bluuebunny/crossref_metadata_2025_split huggingface dataset:
An in vitro analysis of purine‐mediated renal vasoconstriction in rat isolated kidney
Authors: Kenakin Terry P. , Pike Nicholas B. 
Published: July 2012

In the rat isolated perfused kidney, 2‐chloroadenosine and l‐N6‐phenyl‐isopropyl adenosine (l‐PIA) produced a modest vasodilatation.
After kidneys had been pretreated with methoxamine (to elevate vascular tone) and forskolin (to activate adenyl cyclase and reduce vascular tone), both purine agonists produced vasoconstriction at low doses and vasodilatation at higher doses. This was consistent with the working hypothesis that vasoconstriction resulted from activation of A1‐purinoceptors mediating adenyl cyclase inhibition and vasodilatation from activation of A2‐purinoceptors stimulating adenyl cyclase.
These kidney preparations also demonstrated a marked potentiation of purine‐mediated vasoconstriction in the presence of various concentrations of 8‐p‐sulpho‐phenyltheophylline (8‐SPT), a drug reported in the literature to be a competitive antagonist of A1‐and A2‐purinoceptors.
Maximal renal vasoconstriction to 2‐chloroadenosine and l‐PIA was observed in the presence of 10 mm 8‐SPT; the fact that this vasoconstriction was sensitive to the selective A1‐receptor antagonist 8‐(2‐amino‐4‐chlorophenyl)‐1,3‐dipropylxanthine (PACPX) and that the order of potency of agonists for this effect was l‐PIA > 2‐chloroadenosine > d‐PIA > N6‐ethylcarboxamide adenosine (NECA) was consistent with activation of vascular A1‐purinoceptors.
While these data are consistent with the hypothesis that purines activate vascular A1‐and A2‐receptors in the rat isolated kidney, the nature of the results did not allow definitive classification of the receptors mediating the purine effects.
Increased gut cholinergic activity and antagonism of 5‐hydroxytryptamine M‐receptors by BRL 24924: potential clinical importance of BRL 24924
Authors: Sanger G.J. 
Published: July 2012

The mechanisms by which BRL 24924 ([(±)‐(endo)]‐4‐amino‐5‐chloro‐2‐methoxy‐N‐(1‐azabicyclo‐[3.3.1]‐non‐4‐yl) benzamide hydrochloride stimulates gut motility and the relationships between BRL 24924 and 5‐hydroxytryptamine (5‐HT) receptors have been studied.
In guinea‐pig isolated ileum, BRL 24924 (10−4‐10−6 m) increased electrically‐evoked, cholinergically‐mediated contractions, probably by increasing acetylcholine (ACh) release. This action of BRL 24924 was prevented by the presence of high concentrations of 5‐HT, but not by hexamethonium, phentolamine and propranolol, methysergide or ICS 205–930.
The mechanism by which BRL 24924 can increase gut ACh release is not certain, but most likely involves activation of an enteric 5‐HT receptor which differs from those 5‐HT M‐receptors antagonized by ICS 205–930 or by higher concentrations of BRL 24924 in other test systems.
BRL 24924 antagonized 5‐HT‐evoked, cholinergically‐mediated contractions of guinea‐pig isolated ileum (pA2 = 7.56 ± 0.12). Similar and higher concentrations of BRL 24924 did not antagonize contractions evoked by nicotinic receptor stimulation. In rabbit isolated heart, BRL 24924 1–10 nm reduced the tachycardia evoked by 5‐HT.
In anaesthetized rats, BRL 24924 0.3–83 nmol kg−1 i.v. antagonized the Bezold‐Jarisch reflex evoked by 5‐HT; the ID50 for BRL 24924 was 10.2 ± 3.0 nmol kg−1 (3.7 ± 1.1 μg kg−1). A direct action of BRL 24924 on nerve function was excluded.
In rat cortex, BRL 24924 10−6 m did not displace [3H]‐5‐HT or [3H]‐ketanserin binding to 5‐HT1 and 5‐HT2 receptors.
The actions of BRL 24924 are discussed in terms of its potential clinical use as a stimulant of gastric motility and as a 5‐HT M‐receptor antagonist.
The action of noradrenaline on single smooth muscle cells freshly dispersed from the guinea‐pig pulmonary artery
Authors: Byrne N.G. , Large W.A. 
Published: July 2012

