bluuebunny/crossref_metadata_2025_split huggingface dataset:
Formoterol and salbutamol inhibit bradykinin‐ and histamine‐induced airway microvascular leakage in guinea‐pig
Authors: Advenier C. , Qian Y. , Koune J‐D. Law , Molimard M. , Candenas M‐L. , Naline E. 
Published: July 2012

The effects of the β2‐adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea‐pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied.
The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 ± 0.21 (n = 5) and 0.20 ± 0.14 (n = 5) μg kg−1 respectively for salbutamol, and 0.13 ± 0.12 (n = 6) and 0.02 ± 0.01 (n = 6) μg kg−1 respectively for formoterol.
Salbutamol (10 and 30 μg kg−1) and formoterol (1 and 10 μg kg−1) inhibited the increase of microvascular permeability induced by histamine (30 μg kg−1) in the guinea‐pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways.
Salbutamol and formoterol (1 and 10 μg kg−1) abolished the increase in microvascular permeability induced by bradykinin (0.3 μg kg−1). This inhibitory effect of two β‐adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 μg kg−1 of the β‐adrenoceptor agonists. In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10 μg kg−1 of formoterol and salbutamol.
The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10 mg kg−1, i.v. These results suggest that an indirect effect, through non‐adrenergic non‐cholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability.
In conclusion, intravenously injected β‐adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of β2‐adrenoceptor agonists versus bradykinin may occur through activation of presynaptic receptors of the non‐adrenergic non‐cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.
Effect of treatment with vitamin D3 on the responses of the duodenum of spontaneously hypertensive rats to bradykinin and to potassium
Authors: Feres Teresa , Vianna Lucia M. , Paiva Antonio C.M. , Therezinha  , Paiva B. 
Published: July 2012

The diet of spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) and Wistar (NWR) rats was supplemented with either 2% calcium lactate in the drinking water or 12.5 μg vitamin D3 100 g−1 body weight daily by gavage, for 14 days.
The blood pressure of the SHR treated with either calcium or vitamin D decreased to the same levels as that of WKY and NWR.
The response to bradykinin of the SHR isolated duodenum, which is predominantly contractile, upon treatment with vitamin D (but not with calcium), became predominantly relaxant, approaching the normal behaviour of the WKY and NWR duodenum.
The relaxant responses of the SHR and WKY duodenum to potassium were smaller than those of NWR, but treatment with vitamin D increased the response in all three rat strains.
It is concluded that, besides sharing the hypotensive effect of calcium, vitamin D treatment of SHR has an effect on the duodenum smooth muscle which might be due to calmodulin‐dependent activation of calcium‐dependent potassium channels.
Characterization of histamine receptor sub‐types regulating prostacyclin release from human endothelial cells
Authors: Bull Helen A. , Courtney P.F. , Rustin M.H.A. , Dowd Pauline M. 
Published: July 2012

The histamine receptor sub‐types that are involved in the initiation and maintenance of prostacyclin (PGI2) release from human endothelial cells have been investigated.
Endothelial cells cultured from umbilical vein (HUVEC) were incubated with either histamine, the selective H1‐receptor agonists, 2‐methyl histamine (2‐MeHA) or thiazolylethylamine (ThEA), the H1‐agonist/H3‐antagonist, β‐histine (β‐His), the selective H2‐agonist, dimaprit, the H2‐agonist/H3‐antagonist, impromidine, the selective H3‐agonist, (R)α‐methylhistamine ((R)α‐MeHA) and the H3‐antagonist, thioperamide.
The H1‐agonists and the H3‐agonist (R)α‐MeHA induced a concentration (100 nm‐1 mm) and time‐dependent release of PGI2 as determined by radioimmunoassay for 6‐keto‐PGF1α, but were less potent than histamine itself. The rank order of potency was the same following 30 min and 24 h incubation, i.e. histamine > ThEA > 2‐MeHA ≫ β‐His > (R)α‐MeHA.
Histamine and 2‐MeHA (1 μm‐1 mm), ThHEA (10 μm‐1mm) and (R)α‐MeHA (1 mm), but not β‐His, induced a significantly greater increase in PGI2 release after 24 h incubation than after 30 min incubation (P < 0.05).
Neither the selective H2‐agonist, dimaprit, nor the H2‐agonist/H3‐antagonist, impromidine alone induced release of PGI2.6 The H1‐antagonist, mepyramine (10 μm), abolished release of PGI2 induced by histamine, the H1‐agonists and (R)α‐MeHA but the H2‐antagonist cimetidine (10 μm) and the H2/H3‐antagonist, burimamide (10 μm) did not significantly modulate PGI2 release.7 Although the H3‐agonist (R)α‐MeHA induced release of PGI2, it failed to modulate PGI2 release in the presence of histamine.8 Low concentrations of the H3‐antagonist, thioperamide (100 nm) did not modulate histamine release of PGI2 at all but after 24 h incubation, thioperamide (10−4 m) partially reduced PGI2 release in the presence of histamine.9 These results indicate that PGI2 from HUVEC is initiated and maintained via histamine H1‐receptor occupancy. There appears to be no involvement of either H2‐ or H3‐receptors in this particular endothelial cell histaminergic response.
Participation of protein kinase C in endothelin‐1‐induced contraction in rat aorta: studies with a new tool, calphostin C
Authors: Shimamoto Hiroyuki , Shimamoto Yoriko , Kwan Chiu‐Yin , Daniel Edwin E. 
Published: July 2012

