bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐adrenergic, non‐cholinergic neural activation in guinea‐pig bronchi: powerful and frequency‐dependent stabilizing effect on tone
Authors: Lindén A. , Ullman A. , Löfdahl C.‐G. , Skoogh B.‐E. 
Published: July 2012

We examined non‐adrenergic, non‐cholinergic (NANC) stimulation for its stabilizing effect on bronchial smooth‐muscle tone with respect to its regulatory power and the effect of variations in neural impulse frequency.
The guinea‐pig isolated main bronchus (n = 4–12) was pretreated with indomethacin (10 μm) and incubated with atropine (1 μm) and guanethidine (10 μm). Electrical field stimulation (EFS: 1200 mA, 0.5 ms, 240 s) was applied at various levels of tone prior to EFS: first without tone, then at a moderate tone induced by histamine (0.3 μm) and, finally, at a high tone induced by histamine (6 μm). Three different stimulation frequencies (1, 3 or 10 Hz) were used in order to produce moderate to near‐maximum contractile and relaxant NANC neural responses. Both the contractile and the relaxant NANC responses were tetrodotoxin‐sensitive in the guinea‐pig isolated main bronchus (3 Hz).
Without tone prior to EFS, NANC activation (1, 3 or 10 Hz) induced a pronounced contractile response. At a moderate level of tone prior to EFS, NANC activation induced a less pronounced contractile response. At the highest level of tone prior to EFS, NANC activation induced a relaxant response. All these NANC responses adjusted the tone towards a similar level and this ‘stabilization level’ was 56(6)% at 1 Hz, 65(3)% at 3 Hz and 56(5)% at 10 Hz, expressed as a percentage of the maximum histamine‐induced (0.1 mm) tone in each airway preparation.
There was a difference of approximately 90% of maximum between the highest and the lowest tone level prior to NANC activation. This difference was reduced by the converging contractile and relaxant NANC responses and the magnitude of this ‘convergence effect’ was 40(8)% at 1 Hz, 72(4)% at 3 Hz and 90(2)% at 10 Hz.
These findings indicate that NANC neural activation stabilizes bronchial smooth‐muscle tone via a contraction when the tone is low prior to activation and via a relaxation when the tone is high prior to activation. The NANC stabilizing effect on tone appears to be powerful and its magnitude can be controlled by the neural impulse frequency. The level of tone towards which the NANC responses converge does not appear to be markedly altered by variations in the impulse frequency. Our findings are consistent with a regulatory role for NANC responses in the control of bronchial smooth‐muscle tone.
Block of voltage‐dependent sodium currents by the substance P receptor antagonist (±)‐CP‐96,345 in neurones cultured from rat cortex
Authors: Caeser Manfred , Seabrook Guy R. , Kemp John A. 
Published: July 2012

Whole cell patch clamp recordings of voltage‐ and tetrodotoxin‐sensitive Na+ currents were made from cultured rat neocortical neurones (E18). The effects of the non‐peptide NK1 receptor antagonist, (±)‐CP‐96,345 on Na+ currents was examined, relative to the effect of the local anaesthetic lignocaine and tetrodotoxin.
Sodium currents were reversibly depressed by bath application of (±)‐CP‐96,345 with a half‐maximally effective concentration of 18 ± 2 μm at a stimulation frequency of 0.1 Hz. Likewise the concentrations required to half‐maximally inhibit sodium currents by tetrodotoxin and lignocaine were 10 ± 2 nm and 1.3 ± 0.2 mm respectively.
The depression of sodium currents by (±)‐CP‐96,345 (10 μm) was use‐dependent in that raising the stimulus frequency from 0.1 Hz to 10 Hz further decreased the magnitude of sodium currents from 60 ± 5% to 37 ± 5% of control values respectively. Similarly, the depression of sodium currents by lignocaine (500 μm) and tetrodotoxin (30 nm) was also accentuated by raising the stimulus frequency from 0.1 Hz to 10 Hz.
The effect of (±)‐CP‐96,345 was not associated with a change in either the activation or steady‐state inactivation characteristics of these currents, suggesting that its mechanism of action was via open channel blockade.
These data demonstrate that in addition to antagonizing NK1 receptors, (±)‐CP‐96,345 also acts as a channel blocker on sodium channels at micromolar concentrations, an effect which should be taken into consideration when examining the antinociceptive or anti‐inflammatory action of this compound.
Effects of rubidium on responses to potassium channel openers in rat isolated aorta
Authors: Greenwood I.A. , Weston A.H. 
Published: July 2012

