bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anpirtoline, a novel, highly potent 5‐HT1B receptor agonist with antinociceptive/antidepressant‐like actions in rodents
Authors: Schlicker E. , Werner U. , Hamon M. , Gozlan H. , Nickel B. , Szelenyi L , Göthert M. 
Published: July 2012

The purpose of the present study was to relate the effects of the novel drug, anpirtoline, on 5‐hydroxytryptamine (5‐HT) receptor subtypes to its antinociceptive and antidepressant‐like actions in rodents.
Binding assays with rat brain membranes have shown that anpirtoline bound with a much higher affinity to 5‐HT1B receptors (Ki = 28 nm) than to 5‐HT1A (Ki = 150 nm) and 5‐HT2 (Ki = 1.49 μm) receptors.
Like 5‐HT, anpirtoline concentration‐dependently inhibited forskolin‐stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5‐HT1B receptor antagonists such as propranolol and penbutolol.
In superfused rat and pig brain cortex slices preincubated with [3H]‐5‐HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5‐HT. Whereas 5‐HT was equipotent in both tissues (EC50 = 69 nm), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nm) than in rat brain cortex slices (EC50 = 55 nm). The concentration‐response curve for anpirtoline was shifted to the right by metitepine in both preparations.
In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl‐piperazine were effective in reversing the isolation‐induced impairments in mice, an effect shown only by compounds with agonist properties at the 5‐HT1B receptor.
In the electrostimulated pain test using mice, anpirtoline dose‐dependently increased the pain threshold with an ED50 of 0.52 mg kg−1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol.
In the forced swimming test in rats, anpirtoline induced a dose‐related increase in swimming activity. With an ED50 value of 4.6 mg kg−1, i.p., anpirtoline was 4 times more potent than the two standard compounds imipramine and desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of antidepressant drugs.
Anpirtoline exhibits both antinociceptive and antidepressant‐like activities in animals. It is probable that anpirtoline elicits these pharmacological effects via its agonist effect on 5‐HT1B and 5‐HT1A receptors.
The role of nitric oxide in the regional vasodilator effects of endothelin‐1 in the rat
Authors: Fozard John R. , Part Marie‐Louise 
Published: July 2012

The role of nitic oxide (NO) derived from l‐arginine in the regional vasodilator effects of endothelin‐1 has been investigated in anaesthetized, spontaneously hypertensive (SH) rats in which autonomic reflexes were abolished by ganglion blockade. The experimental design incorporated animals infused with phenylephrine to mimic the peripheral vasoconstrictor effects of the NO biosynthesis inhibitors and a single dose per animal paradigm to obviate problems of tachyphylaxis to the vasodilator effects of endothelin‐1.
Infusion of the inhibitor of NO synthase, N‐monomethyl‐l‐arginine (l‐NMMA) at a dose (5 mg kg−1 min−1) which maximally raised blood pressure did not influence either the fall in blood pressure or the vasodilator responses induced in the hindquarters and carotid vascular beds by endothelin‐1 (1 nmol kg−1, i.v.). The duration (but not the initial magnitude) of the vasodepressor response to endothelin‐1 was however significantly attenuated (by 49%) during infusion of the more potent inhibitor of NO synthase, NG‐nitro‐l‐arginine methyl ester (l‐NAME), 2 mg kg−1 min−1.
Increasing the dose of l‐NAME to 10 and 25 mg kg−1 min−1 significantly attenuated, but did not abolish, the falls in blood pressure and hindquarters vasodilator responses to acetylcholine, 1 μg kg−1, and endothelin‐1, 1 nmol kg−1 min−1. The effects were selective in that vasodepressor responses to the endothelium‐independent vasodilator, sodium nitroprusside, 1–10 μg kg−1 min−1, were unaltered.
The data indicate that NO generated de novo from l‐arginine mediates a significant component of the vasodilator effect of endothelin‐1 in the anaesthetized, ganglion‐blocked SH rat. However, a major component of the vasodepressor effects of both endothelin‐1 and acetylcholine may occur independently of this mechanism.
Platelet‐activating factor (PAF) plays an important role in the immediate asthmatic response in guinea‐pig by augmenting the response to histamine
Authors: Morooka Shigeaki , Uchida Masako , Imanishi Noriaki 
Published: July 2012

