bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanical and biochemical responses to endothelin‐1 and endothelin‐3 in bovine bronchial smooth muscle
Authors: Nally Jane E. , McCall Raymond , Young Louise C. , Wakelam Michael J.O. , Thomson Neil C. , McGrath John C. 
Published: July 2012

In this study, mechanical responses to endothelin‐1 and endothelin‐3 were examined in bovine bronchial smooth muscle. In addition, the involvement of phosphatidylinositol 4,5‐bisphosphate hydrolysis (PIP2) in the responses to these peptides was assessed by measurement of inositol (1,4,5) trisphosphate (I(1,4,5)P3) production using a specific mass assay.
ET‐1 evoked contractions of bovine bronchi which were concentration‐dependent and initiated at between 10−9m and 10−8m. ET‐1‐evoked responses were unaffected by slight elevation of tone with potassium chloride (3 × 10−2m), methacholine (10−6m) or U46619 (10−7m).
Contractions to ET‐1 were not altered by pre‐incubation with atropine (10−5m), indomethacin (10−5m), nifedipine (10−5m), phosphoramidon (3.67 × 10−5m) or by removal of the epithelium.
ET‐3 evoked small contractions which were not concentration‐dependent. In the presence of phosphoramidon (3.67 × 10−5m) however, concentration‐dependent contractions were obtained to ET‐3 which were unaffected by atropine (10−5m) or by removal of the epithelium, but were significantly attenuated by indomethacin (10−5m). Nifedipine (10−5m) virtually abolished this response.
Both ET‐1 and ET‐3 (in the presence of phosphoramidon)‐evoked contractions were significantly enhanced by the presence of the phorbol ester phorbol 12,13‐dibutyrate (10−8m). Neither ET‐1‐, nor ET‐3‐mediated responses were antagonized by the protein kinase C (PKC) inhibitor, Ro 31–8220 (3 × 10−9–3 × 10−8m).
ET‐1 (3 × 10−7m) evoked a biphasic rise in levels of I(1,4,5)P3 which was unaltered by pre‐incubation with atropine, whilst ET‐3 (10−10–3 × 10−7m) failed to alter levels of I(1,4,5)P3 at any time point examined, even in the presence of phosphoramidon (3.67 × 10−5m).
These results suggest that, in bovine bronchial smooth muscle, ET‐1 does not evoke contraction via cyclo‐oxygenase metabolites, does not evoke release of the neurotransmitter substance acetylcholine, or require calcium influx via dihydropyridine‐sensitive channels. ET‐1 evokes I(1,4,5)P3 production, but stimulation of protein kinase C may not be critical for the associated contraction. In contrast, ET‐3‐evoked contractions are partly mediated by cyclo‐oxygenase metabolites. ET‐3 does not stimulate PIP2 hydrolysis, nor activate PKC, but may, either directly or as a requirement of intermediates released in response to ET‐3, rely upon extracellular calcium.
Influence of S‐nitrosothiols and nitrate tolerance in the rat gastric fundus
Authors: Barbier A.J.M. , Lefebvre R.A. 
Published: July 2012