Calphostin C at 10−6 m was shown to be selective and highly effective in inhibiting contractile responses of rat aortae to 12‐o‐tetradecanoylphorbol‐13‐acetate, while it had no effect on contractile responses to elevated KCl.
In the rat aorta, endothelin‐1 (ET‐1) developed a sustained tonic contraction dose‐dependently in both normal Ca2+‐containing Krebs and Ca2+‐free Krebs containing 1 mm EGTA. Calphostin C (10−6 m), a selective protein kinase C inhibitor, antagonized the maximal tensions for cumulative addition of 10−8 m ET‐1 by 13.2% in Ca2+‐containing medium and 25.8% in Ca2+‐free Krebs containing 1 mm EGTA.
In both Ca2+‐containing medium and Ca2+‐free Krebs containing 1 mm EGTA, precontraction with 10−8 m ET‐1 had no effects on the contractile response to subsequently added 10−6 m 12‐o‐tetradecanoylphorbol‐13‐acetate (TPA), an activator of protein kinase C.
In Ca2+‐free Krebs containing 1 mm EGTA, precontraction with 10−6 m TPA potentiated the contractile response to subsequently added 10−8 m ET‐1, whereas this potentiation was abolished by pretreatment with 10−6 m calphostin C. The mechanism of the TPA‐induced potentiating effect remains to be determined.
These results suggest that the participation of protein kinase C in the 10−8 m ET‐1‐induced contraction may be 13.2% and 25.8% in the presence and absence of extracellular Ca2+, respectively, and that mechanisms other than protein kinase C may be predominantly responsible for ET‐1‐induced tonic contraction.
Capsazepine reversal of the antinociceptive action of capsaicin in vivo
Authors: Perkins M.N. , Campbell E.A. 
Published: July 2012

This study was designed to investigate the antinociceptive activity of capsaicin in acute and persistent nocifensor behavioural models and to determine whether this was mediated via a specific receptor interaction, by use of the antagonist, capsazepine.
Capsaicin administered systemically in low doses produced antinociception in the knee joint hyperalgesia, rat paw pressure, rat and mouse tail flick and mouse hot plate nocifensor models with similar efficacy in all tests.
The novel competitive capsaicin antagonist, capsazepine, prevented the capsaicin‐induced antinociception when administered systemically in the range 50–100 μmol kg−1.
Capsazepine administered by itself had no antinociceptive actions.
These data describe a joint hyperalgesic model in the rat which does not rely on extreme nocifensor behavioural endpoints and it is suggested this is a useful model for investigating mechanisms in persistent pain.6 This is the first demonstration of antagonism by capsazepine of the behavioural antinociceptive properties of capsaicin and provides further evidence that capsaicin acts to reduce nociceptive thresholds via a specific receptor.
Effects of the bradykinin antagonist, HOE 140, in experimental acute pancreatitis
Authors: Griesbacher T. , Lembeck F. 
Published: July 2012

