sprague‐Dawley (SD) control strain (n = 7) were chronically instrumented for the measurement of cardiac haemodynamics. The hypertension in TG rats (mean blood pressure 181±9 mmHg) was entirely attributable to a reduction in total peripheral conductance (TG rats=169 ± 7, SD rats=292 ± 15 μl min−1 mmHg−1 100g−1) since cardiac index was not different in the two strains (TG rats = 30.5±1.2, SD rats = 29.5 ± 1.6 ml min−1 100g−1).
In other animals instrumented for the assessment of regional haemodynamics, the extent of peripheral vasoconstriction was similar in renal, mesenteric and hindquarters vascular beds in the TG rats (reduction in vascular conductance relative to SD rats = 42%, 46% and 49%, respectively).
During an 8 h observation period with saline infusion, or following injection of losartan (10 mg kg−') in SD rats there was no hypotension or regional vasodilatation. With infusion of the endothelin antagonist, SB 209670 (10 μg kg−1 min−), there was a slight hypotension, but no significant vasodilatation; co‐administration of losartan and SB 209670 caused a similar profile of effect, although the hypotension was increased 4 With the same experimental protocol in TG rats, losartan caused a biphasic, progressive fall in mean arterial blood pressure accompanied by renal, mesenteric and hindquarters vasodilatation. Although the response to SB 209670 was not biphasic, its hypotensive and vasodilator effects were not different from those of losartan after 8 h. In the combined presence of losartan and SB 209670, mean arterial blood pressure (116 ± 5 mmHg) was significantly lower than with SB 209670 (132±4mmHg) or losartan (136 ± 6 mmHg) alone, and renal, mesenteric and hindquarters vascular conductances (61 + 3, 90+14 and 52+4 [kHz mmHg−1]103, respectively) were higher than the corresponding values following either SB 209670 (49±4, 52±4 and 34±3 [kHz mmHg−1]103, respectively) or losartan (43±5, 59±3 and 35±4 [kHz mmHg−1]103, respectively) alone. These results indicate the maintenance of hypertension in TG rats is dependent upon renal, mesenteric and hindquarters vasoconstriction, mediated by angiotensin II (AII) and endothelin (ET). Since we found that plasma ET‐1 levels in TG rats (12.06±2.87 pmol 1−1) were lower than in SD rats (21.53±3.94 pmol 1−1), then it is possible that locally‐generated, rather than circulating ET‐1 contributes to the widespread vasoconstriction in TG rats.
Stimulation by endothelin‐1 of mitogen‐activated protein kinases and DNA synthesis in bovine tracheal smooth muscle cells
Authors: Malarkey Kevin , Chilvers Edwin R. , Lawson Mark F. , Plevin Robin 
Published: July 2012

In cultures of bovine tracheal smooth muscle cells, platelet‐derived growth factor‐BB (PDGF), bradykinin (BK) and endothelin‐1 (ET‐1) stimulated the tyrosine phosphorylation and activation of both pp42 and pp44 kDa forms of mitogen‐activated protein (MAP) kinase.
Both ET‐1 and PDGF stimulated a sustained activation of MAP kinase whilst the response to BK was transient.
Activation of MAP kinase occurred in a concentration‐dependent manner (EC50 values: ET‐1, 2.3±1.3 nM; BK, 8.7±4.1 nM, PDGF, 9.7±3.2 ng ml−1).
Pretreatment with the protein kinase C (PKC) inhibitor Ro‐318220, significantly reduced ET‐1 activation of MAP kinase at 2 and 5 min but enhanced MAP kinase activation at 60 min.
Following chronic phorbol ester pretreatment, BK‐stimulated activation of MAP kinase was abolished whilst the responses to PDGF and ET‐1 were only partly reduced (80 and 45% inhibition respectively).
Pretreatment with pertussis toxin reduced ET‐1 stimulated activation of MAP kinase particularly at later times (60 min), but left the responses to both PDGF and BK unaffected.
