bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative effects of l‐NOARG and l‐NAME on basal blood flow and ACh‐induced vasodilatation in rat diaphragmatic microcirculation
Authors: Chang Han‐Yu , Chen Chang‐Wen , Hsiue Tzuen‐Ren 
Published: August 2006

The effects of Nω‐nitro‐l‐arginine (l‐NOARG) and Nω‐nitro‐l‐arginine methyl ester (l‐NAME) on diaphragmatic microcirculation in male Sprague‐Dawley rats were assessed under basal conditions and after acetylcholine (ACh) stimulation. In addition, l‐arginine (l‐arg) was used with the aim of preventing l‐NOARG and l‐NAME from inhibiting ACh‐induced vasodilatation, in order to explore the possibility that l‐NOARG is not only a nitric oxide (NO) synthase inhibitor but also a muscarinic receptor antagonist.
Male Sprague‐Dawley rats were anaesthetized with urethane and mechanically ventilated. The left hemi‐diaphragm of each rat was prepared and microvascular blood flow was recorded during continuous superfusion with bicarbonate‐buffered prewarmed Ringer solution by using laser‐Doppler flowmetry. The drugs were topically applied to the surface of the hemi‐diaphragm.
Baseline microvascular blood flow was unaffected after 15 min superfusion with any one of the following agents: l‐NOARG (0.1 mm), l‐NAME (0.1 mm), l‐arg (10 mm).
ACh (0.03 mm, 0.1 mm and 0.3 mm) elicited a significant increase of microvascular blood flow (171±16%, 214±55%, and 323±68% of baseline values, respectively), via interaction with the muscarinic receptor, for the vasodilator response was severely inhibited by 15 min superfusion with atropine (0.3 mm).
Following 15 min superfusion with either of the l‐arg analogues (0.1 mm), the ACh‐induced vasodilator response was significantly inhibited. Pretreatment with l‐arg (10 mm) for 5 min, followed by co‐administration of l‐arg (10 mm) and l‐NOARG (0.1 mm) for another 15 min significantly prevented the inhibitory effect of l‐NOARG on ACh‐induced vasodilatation. However, a similar pretreatment schedule with l‐arg failed to prevent l‐NAME from exerting its inhibitory effect.
Neither of the l‐arg analogues potentiated sodium nitroprusside (10 μm and 30 μm)‐induced vasodilatation. However, adenosine (0.1 mm)‐induced vasodilatation was slightly but significantly attenuated by either l‐NOARG (0.1 mm) or l‐NAME (0.1 mm), an effect which was prevented by l‐arg (10 mm).
In conclusion, an increase in endothelium‐dependent blood flow stimulated by ACh may occur in diaphragmatic microcirculation of anaesthetized rats independently of low baseline NO activity. The results also suggest that l‐NAME has muscarinic receptor antagonist action in addition to its ability to inhibit NO synthase. Thus, we suggest that l‐NAME should not be used as a specific NO synthase inhibitor in the rat diaphragm in situations in which there is potential for muscarinic receptors to be stimulated.

British Journal of Pharmacology (1997) 120, 326–332; doi:10.1038/sj.bjp.0700896
Effect of Nω‐nitro‐l‐arginine methyl ester, a nitric oxide synthesis inhibitor, on stress‐ and morphine‐induced prolactin release in male rats
Authors: Matton A , Bollengier F , Finné E , Vanhaelst L 
Published: August 2006