To investigate the role of platelet activating factor (PAF) in the immediate asthmatic response, we examined the bronchial reactivity to histamine after administration of PAF to guinea‐pigs or antigen challenge to passively sensitized guinea‐pigs.
A bolus injection of PAF (20–40 ng kg−1), which did not cause a significant increase in intrathoracic pressure (ITP), augmented the bronchial response to histamine almost 8 fold. This airway hyperreactivity was observed even 1 min after PAF treatment.
A subthreshold dose of antigen (0.01 mg kg−1, i.v.) also provoked hyperreactivity to histamine, which became significant 6 and 11 min after the antigen treatment.
The specific PAF‐antagonists, SM‐10661 and CV‐6209 (i.v.) dose‐dependently inhibited both PAF‐and antigen‐induced airway hyperreactivities to histamine.
These results suggest that PAF plays an important role in antigen‐induced acute airway responses by augmenting the activities of spasmogens.
Inhibition by adrenergic neurone blocking agents of the relaxation induced by BRL 38227 in vascular, intestinal and uterine smooth muscle
Authors: Berry J.L. , Small R.C. , Hughes S.J. , Smith R.D. , Miller A.J. , Hollingsworth M. , Edwards G. , Weston A.H. 
Published: July 2012

The adrenergic neurone blocking agents, guanethidine and bretylium, have been tested for inhibitory activity against the actions of some relaxant drugs (BRL 38227, noradrenaline, sodium nitroprusside, theophylline) in vascular, intestinal and uterine smooth muscle.
In guinea‐pig isolated taenia caeci pre‐contracted with KCl (25 mm), BRL 38227 (0.1–10 μm) and noradrenaline (10 nm‐100 μm) each caused concentration‐dependent relaxation. Guanethidine and bretylium (50 μm) each antagonized the relaxation to BRL 38227 but not that to noradrenaline. At high concentration (500 μm), the adrenergic neurone blocking agents antagonized the action of BRL 38227 and, to some extent, that of noradrenaline.
In rat isolated aorta pre‐contracted with noradrenaline (300 nm), BRL 38227 (0.0125–3.2 μm) and sodium nitroprusside (0.3–100 nm) each produced concentration‐dependent smooth muscle relaxation. Guanethidine and bretylium (5–500 μm) each antagonized the action of BRL 38227 without antagonizing that of sodium nitroprusside.
Rats were pretreated with 17‐β oestradiol benzoate. Tension waves were then induced from segments of isolated, oestrogen‐dominated uterus by transmural electrical stimulation or by oxytocin (0.2 nm). These tension waves were inhibited by BRL 38227 (0.025–3.2 μm) or theophylline (0.05–0.8 mm) in a concentration‐dependent manner. Guanethidine (50 μm) antagonized the action of BRL 38227 in both the electrically‐ and oxytocin‐driven tissues. In the electrically‐driven tissues, guanethidine (50 μm) did not antagonize the inhibition to theophylline.
In KCl (25 mm)‐treated guinea‐pig taenia caeci, guanethidine (50 μm) inhibited the efflux of 86Rb+ evoked by BRL 38227 (10 μm) but not that evoked by noradrenaline (10 μm). In contrast, apamin (100 nm) reduced the efflux of 86Rb+ which was promoted by noradrenaline, but did not affect efflux induced by BRL 38227.6 It is concluded that the adrenergic neurone blocking agents, guanethidine and bretylium (each at 50 μm), selectively inhibit the relaxant action of BRL 38227 in vascular, intestinal and uterine smooth muscle. If this inhibition reflects direct blockade of the K+‐channel (KKCO) which is opened by BRL 38227, then the adrenergic neurone blocking agents act as inhibitors selective for KKCO as opposed to the small, apamin‐sensitive (SKCa) and large (BKCa) conductance, Ca2+‐dependent K+‐channels.
The actions of two sensory neuropeptides, substance P and calcitonin gene‐related peptide, on the canine hepatic arterial and portal vascular beds
Authors: Withrington P.G. 
Published: July 2012