Responses to ionophoretically‐applied noradrenaline were investigated with micro‐electrodes in whole tissue preparations and with patch pipettes in isolated cells dispersed from the guinea‐pig pulmonary artery.
In whole tissue and dispersed cells noradrenaline evoked monophasic depolarizations which had a similar time course.
In dispersed cells the amplitude of electronic potentials was reduced during the noradrenaline‐evoked depolarization. Under voltage clamp noradrenaline elicited an inward current, which persisted in 18 mm external potassium with the membrane potential set at the potassium equilibrium potential.
In voltage clamp experiments the amplitude of current steps to hyperpolarizing voltage jumps was increased during the noradrenaline‐induced inward current. These data suggest that the depolarization to noradrenaline in the guinea‐pig pulmonary artery is mediated by an increase in membrane conductance.
Developmental responses to opioids reveals a lack of effect on stress‐induced corticosterone levels in neonatal rats
Authors: Bailey Clare C. , Kitchen Ian 
Published: July 2012

The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development.
Neonatal rats of either sex were injected with morphine (5–50 mg kg−1), fentanyl (10–100 μg kg−1), buprenorphine (0.1 − 30 mg kg−1) or naloxone (0.1 − 10 mg kg−1) and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg−1, co‐administered) were carried out for the opioid agonists.
In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress‐induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates.
High doses of naloxone (10 mg kg−1) significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals. A dose of naloxone (1 mg kg−1) which had no significant effect on the corticosterone response inhibited the effects of morphine, fentanyl and buprenorphine in 45 day old and adult rats.
This late development of opioid action is unusual in comparison with the maturation of endogenous peptides, receptors and antinociceptive responses and suggests that alternative mechanisms may be involved in stress‐control in the neonate.
The effect of vasoactive intestinal peptide on smooth muscle tone and mucus secretion from the ferret trachea
Authors: Webber S.E. , Widdicombe J.G. 
Published: July 2012

The effect of vasoactive intestinal peptide (VIP) was examined on the smooth muscle contraction and mucus secretion produced by methacholine and phenylephrine in the ferret whole trachea in vitro.
VIP (0.5 to 800 nm) produced a concentration‐dependent relaxation of the ferret trachea contracted by methacholine (1 μm) and phenylephrine (10 μm). The concentration‐response curves for methacholine‐and phenylephrine‐induced contractions were both shifted to the right by VIP (0.1 μm).
Methacholine‐induced secretion was inhibited in a concentration‐dependent manner by VIP, whereas that due to phenylephrine was enhanced. The concentration‐response curve for methacholine‐induced secretion was shifted to the right by VIP, whereas the curve for phenylephrine was shifted to the left.
Methacholine produced a concentration‐dependent increase in the rate of output of lysozyme from the ferret trachea with no corresponding increase in the concentration of lysozyme in the mucus. Phenylephrine produced a concentration‐dependent increase in the rate of output and in the concentration of lysozyme.
VIP (0.1 μm) significantly increased the concentration of lysozyme in the mucus produced by methacholine with no increase in the rate of lysozyme output. However, the rate of lysozyme output due to phenylephrine was significantly increased by VIP (0.1 μm) with no increase in concentration.
We suggest that VIP inhibits secretion from mucous cells stimulated by methacholine, and enhances the secretion produced by phenylephrine from serous cells.
Influence of α‐chymotrypsin and trypsin on the non‐adrenergic non‐cholinergic relaxation in the rat gastric fundus
Authors: De Beurme Freya A. , Lefebvre Romain A. 
Published: July 2012