The effect of the nitric oxide synthesis inhibitor Nω‐nitro‐l‐arginine methyl ester (l‐NAME) was investigated on stress‐ and morphine‐induced prolactin (PRL) secretion in vivo in male rats, by use of a stress‐free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein.
Three doses of l‐NAME were tested (1, 10 and 30 mg kg−1) and were given intraperitoneally one hour before blood sampling; control rats received saline. After the first blood sample, rats received an initial intravenous injection of morphine (3, 6 or 12 mg kg−1) or were subjected to immobilization stress. In the case of a morphine administration, rats received a second dose of morphine (3, 6 or 6 mg kg−1, respectively) 90 min later, when tolerance had developed, while rats subjected to immobilization stress received 6 mg kg−1 morphine 90 min after onset of stress.
l‐NAME had no effect on basal plasma PRL concentration. However, it potentiated acute morphine‐induced PRL secretion and attenuated the subsequent tolerance in a dose‐dependent way. Immobilization stress‐induced PRL secretion was inhibited dose‐dependently by l‐NAME, as was its subsequent tolerance to morphine; however, in this case, in a reversed dose‐dependent way.
When the highest dose of morphine (12 mg kg−1) was combined with the highest dose of l‐NAME pretreatment (30 mg kg−1), all rats showed a dramatic potentiation of the morphine‐induced PRL rise compared to controls. Moreover, all of these rats died within 90 min after the administration of morphine.
These results show that NO plays a role in the acute opioid action on PRL release during stress as well as in the development of tolerance to the opioid effect, and some possible mechanisms are discussed.

British Journal of Pharmacology (1997) 120, 268–272; doi:10.1038/sj.bjp.0700899
Effects of inhibitors of phosphodiesterase, on antigen‐induced bronchial hyperreactivity in conscious sensitized guinea‐pigs and airway leukocyte infiltration
Authors: Danahay Henry , Broadley Kenneth J 
Published: August 2006

The aim of this study was to determine the effects of inhibitors of phosphodiesterase (PDE) on the early and late phase bronchoconstriction in sensitized, conscious guinea‐pigs and the subsequent development of acute airway hyperreactivity to the inhaled thromboxane mimetic, U46619, and leukocyte infiltration following ovalbumin (OvA) challenge.
Following an inhalation challenge with OvA, there was an early bronchoconstriction which peaked at 15 min with recovery after 3–4 h. A late phase bronchoconstriction occurred between 17 and 24 h after challenge. The PDE 4 inhibitors, Ro 20‐1724 (3 mg kg−1, i.p.) and rolipram (1 mg kg−1, i.p.) administered 30 min before and 6 h after antigen challenge (double dosing regimen), did not affect the development of the early or late phase responses.
Seventeen to twenty four hours following an acute OvA or saline challenge, a consistently greater bronchoconstrictor response to inhaled U46619 was observed in the OvA challenged group. This increase in responsiveness was significantly attenuated by the administration of Ro 20‐1724 and rolipram 30 min before and 6 h after antigen challenge (P<0.05); this was not attributable to a residual bronchodilator effect of these compounds. There was a trend towards inhibition of the hyperreactivity to U46619 by aminophylline but not by the PDE3 inhibitors, siguazodan or SKF 95654.
Aminophylline, rolipram and Ro 20‐1724 when administered as the double dose regimen attenuated the rise in macrophages, eosinophils and neutrophils recovered in bronchial lavage fluid 17 to 24 h after antigen challenge.
The dose of Ro 20‐1724 given at 6 h post challenge was essential for attenuation of airway hyperreactivity and to protect against leukocyte influx.
In summary, aminophylline, rolipram and Ro 20‐1724 have anti‐inflammatory effects against antigen‐induced airway leukocyte infiltration. Rolipram and Ro 20‐1724 additionally attentuated the development of acute airway hyperreactivity, effects which are probably mediated through inhibition of PDE type 4. A dose of PDE inhibitor 6 h after the antigen challenge appears to be essential to achieve this protection. Inhibitors of PDE type 3 were generally without effect. However, there was no effect of rolipram or Ro 20‐1724 on the development of either the early or late phase type responses.

British Journal of Pharmacology (1997) 120, 289–297; doi:10.1038/sj.bjp.0700901
Prominent sympathetic purinergic vasoconstriction in the rabbit splenic artery: potentiation by 2,2′‐pyridylisatogen tosylate
Authors: Ren Lei‐Ming , Burnstock Geoffrey 
Published: August 2006