The relaxant responses of S‐nitroso‐l‐cysteine (CysNO), S‐nitroso‐N‐acetyl‐d,l‐penicillamine (SNAP), S‐nitroso‐N‐acetyl‐l‐cysteine (SNAC) and S‐nitrosoglutathione (GSNO) in the rat gastric fundus (forestomach) were studied and compared to the relaxant responses obtained in response to nitric oxide (NO) and electrical field stimulation (EFS, 10 s trains) of non‐adrenergic non‐cholinergic (NANC) nerves.
CysNO (10−7–3 × 10−4m) caused transient relaxation of the precontracted rat gastric fundus, comparable to the response to NO (10−4–10−4m) and EFS. SNAP, SNAC and GSNO elicited more sustained relaxations.
The cyclic GMP‐specific phosphodiesterase inhibitor, zaprinast (3 × 10−5m), increased the relaxant effect of CysNO, SNAP and GSNO while the NO‐synthase inhibitor, NG‐nitro‐l‐arginine (l‐NOARG, 3 × 10−4m) had no influence.
In the presence of LY 83583 (10−5m), which releases superoxide anions, the relaxant response to NO and CysNO was decreased, whereas that to all other stimuli was unaltered. The inhibitory effect of LY 83583 on CysNO‐induced relaxations was prevented by superoxide dismutase (SOD, 1000 u ml−1).
Tissues incubated for 1 h with 5.5 × 10−4m nitroglycerin (GTN) became tolerant to GTN. In this condition, the relaxant response to 10−5m NO was maintained, while the relaxations by EFS (8 Hz) and 3 × 10−5m SNAP were significantly decreased. The reduction of the response to the other S‐nitrosothiols was not significant.
The combination of nitrate tolerance and 10−5m LY 83583 caused a significantly larger inhibition of the relaxant response to EFS (8 Hz) than nitrate tolerance alone. The combination of LY 83583 and GTN tolerance reduced the relaxant effect of 10−5m NO to a similar extent to LY 83583 alone, while the relaxant response to 10−4m GTN was reduced to the same extent as after 1 h exposure to 5.5 × 10−4m GTN alone.
It is concluded that S‐nitrosothiols potently relax the rat gastric fundus, possibly by a cyclic GMP‐dependent mechanism and S‐nitrosothiols such as SNAC and GSNO may be involved in NANC neurotransmission.
Prevention by NMDA receptor antagonists of the centrally‐evoked increases of cardiac inotropic responses in rabbits
Authors: Monassier Laurent , Tibiriça Eduardo , Roegel Jean‐Christophe , Mettauer Bertrand , Feldman Josiane , Bousquet Pascal 
Published: July 2012

The purpose of this study was to investigate further the role of the excitatory amino acid (EAA) system of neurotransmission, particularly of the NMDA receptor, in the central regulation of cardiac function.
Electrical stimulation of the paraventricular nucleus of the hypothalamus (PVN) in pentobarbitone anaesthetized rabbits induced a cardiovascular response mainly characterized by a positive inotropic effect, hypertension and a marked increase in the myocardial oxygen demand index.
The intracerebroventricular (i.c.v.) or intravenous (i.v.) injection of different EAA antagonists acting on different sites of the NMDA receptor/channel complex dose‐dependently blunted the excitatory cardiovascular effects of PVN stimulation.
5,7 Dichlorokynurenic acid was used as a specific glycine site antagonist and 2‐amino‐5‐phosphonovaleric acid was used to block the agonist recognition site; ketamine was used as a channel blocker site antagonist and ifenprodil as a blocker of the polyamine binding site.
5,7 Dichlorokynurenic acid (125 and 250 μg kg−1, i.c.v.) virtually abolished the cardiovascular responses, inducing only haemodynamic depression at the highest dose used. 2‐Amino‐5‐phosphonovaleric acid (0.1 to l.0 mg kg−1, i.c.v.) elicited a reduction of the peak values observed during PVN stimulation which was accompanied by a decrease of the basal cardiovascular parameters. Ketamine (2.5 and 10 mg kg−1) and ifenprodil (1 mg kg−1), injected intravenously, blocked the haemodynamic response induced by PVN stimulation without marked reduction of the basal haemodynamics.
It is concluded that glutamate neurotransmission is not only involved in vasomotor tone control but also in the central control of cardiac function and can therefore modulate the myocardial oxygen demand.
Adenosine‐induced hyperpolarization of the membrane voltage in rat mesangial cells in primary culture
Authors: Pavenstädt Hermann , Ruh Joachim , Greger Rainer , Schollmeyer Peter 
Published: July 2012