ET‐1 also stimulated a 3 fold increase in [3H]‐thymidine incorporation which was abolished by pertussis toxin pretreatment. In contrast, PDGF stimulated a 131 fold increase in [3H]‐thymidine incorporation which was not affected by pertussis toxin.
These results suggest that a pertussis toxin‐sensitive activation of MAP kinase may play an important role in ET‐1‐stimulated DNA synthesis but that activation of MAP kinase alone is not sufficient to induce the magnitude of DNA synthesis observed in response to PDGF.
The effect of a synthetic 7‐thiaprostaglandin E1 derivative, TEI‐6122, on monocyte chemoattractant protein‐1 induced chemotaxis in THP‐1 cells
Authors: Tanaka Hiroko , Minoshima Toru , Endo Noriaki 
Published: July 2012

The ability of various prostaglandins (PGs) to inhibit monocyte chemotaxis induced by monocyte chemoattractant protein‐1 (MCP‐1) was investigated with a human monocytic leukaemia cell line, THP‐1. Moreover, to investigate the mechanism of the inhibitory action of PGs the involvement of either intracellular adenosine 3″:5″‐cyclic monosphosphate (cyclic AMP) accumulation or intracellular Ca2+ mobilization was studied.
TEI‐6122, a synthetic 7‐thia‐PGE, derivative, inhibited chemotaxis of THP‐1 cells induced by MCP‐1 with an IC50 of 1.5 pM. Its inhibitory activity was 1000 fold more than that of PGE1 and PGE2 (IC50=2.8 nM and 0.9 nM, respectively), which were more potent than other PGs such as PGA1, PGA2, PGF2α and PGI2 (IC50≥1 μm).
With respect to the effect on intracellular cyclic AMP accumulation in THP‐1 cells, TEI‐6122 was as potent as PGEI and PGE2, which were approximately 100 to 1000 fold more potent than the other PGs such as PGA1, PGA2 and PGI2. The minimum concentration of TEI‐6122 required to increase intracellular cyclic AMP accumulation in THP‐1 cells was 1 nM.
TEI‐6122 and PGE1 (4 μm) transiently increased intracellular calcium levels in THP‐1 cells. When added prior to MCP‐1, both PGs partially suppressed the increased in Ca2+ caused by this cytokine. There were no significant differences between the activity of TEI‐6122 and PGEI in either respect.
It is concluded that TEI‐6122, a synthetic 7‐thia‐PGE, derivative is a much more potent inhibitor of MCP‐1‐induced THP‐1 cell chemotaxis than PGEI and PGE2 which are the best inhibitors among the natural PGs tested, while neither intracellular cyclic AMP accumulation nor effects on Ca2+ mobilization account for the extremely potent inhibitory activity of TEI‐6122. Thus, either a novel PGE2 receptor (EP receptor) or a novel intracellular signal transduction system may be involved in the extremely potent chemotaxis inhibitory activity of TEI‐6122.
2‐Naphthalenesulphanyl‐L‐aspartyl‐2‐(phenethyl) amide (2‐NAP) and food intake in rats: evidence that endogenous peripheral CCK does not play a major role as a satiety factor
Authors: Ebenezer I.S. , Baldwin B.A. 
Published: July 2012

The demonstration that systemic administration of the CCKA receptor antagonist, devazepide, increases food intake in rats has provided the strongest support for the hypothesis that endogenous peripherally released cholecystokinin (CCK) acts as a satiety factor. However, interpretation of these results has been confounded by the fact that devazepide can enter the brain from the systemic circulation and may increase food intake by a central action. The present study was therefore undertaken to confirm the hypothesis that endogenous peripheral CCK is a satiety factor by investigating the effects of a novel CCKA receptor antagonist, 2‐NAP, which is unlikely to cross the blood brain barrier, on food intake in rats.
2‐NAP (1–16 mg kg−1, i.p.) had no significant effects on the intake of a test meal in rats.