Vasoconstrictions induced by transmural electrical field stimulation were frequency‐dependent from 2 to 32 Hz in the rabbit isolated splenic artery. All contractions were abolished in the presence of tetrodotoxin 1 μm or guanethidine 100 μm. Stimulation at a frequency of more than 32 Hz induced both neurogenic and myogenic responses.
Prazosin (1 μm) did not significantly affect vascular contractions to electrical stimulation. Desensitization of P2X‐purinoceptors with α,β‐methylene ATP (α,β‐meATP, 3 μm) abolished the contractions to stimulation at 2–8 Hz and inhibited more than 80% of the vascular response at 16 Hz, but it did not significantly change the responses at 32 Hz. Contractile responses at 32 Hz were inhibited by a combination of prazosin and α,β‐meATP. Effects of pyridoxal‐phosphate‐6‐azophenyl‐2′, 4′‐disulphonic acid tetrasodium salt (a selective P2X‐purinoceptor antagonist) and suramin (a competitive P2‐purinoceptor antagonist) on the neurogenic responses were investigated in this study.
2,2′‐Pyridylisatogen tosylate (PIT, 0.3–3 μm) significantly potentiated the vasoconstrictions to electrical stimulation at 2–32 Hz in a concentration‐dependent manner. Potentiated responses were restored to the control level 30 min after washing. Concentration‐dependent response curves for noradrenaline (NA) or α,β‐meATP were not significantly changed by 3 μM PIT, and vasoconstriction by adenosine 5′‐triphosphate (ATP, 300 μm) was unaffected by PIT. Coomassie brilliant blue‐G (1 μm), which shares the potentiating effect on a recombinant P2Y‐purinoceptor with PIT (King et al., 1996), did not inhibit or potentiate the purinergically‐mediated component of the response to sympathetic nerve stimulation. The selective α2‐adrenoceptor antagonist yohimbine (1 μm) also potentiated the vascular responses to electrical stimulation.
The present results indicate that ATP evokes postjunctional contractile responses at low and high frequency electrical stimulation of sympathetic nerves supplying the rabbit splenic artery. PIT potentiates the responses to sympathetic (purinergic) nerve stimulation; this appears to be mainly via prejunctional rather than postjunctional actions.
The effect of pretreatment with a δ2‐opioid receptor antisense oligodeoxynucleotide on the recovery from acute antinociceptive tolerance to δ2‐opioid receptor agonist in the mouse spinal cord
Authors: Narita Minoru , Mizoguchi Hirokazu , Kampine John P. , Tseng Leon F. 
Published: August 2006

An intrathecal (i.t.) injection of a selective δ2‐opioid receptor agonist, [D‐Ala2]deltorphin II, produced an acute antinociceptive tolerance to the antinociceptive effect of a subsequent i.t. challenge of [d‐Ala2]deltorphin II. This acute tolerance lasted 3 to 9 h and completely subsided by 12 h. The experiments were designed to examine the effect of pretreatment with an antisense oligodeoxynucleotide to δ2‐opioid receptor mRNA (δ‐AS oligo) on the recovery from tolerance to [D‐Ala2]deltorphin II‐induced antinociception in male ICR mice.
Pretreatment with δ‐AS oligo (1.63 to 163 pmol, i.t.), but not mismatched oligo (MM oligo) (163 pmol), prevented the recovery from acute tolerance to [D‐Ala2]deltorphin II‐induced antinociception in a dose‐dependent manner. However, treatment with δ‐AS oligo (163 pmol) did not prevent the recovery from tolerance to either the μ‐opioid receptor agonist [D‐Ala2,NMePhe4,Gly(ol)5]enkephalin (DAMGO) or the κ‐opioid receptor agonist U50,488H, indicating subtype specificity in the mechanism by which δ‐AS oligo inhibits recovery from δ2‐opioid tolerance.
Treatment with [D‐Ala2]deltorphin II (i.t.) significantly reduced the binding of [tyrosyl‐3,5‐3H(N)]‐Tyr‐D‐Ser‐Gly‐Phe‐Leu‐Thr ([3H]‐DSLET), a δ2‐opioid receptor agonist ligand, in the spinal cord 3 h after treatment, but binding returned to control levels by 24 h after treatment. However, [3H]‐DSLET binding in the spinal cord remained significantly reduced at 24 h if δ‐AS oligo (163 pmol) was coadministered with [D‐Ala2]deltorphin II (6.4 nmol).
Based on these findings, it is concluded that a single stimulation of spinal cord δ2‐opioid receptors by intrathecally‐administered [D‐Ala2]deltorphin II induces a long‐lasting desensitization of δ2‐opioid receptors to [D‐Ala2]deltorphin II. Recovery from δ2‐opioid receptor‐mediated antinociceptive tolerance apparently depends on replenishment by newly synthesized δ2‐opioid receptor protein rather than immediate reversal of δ2‐opioid receptors.
β‐Adrenoceptor mediated facilitation of noradrenaline and adenosine 5′‐triphosphate release from sympathetic nerves supplying the rat tail artery
Authors: Brock James A , Bridgewater Melissa , Cunnane Thomas C 
Published: August 2006

