bluuebunny/crossref_metadata_2025_split huggingface dataset:
The glycine/NMDA receptor antagonist, R‐(+)‐HA‐966, blocks activation of the mesolimbic dopaminergic system induced by phencyclidine and dizocilpine (MK‐801) in rodents
Authors: Bristow L.J. , Hutson P.H. , Thorn L. , Tricklebank M.D. 
Published: July 2012

The effects of the glycine/N‐methyl‐d‐aspartate (NMDA) receptor antagonist, R‐(+)‐HA‐966 on the neurochemical and behavioural responses to phencyclidine (PCP) and dizocilpine (MK‐801) have been determined in rodents.
In rats, pretreatment with PCP (5 and 10 mg kg−1) or MK‐801 (0.25 and 0.5 mg kg−1) dose‐dependently stimulated dopamine turnover in nucleus accumbens, amygdala and medial prefrontal cortex, but had no effect in striatum. In contrast, pretreatment with (+)‐HA‐966 (10 and 30 mg kg−1) did not affect dopamine turnover in any brain region investigated.
Pretreatment with (+)‐HA‐966 (10 and 30 mg kg−1) significantly antagonized the stimulation of dopamine turnover induced by both PCP (10 mg kg−1) and MK‐801 (0.5 mg kg−1) in rat nucleus accumbens, amygdala and medial prefrontal cortex.
Intracerebral dialysis studies in conscious rats demonstrated that systemic injection of PCP (10 mg kg−1) markedly stimulated dopamine release from the nucleus accumbens, an effect that was abolished by pretreatment with (+)‐HA‐966 (30 mg kg−1).
Pretreatment with PCP (3–30 mg kg−1) or MK‐801 (0.1–1.6 mg kg−1) significantly increased locomotor activity in mice. In contrast, subcutaneous injection of (+)‐HA‐966 (10–100 mg kg−1) failed to stimulate activity.
Pretreatment with (+)‐HA‐966 (10 and 30 mg kg−1) dose‐dependently antagonized both PCP (10 mg kg−1) and MK‐801 (0.4 mg kg−1) induced hyperactivity in mice.
Blockade of PCP‐induced hyperactivity by (+)‐HA‐966 is unlikely to be explained by the induction or potentiation of sedation/ataxia since PCP‐induced rotarod deficits were not significantly different in mice pretreated with (+)‐HA‐966 (30 mg kg−1) or saline.
The results demonstrate that (+)‐HA‐966 antagonizes both the neurochemical and behavioural effects of PCP and MK‐801, possibly through interactions at the glycine/NMDA receptor.
Prejunctional modulation of the nitrergic innervation of the canine ileocolonic junction via potassium channels
Authors: De Man Joris G. , Boeckxstaens Guy E. , Pelckmans Paul P. , De Winter Benedicte Y. , Herman Arnold G. , Van Maercke Yvan M. 
Published: July 2012

The effects of different K+ channel blockers were studied on nitric oxide (NO)‐mediated non‐adrenergic non‐cholinergic (NANC) relaxations in the canine ileocolonic junction.
The non‐selective blockers of K+ channels, 4‐aminopyridine (4‐AP) and tetraethylammonium (TEA) and the blocker of large conductance Ca2+‐activated K+ channels, charybdotoxin, potently enhanced the NANC relaxations induced by low frequency stimulation. The blocker of small conductance Ca2+‐activated K+ channels, apamin, had no effect on electrically‐induced NANC relaxations.
NANC nerve‐mediated relaxations induced by adenosine 5′‐triphosphate (ATP), acetylcholine (ACh) and γ‐aminobutyric acid (GABA) were significantly enhanced by 4‐AP and charybdotoxin but not by apamin. TEA significantly enhanced the NANC relaxations in response to GABA and ATP while that in response to ACh was abolished.
None of the K+ channel blockers had an effect on the dose‐response curve to NO, on the noradrenaline‐induced contraction or on the relaxation to nitroglycerine (GTN).
From these results we conclude that inhibition of prejunctional K+ channels increases the nitrergic relaxations induced by electrical and chemical receptor stimulation of NANC nerves and thus suggests a regulatory role for these prejunctional K+ channels in the release of NO from NANC nerves in the canine ileocolonic junction.
Adenylate cyclase‐mediated vascular responses of rabbit aorta, mesenteric artery and skin microcirculation
Authors: Wilson A.J. , Warren J.B. 
Published: July 2012

The importance of adenylate cyclase‐mediated vascular relaxation in the macro and microcirculation was assessed in rabbit aortic and coeliac artery bioassay rings in vitro and skin microvessels in vivo.
The neuropeptide pituitary adenylate cyclase‐activating polypeptide (PACAP38), the β‐agonist, isoprenaline, and the prostaglandins, PGE1 and PGE2, were compared with the activity of nitroprusside, which acts by stimulating guanylate cyclase.
In aortic tissue the relative relaxant potencies were (−log m EC50, 100% = response to nitroprusside 10−6 m): nitroprusside 7.0, PACAP38 6.8, isoprenaline 6.3; PGE1 and PGE2 were weak constrictors. In coeliac artery rings relative potencies were (−log m EC50, 100% = response to nitroprusside 10−5 m): PACAP38 6.6, PGE1 6.6, nitroprusside 6.5, PGE2 4.9, and isoprenaline 4.3.
Comparative potencies when injected into anaesthetized rabbit skin in vivo were (−log mol/site required to increase blood red cell flux by 75%): PACAP38 13.0, PGE2 10.7, isoprenaline 9.7, PGE1 9.1, nitroprusside < 7.
Nitroprusside, the most effective relaxant tested in the aorta, was 107 fold less potent than PACAP in its effect on skin blood flow. PGE1 and PGE2 were constrictors of the aorta, of intermediate effect in the coeliac artery, but potent vasodilators of the microcirculation.
In this model, the importance of adenylate cyclase‐mediated vascular relaxation increases with decreasing vessel size.
Enhancement by calcitonin gene‐related peptide of nicotinic receptor‐operated noncontractile Ca2+ mobilization at the mouse neuromuscular junction
Authors: Kimura Ikuko , Tsuneki Hiroshi , Dezaki Katsuya , Kimura Masayasu 
Published: July 2012