The effect of adenosine on membrane voltage and ion currents was studied in rat mesangial cells in primary culture. Membrane voltage was measured with the patch clamp technique in the slow‐ or fast whole cell configuration. The resting membrane voltage of mesangial cells was −48±0.5mV. Adenosine (10−8−10−3 m) induced a sustained and concentration‐dependent hyperpolarization of membrane voltage (ED50≅6 × 10−7m). Adenosine (10−5m) hyperpolarized the membrane voltage by 14 ± 0.5 mV. During the hyperpolarization ion currents were monitored simultaneously. An increase of the outward current by 51 ± 11% was observed.
An increase of the extracellular K+ concentration (from 3.6 to 18.6 m) caused a depolarization of membrane voltage to −34 ± 2 mV. In the presence of increased K+ the hyperpolarization of membrane voltage induced by adenosine was significantly attenuated by 61 ± 5%. The K+‐channel blocker, Ba2+ (5 × 10−3m) depolarized membrane voltage to −24 ± 2mV. In the presence of Ba2+ the adenosine‐induced hyperpolarization was significantly inhibited by 72 ± 8%.
Preincubation of the adenosine antagonist, 8‐phenyltheophylline (10−4m) significantly inhibited the adenosine (10−5 m) mediated membrane voltage response by 67 ± 8%. The adenosine agonists 5‐N‐ethylcarboxamidoadenosine (NECA), R‐(−)N6‐(2‐phenylisopropyl)adenosine (R‐(−)−PIA), S‐(+)‐N6‐(2‐phenylisopropyl)adenosine (S‐(+)‐PIA), N6‐[2‐(3,5‐dimethoxyphenyl)‐2‐(2‐methylphenyl)‐ethyl]adenosine (DPMA), and 2‐chloroadenosine (2‐CA) also hyperpolarized membrane voltage of mesangial cells. The rank order of potency of the agonists at 10−5 m was NECA > adenosine = > R‐(−)−PIA = DPMA = 2‐CA > S‐(+)‐PIA.
Stimulation of cyclic AMP by forskolin induced a concentration‐dependent hyperpolarization of membrane voltage (ED50≅2 × 10−7m). Application of forskolin (10−5m) in the presence of adenosine (10−4m) had no additive hyperpolarizing effect on the membrane voltage.
Activation of protein kinase C by phorbol 12,13 dibutyrate (PDBu) induced a sustained depolarization of membrane voltage (ED50≅5 × 10−9m). In the presence of PDBu, adenosine (10−5m) still hyperpolarized membrane voltage of mesangial cells.
The data indicate that adenosine activates K+‐conductance via an A2 receptor in mesangial cells; the activation of the K+‐conductance, which is probably mediated by cyclic AMP led to a hyperpolarization of membrane voltage.
The 5‐HT1‐like receptor mediating the increase in canine external carotid blood flow: close resemblance to the 5‐HT1D subtype
Authors: Villalón Carlos M. , Terrón José A. 
Published: July 2012

It has recently been shown that the increase in external carotid blood flow induced by 5‐hydroxytryptamine (5‐HT) in the anaesthetized dog, being mimicked by 5‐carboxamidotryptamine (5‐CT), inhibited by methiothepin, vagosympathectomy and sympatho‐inhibitory drugs, and resistant to blockade by ritanserin and MDL 72222, is mediated by stimulation of prejunctional 5‐HT1‐like receptors leading to an inhibitory action on carotid sympathetic nerves; these 5‐HT1‐like receptors are unrelated to either the 5‐HT1A, 5‐HT1B or 5‐HT1C (now 5‐HT2C) receptor subtypes. Inasmuch as 5‐CT, 5‐methoxytryptamine, sumatriptan and metergoline display high affinity, amongst other 5‐HT binding sites, for the 5‐HT1D subtype, in the present study we have used these drugs in an attempt to determine whether the above inhibitory prejunctional 5‐HT1‐like receptors correlate with the 5‐HT1D subtype.
One‐minute intracarotid (i.c.) infusions of 5‐HT (0.3, 1, 3 and 10 μg), 5‐CT (0.01, 0.03, 0.1 and 0.3 μg), 5‐methoxytryptamine (1, 3, 10 and 30 μg) and sumatriptan (1, 3, 10, 30 and 100 μg) resulted in dose‐dependent increases in external carotid blood flow (without changes in mean arterial blood pressure or heart rate) with the following rank order of agonist potency: 5‐CT> >5‐HT > 5‐methoxytryptamine ≤ sumatriptan. Interestingly, sumatriptan‐induced vasodilatation was followed by a more pronounced vasoconstriction.
The external carotid vasodilator effects of 5‐HT, 5‐CT, 5‐methoxytryptamine and sumatriptan were dose‐dependently and specifically antagonized by metergoline (10, 30 and/or 100 μg kg−1, i.v.). In addition, 5‐methoxytryptamine‐ and sumatriptan‐induced vasodilator effects were, respectively, markedly inhibited or abolished after vagosympathectomy, as previously shown for 5‐CT and 5‐HT.
Sumatriptan showed tachyphylaxis in its vasodilator component and antagonized 5‐HT‐induced external carotid vasodilatation in a specific manner, suggesting that a common site of action may be involved.
Taken together, the above results support our contention that 5‐HT, 5‐CT, 5‐methoxytryptamine and sumatriptan produce external carotid vasodilatation in the dog by an action that might primarily involve a prejunctional inhibition on carotid sympathetic nerves; a secondary component of this vasodilator response may be postsynaptic (endothelium‐dependent and/or even directly on the vasculature). Based on the rank order of agonist potency, inhibition by vagosympathectomy and blockade by metergoline, we suggest that the inhibitory prejunctional 5‐HT1‐like receptors mediating external carotid vasodilatation in the dog closely resemble the 5‐HT1D receptor subtype. The pharmacological profile of these receptors is similar (sympathetic nerves of the rat kidney and human saphenous vein, as well as porcine coronary endothelium) to other putative 5‐HT1D receptors mediating vascular responses.
Investigation of the endogenous chemoattractants involved in 111In‐eosinophil accumulation in passive cutaneous anaphylactic reactions in the guinea‐pig
Authors: Weg Vivian B. , Watson Malcolm L. , Faccioli Lucia H. , Williams Timothy J. 
Published: July 2012