Pretreatment of rats with 2‐NAP (2 mg kg−1, s.c.) abolished the inhibitory effects of exogenous peripheral CCK (5 μg kg−1, i.p.) on food intake.
In agreement with previous results, devazepide (50–200 μg kg−1, i.p.) significantly increased the intake of a test meal in rats.
The observations that 2‐NAP, which is unlikely to penetrate the blood brain barrier, had no effect on food intake, but that 2‐NAP abolished the suppressant effect of exogenous peripheral CCK, suggest that endogenously released peripheral CCK is not important as a satiety factor in rats.
Changes in benzodiazepine‐GABA receptor coupling in an accumbens‐habenula circuit after chronic diazepam treatment
Authors: Brett R.R. , Pratt J.A. 
Published: July 2012

The effects of subacute and of chronic diazepam treatment upon binding to the GABAA receptor have been examined by use of receptor autoradiography for determining flunitrazepam (FNZP) binding, GABA enhancement of FNZP binding, SR 95531 2‐(3″‐carboxy‐2″, propyl)‐3‐amino‐6‐p‐methoxyphe‐nylpyridazinium bromide) binding and GABA binding in parallel sections from rat brain. Prior to the autoradiographic procedures, a behavioural assessment of the rats was made in the elevated plus‐maze test of anxiety.
Rats receiving diazepam either subacutely (3 days) or chronically (28 days) by both continuous release, from previously implanted subcutaneous silastic capsules, or by daily injection (5 mg kg−1) did not display changes in FNZP or GABA binding in any of the 47 brain structures analysed. Similarly, there were no significant effects of treatment upon mean total entries or on the open:total ratio for entries in the elevated plus‐maze.
There were reductions in the GABA enhancement of FNZP binding in the nucleus accumbens and central grey after subacute diazepam treatment. This effect persisted in the nucleus accumbens after chronic treatment. Less marked effects occurred in the lateral habenula, dorsal raphe and substantia nigra pars compacta. In the dorsal tegmental nucleus, GABA enhancement of FNZP binding was enhanced after chronic treatment and this was accompanied by reductions in SR 95531 binding. Treatment did not otherwise affect SR 95531 binding, with the exception of the dorsal raphe where binding was decreased after subacute treatment.
In general, the patterns of binding produced by the two different treatment routes were very similar. However, SR 95531 binding was lower in certain hippocampal fields in the i.p. treated animals compared to the rats implanted with silastic capsules.
It is concluded that repeated administration of diazepam evokes changes in benzodiazepine and GABA receptor coupling, and to a lesser extent changes in low affinity GABA binding, in certain interrelated brain structures of which an accumbens‐habenula circuit is a central feature. These changes occur soon after the initiation of diazepam treatment, suggesting that they are unlikely to account for tolerance to the anxiolytic effects of diazepam but may trigger and/or accompany other critical neurochemical events.
Comparison between novel steroid‐like and conventional nonsteroidal antioestrogens in inhibiting oestradiol‐ and IGF‐I‐induced proliferation of human breast cancer‐derived cells
Authors: de Cupis Alessandra , Noonan Douglas , Pirani Paolo , Ferrera Alessandra , Clerico Luana , Favoni Roberto E. 
Published: July 2012

This study has two specific aims: (a) to compare the antioestrogenic activity of two steroidal analogues of 17β‐oestradiol, the 7α‐alkylamide, ICI 164, 384 and the 7α‐alkylsulphinylamide, ICI 182, 780, with that of the triphenylethylene‐derived compound 4OH‐tamoxifen on a pool of human breast cancer cell lines (HBCCL) with a range of hormonal responsiveness and acquired antioestrogen resistance and (b) to investigate the ability of such antioestrogens to modulate the potent breast carcinoma growth‐stimulatory activity of the ‘IGF‐I system’.