The effects of prejunctional β‐adrenoceptor activation on electrically evoked noradrenaline (NA) and adenosine 5′‐triphosphate (ATP) were studied by use of continuous amperometry and conventional intracellular recording techniques. Excitatory junction potentials (e.j.ps) were used as a measure of ATP release, and NA‐induced slow depolarizations and oxidation currents as measures of NA release, from postganglionic sympathetic nerves innervating the rat tail artery in vitro.
Isoprenaline (0.1 μm) increased the amplitude of e.j.ps, slow depolarizations and oxidation currents evoked by short trains of stimuli at 1 to 4 Hz. The facilitatory effect of isoprenaline on e.j.ps and oxidation currents was most pronounced on responses evoked by the first stimulus in a train.
Isoprenaline (0.1 μm) did not detectably alter the amplitude‐frequency distribution of spontaneous e.j.ps.
The facilitatory effect of isoprenaline on e.j.ps, slow depolarizations and oxidation currents was abolished by the β‐adrenoceptor antagonist, propranolol (0.1 μm). Propranolol alone had no effect on e.j.ps, slow depolarizations or oxidation currents.
Thus, activation of prejunctional β‐adrenoceptors increases the release of both NA and ATP from postganglionic sympathetic nerves. The findings are consistent with the hypothesis that NA and ATP are released from the same population of nerve terminals and presumably from the same vesicles.

British Journal of Pharmacology (1997) 120, 769–776; doi:10.1038/sj.bjp.0700959
Postnatal development of δ‐opioid receptor subtypes in mice
Authors: Negri L , Severini C , Lattanzi R , Potenza R L , Melchiorri P 
Published: August 2006

The density and affinity of binding sites for the δ‐selective opioid ligands [3H]‐[d‐Ala2, Asp4]deltorphin (DELT‐I), [3H]‐[d‐Ala2Glu4]‐deltorphin (DELT‐II), [3H]‐[d‐Pen2,d‐Pen5]enkephalin (DPDPE), and [3H]‐naltrindole (NTI) were determined in whole brain from 10, 15, 25 and 60 day‐old C57BL mice.
At all ages, the analyses of the homologous displacement curves, gave best fits to single rather than to multiple site models. The binding capacity (Bmax) labelled by [3H]‐NTI was about one half that labelled by [3H]‐DELT‐I, [3H]‐DELT‐II and [3H]‐DPDPE. In 25 and 60 day‐old mouse brain the DPDPE Bmax was 25% less than the deltorphin‐II Bmax.
In saturation experiments, specific binding of [3H]‐DELT‐I on adult mouse brain homogenates was best fitted by a two‐site model (34% high affinity site, Kd=1.08 nm and 66% low affinity sites, Kd=39.9 nm).
DPDPE produced a biphasic inhibition of specific [3H]‐DELTI‐I binding, from 15 days of age onwards. The relative percentage of high and low affinity sites was 72% and 28% in 15 day‐, 65% and 35% in 25 day‐ and 30% and 70% in 60 day‐old mice.
In adult mouse brain labelled with [3H]‐DELT‐I, DELT‐II recognized 71% of high‐affinity and 29% of low‐affinity sites. DELT‐I and DPDPE produced monophasic inhibition of specific [3H]‐DELT‐II binding to brain homogenates of adult mice.
These data suggest that a sub‐population of δ‐sites (probably the δ2‐subtype), recognized by DELT‐I, with high affinity for DELT‐II and low affinity for DPDPE develops from 25 days onward.
In electrically stimulated mouse vas deferens (MVD) the rank order of potency of the three δ‐agonists was: DELT‐I> DELT‐II> DPDPE in 10 day‐old mice, and: DELT‐I= DELT‐II> DPDPE, from 25 days onward. During this time, the potency of DELT‐II increased about 15 fold whereas the potency of DELT‐I and DPDPE increased only 5 times. The higher efficacy of DELT‐II could depend on receptor maturation towards the δ2‐subtype.