Eosinophil accumulation and plasma extravasation are features of type I allergic responses. In an attempt to characterize the mediators of these responses, we have examined the local accumulation of 111In‐eosinophils and leakage of 125I‐human serum albumin (125I‐HSA) during passive cutaneous anaphylaxis (PCA) reactions and in response to defined inflammatory mediators in the guinea‐pig. Animals were passively sensitized by intradermal injection of anti‐bovine gamma globulin antibody (50 μl, 1/50 dilution). After 20–24 h, animals were injected intravenously with 111In‐eosinophils and 125I‐HSA for the measurement of cell accumulation and plasma leakage, respectively.
When injected into sensitized sites, antigen caused a dose‐related increase in the accumulation of 111In‐eosinophils and plasma leakage in guinea‐pig skin. Time course experiments over 24 h revealed that the maximal rate of 111In‐eosinophil accumulation occurred over the first 90 min, with little accumulation at later time points. Plasma leakage was completed within the first 30 min after challenge. Responses to the mast cell degranulator, compound 48/80, exhibited very similar responses to the PCA reaction.
Co‐injection of antigen with the PAF antagonist, WEB 2086 (10−7 mol/site) or the 5‐lipoxygenase inhibitor, PF 5901 (10−7 mol/site) did not significantly alter the accumulation of 111In‐eosinophils or plasma leakage, whereas these drug doses abolished responses to exogenous PAF (10−9 mol/site) and arachidonic acid (AA, 3 × 10−8 mol/site), respectively. The H1 receptor antagonist chlorpheniramine (2.5 × 10−8 mol/site) did not reduce antigen‐induced 111In‐eosinophil accumulation. Drug combinations were also injected with antigen into sensitized sites, but were unable to reduce 111In‐eosinophil accumulation.
These results indicate that anaphylactic eosinophil accumulation in this model involves mediators other than histamine, PAF or lipoxygenase products. This is in contrast to plasma leakage in this reaction, which can be abolished by a combination of antagonists blocking these mediators.
Inhibition by KF17837 of adenosine A2A receptor‐mediated modulation of striatal GABA and ACh release
Authors: Kurokawa Masako , Kirk Ian P. , Kirkpatrick Karen A. , Kase Hiroshi , Richardson Peter J. 
Published: July 2012