The two peptides, calcitonin gene‐related peptide (CGRP) and substance P (SP) were administered individually as bolus injections into the separately perfused hepatic arterial and portal vascular beds of the anaesthetized dog to assess their actions and relative molar potencies at these sites.
CGRP caused an immediate dose‐related increase in hepatic arterial flow when injected close‐arterially, reflecting a fall in resistance. This vasodilator effect was slightly increased by the prior administration of the selective β2‐adrenoceptor antagonist, ICI 118,551.
On a molar basis, CGRP was more potent as an hepatic arterial vasodilator than the non‐selective β‐adrenoceptor agonist, isoprenaline (Iso).
Intra‐portal injection of CGRP also evoked hepatic arterial vasodilatation unaccompanied by other cardiovascular changes.
CGRP in doses up to 10 nmol had no effect on portal vascular resistance when administered intra‐portally.6 SP evoked a rapid, dose‐related increase in hepatic arterial flow when injected intra‐arterially. The molar ED50 for this hepatic vasodilatation was 40.2 fmol, significantly less than the ED50 for either CGRP or Iso. SP was the most potent hepatic arterial vasodilator yet examined. The vasodilator effect of SP was slightly potentiated by prior β2‐adrenoceptor blockade.7 SP caused hepatic arterial vasodilatation when administered by intra‐portal injection; its absolute and relative potency was much reduced.8 SP when injected intra‐portally caused a graded increase in hepatic portal inflow resistance. The molar potency for this portal vasoconstriction was significantly greater than that for noradrenaline (NA); however, the maximum increase in portal resistance was significantly less to SP than to NA.9 In view of the location of the peptides CGRP and SP within the afferent innervation of the liver, it is proposed that they play an important function in controlling the hepatic microvasculature in response to sensory stimuli, particularly those arising from changes in portal blood composition secondary to change in metabolic activity within the gastrointestinal tract (GIT).10 Since the peptides are released from the GIT into the hepatic portal inflow, they may modify hepatic arterial blood flow, the extent of which is related to events within the GIT.
A perfusion system for the long term study of macrophage activation
Authors: Assreuy Jamil , Moncada Salvador 
Published: July 2012

A closed system was developed for perfusing J774 macrophages in columns. The cells were perfused for up to 100 h, at which time they were still viable.
Stimulation with increasing concentrations (0.01–10 μg ml−1) of bacterial lipopolysaccharide (LPS) caused the cells to produce increasing amounts of nitrite in the perfusion medium. This production was time‐dependent, reaching a plateau by 48–50 h.
The nitrite accumulation caused by 0.1 μg ml−1 of LPS was augmented by priming the cells for 2 h with increasing amounts of interferon‐γ. The nitrite accumulation also reached a plateau under these conditions.
N‐iminoethyl‐l‐ornithine (l‐NIO, 30 μm) completely inhibited the accumulation of nitrite whereas dexamethasone (0.3 μm) caused 60–70% inhibition.
Perfusion of the cells without l‐arginine prevented the nitrite accumulation. Replacement of this amino acid after 20 or 50 h of perfusion led to a rapid generation of nitrite, the levels of which continued to increase for the duration of the experiment.6 Thus, the perfusion system can be used to study the kinetics of the activation of the NO synthase and most likely other parameters in J774 cells and probably other cells in culture. An observation already of interest is that the ‘disappearance’ of the NO synthase after its activation can be prevented or reduced by removal of l‐arginine from the medium.
Rabbit isolated renal artery contractions by some tryptamine derivatives, including 2‐methyl‐5‐HT, are mediated by a 5‐HT1‐like receptor
Authors: Tadipatri Sreekanth , Feniuk Wasyl , Saxena Pramod R. 
Published: July 2012