British Journal of Pharmacology (1997) 120, 989–994; doi:10.1038/sj.bjp.0700990
Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones
Authors: Pisani Antonio , Calabresi Paolo , Centonze Diego , Bernardi Giorgio 
Published: August 2006

The interactions between N‐methyl‐d‐aspartate (NMDA) and metabotropic glutamate receptors (mGluRs) were investigated in striatal slices, by utilizing intracellular recordings, both in current‐ and voltage‐clamp mode.
Bath‐application (50 μm) or focal application of NMDA induced a transient membrane depolarization, while in the voltage‐clamp mode, NMDA (50 μm) caused a transient inward current. Following bath‐application of the non‐selective mGluR agonist 1S,3R‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3R‐ACPD, 10 μm), NMDA responses were reversibly potentiated both in current (197±15% of control) and voltage‐clamp experiments (200±18% of control).
Bath‐application of the group I mGluR agonist (RS)‐3,5‐dihydroxyphenylglycine (3,5‐DHPG, 10–300 μm) resulted in a dose‐dependent potentiation of NMDA‐induced membrane depolarization (up to 400±33% of control). This potentiation was either prevented by preincubation with (RS)‐α‐methyl‐4‐carboxyphenylglycine (RS‐α‐MCPG, 300 μm), or blocked when applied immediately after 3,5‐DHPG wash‐out.
Neither (2S,1′S,2′S)2‐(2′‐carboxycyclopropyl)glycine (L‐CCG I, up to 100 μm) nor (2S,1′R,2′R,3′R)‐2‐(2,3‐dicarboxycyclopropyl)‐glycine (DCG‐IV, 1 μm), agonists for group II mGluRs caused any change in NMDA responses. Likewise, l‐serine‐O‐phosphate (l‐SOP, 30 μm), agonist for group III mGluRs, did not affect the NMDA‐induced depolarization.
The enhancement of the NMDA responses was mimicked by phorbol‐12,13‐diacetate (PDAc, 1 μm) which activates protein kinase C (PKC). The 3,5‐DHPG‐mediated potentiation of the NMDA‐induced depolarization was prevented by preincubation with staurosporine (100 nm) or calphostin C (1 μm), antagonists of PKC.
Electrophysiological responses to α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) receptor activation were not affected by agonists for the three‐classes of mGluRs.
The present data suggest that group I mGluRs exert a positive modulatory action on NMDA responses, probably through activation of PKC. This functional interaction in the striatum appears of crucial importance in the understanding of physiological and pathological events, such as synaptic plasticity and neuronal death, respectively.

British Journal of Pharmacology (1997) 120, 1007–1014; doi:10.1038/sj.bjp.0700999
Role of eicosanoids in alteration of membrane electrical properties in isolated mesenteric arteries of salt‐loaded, Dahl salt‐sensitive rats
Authors: Fujii Koji , Onaka Uran , Ohya Yusuke , Ohmori Susumu , Tominaga Mitsuhiro , Abe Isao , Takata Yutaka , Fujishima Masatoshi 
Published: August 2006