In a physiological salt solution (PSS) in which potassium (K) was replaced by rubidium (Rb), segments of rat aorta precontracted with 20 mm RbCl were fully relaxed by K‐channel openers with an order of potency levcromakalim > cromakalim > aprikalim > RP 49356. These relaxations were inhibited by glibenclamide.
Segments of rat aorta bathed in normal PSS and precontracted with 20 mm KCl were also relaxed by these K‐channel openers with an order of potency levcromakalim > cromakalim > aprikalim > RP 49356. These relaxations were glibenclamide‐sensitive. However, the absolute potencies of the K‐channel openers were approximately four times greater in normal PSS than in RbPSS.
In RbPSS, minoxidil sulphate relaxed segments of aorta precontracted with 20 mm RbCl by approximately 20% whereas in normal PSS it fully relaxed those contracted with 20 mm KCl.
In RbPSS, levcromakalim‐induced relaxation of aortic segments precontracted with 20 mm RbCl was initially well‐maintained but then faded by approximately 60% of the initial relaxation to a new, stable level. Subsequent exposure to RP 49356 or to higher concentrations of levcromakalim was without further relaxant effect. Similar changes were observed when RP 49356 was the initial relaxant and tissues were exposed to either RP 49356 or levcromakalim. In normal PSS, levcromakalim‐ or RP 49356‐induced relaxation of contractions produced by 20 mm KCl was well‐maintained.
In RbPSS, minoxidil sulphate‐induced relaxation of aortic segments precontracted with 20 mm RbCl was well‐maintained. Subsequent exposure to either levcromakalim or to RP 49356 produced further tissue relaxation.
In RbPSS, levcromakalim produced no detectable increase in either 86Rb‐ or 42K‐efflux from rat aortic strips. In normal PSS, a significant increase in the exchange of both isotopes was detected.
Levcromakalim hyperpolarized segments of rat aorta bathed both in normal PSS and after depolarization by the addition of 20 mm KCl. Exposure to RbPSS depolarized the tissue and under these conditions, levcromakalim had no effect on membrane potential.
In Rb‐ and normal PSS, levcromakalim produced a similar degree of inhibition of the refilling of the noradrenaline‐sensitive Ca store.
It is concluded that millimolar concentrations of Rb inhibit the plasmalemmal ATP‐sensitive K‐channels (KAtp) which are the target of the K‐channel openers. The relaxant actions of the K‐channel openers in both normal and Rb‐PSS and the inhibition of these effects by glibenclamide may reflect a functional interaction between these agents at ATP‐binding sites associated with both KATP and with intracellular structures including Ca stores.
A mechanism underlying dopamine D1 and D2 receptor‐mediated inhibition of dopaminergic neurones in the ventral tegmental area in vitro
Authors: Momiyama Toshihiko , Todo Naoyuki , Sasa Masashi 
Published: July 2012