For the chemosensitivity investigations we used a long‐term colorimetric and the short‐term thymidine incorporation assay; we analysed IGF‐I in conditioned media by a radioimmunoassay, IGF‐I mRNA in the cells by RT‐PCR and molecular species of IGF‐I‐binding proteins, secreted in conditioned media, by Western ligand blot. IGF‐I receptors were assayed on cell monolayers by binding studies and by Scatchard analysis, we calculated KD, Bmax and sites/cell.
Our results indicate that ICI 182, 780 and ICI 164, 384 are 1.5‐5.5 fold more potent than 40H‐tamoxifen in inhibiting the basal proliferation of oestrogen‐receptor positive (ER +) breast cancer cell lines. Moreover we demonstrate the capacity of ICI 182, 780 and ICI 164, 384 to reduce, in a time‐dependent fashion, oestrogen‐ and/or IGF‐I‐stimulated growth of ER + cell lines, possibly by negatively interfering with an IGF‐I‐like material secretion and IGF‐I‐receptor number.
Our data provide the first evidence that, on ER+ human breast carcinoma cell lines, steroidal antioestrogens inhibit cell growth and modulate the IGF‐I mitogenic system. The mechanism of this latter effect has yet to be identified.
Adenosine receptor‐mediated relaxation of guinea‐pig precontracted, isolated trachea
Authors: Losinski Amanda , Alexander Stephen P.H. 
Published: July 2012

We have investigated the pharmacological profile of the adenosine receptor mediating relaxation of the carbachol pre‐contracted guinea‐pig trachea.
5″‐N‐Ethylcarboxamidoadenosine (NECA) and 2‐chloroadenosine elicited concentration‐dependent relaxations with pD2 (‐log10 half‐maximal values) of 6.37±0.04 and 5.25±0.09, with maximal relaxations of 73±7 and 208±38%, respectively. In the presence of 10 μm NECA, 2‐chloroadenosine was able to relax the tissue further with a pD2 value of 4.74±0.11 and a maximal response of 252±68%.
CGS 21680, APEC and adenosine failed to elicit significant relaxations of precontracted tracheal rings at concentrations below 10 μm. At 10 μm, adenosine analogues elicited relaxations with the following order of magnitude (% relaxation): 2‐chloroadenosine (75±16%)=NECA (69±16%)>APEC (25±8%)>CGS 21680 (11±2%)>adenosine (6±4%).
NECA‐induced relaxation of precontracted trachea was antagonized by adenosine receptor antagonists with the rank order of apparent affinity (Ki, nM): PD 115, 199 (27±8) = XAC (43±11)> CP 66, 713(285±89) = DPCPX (316±114).
We conclude that the adenosine analogue‐induced relaxation of guinea‐pig tracheal rings fails to fit into the current classification of A2 adenosine receptors.
Effects of the novel anti‐inflammatory compounds, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl] methanesulphonamide (NS‐398) and 5‐methanesulphonamido‐6‐(2, 4‐difluorothiophenyl)‐1‐indanone (L‐745, 337), on the cyclo‐oxygenase activity of human blood prostaglandin endoperoxide synthases
Authors: Panara Maria R. , Greco Anita , Santini Giovanna , Sciulli Maria G. , Rotondo Maria T. , Padovano Roberto , di Giamberardino Maria , Cipollone Francesco , Cuccurullo Franco , Patrono Carlo , Patrignani Paola 
Published: July 2012

We have evaluated the selectivity of ketoprofen and two novel nonsteroidal anti‐inflammatory drugs, N‐[2‐(cyclohexyloxy)‐4‐nitrophenyl]methanesulphonamide (NS‐398) and 5‐methanesulphonamido‐6‐(2, 4‐difluorothiophenyl)‐1‐indanone (L‐745, 337), in inhibiting the cyclo‐oxygenase activity of prostaglandin endoperoxide synthase‐2 (PGHS‐2) vs PGHS‐1 in human blood monocytes and platelets, respectively.