Despite the fact that 5‐hydroxytryptamine (S‐HT)‐induced contractions of the rabbit isolated renal artery are mediated by a receptor belonging to the heterogeneous 5‐HT1‐like category, we observed that the so‐called selective 5‐HT3 receptor agonist, 2‐methyl‐5‐HT, caused a concentration‐dependent contraction of this vessel. This study was therefore undertaken to analyze the effects of 2‐methyl‐5‐HT in the renal artery segments, either quiescent or precontracted with U46619 (10−7 m). α‐Methyl‐5‐HT and 5‐methoxytryptamine, which have high affinities for 5‐HT2 and 5‐HT4 receptors, respectively, were used for comparison.
In the precontracted vessel segments, the maximum contractile responses obtained with 2‐methyl‐5‐HT, α‐methyl‐5‐HT, 5‐methoxytryptamine and 5‐HT were similar to those in the quiescent segments. However the pD2 values were higher in the precontracted segments, making them about 4–100 fold more sensitive.
Neither MDL 72222 (10−6 m) nor tropisetron (3 × 10−6 m) suppressed renal artery contractions elicited by 5‐HT, 2‐methyl‐5‐HT, α‐methyl‐5‐HT or 5‐methoxytryptamine, thus ruling out the involvement of 5‐HT3 as well as 5‐HT4 receptors.
On the other hand, both methiothepin (10−8 and 10−7 m) and ketanserin (10−7 and 10−6 m) caused a rightward shift of agonist concentration‐effect curves. The two antagonists had similar pA2 values against the different agonists tested on either quiescent or precontracted vessels, but ketanserin (apparent pA2: 6.6 to 7.0) was between 20–100 fold less potent than methiothepin (apparent pA2: 8.4 to 8.8).
The results of this functional study permit us to conclude that the contractile effects of 2‐methyl‐5‐HT as well as α‐methyl‐5‐HT and 5‐methoxytryptamine on the rabbit isolated renal artery are mediated by a 5‐HT1‐like receptor. Since, in addition, the reported ligand binding affinity of 2‐methyl‐5‐HT at 5‐HT3 receptors is similar to both the ligand binding affinity and the functional pD2 at 5‐HT1 sites, this compound cannot be regarded as a selective 5‐HT3 receptor agonist. Similarly, α‐methyl‐5‐HT and 5‐methoxytryptamine have only a limited selectivity for 5‐HT2 and 5‐HT4 receptors, respectively.
Investigations into neuropeptide Y‐mediated presynaptic inhibition in cultured hippocampal neurones of the rat
Authors: Bleakman David , Harrison Neil L. , Colmers William F. , Miller Richard J. 
Published: July 2012

We have examined the effects of neuropeptide Y (NPY) on synaptic transmission and [Ca2+]i signals in rat hippocampal neurones grown in culture. [Ca2+]i in individual neurones displayed frequent spontaneous fluctuations often resulting in an elevated plateau [Ca2+]i. These fluctuations were reduced by tetrodotoxin (1 μm) or combinations of the excitatory amino acid antagonists 6‐cyano‐7‐dinitroquinoxaline (CNQX) (10 μm) and aminophosphonovalerate (APV) (50 μm), indicating that they were the result of glutamatergic transmission occurring between hippocampal neurones.
[Ca2+]i fluctuations were also prevented by Ni2+ (200 μm), by the GABAB receptor agonist, baclofen (10 μm) and by NPY (100 nm) or Y2 receptor‐selective NPY agonists. Following treatment of cells with pertussis toxin, NPY produced only a brief decrease in [Ca2+]i fluctuations which rapidly recovered.
Perfusion of hippocampal neurones with 50 mm K+ produced a large rapid increase in [Ca2+]i. This increase was slightly reduced by NPY or by a combination of CNQX and APV. The effects of CNQX/APV occluded those of NPY. NPY had no effect on Ba2+ currents measured in hippocampal neurones under whole cell voltage‐clamp even in the presence of intracellular GTP‐γ‐S. On the other hand, Ba2+ currents were reduced by both Cd2+ (200 μm) and baclofen (10 μm).
Current clamp recordings from hippocampal neurones demonstrated the occurrence of spontaneous e.p.s.ps and action potential firing which were accompanied by increases in [Ca2+]4. This spontaneous activity and the accompanying [Ca2+]i signals were prevented by application of NPY (100 nm). When hippocampal neurones were induced to fire trains of action potentials in the absence of synaptic transmission, these were accompanied by an increase in cell soma [Ca2+]i. NPY (100 nm) had no effect on these cell soma [Ca2+]i signals. NPY (100 nm) also had no effect on inward currents generated in hippocampal neurones by micropipette application of glutamate (50 μm).
Thus, NPY is able to abolish excitatory neurotransmission in hippocampal cultures through a pertussis toxin‐sensitive mechanism. However, no effect of NPY on Ca2+ influx into the cell soma of these hippocampal neurones could be discerned. These results are consistent with a localized presynaptic inhibitory effect of NPY on glutamate release in hippocampal neurones in culture.
Antagonism of synaptic potentials in ventral horn neurones by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione: a study in the rat spinal cord in vitro
Authors: King A.E. , Lopez‐Garcia J.A. , Cumberbatch M. 
Published: July 2012