An intracellular recording study was performed to elucidate the mechanism underlying D1 and D2 receptor‐mediated inhibition of neuronal activities of dopaminergic neurones in the ventral tegmental area (VTA) using slice preparations of the rat brain.
VTA neurones were classified into type I and type II neurones according to the shape of the action potential, which correspond to dopaminergic and non‐dopaminergic neurones, respectively.
Addition of dopamine (10 μm) and quinpirole (1–100 μm) to the bath hyperpolarized the membrane of the type I neurones concomitantly with an increase in membrane conductance and an inhibition of action potentials which occurred spontaneously and were elicited by depolarizing pulses applied to the cell. However, quinpirole (10 μm) had no effect on the threshold for action potentials induced by a depolarizing pulse.
These quinpirole (10 μm)‐induced effects were antagonized by simultaneous application of domperidone (5 μm), a D2 receptor antagonist.
The amplitude of quinpirole (10 μm)‐induced hyperpolarization was decreased by increasing the potassium concentration in the perfusing fluid or simultaneous application of tetraethylammonium (10 μm).
SKF 38393 (10 or 100 μm), a D1 receptor agonist, had no effect on the resting membrane potential or action potential firing induced by a depolarizing pulse applied to the cell. However, when SKF 38393 (10 μm) was applied simultaneously with quinpirole (10 μm), the threshold for action potential generation was elevated by 5–6 mV, although there was no enhancement of hyperpolarization induced by quinpirole.
The elevation of the threshold for action potentials induced by SKF 38393 in the presence of quinpirole was antagonized by simultaneous application of SCH 23390 (5 μm), a D1 receptor antagonist.
Dopamine (10 μm), quinpirole (10 or 100 μm) and SKF 38393 (10 or 100 μm) had no effect on the resting membrane potential or spontaneously occurring action potentials in type II neurones.
These findings suggest that activation of dopamine D2 receptors of dopaminergic neurones in the VTA increases potassium conductance, thereby hyperpolarizing the membrane and eventually inhibiting neuronal activities. They also suggest that simultaneous activation of both D1 and D2 receptors enhances the D2 receptor‐mediated inhibitory effects by elevation of the threshold for action potential generation.
Evidence that a form of ATP uncomplexed with divalent cations is the ligand of P2y and nucleotide/P2u receptors on aortic endothelial cells
Authors: Motte S. , Pirotton S. , Boeynaems J.M. 
Published: July 2012

The response of bovine aortic endothelial cells to adenosine 5′‐triphosphate (ATP) is mediated by both P2y and nucleotide/P2u receptors. In order to determine which form of the nucleotide is the true ligand of these receptors, we have investigated the effects of divalent cations on ATP‐, uridine 5′‐triphosphate (UTP)‐ and 2 methylthioadenosine 5′‐triphosphate (2MeSATP)‐induced inositol phosphate accumulation in these cells.
Omisson of Mg2+ from a calcium‐free incubation buffer caused a shift to the left of the ATP concentration‐action curve.
In the presence of EDTA (1 mm), the basal level of inositol trisphosphate (InsP3) was markedly increased and the absolute maximal response to ATP was decreased; however, the response to low concentrations of ATP was enhanced.
When the results were plotted in terms of calculated ATP4‐ concentrations, the concentration‐response curves obtained in the presence of 1.25 mm Mg2+ lay closer to the respective curves obtained when Mg2+ was omitted from the medium or when Mg2+ was omitted and EDTA (1 mm) was added. The curves became almost superimposable when the baseline value was subtracted.
A similar shift to the left of the concentrations‐action curves was also observed with both UTP and 2MeSATP.
Our data provide evidence that a form of ATP uncomplexed with divalent cation is the preferential agonist of both the nucleotide/P2u and the P2y receptors expressed on bovine aortic endothelial cells.
The effects of evening primrose oil on nerve function and capillarization in streptozotocin‐diabetic rats: modulation by the cyclo‐oxygenase inhibitor flurbiprofen
Authors: Cameron Norman E. , Cotter Mary A. , Dines Kevin C. , Robertson Sharon , Cox Dominic 
Published: July 2012