Relaxations of the rat gastric fundus were induced by electrical stimulation of the non‐adrenergic non‐cholinergic (NANC) neurones, by vasoactive intestinal polypeptide (VIP), by noradrenaline and by isopropylnoradrenaline. The influence of α‐chymotrypsin and trypsin thereupon was studied.
α‐Chymotrypsin 2 u ml−1, present for 30 min, antagonized completely the VIP‐induced relaxation, but not the stimulation‐induced relaxation; α‐chymotrypsin 10 u ml−1 also partially antagonized the stimulation‐induced relaxation. When α‐chymotrypsin 2 u ml−1 was added after the relaxation had occurred, it antagonized completely the VIP‐induced relaxation, but it also partially antagonized the stimulation‐induced relaxation. The partial antagonism of the stimulation‐induced relaxation was more pronounced with α‐chymotrypsin 10 u ml−1.
Trypsin, 10−6 m and 3 × 10−6 m, had effects on VIP‐and stimulation‐induced relaxations similar to those of α‐chymotrypsin.
The relaxations induced by noradrenaline and isopropylnoradrenaline were not influenced by α‐chymotrypsin or trypsin, respectively.
The results suggest that a peptide, possibly VIP, is involved in the NANC relaxation of the rat gastric fundus.
Effects of l‐serine borate on antagonism of leukotriene C4‐induced contractions of guinea‐pig trachea
Authors: Charette L. , Jones T.R. 
Published: July 2012

The antagonist activity of three leukotriene D4 (LTD4) receptor antagonists and a number of bronchodilators was determined against LTC4‐induced contractions of guinea‐pig isolated tracheal chains in the absence and presence of the γ‐glutamyltranspeptidase inhibitor, l‐serine borate (SB).
The LTD4 receptor antagonists FPL‐55712, L‐649,923 and L‐648,051 effectively antagonized LTC4 responses in the absence of SB but were ineffective in the presence of 15 and/or 45 mm SB.
Salbutamol > isobutylmethylxanthine (IBMX) > dibutyryl cyclic AMP > aminophylline > nifedipine antagonized contractions to LTC4 in the absence of SB. In contrast, in the presence of SB the antagonist activity of all of these agents except nifedipine was significantly reduced. The antagonist activity of the Ca2+ entry blocker, nifedipine, was similar in the absence and presence of SB.
Salbutamol and IBMX were potent functional antagonists of LTE4‐induced contractions both in the absence and presence of SB.
These results are consistent with the hypothesis that there are contractile LTC4 receptor mechanisms in guinea‐pig trachea which are unmasked by SB and are not blocked by LTD4 receptor antagonists and which are less effectively down modulated by cyclic AMP‐dependent bronchodilators.
Complex effects of Gillichthys urotensin II on rat aortic strips
Authors: Gibson A. 
Published: July 2012

The aim of this study was to determine whether the fish neuropeptide, Gillichthys urotensin II (GUII), possesses significant biological activity on rat aortic strips.
On intact strips, pre‐contracted by noradrenaline (100 nm), low concentrations (0.1‐0.5 nm) of GUII produced relaxations, while higher concentrations (1–10 nm) caused further contraction. On strips rubbed to remove endothelial cells, relaxations were absent but contractile responses to higher concentrations of GUII remained.
GUII (0.2–10 nm) produced dose‐related contractions of quiescent, intact aortic strips. These contractions consisted of two components, tonic and phasic, and were potentiated in rubbed strips and in the presence of the antioxidant drug hydroquinone (10 μm).
Mepacrine (40 μm) and p‐bromophenacyl bromide (50 μm) completely abolished contractions to GUII, but indomethacin (10 μm) and nordihydro‐guaiaretic acid (10 μm) were without effect.
The phasic, but not the tonic, component of the contractile response was inhibited by nitrendipine (200 nm), and was absent in bathing medium from which Ca2+ had been omitted. Addition of EGTA (2 mm) to Ca2+‐free bathing medium abolished the residual tonic component.
GUII‐induced contractions were completely abolished by the calmodulin antagonists trifluoperazine (50 μm) and W‐7 (30 μm).
It is concluded that GUII, previously considered devoid of significant activity on mammalian tissues, produces potent endothelium‐dependent relaxations and endothelium‐independent contractions of rat aorta, and possible mechanisms underlying each response are discussed.
Studies on the mechanism by which indomethacin increases the anticancer effect of methotrexate
Authors: Bennett A. , Gaffen J.D. , Melhuish P.B. , Stamford I.F. 
Published: July 2012