The novel bradykinin antagonist, HOE 140, completely blocked the fall in rabbit blood pressure caused, not only by i.v. bradykinin, but also by i.v. kallikrein. This shows that both the effects of exogenously administered bradykinin and those of endogenously released kinins are antagonized by HOE 140.
Acute pacreatitis was induced in rats by i.v. infusion of the cholecystokinin analogue, caerulein. This treatment resulted in massive oedema of the pancreas, increased activities of amylase and lipase in serum and a characteristic, biphasic fall in blood pressure.
HOE 140 prevented the caerulein‐induced pancreatic oedema and the second phase of hypotension whereas NPC 349, a widely used, but short‐acting, bradykinin antagonist did not show a significant inhibition. HOE 140, in contrast to its inhibitory effects on caerulein‐induced pancreatic oedema and hypotension, significantly augmented the increases in amylase and lipase activities in serum.
It is concluded that in this model of acute pancreatitis, the release of kinins induces pancreatic oedema and hypotension. Prevention by HOE 140 of the kinin‐induced oedema allows the pancreatic enzymes to leave the tissue without hindrance and thus will diminish subsequent pathological events. It is suggested that the results obtained with the highly potent and long‐acting bradykinin antagonist, HOE 140, provide a pharmacological basis for a clinical trial in acute pancreatitis.
The actions of capsaicin applied topically to the skin of the rat on C‐fibre afferents, antidromic vasodilatation and substance P levels
Authors: Lynn B. , Ye W. , Cotsell B. 
Published: July 2012

Single applications of solutions of capsaicin were made to the intact skin of anaesthetized rats and the effects on cutaneous blood flow and the firing of C‐nociceptor afferents determined. Blood flow was measured by laser‐Doppler flowmetry. C‐fibre activity was recorded from filaments dissected from the saphenous nerve.
Following the application of a capsaicin solution (concentration ≥ 1 mm) to rat saphenous skin, low frequency firing occurred in C‐polymodal nociceptors that sometimes continued for > 10 min. At the some time, large increases in skin blood flow occurred exceeding 300% in some instances.
After the initial excitation, some C‐polymodal nociceptors lost their sensitivity to pressure whilst their sensitivity to heat was lost or enhanced depending on the vehicle used.
Sensitivity of C‐polymodal nociceptors to heat recovered in > 1 day following a single application of 33 mm capsaicin. Thresholds to mechanical pressure, however, were still significantly elevated by 123% on day 1, but had recovered on day 2.
Vasodilatation in response to saphenous nerve stimulation (‘antidromic vasodilatation’) was significantly reduced by 35%, 2 days after a single application of 33 mm capsaicin, but was normal at 4 days.6 Following a single application of 33 mm capsaicin, skin substance P levels fell to only half the normal value at day 1 and remained at this level throughout the 4 day period examined.7 It is suggested that the ability of relatively low concentrations of capsaicin to desensitize C‐fibre nociceptors may underlie the analgesic action of topical capsaicin in man.
NG‐hydroxy‐L‐arginine prevents the haemodynamic effects of nitric oxide synthesis inhibition in the anaesthetized rat
Authors: Walder Claire E. , Thiemermann Christoph , Vane John R. 
Published: July 2012

We have investigated the effects of l‐hydroxy‐l‐arginine (l‐HOArg), an intermediate in the biosynthesis of nitric oxide (NO) from l‐arginine (l‐Arg), on the haemodynamic effects (systemic blood pressure and renal blood flow) of the NO synthesis inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME) in the anaesthetized rat.
l‐Arg or l‐HOArg (3 mg kg−1 min−1), but not d‐arginine (d‐Arg) or NG‐hydroxy‐d‐arginine (d‐HOArg), elicited a slight but significant increase in total renal blood flow (RBF) of 11 ± 2% and 11 ± 1%. Since mean arterial blood pressure (MAP) did not change this dose of l‐Arg or l‐HOArg resulted in a reduced renal vascular resistance (RVR) of the same magnitude.
Bolus injections of l‐NAME, at 0.3 or 1 mg kg−1 i.v., produced a significant fall in RBF of 11 ± 2% and 32 ± 5% and an increase in MAP of 7 ± 3 mmHg and 22 ± 5 mmHg, respectively. Consequently, RVR was elevated by 21 ± 5% and 52 ± 10%.
l‐Arg or l‐HOArg (3 mg kg−1 min−1) reduced the l‐NAME‐induced (0.3 or 1 mg kg−1) falls in RBF and increases in RVR by more than 65%. Neither d‐Arg nor d‐HOArg (3 mg kg−1 min−1) had any significant effect on the changes in RBF or RVR induced by l‐NAME.
l‐Arg or l‐HOArg (3 mg kg−1 min−1) attenuated the pressor effect of l‐NAME (3 mg kg−1) by 73% and 64%, respectively, while neither the d‐isomer of arginine nor hydroxyarginine had any effect.6 These results demonstrate that l‐HOArg antagonizes the haemodynamic effects of NO‐biosynthesis inhibition in vivo, thus supporting the hypothesis that l‐HOArg is an intermediate in the formation of NO from l‐Arg.
L‐689,660, a novel cholinomimetic with functional selectivity for M1 and M3 muscarinic receptors
Authors: Hargreaves R.J. , McKnight A.T. , Scholey K. , Newberry N.R. , Street L.J. , Hutson P.H. , Semark J.E. , Harley E.A. , Patel S. , Freedman S.B. 
Published: July 2012