The role of eicosanoids in altered membrane electrical properties of Dahl salt‐sensitive (DS) rats was investigated, by use of conventional microelectrodes technique, in isolated superior mesenteric arteries of DS rats and Dahl salt‐resistant (DR) rats fed either a high or low salt diet.
The membrane was significantly depolarized in salt‐loaded DS rats compared with the other three groups. In addition, the arteries of salt‐loaded DS rats exhibited spontaneous electrical activity.
Spontaneous electrical activity in salt‐loaded DS rats was inhibited by the following: indomethacin, a cyclo‐oxygenase inhibitor; ONO‐3708, a prostaglandin H2/thromboxane A2 receptor antagonist; OKY‐046, a thromboxane A2 synthase inhibitor; nicardipine, a Ca2+‐channel antagonist and by Ca2+‐free solution. In addition, spontaneous electrical activity was enhanced by a thromboxane A2 analogue and by prostaglandin H2. Spontaneous electrical activity was unaffected by phentolamine, atropine and tetrodotoxin.
Membrane potential in arteries of salt‐loaded DS rats was not affected by either indomethacin or ONO‐3708.
Spontaneous contraction, sensitive to indomethacin, was present, and contractile sensitivity to high potassium solution was enhanced in arteries of salt‐loaded DS rats.
These findings suggest that eicosanoid action, together with membrane depolarization, may lead to the activation of voltage‐dependent Ca2+‐channels, thereby causing spontaneous electrical activity in mesenteric arteries of salt‐loaded DS rats. In addition, tension data suggest that these changes in membrane properties are related to enhanced contractile activities in salt‐loaded DS rats. Mechanisms of depolarization remain to be determined.

British Journal of Pharmacology (1997) 120, 1207–1214; doi:10.1038/sj.bjp.0701023
SCA 40: studies of the relaxant effects on cryopreserved human airway and vascular smooth muscle
Authors: Müller‐Schweinitzer E. , Fozard J. R. 
Published: August 2006

6‐Bromo‐8‐methylaminoimidazol[1,2‐a]pyrazine‐2carbonitrile (SCA 40) has been claimed to induce relaxation in guinea‐pig trachea by opening high conductance, calcium‐activated potassium (BKCa) channels. The mechanism of action of SCA 40 has now been further investigated in ring preparations from cryopreserved human airway and vascular smooth muscle preparations in vitro.
Human bronchi with spontaneous tone relaxed in response to SCA 40 in a biphasic way. A high affinity component (pD2 8.61±0.21; mean±s.e.mean) accounted for 30% of the response and a low affinity component (pD2 6.53±0.14) for the remaining 70%. In contrast, in bronchi contracted with carbachol, 1 μm, the concentration‐response curve to SCA 40 was monophasic and yielded a pD2 of 6.31±0.29.
SCA 40 relaxed pulmonary and mesenteric arteries and peripheral veins which had been precontracted by 10 nm U46619 nearly completely and in a monophasic way; the pD2 values were 6.37±0.08, 6.17±0.15 and 5.45±0.25, respectively.
Lemakalim, an opener of ATP‐dependent potassium (KATP) channels, also relaxed human bronchi under spontaneous tone and the vascular tissues. NS 1619, a recognised opener of BKca channels, was inactive up to 10 μm on bronchial and vascular tissues.
The SCA 40‐induced relaxation of human bronchi was reduced concentration‐dependently in the presence of high potassium chloride (20 and 80 mm). However, in the presence of 80 mm KCl and nifedipine, 30 nm, SCA 40 fully relaxed the remaining contractile response with pD2 values of 8.08±0.13 and 5.27±0.13 for the high and low affinity component, respectively.
Relaxation responses to SCA 40 in human bronchi were resistant to blockade by glibenclamide at concentrations up to 10 μm (which blocked the relaxant response to lemakalim), quinine (30 μm), apamin (100 nm), tetraethylammonium (0.11 mm) and charybdotoxin (10100 nm), thus excluding the involvement of a variety of K+ channels including KATP and KCa channels.
In bronchi contracted with carbachol, 1 μm, the nature of the interaction between SCA 40 and the β2‐adrenoceptor agonist, salbutamol, was synergistic.
These experiments establish that SCA 40 is a potent relaxant of human bronchial smooth muscle manifesting spontaneous tone. A low affinity relaxant component has its counterpart in the relaxation seen in both human arterial and venous smooth muscle. The consensus of the evidence suggests that K+ channel opening is not the basis of the relaxant response to SCA 40. Furthermore, BKCa channels appear to be of minor importance in the regulation of human airway smooth muscle tone. Our data suggest that inhibition of an adenosine 3′ : 5′‐cyclic monophosphate phosphodiesterase may contribute, at least to the low affinity relaxant component of SCA 40. However, the exact mechanism mediating the SCA 40‐induced relaxation of human airways remains to be defined.

British Journal of Pharmacology (1997) 120, 1241–1248; doi:10.1038/sj.bjp.0701037