The effect of the A2A adenosine receptor agonist, 2‐p‐(‐2‐carboxyethyl)phenethyl‐amino‐5′‐N‐ethylcarboxamidoadenosine (CGS 21680) on the potassium evoked release of [3H]‐γ‐aminobutyric acid ([3H]‐GABA) from nerve terminals derived from the caudate‐putamen and the globus pallidus of the rat was compared. In both preparations CGS 21680 (1 nm) inhibited the [3H]‐GABA release evoked by 15 mm KCl but had no effect on that evoked by 30 mm KCl.
The ability of CGS 21680 (1 nm) to inhibit the release of [3H]‐GABA from striatal nerve terminals was unaffected by the presence of the GABA receptor antagonists, bicuculline (10 μm), phaclofen (100 μm) and 2‐hydroxysaclofen (100 μm). Similarly the opioid receptor antagonist, naloxone (10 μm), the adenosine A1 receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 40 nm), and the cholinoceptor antagonists, mecamylamine (10 μm) and atropine (100 nm) had no effect on this inhibition.
The ability of CGS 21680 (0.1 nm) to stimulate the release of [3H]‐acetylcholine ([3H]‐ACh) from striatal nerve terminals was unaffected by the presence of bicuculline (10 μm), 2‐hydroxysaclofen (100 μm), phaclofen (100 μm), naloxone (10 μm) and DPCPX (4 nM).
The novel A2A receptor antagonist, (E)‐8‐(3,4‐dimethoxystyryl)‐1,3‐dipropyl‐7‐methylxanthine (KF 17837), blocked the CGS 21680 (1 nm)‐induced inhibition of [3H]‐GABA efflux with an EC50 of approximately 30 nm and also antagonized the CGS 21680 (0.1 nm)‐induced stimulation of [3H]‐ACh release with an EC50 of approximately 0.3 nm.
It is concluded that the A2A adenosine receptor is present on both GABAergic and cholinergic nerve terminals of the rat striatum and that in both the caudate‐putamen and the globus pallidus this receptor inhibits [3H]‐GABA release. No evidence was seen for a difference in the ligand binding sites of this receptor in the two groups of nerve terminals.
Action of adenosine receptor antagonists on the cardiovascular response to defence area stimulation in the rat
Authors: St Lambert J.H. , Dawid‐Milner M.S. , Silva‐Carvalho L. , Spyer K.M. 
Published: July 2012

The action of adenosine in the mediation of the cardiovascular changes associated with the defence reaction has been investigated in the rat using two A1 receptor antagonists.
Cumulative doses of 1,3 dipropyl‐cyclopentylxanthine (DPCPX) (0.3–3 mg kg−1) and ethanol (0.03–0.25 ml) and bolus doses of DPCPX (3 mg kg−1) and 8‐sulphophenyltheophylline (8‐SPT) (20 mg kg−1) were given into α‐chloralose, paralysed and artificially ventilated rats. Recordings were made of arterial blood pressure and heart rate.
Ethanol, the vehicle for DPCPX, failed to modify the magnitude of the defence response; however, cumulative doses of DPCPX produced a dose‐dependent decrease in the HDA (hypothalamic defence area)‐evoked increase in arterial blood pressure, accompanied by a similar fall in the magnitude of the evoked heart rate response.
The evoked rise in arterial blood pressure was reduced significantly by intravenous injection of DPCPX (3 mg kg−1) but not 8‐SPT (20 mg kg−1), a purely peripherally acting adenosine antagonist.
These results suggest that adenosine acting at A1 receptors located in the central nervous system, is involved in the HDA‐evoked pressor response. Whilst the site of action of the A1 receptors is not known, possible locations are discussed.
Hydrolysis of iodine labelled urodilatin and ANP by recombinant neutral endopeptidase EC. 3.4.24.11
Authors: Abassi Zaid A. , Golomb Eliahu , Agbaria Riad , Roller Peter P. , Tate John , Keiser Harry R. 
Published: July 2012