The rat spinal cord in vitro has been used to assess the effect of 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) on the dorsal root evoked extracellular ventral root reflex (DR‐VRR) and the intracellular excitatory postsynaptic potential (e.p.s.p.) in ventral horn neurones and motoneurones.
CNQX (1–5 μm) produces a selective and dose‐dependent reduction in the amplitude of the monosynaptic component of the DR‐VRR recorded from lumbar spinal segments.
With low intensity dorsal root stimulation CNQX selectively attenuates the amplitude of the short latency intracellular e.p.s.p. (70% reduction, P < 0.005) and its rise‐time (75%, P < 0.01) without affecting the half‐time to decay.
When high intensity stimulation is used CNQX significantly attenuates the amplitude of the e.p.s.p. (56%, P < 0.005), rise‐time (76%, P < 0.01) and abolishes the short latency spike. In addition longer latency synaptic components are attenuated and the half‐time to decay significantly reduced (47%, P < 0.005).
The results with CNQX are compared to d‐aminophosphonovalerate and discussed in relation to the recruitment of low versus high threshold afferents. The data supports an involvement of non‐NMDA receptors in transmission through both mono‐ and polysynaptic pathways in the ventral horn.
Calmidazolium, a calmodulin inhibitor, inhibits endothelium‐dependent relaxations resistant to nitro‐l‐arginine in the canine coronary artery
Authors: Illiano Stephane , Nagao Tetsu , Vanhoutte Paul M. 
Published: July 2012

The role of calmodulin in endothelium‐dependent relaxations in the canine coronary artery, was investigated by use of the inhibitor of calmodulin, calmidazolium.
The endothelium‐dependent relaxations to adenosine diphosphate (ADP) and nebivolol, a β‐adrenoceptor antagonist, in control solution, and to bradykinin in high potassium solution (to inhibit endothelium‐dependent hyperpolarization), were abolished by nitro‐l‐arginine (30 μm), an inhibitor of nitro oxide‐synthase. Calmidazolium (10 μm) did not inhibit these relaxations.
Calmidazolium did not affect the endothelium‐independent relaxations to SIN‐1, an exogenous donor of nitric oxide (NO).
The relaxations to bradykinin and to the calcium ionophore A23187 in control solution were inhibited to a small extent by calmidazolium (10 μm).
Bradykinin and A23187 induced relaxations in the presence of nitro‐l‐arginine (30 μm) that were abolished by calmidazolium (10 μm) but not affected by glibenclamide (10 μm), an inhibitor of ATP‐sensitive K+ channels.6 The endothelium‐independent relaxations to lemakalim, an ATP‐sensitive K+ channel opener, were not affected by calmidazolium (10 μm) but were inhibited by glibenclamide (10 μm).7 These results suggest that calmidazolium does not inhibit the endothelium‐dependent relaxations due to endothelium‐derived NO in the canine coronary artery but inhibits either the production of endothelium‐derived hyperpolarizing factor (EDHF) from endothelial cells or its effects on vascular smooth muscle cells. Furthermore these results suggest that EDHF contributes to endothelium‐dependent relaxations in the canine coronary artery.
Reduced relaxant potency of nitroprusside on pulmonary artery preparations taken from rats during the development of hypoxic pulmonary hypertension
Authors: Wanstall Janet C. , Hughes Ian E. , O'Donnell Stella R. 
Published: July 2012