L‐689,660, 1‐azabicyclo[2.2.2]octane, 3‐(6‐chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (pKD (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L‐689,660 had a low ratio (34) of pKD (apparent) values for the displacement of binding of the antagonist [3H]‐N‐methylscopolamine ([3H]‐NMS) compared with the displacement of the agonist [3H]‐oxotremorine‐M ([3H]‐Oxo‐m), in rat cerebral cortex. Low NMS/Oxo‐M ratios have been shown previously to be a characteristic of compounds that are low efficacy partial agonists with respect to stimulation of phosphatidyl inositol turnover in the cerebral cortex.
L‐689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M1 muscarinic receptors in the rat superior cervical ganglion, L‐689,660 was a potent (pEC50 7.3 ± 0.2) full agonist in comparison with (±)‐muscarine. At M3 receptors in the guinea‐pig ileum myenteric plexus‐longitudinal muscle or in trachea, L‐689,660 was again a potent agonist (pEC50 7.5 ± 0.2 and 7.7 ± 0.3 respectively) but had a lower maximum response than carbachol. In contrast L‐689,660 was an antagonist at M2 receptors in guinea‐pig atria (pA2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices.
The putative M1‐selective muscarinic agonist, AF102B (cis‐2‐methylspiro‐(1,3‐oxathiolane 5,3′)‐quinuclidine hydrochloride) was found to have a profile similar to L‐689,660 but had up to 100 times less affinity in binding and functional assays. RS‐86 (2‐ethyl‐8‐methyl‐2,8‐diazospiro[4,5]decan 1,3‐dione hydrochloride) also had lower affinity than L‐689,660, and had no binding selectivity for muscarinic receptor subtypes. RS‐86 had a higher NMS/Oxo‐M ratio than L‐689,660 and was a full agonist at M1, M2 and M3 receptors in the functional pharmacological assays.
The functional selectivity of L‐689,660 in muscarinic pharmacological assays is consistent with the effects of a low efficacy partial agonist in tissues with different effective receptor reserves.
The role of endothelial cells in the relaxations induced by 13‐hydroxy‐ and 13‐hydroperoxylinoleic acid in canine arteries
Authors: De Meyer Guido R.Y. , Bult Hidde , Verbeuren Tony J. , Herman Arnold G. 
Published: July 2012

One of the major fatty acids in the arterial wall is linoleic acid. It has been shown that its 13‐hydroxy metabolite (13‐HODE) is generated in significant amounts by cultured endothelial cells. The aim of the present study was to investigate the relaxations to 13‐HODE and its hydroperoxyprecursor (13‐HPODE) and to examine the role of the endothelial cells.
Ring segments of canine circumflex and splenic artery were mounted in organ chambers for isometric tension recording. During contractions induced by prostaglandin F2α or noradrenaline, 13‐HODE and 13‐HPODE evoked dose‐dependent relaxations. Removal of the endothelial cells reduced the relaxations to 13‐HODE, but had no effect on those elicited by 13‐HPODE.
Indomethacin and meclofenamate (0.3 μm to 30 μm) blocked the relaxations evoked by 13‐HODE and 13‐HPODE in endothelium‐denuded rings. In segments with endothelium, both cyclo‐oxygenase inhibitors again abolished the relaxations to 13‐HODE, but only diminished those to 13‐HPODE.
Prostacyclin biosynthesis, as measured by radioimmunoassay, increased upon incubation with 13‐HODE and 13‐HPODE (10 μm). Bioassay of the release of nitric oxide (NO) indicated that NO was not involved in the relaxations elicited by either metabolite. Moreover, l‐NG‐nitroarginine (100 μm), a specific inhibitor of NO synthesis, did not influence the relaxations to 13‐HODE and 13‐HPODE. The responses to 13‐HPODE were also not altered by superoxide dismutase.
In the splenic artery 13‐HPODE and 13‐HODE induced contractions above 3 μm which were blocked by the thromboxane receptor antagonist, daltroban. In the circumflex artery contractile responses to high concentrations of 13‐HODE could be observed only after inhibition of cyclo‐oxygenase.6 We conclude that the vasodilatation induced by 13‐HODE and 13‐HPODE was due to stimulation of prostacyclin biosynthesis both in the endothelium and smooth muscle cells or other subendothelial structures. An additional, unidentified intermediate, which was neither NO nor a cyclo‐oxygenase product nor superoxide anion, contributed to the relaxations to 13‐HPODE in arteries with endothelium.
In vitro denervation of the rat vas deferens through hypothermic storage
Authors: Jurkiewicz N.H. , Garcia A.G. , Jurkiewicz A. 
Published: July 2012