The aims of this study were first, to examine whether deficits in nerve conduction in streptozotocin‐diabetic rats could be reversed by a 10% dietary supplement of evening primrose oil. Second, to determine the time‐course of reversal, and third, to assess whether the effects could be blocked by the cylco‐oxygenase inhibitor flurbiprofen (5 mg kg−1 day−1).
One‐month diabetes produced 20% and 15% deficits in sciatic motor and saphenous sensory conduction velocity respectively, which were maintained over 2 months diabetes.
The effect of 1‐month evening primrose oil treatment on abnormalities caused by an initial month of untreated diabetes was examined. Motor and sensory nerve conduction velocity were restored to the non‐diabetic level.
Resistance to hypoxic conduction failure was investigated for sciatic nerve trunk in vitro. The 80% conduction failure times were 29% and 55% prolonged by 1‐ and 2‐month diabetes respectively. Evening primrose oil did not reverse the increased hypoxic resistance following 1‐month untreated diabetes.
Sciatic nerve endoneurial capillary density was not significantly affected by diabetes, but was 16% increased in diabetic rats with reversal by evening primrose oil treatment for 1 month compared to 2‐month untreated diabetes.
Serial motor conduction velocity measurement after 3‐month untreated diabetes revealed complete normalization by evening primrose oil within 4 days. Cessation of treatment resulted in a rapid decline in conduction velocity over 24 h.
In a preventive study of 2‐month duration, 6 groups of rats were used. These comprised non‐diabetic controls, diabetic rats, and evening primrose oil‐treated diabetic rats, both with and without flurbiprofen treatment. Flurbiprofen had no significant effect in non‐diabetic rats, but produced an 11% worsening of motor conduction velocity and a 21% reduction of sciatic capillary density in diabetic rats. Evening primrose oil prevented the decreases in conduction velocity and increased hypoxic resistance with diabetes, and caused a 23% increase in capillary density. Flurbiprofen completely blocked the effect of evening primrose oil on conduction velocity, resistance to hypoxia, and capillarization.
Six main conclusions were reached. First, evening primrose oil rapidly reverses conduction deficits in diabetic rats. Second, the effects of treatment may be very short‐lived, suggesting a primary metabolic action. Third, evening primrose oil cannot reverse established changes in hypoxic resistance over 1‐month treatment. Fourth, long‐term treatment causes angiogenesis, suggesting a vascular action. Fifth, products of cyclo‐oxygenase‐mediated metabolism are necessary for maintaining vasa nervorum integrity in diabetic rats. Sixth, evening primrose oil probably acts by providing substrate for vasodilator prostanoid synthesis by vasa nervorum.
Acetylcholine‐induced endothelium‐independent relaxations in monkey isolated superior and inferior caval veins
Authors: Fukushima Sachiyo , Ohhashi Toshio 
Published: July 2012

We examined the effects of acetylcholine (ACh), isoprenaline (Isop) and Ca‐ionophore, A23187 on monkey isolated superior (SCV) and inferior caval veins (ICV) with and without intact endothelium, which had been partially contracted by 2× 10−6–5 × 10−6 m prostaglandin F2α (PGF2α).
Low concentrations of ACh (10−10–10−9m) produced a dose‐dependent relaxation in the precontracted venous segments with endothelium. ACh at concentrations more than 10−7 m elicited a transient contraction followed by a relaxation in these segments.
An addition of 5 × 10−7 m A23187 induced about 60% of maximum relaxation produced by 10−5 m sodium nitroprusside (SNP) in each venous segment with endothelium.
Isop (10−10–10−5m) caused a dose‐related relaxation in the precontracted caval veins with intact endothelium.
Removal of endothelium caused no significant effect on the ACh‐induced dual responses but a significant inhibition of the A23187‐induced relaxation.
Pretreatment with atropine antagonized competitively the ACh‐induced relaxations in the endothelium‐intact and endothelium‐denuded caval veins. The Schild plot analysis showed that the pA2 values of the segments with and without endothelium were 9.72 ± 0.14 (n = 5) and 10.01 ± 0.23 (n = 6) in the ICV; and 9.95 ± 0.20 (n = 5) and 9.70 ±0.10 (n = 5) in the SCV, respectively.
Pretreatment with 5 × 10−5 m aspirin, 3 × 10−5 m NG‐nitro‐l‐arginine methylester, 1 mm tetraethylammonium, or 3 × 10−6 m glibenclamide caused no significant effect on the basal tone, ACh‐induced transient contraction, and ACh‐induced relaxation in the precontracted venous segments with and without endothelium.
Pretreatment with 10−5 m methylene blue produced a significant reduction of the ACh‐ and SNP‐induced relaxations in the precontracted venous segments with and without endothelium. The pretreatment with the same concentration of methylene blue, however, caused no significant effect on the Isop‐induced relaxation in venous segments with endothelium.
The results suggest that ACh acts directly on the venous smooth muscle cells via a high‐affinity muscarinic receptor subtype to accumulate cellular cyclic GMP producing endothelium‐independent relaxation in the monkey caval veins.
Metabolism of endothelin‐1 and big endothelin‐1 by recombinant neutral endopeptidase EC.3.4.24.11
Authors: Abassi Zaid A. , Golomb Eliahu , Bridenbaugh Robert , Keiser Harry R. 
Published: July 2012