Urodilatin is a 32 amino‐acid peptide of similar sequence to atrial natriuretic peptide (ANP), with four additional amino‐acids at the N‐terminus. Although ANP and urodilatin bind to the same receptors with similar affinities, urodilatin is more active than ANP as a natriuretic agent. Previous studies, using neutral endopeptidase EC 3.4.24.11 (NEP) derived from crude membrane preparations, were inconclusive, but suggested that urodilatin was more resistant than ANP to degradation by this enzyme. In the present study, we compared the degradation rates of [125I]‐urodilatin and [125I]‐ANP by pure recombinant NEP (rNEP).
Incubation of radioactively labelled ANP with rNEP resulted in a much more rapid degradation of the peptide than that for labelled urodilatin.
Both phosphoramidon and SQ‐28,603, potent inhibitors of NEP, completely protected both peptides from metabolism by rNEP.
The circular dichroism spectra of the two peptides indicate that they are very similar and exist largely in unordered or flexible conformations.
These results support the relative resistance of urodilatin to NEP, and indicate that urodilatin may be of use as a therapeutic agent, in conditions in which ANP is ineffective.
The electrophysiological effects of antiarrhythmic potential of a secoaporphine, N‐allylsecoboldine
Authors: Wu Mei‐Hwan , Su Ming‐Jai , Lee Shoei‐Sheng , Young Ming‐Long 
Published: July 2012

A satisfactory antiarrhythmic potential of N‐allylsecoboldine, a synthetic derivative of secoaporphine, has been documented. Its effects on the ionic currents of cardiac myocytes and the influence on the electrophysiological properties of the conduction system in Langendorff perfused hearts were investigated.
Ionic currents were studied by voltage clamp in the whole cell configuration. N‐allylsecoboldine blocked the Na channel with a leftward‐shift of its half voltage‐dependent inactivation and a slower rate of recovery from the inactivation state. Similarly, calcium inward currents were inhibited but to a much smaller extent.
N‐allylsecoboldine inhibited the 4‐AP‐sensitive transient outward K current. Currents through the K1 channels were also reduced.
As compared with quinidine, N‐allylsecoboldine caused a comparable degree of block on Na and K1 currents but blocked to a lesser extent the Ca and Ito currents.
In the perfused whole‐heart model, N‐allylsecoboldine caused a dose‐dependent prolongation in sinoatrial, atrioventricular and His‐Purkinje system conduction intervals and prolonged the effective refractory periods of the atrium, AV node, His‐Purkinje system and ventricle. However, the basic cycle length was not significantly affected. As compared to quinidine, N‐allylsecoboldine exerted less pronounced effects on both the basic cycle length and the atrial and AV nodal refractory periods.
We conclude that N‐allylsecoboldine predominantly blocks Na and K1 channels and in similar concentrations partly blocks Ca channels and Ito. These effects result in a modification of the electrophysiological properties of the conduction system which provides a satisfactory therapeutic potential for the treatment of cardiac arrhythmias.
Nitric oxide as a mediator of the laxative action of magnesium sulphate
Authors: Izzo Angelo A. , Gaginella Timothy S. , Mascolo Nicola , Capasso Francesco 
Published: July 2012

Magnesium sulphate was studied for its effects on diarrhoea, fluid secretion, gastrointestinal transit and nitric oxide (NO) synthase activity in rats.
At a dose of 2 g kg−1 orally magnesium sulphate produced diarrhoea that was delayed in onset and intensity in a dose‐related manner by the NO synthase inhibitor NG‐nitro‐L‐arginine methyl ester (l‐NAME). This was prevented by the NO precursor, l‐arginine and the NO donating compound, isosorbide‐5‐mononitrate (IMN).
Nitric oxide synthase activity was stimulated in gut tissue from rats given magnesium sulphate and this was inhibited by l‐NAME. Dexamethasone (1 mg kg−1, i.p.), an inhibitor of inducible NO synthase, had no effect on magnesium sulphate‐induced diarrhoea.
Magnesium sulphate stimulated fluid and electrolyte accumulation in the intestinal lumen; these effects were prevented by l‐NAME but not d‐NAME.
Gastrointestinal transit of a non‐absorbable marker (charcoal suspension) was increased by oral magnesium sulphate from a mean value of 54.1% to 72.9% (P<0.01), and this was prevented by pretreatment with l‐NAME.
The results demonstrate that oral magnesium sulphate produces diarrhoea in rats by increasing the accumulation of fluid in the intestinal lumen and enhancing flow from the proximal to distal intestine. The mechanism involves release of NO, probably through stimulation of the constitutive form of NO synthase. Whether or not the effects of magnesium sulphate are due to an osmotic action or an intrinsic effect of the magnesium or sulphate ions cannot be determined from these experiments.