The effect of indomethacin on the response of the NC carcinoma to methotrexate has been examined in vivo and in vitro.
Survival was prolonged in mice treated with indomethacin 1.25 mg kg−1 twice daily plus methotrexate 4 mg kg−1 daily, compared to mice given either drug alone or controls.
Indomethacin 1 μg ml−1 increased the killing of cultured NC cells by methotrexate. This was not due to displacement of methotrexate from binding sites on the serum proteins. Nor was it due (entirely) to inhibition of prostaglandin synthesis, since flurbiprofen did not mimic the effect. Inhibition of cyclic AMP phosphodiesterase seems unlikely to explain the effect of indomethacin since theophylline had little or no effect on NC cell killing by methotrexate.
Indomethacin 1 μg ml−1 increased the accumulation of tritium in NC cells incubated with [3H]‐methotrexate.
In contrast, with normal epithelial cells from human embryonic intestine, indomethacin 1 μg ml−1 did not alter the cytotoxicity of methotrexate or the accumulation of tritium during incubation with [3H]‐methotrexate.
The beneficial interaction between indomethacin and methotrexate may have therapeutic potential in man.
Coexistence of carriers for dopamine and GABA uptake on a same nerve terminal in the rat brain
Authors: Bonanno Giambattista , Raiteri Maurizio 
Published: July 2012

The ability of γ‐aminobutyric acid (GABA) to affect the release of [3H]‐dopamine in rat brain synaptosomes prepared from corpus striatum, frontal cortex and hypothalamus and prelabelled with the radioactive catecholamine in the presence of desipramine was examined.
GABA (10–300 μm) increased in a concentration‐dependent way the basal release of [3H]‐dopamine from striatum and cortical synaptosomes; however, its effect was much less pronounced in hypothalamic nerve terminals. 2,4‐Diaminobutyric acid (DABA) mimicked GABA although less potently.
Neutral amino acids such as leucine, valine or α‐aminoisobutyric acid (100–300 μm) did not affect or increased minimally the release of [3H]‐dopamine.
The GABA‐induced [3H]‐dopamine release was not prevented by the GABAA‐receptor antagonists, bicuculline or picrotoxin. The GABAA‐receptor agonist, muscimol (10–300 μm), displayed only a very weak, not significant, enhancing effect on [3H]‐dopamine release. The GABAB‐receptor agonist (—)‐ baclofen (100 or 300 μm) had no effect.
Three novel and selective inhibitors of GABA uptake, N‐(4,4‐diphenyl‐3‐butenyl)‐nipecotic acid (SK&F 89976A), N‐(4,4‐diphenyl‐3‐butenyl)‐guvacine (SK&F 100330A) and N‐(4,4‐diphenyl‐3‐butenyl)‐homo‐β‐proline (SK&F 100561) potently counteracted the enhancing effect of GABA on [3H]‐dopamine release. Nipecotic acid also reduced the effect of GABA.
It is concluded that carriers for the uptake of dopamine and GABA may coexist on the same nerve terminal in the rat brain.
A facilitatory effect of bicuculline on the enteric neurones in the guinea‐pig isolated colon
Authors: Frigo G.M. , Galli A. , Lecchini S. , Marcoli M. 
Published: July 2012