Inhibitors of neutral endopeptidase EC.3.4.24.11 (NEP) have been shown to attenuate the hypertensive effect of big‐endothelin‐1 (BET‐1) in rats. To determine whether NEP converts BET‐1 to endothelin‐1 (ET‐1), the effect of a recombinant NEP (rNEP) on BET‐1 and on ET‐1 was assessed in vitro.
Incubation of [125I]‐ET‐1 with 1 μg ml−1 of rNEP resulted in degradation of the peptide within minutes. Increase in the amount of rNEP to 10 μg ml−1 led to total cleavage of [125I]‐ET‐1 within seconds.
Phosphoramidon (10 μm) or SQ‐28,603 (100 μm) totally suppressed the degradation of [125I]‐ET‐1 by rNEP.
The degradation of [125I]‐BET‐1 by either 1 or 10 μg ml−1 of rNEP was much slower than that of [125I]‐ET‐1. Again, both phosphoramidon and SQ 28,603 protected the peptide from degradation.
Intact [125I]‐ET‐1 was not observed when [125I]‐BET‐1 was incubated with rNEP.
These data show that neutral endopeptidase EC.3.4.24.11 is not an endothelin converting enzyme.
The effects of α2‐adrenoceptor antagonists on the inhibition of 1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOI)‐induced head shakes by 5‐HT1A receptor agonists in the mouse
Authors: Dursun Serdar M. , Handley Sheila L. 
Published: July 2012

8‐Hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT), gepirone, buspirone and ipsapirone dose‐dependently antagonized the head‐shakes induced by 1‐(2,5‐dimethoxy 4‐iodophenyl)‐2‐amino propane hydrochloride (DOI) (1.0 mg kg−1) in mice, when these agents were given i.p. 10 min beforehand.
para‐Chlorophenylalanine (pCPA) abolished the effect of 8‐OH‐DPAT (0.1 mg kg−1) and of buspirone (1.0 mg kg−1). (±)‐Pindolol (5.0 mg kg−1) also antagonized the effect of 8‐OH‐DPAT(0.1 mg kg−1).
The α2‐adrenoceptor antagonists, RX811059 (1.0 mg kg−1), idazoxan (0.5 mg kg−1), yohimbine (1.0 mg kg−1) and 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) (2.0 mg kg−1) i.p. prevented the antagonistic effect of 8‐OH‐DPAT (0.1 mg kg−1) on DOI‐head‐shakes.
Orally‐administered buspirone, given 60 min beforehand, only reduced DOI‐head‐shakes at doses of 60 mg kg−1 and above. However, when buspirone (1.0 mg kg−1) was administered orally twice daily for 21 days, DOI‐head‐shakes were significantly reduced when tested 60 min after the first daily dose on days 5, 12 and 21 and 48 h after withdrawal.
A single oral dose of buspirone (1.0 mg kg−1) strongly antagonized DOI‐head‐shakes when given 24 h after the last of 4 daily doses of 1‐PP (2.0 mg kg−1, p.o.) but had no effect on DOI‐head‐shakes 24 h after the last of 4 daily doses of water (p.o.).
A single oral dose of 1‐PP (2.0 mg kg−1) abolished the inhibitory effect of i.p. buspirone (1.0 mg kg−1) on DOI‐head‐shakes in mice which had received water (p.o.) daily on the 4 previous days but not in mice which had received 1‐PP (2.0 mg kg−1, p.o.) on these days.
The ability of 5‐HT1A receptor agonists to antagonize DOI‐head‐shakes may be due to an effect at presynaptic 5‐HT receptors. It is suggested that 1‐PP, formed from buspirone, may act at α2‐adrenoceptors to prevent acutely administered oral buspirone from antagonizing DOI‐head shakes, but that tolerance occurs to this effect of 1‐PP, thus revealing the inhibitory effect of buspirone when the latter is given repeatedly.
Contraction of the rat isolated spleen mediated by adenosine A1 receptor activation
Authors: Fozard J.R. , Milavec‐Krizman M. 
Published: July 2012