Heparinized whole blood samples were drawn from healthy volunteers pretreated with aspirin, 300 mg 48 h before sampling, to suppress the activity of platelet PGHS‐1 and incubated at 37°C for 24 h with increasing concentrations of the test compounds in the presence of lipopolysaccharide (LPS, 10 μg ml−1). Immunoreactive PGE2 levels were measured in plasma by a specific radioimmunoassay as an index of the cyclo‐oxygenase activity of LPS‐induced monocyte PGHS‐2.
The effects of the same inhibitors on platelet PGHS‐1 activity were assessed by allowing whole blood samples, drawn from the same subjects in aspirin‐free periods, to clot at 37°C for 1 h in the presence of the compounds and measuring immunoreactive thromboxane B2 (TXB2) levels in serum by a specific radioimmunoassay.
Under these experimental conditions, ketoprofen enantioselectively inhibited the cyclo‐oxygenase activity of both PGHS‐1 and PGHS‐2 with equal potency (IC50 ratio: approx. 0.5 for both enantiomers), while L‐745, 337 and NS‐398 achieved selective inhibition of monocyte PGHS‐2 (IC50 ratio: > 150). L‐745, 337 and NS‐398 did not affect LPS‐induced monocyte PGHS‐2 biosynthesis to any detectable extent.
We conclude that L‐745, 337 and NS‐398 are selective inhibitors of the cyclo‐oxygenase activity of human monocyte PGHS‐2. These compounds may provide adequate tools to test the contribution of this novel pathway of arachidonate metabolism to human inflammatory disease.
Characteristics of the NANC post‐stimulus (‘rebound’) contraction of the urinary bladder neck muscle in sheep
Authors: Thornbury K.D. , Donaghy K.M. , Peake Jennifer 
Published: July 2012

Strips of muscle from sheep bladder neck were set up for tension recording and subjected to electrical field stimulation (EFS) to stimulate their intramural nerves.
In the presence of atropine (1 μm) and guanethidine (1 μm), the response to 1 Hz EFS was biphasic, characterized by a relaxation during the stimulus period, followed by a post‐stimulus contraction. A similar biphasic response was also seen following bolus application of nitric oxide (NO).
In the absence of atropine and guanethidine, the relaxations were masked by contractions during stimulation; however, the post‐stimulus contractions were unaffected. L‐NAME (100 μm) blocked the post‐stimulus contractions and L‐arginine (1 mM) restored them, suggesting that they were NO‐mediated.
M&B 22948, a phosphodiesterase inhibitor, prolonged the relaxations and abolished the post‐stimulus contractions. This suggests that rapid removal of cyclic GMP is required for post‐stimulus contraction to occur.
When the number of pulses in the stimulus train was kept constant, the size of the post‐stimulus contraction increased as the duration of the preceding period of stimulation increased. Maximal post‐stimulus contractions were obtained following stimulation for >40 s.
The L‐channel antagonist, nifedipine (1 μm) and verapamil (1 μm), had little effect on the amplitude of the post‐stimulus contractions. 7 In contrast, ryanodine (8 μm) reduced the post‐stimulus contractions by over 90%. Caffeine (20 mM) also abolished the post‐stimulus contractions and cyclopiazonic acid (CPA, 10 μm) reduced them by 76%. However, in the presence of CPA a slower post‐stimulus contraction developed. Nifedipine (1 μm) reduced this by 40%.
In conclusion, these results support a role for NO in the post‐stimulus contraction of the sheep bladder neck muscle. The post‐stimulus contraction depends more on release of intracellular Ca2+, than Ca2+ influx through L‐type channels.
Roles of endothelin receptors in the regional and systemic vascular responses to ET‐1 in the anaesthetized ganglion‐blocked rat: use of selective antagonists
Authors: Allcock Graham H. , Warner Timothy D. , Vane John R. 