The rat vas deferens was excised, stored at 4–6°C and tested after 24, 48, 72 or 96 h for its contractile activity and for the presence of innervation.
The maximal contractile capacity of the vas, tested through cumulative concentrations of barium chloride (3 × 10−2 m) was progressively reduced from about 110 mm to about 63 mm after 72 h, without further decay after 96 h. Spontaneous rhythmic contractions were practically absent.
A loss of endogenous pools of catecholamines was indicated by four parameters: (a) a decline of about 80% after 24 h and of more than 95% after 48 h of the contractile effect of the indirect sympathomimetic agonist tyramine; (b) a fall of about 20%, 50% and 85% on the concentration of noradrenaline, respectively after 24, 48 and 72 h; (c) a fall of about 25% and 90% after respectively 24 and 48 h, of the activity of dopamine‐β‐hydroxylase (DBH); (d) a decline of noradrenaline‐induced histofluorescence on cross sections of the vas.
A loss of neuronal uptake capacity was indicated by: (a) a progressive variation of the apparent affinity for adrenaline, expressed as pD2 values, that increased by about 1.5 log units (corresponding to a 30 fold potentiation) after 72 h, and (b) a reduction of the ability of cocaine to potentiate the contractile effects of adrenaline.
The pD2 values for barium chloride, 5‐hydroxytryptamine (5‐HT) and histamine were not significantly changed, while the corresponding value for acetylcholine was slightly but significantly reduced by about 0.8 log units.6 The maximal heights of concentration‐response curves for noradrenaline, acetylcholine, histamine and 5‐HT were reduced by 42–66% in relation to controls. However, when this reduction was measured in relation to the corresponding barium effect, by means of the relative responsiveness ratio (p), a small though significant increase was observed for noradrenaline, and a fall for the other drugs.7 It is concluded that: (1) the values for the various biochemical and pharmacological parameters decline at different rates, though revealing altogether that denervation is completed by at least 85% after 72 h of hypothermic storage; (2) two of the results, i.e., the lack of spontaneous rhythmic contractions and the lack of increased contractile effects for acetylcholine, 5‐HT and histamine, indicate that in these conditions the vas is devoid of the so‐called nonspecific signs of denervation.
Histamine H3 receptors modulate the release of [3H]‐acetylcholine from slices of rat entorhinal cortex: evidence for the possible existence of H3 receptor subtypes
Authors: Clapham J. , Kilpatrick G.J. 
Published: July 2012

The effect of agents which interact with the histamine H3 receptor on potassium‐stimulated tritium release from slices of rat entorhinal cortex preloaded with [3H]‐choline is described. We have examined the effects of the selective H3 receptor agonist, (R)‐α‐methylhistamine (RAMH), and a number of H3 receptor antagonists, including the selective compound thioperamide, on the potassium‐stimulated release of tritium.
In the presence of mepyramine and ranitidine, RAMH (0.01–10 μm) inhibited potassium‐stimulated tritium release in a concentration‐dependent manner, EC50 = 0.11 μm. The maximum inhibition was approximately 50%.
Thioperamide displaced the RAMH concentration‐response curve to the right yielding a pKB value of 8.4. There was no change in the maximum response to RAMH.
Other H3 receptor antagonists, including impromidine and burimamide, also caused rightwards displacement of the linear portion of the RAMH concentration‐response curve. However, phenylbutanoylhistamine and betahistine, which are reported to be relatively potent H3 receptor antagonists, showed very low affinity.
Thioperamide (0.001–1 μm) alone enhanced the potassium‐stimulated release of tritium in a concentration‐dependent manner. Maximum effects were observed at 0.1–1 μm thioperamide, enhancing release by approximately 20%.
Results are discussed in terms of the regulatory role of H3 receptors on acetylcholine release and the possible existence of H3 receptor subtypes.