Relaxant responses to nitroprusside were examined on U46619‐contracted pulmonary artery ring preparations from rats exposed to hypoxia, in chambers containing 10% oxygen, for 1, 3, or 14 days, or for 14 days followed by 12 days in room air. Control rats were housed in room air.
After 3 days of hypoxia (but not 1 day), rats had elevated pulmonary artery pressure, right ventricular hypertrophy and polycythemia. After 14 days of hypoxia there was, in addition, hypertrophy of the pulmonary artery. In rats returned to room air for 12 days after 14 days of hypoxia, there was still some right ventricular and vascular hypertrophy but no increase in pulmonary artery pressure or polycythemia.
The potency (neg log EC50) of nitroprusside on pulmonary arteries taken from rats after 3 or 14 days of hypoxia was significantly less than on preparations from control rats (3 and 11 fold, respectively). This was not seen after 1 day of hypoxia or after 14 days of hypoxia followed by 12 days in room air. Removal of the endothelium from the preparations had no effect on the potency of nitroprusside in control or hypoxic rats (14 days).
In preparations from hypoxic, but not control, rats (14 days), the maximum response to nitroprusside was > 100% (177% reversal of the U46619 contraction) in the absence, but not in the presence, of the endothelium, indicating that pulmonary arteries from hypoxic rats had inherent tone which could be counteracted by a relaxing factor from the endothelium.
Exposure of rats to hypoxia (14 days) did not affect the potency of nitroprusside on aorta or trachea.6 It is concluded that exposure of rats to hypoxia results in reversible desensitization of the vascular smooth muscle of pulmonary artery to nitroprusside. The time course of this desensitization suggests that it is probably associated with the elevated pulmonary artery pressure or maintained hypoxaemia rather than with the vascular hypertrophy.7 It is postulated that the increase in pulmonary artery pressure and/or the maintained hypoxaemia may cause chronic release of nitric oxide from the pulmonary vascular endothelium or smooth muscle resulting in desensitization of soluble guanylate cyclase to the action of nitroprusside.
Effect of the thromboxane A2‐mimetic U46619 on 5‐HT1‐like and 5‐HT2 receptor‐mediated contraction of the rabbit isolated femoral artery
Authors: MacLennan Stephen J. , Martin Graeme R. 
Published: July 2012

The influence of the thromboxane A2‐mimetic U46619 (11α,9α‐epoxymethano PGH2) on 5‐hydroxytryptamine (5‐HT)‐induced contractions of the rabbit isolated femoral artery has been examined.
In the absence of U46619, 5‐HT responses were mediated predominantly by 5‐HT2‐receptors as judged by potent, surmountable antagonism by the selective 5‐HT2 receptor antagonists, spiperone and ketanserin. Both antagonists unmasked a population of 5‐HT1‐like receptors which accounted for approximately 10–15% of the 5‐HT maximum response.
In the presence of U46619 (3–10 nm), 5‐HT‐induced contractions were largely resistant to blockade by 5‐HT2 receptor antagonists since 5‐HT1‐like receptor‐mediated contraction now accounted for approximately 60% of the 5‐HT maximum response.
These results show that activation of thromboxane A2 receptors in a tissue possessing both 5‐HT2 and 5‐HT1‐like receptors can convert 5‐HT‐induced contraction from one mediated predominantly by 5‐HT2 receptors to one which is mediated predominantly by 5‐HT1‐like receptors.