Published: July 2012

Endothelin‐1 (ET‐1) produces vasoconstriction, via activation of ETA and ETB receptors on vascular smooth muscle, and vasodilatation via ETB receptors on endothelial cells. Here we have used the ETA receptor‐selective antagonist, BQ‐123, the ETB receptor‐selective antagonist, BQ‐788 and the ETA/ETB receptor non‐selective antagonist, PD 145065, to study the role of these receptors in mediating the haemodynamic changes induced by an infusion of ET‐1 to the anaesthetized ganglion‐blocked rat.
Infusion of ET‐1 (10 pmol kg−1 min−1) increased the mean arterial pressure (MAP) by 57.5 ± 5.1 mmHg over 70 min. This pressor response was reduced by about 50% by coinfusion of BQ‐123 (10 nmol kg−1 min−1), but was unaffected by either BQ‐788 (10 nmol kg−1 min−1) or PD 145065 (10 nmol kg−1 min−1).
After infusion of ET‐1 for 70 min the cardiac output had fallen from 102.6±11.3 to 55.7 ± 7.6 ml min−1 and the total peripheral resistance had increased from 3.24 ± 0.6 to 10.0±0.8 mmHg ml−1 min−1 (per 100g body weight). BQ‐123 decreased the magnitudes of these changes whereas BQ‐788 potentiated them. PD 145065 was without effect.
ET‐1 increased the vascular resistances of all the organs studied except the brain and stomach. These changes were attenuated by BQ‐123 in the kidneys, skin, adrenal glands and caecum and potentiated by BQ‐788 in the kidneys, small intestine, large intestine and mesentery. PD 145065 had little effect on the individual tissues.
Thus, BQ‐123, a selective ETA receptor antagonist, inhibits the pressor and vascular constrictor effects of ET‐1 more actively than PD 145065. As BQ‐788 potentiates some of the vasoconstrictor effects of ET‐1 and increases the effects of ET‐1 on total peripheral resistance, the predominant role of ETB receptors in the rat circulation is to limit the pressor effects of ET‐1.
Comparative behavioural profile of centrally administered tachykinin NK1, NK2 and NK3 receptor agonists in the guinea‐pig
Authors: Piot Odile , Betschart Josette , Grall Isabelle , Ravard Sophie , Garret Claude , Blanchard Jean‐Charles 
Published: July 2012

The NK, tachykinin receptor agonists, septide, [Sar9, Met(O2)11]SP and [Pro9]SP produced locomotor hyperactivity (10–20 min) when injected intracerebroventricularly (i.c.v.) in the guinea‐pig. Producedlocomotor The most potent in eliciting this hyperactivity was septide (from 0.63 to 5 μg), compared to [Sar9, Met(O2)11]SP, which was active at 2.5 and 5 μg and [Pro9]SP which induced a non‐significant increase even at 10 μg.
Wet‐dog shakes were elicited by septide, [Sar9, Met(O2)11]SP and [Pro9]SP injected by the i.c.v. route in the guinea‐pig. [Sar9, Met(O2)11]SP, active from 0.16 to 2.5 μg was more potent than septide (active at 1.25 μg) and [Pro9]SP (active at 0.63 μg) in eliciting such behaviour. To a lesser extent, grooming was also observed after injection of these agonists.
The NK2 tachykinin receptor agonist, [Lys5, MeLeu9, Nle10]NKA(4–10), up to the dose of 10 μg i.c.v. had no effect in the guinea‐pig. It neither modified locomotor activity nor induced a characteristic behavioural response. At higher doses (20μg), some toxic effects were noted.
The NK3 tachykinin receptor agonist, senktide, contrasts with the NK1 receptor agonists in that it elicited only wet‐dog shakes, at doses ranging from 0.32 to 1.25 μg. It neither modified locomotor activity (1 pg) nor induced grooming (up to 5 μg) in the guinea‐pig.
To our knowledge, these results are the first demonstration that the guinea‐pig could be useful to differentiate tachykinin agonists on the basis of their behavioural profile, distinct from those obtained in mice and rats.