Changes in the efficiency of the peristaltic reflex, acetylcholine (ACh) output and motor responses to transmural and periarterial nerve stimulation produced by bicuculline and y‐aminobutyric acid (GABA) receptor desensitization were investigated in the guinea‐pig isolated colon.
Bicuculline, at concentrations unable to affect spontaneous colonic motility and lacking anticholinesterase activity, produced a dose‐dependent increase of both the efficiency of the peristaltic reflex and the stimulated ACh output. Such effects could not be observed in GABA‐desensitized preparations.
A frequency‐dependent potentiation of the cholinergic excitatory and non‐adrenergic non‐cholinergic (NANC) inhibitory responses to transmural stimulation was also observed in the presence of bicuculline. Conversely bicuculline exhibited an inhibitory effect on the relaxation induced by periarterial nerve stimulation.
Acute GABA‐desensitization was unable to affect the contractile responses to transmural stimulation, the ACh output and the efficiency of the peristaltic reflex. On the contrary, desensitization was able to mimic the effects of bicuculline on the inhibitory responses to both transmural and periarterial nerve stimulation.
Our results are consistent with a significant role played by an intrinsic GABAergic pathway in the modulation of both cholinergic excitatory and NANC inhibitory neurones. The hypothesis is advanced that a feed‐back modulation carried out through bicuculline‐sensitive GABAergic synapses could operate during the propagation of peristaltic motor activity.
Muscarinic receptors mediate negative and positive inotropic effects in mammalian ventricular myocardium: differentiation by agonists
Authors: Korth Michael , Kühlkamp Volker 
Published: July 2012

The concentration‐dependence of the negative and positive inotropic effect of choline esters and of oxotremorine was studied in isometrically contracting papillary muscles of the guinea‐pig. The preparations were obtained from reserpine‐pretreated animals and were electrically driven at a frequency of 0.2 Hz.
In the presence of the phosphodiesterase inhibitor 3‐isobutyl‐1‐methyl xanthine (IBMX, 100 μmol I−1), choline esters and oxotremorine produced concentration‐dependent negative inotropic effects. Oxotremorine exhibited the highest negative inotropic potency (with a half‐maximal effective concentration, EC50, of 20 nmol l−1) followed by carbachol (139 nmol l−1), methacholine (490 nmol l−1), acetylcholine in the presence of lO μmol l−1 physostigmine (1.36 μmol l−1 and bethanechol (10 μmol l−1)). Atropine was a competitive antagonist of the negative inotropic effects. Carbachol and oxotremorine decreased Vmax, overshoot and duration of slow Ca2+‐dependent action potentials which had been elicited in the presence of 100 μmol l−1 IBMX.
Choline esters produced a concentration‐dependent positive inotropic effect. With an EC50 of 32 μmol l−1, carbachol was the most potent compound, followed by methacholine (35 μmol l−1), acetylcholine in the presence of 10 μmol l−1 physostigmine (46 μmol l−1) and bethanechol (142 μmol l−1). Compared to carbachol and methacholine which increased force by 100% of control, the increase induced by acetylcholine and bethanechol was only 64 and 58%, respectively. Atropine shifted the concentration‐effect curves of all choline esters to higher concentrations. Choline esters caused intracellular Na+ activity to increase in the quiescent papillary muscle. This effect was reversed by atropine.
Oxotremorine produced a small concentration‐dependent positive inotropic effect (about 30% of the maximal effect of carbachol) which was resistant to atropine. Oxotremorine was a potent inhibitor of the positive inotropic effect of choline esters, and did not cause an increase in intracellular Na+ activity in the quiescent papillary muscle.
The results show that muscarinic receptors of the ventricular myocardium mediate two inotropic effects, which are opposite in direction and differ in their concentration‐dependence by a factor of 100. Although agonists differentiate between both inotropic effects, it is unknown whether the receptors involved represent receptor states or separate receptor subpopulations. The negative inotropic effect of choline esters and of oxotremorine can be best explained by adenylate cyclase inhibition. While stimulation of phosphoinositide hydrolysis might have been responsible for the positive inotropic effect of choline esters via modulation of cation‐fluxes across the cell membrane, such a mechanism was not involved in the positive inotropic effect of oxotremorine.
The effect of nicotine on motoneurones of the immature rat spinal cord in vitro
Authors: Blake J.F. , Evans R.H. , Smith D.A.S. 
Published: July 2012