A series of adenosine receptor agonists of varying degrees of selectivity induced concentration‐dependent contraction of the rat isolated spleen. With the exception of the response to the selective A2A receptor agonist, 2‐[p‐(2‐carboxyethyl)phenylethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS 21680), responses to each ligand were blocked surmountably and to a broadly similar extent by 8‐p‐sulphophenyltheophylline (10−5 m).
There was a significant correlation between the pEC50 values obtained on the spleen and the binding affinities (pKD; measured with [3H]‐NECA) for the A1 receptor of pig striatum (r = 0.98, P < 0.001) but not the A2A receptor (r = 0.14, NS).
The antagonist potencies of 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) and 9‐chloro‐2‐furyl [1,2,3]triazolo[1,5‐C]quinazoline‐5‐amine (CGS 15943) were measured against the prototype selective A1 receptor agonist, R‐N6‐phenylisopropyladenosine (R‐PIA). The resulting pKB values of 8.67 and 7.70, respectively are consistent with the A1 receptor subtype mediating splenic contraction.
The response to R‐PIA was unaltered in the presence of a concentration (10−7 m) of CGS 21680 which is 6 fold its KD concentration at the A2A binding site in pig striatum but below the threshold for causing contraction per se; thus, A2A receptors inhibitory to contraction appear to be absent.
The response to R‐PIA was resistant to blockade by prazosin (10−7 m) and by nifedipine (10−6 m) but partially blocked by indomethacin (10−6 m).
The results show that the rat isolated spleen responds to adenosine receptor agonists with contraction. Both the relative potencies of agonists and the effects of antagonists indicate mediation by the A1 receptor subtype. α1‐Adrenoceptor activation is not involved in contraction but a role for products of cyclo‐oxygenase and calcium from a source not dependent on entry through L‐channels is implicated.
α2‐Adrenoceptor‐mediated modulation of the nitrergic innervation of the canine isolated ileocolonic junction
Authors: Boeckxstaens G.E. , De Man J.G. , Pelckmans P.A. , Herman A.G. , Van Maercke Y.M. 
Published: July 2012

The effects of specific α‐adrenoceptor agonists and antagonists on electrically‐evoked non‐adrenergic non‐cholinergic (NANC) relaxations, previously demonstrated as nitrergic, were investigated in isolated circular muscle strips of the canine ileocolonic junction.
During a substance P‐induced contraction and in the presence of atropine and guanethidine, the specific α1‐adrenoceptor agonist, phenylephrine and antagonist, prazosin, as well as the specific α2‐adrenoceptor antagonist, yohimbine, had no effect on the NANC relaxations evoked by electrical field stimulation. In contrast, clonidine and the more specific α2‐adrenoceptor agonist, UK‐14,304, significantly reduced the electrically‐induced relaxations, preferentially those in response to low frequency stimulation. The inhibitory effect of UK‐14,304 on these relaxations was antagonized by yohimbine.
During a noradrenaline‐induced contraction, clonidine, but not UK‐14,304 significantly augmented the relaxations to electrical stimulation.
The adrenoceptor agonists and antagonists used had no effect on concentration‐response curves to NO or on the relaxation induced by nitroglycerin.
These results indicate that stimulation of prejunctional α2‐adrenoceptors inhibits the nitrergic NANC relaxations induced by field stimulation and thus suggest prejunctional regulation of nitric oxide release via α2‐adrenoceptors in the canine ileocolonic junction.