Nicotine [(–)‐nicotine di(+)‐tartrate 1–50 μm] produced depolarization of motoneurones as recorded from ventral roots of immature (1–5 day old) rat hemisected spinal cord preparations. This action of nicotine was accompanied by marked desensitization which persisted for at least 2 h following a 2 min application.
Ventral roots sectioned from the spinal cord, which were sensitive to glycine, failed to respond to nicotine.
Blockade of regenerative electrical activity with tetrodotoxin produced a mean reduction of 39% in the response to 10 μm nicotine.
In order to avoid desensitization, blocking agents were tested for their ability to suppress the initial response to a 2 min application of 10 μm nicotine (0.58 mV ± 0.07 s.e.mean, 21 preparations) in 4 or more naive preparations. Responses to nicotine (10 μm) were significantly reduced by 10 μm hexamethonium and were abolished by 250 μm hexamethonium but were resistant to the following antagonists:‐ atropine (1 μm), phentolamine (2 μm), strychnine (10 μm), kynurenic acid (2mm) and a mixture of bicuculline (50 μm) and picrotoxin (50 μm).
It is concluded that the depolarizing responses to nicotine may be due to the presence of nicotinic receptors either on the motoneurone membrane or on nerve terminals adjacent to motoneurones which release an unidentified neurotransmitter.
A 7‐phenyl substituted triazolopyridazine has inverse agonist activity at the benzodiazepine receptor site
Authors: Biziere K. , Bourguignon J.J. , Chambon J.P. , Heaulme M. , Perio A. , Tebib S. , Wermuth C.G. 
Published: July 2012

To investigate further the structural requirements for benzodiazepine (BZD) receptor ligands, we synthesized SR95195, [7‐phenyl‐3‐methyl‐1,2,4‐triazolo‐(4,3‐b) pyridazine], a positional isomer of the 6‐phenyl‐triazolo‐pyridazines, which were the first non‐BZD derivatives to exhibit high affinity for the BZD receptor and BZD‐like activity in vivo.
In vitro, SR95195 displaced specifically bound [3H]‐flunitrazepam from rat cerebellar and hippocampal membranes with respective IC50 values of 4 and 8 μm.
In vivo, SR95195 lacked BZD‐like activity. At high doses SR95195 induced clonic seizures in mice (threshold convulsant dose: 150 mg kg−1; CD50: 160 mg kg−1 i.p.) which were antagonized by Ro 15–1788. At non‐convulsant doses (25 mg kg−1 i.p. and 100 mg kg−1 i.p.). SR95195 significantly decreased punished responding in an operant conflict procedure in the rat, suggesting SR95195 has intrinsic anxiogenic activity.
SR95195, in mice, reversed the anticonvulsant and myorelaxant actions of diazepam 3 mg kg−1, orally (respective ED50 values: 45 mg kg−1 i.p. and 44 mg kg−1 i.p.). In an operant‐conflict test in rats, SR95195 at non‐anxiogenic doses, antagonized the disinhibitory action of diazepam 4 mg kg−1, i.p. (ED50: 8.6 mg kg−1, i.p.), but not that of pentobarbitone 15 mg kg−1, i.p.
It is concluded that SR95195 has the pharmacological profile of an inverse BZD agonist and that displacing the phenyl from the 6‐ to the 7‐position in the triazolopyridazine series causes a shift from agonist to inverse agonist type activity at the BZD receptor site.