The involvement of calcitonin gene‐related peptide (CGRP) in the mechanism of nicotinic acetylcholine receptor‐operated noncontractile Ca2+ mobilization (not accompanied by twitch tension) was investigated by measuring Ca2+‐aequorin luminescence at the neuromuscular junction of mouse diaphragm muscle treated with neostigmine.
Noncontractile Ca2+ transients were enhanced by 4‐aminopyridine (100 μm), a K+ channel blocker, and inhibited by botulinum toxin (1–100 μg, i.p.) and hexamethonium (10–100 μm), a neuronal nicotinic receptor antagonist.
Noncontractile Ca2+ transients were diminished by CGRP8–37 (10–20 μm), a CGRP antagonist. CGRP (0.3–10 nm) prolonged the duration of noncontractile Ca2+ transients. The effect of CGRP was suppressed by CGRP8_37 (0.1 μm).
Noncontractile Ca2+ transients were inhibited by H‐89 (0.1–1 μm), a protein kinase‐A inhibitor. The catalytic subunit of protein kinase‐A and AA373 (300 μm), a protein kinase‐A activator, prolonged the duration of noncontractile transients. The prolongations either by CGRP or by AA373 were not observed in the presence of H‐89 (0.1 μm).
Contractile (accompanied by twitch tension) but not noncontractile Ca2+ transients were decreased by 12‐O‐tetradecanoyl phorbol 13‐acetate (TPA, 0.3–1 μm), a protein kinase‐C activator. Phospholipase A2 increased only contractile Ca2+ transients. Calmodulin‐related agents affected neither type of Ca2+ transients.
These results provide the first evidence that nicotinic acetylcholine receptor‐operated noncontractile Ca2+ mobilization is promoted by nerve‐released CGRP activating protein kinase‐A, and is dependent on the accumulated amounts of acetylcholine at the neuromuscular junction where desensitization might readily develop.
Differential effects of acetylcholine, nitric oxide and levcromakalim on smooth muscle membrane potential and tone in the rabbit basilar artery
Authors: Plane Trances , Garland Christopher J. 
Published: July 2012

Endothelium‐dependent hyperpolarization of smooth muscle cells in isolated, pre‐contracted segments of rabbit basilar artery in response to acetycholine (100 μm) was abolished in the presence of glibenclamide (10 μm).
Acetylcholine‐evoked relaxation was unaffected by either glibenclamide or 65 mm potassium chloride, indicating that the change in membrane potential did not form an essential component of relaxation and that high concentrations of potassium did not inhibit the release or action of endothelium‐derived relaxing factor in this vessel.
Saturated solutions of nitric oxide (NO) gas in solution (150 μm), which evoked maximal relaxation of arterial segments pre‐contracted and depolarized by noradrenaline (10–100 μm), did not alter the membrane potential of either unstimulated or depolarized smooth muscle cells.
The potassium channel opener levcromakalim, evoked concentration‐dependent relaxation and hyperpolarization in pre‐constricted smooth muscle cells. The threshold concentrations for hyperpolarization and relaxation, the EC50 values and the maximally effective concentration of levcromakalim (around 30 nm, 150 nm and 10 μm, respectively) were not significantly different, and both components of the response were inhibited by glibenclamide (10 μm), indicating a close coupling between the two responses.
In the presence of 65 mm potassium chloride, the hyperpolarization to levcromakalim was abolished, while a small relaxation (25 ± 4%) persisted, indicating an additional mechanism for relaxation to this agent.
These results show that different mechanisms underlie the relaxant action of potassium channel openers, NO and endothelium‐derived factors in cerebral arteries and provide further evidence that in the basilar artery, in contrast to some other vessels, endothelium‐dependent hyperpolarization to acetylcholine is not important for smooth muscle relaxation.
Characterization of receptors for endothelins in the perfused arterial and venous mesenteric vasculatures of the rat
Authors: D'Orléans‐Juste Pedro , Claing Audrey , Warner Timothy D. , Yano Mitsuo , Télémaque Sabine 
Published: July 2012

Endothelin−1 and −3 induced marked arterial and venous constrictions in the perfused mesenteric vasculature of the rat with endothelin‐3 being at least 20 times less active than endothelin‐1, on both arterial and venous sides of the vasculature.
Two ETB selective agonists, BQ‐3020 and IRL 1620 (500 pmol), induced weak constrictions of the venous mesenteric vasculature and were inactive in the arterial side at doses up to 1000 pmol.
In mesenteric vasculatures precontracted with either methoxamine (arterial side) or the thromboxane A2‐mimetic, U46619 (venous side), acetylcholine or bradykinin produced vasodilatations of both arterial and venous vessels, whereas endothelin‐3 induced vasodilatations only on the arterial side.
A selective ETA receptor antagonist, BQ‐123, blocked, in a concentration‐dependent and reversible fashion, the vasoconstrictions induced by endothelin‐1 on both sides of the mesenteric circulation (IC50; arterial side: 0.013 μm; venous side: 0.032 μm).
In contrast, the vasodilator responses induced by endothelin‐3 on the arterial side of the precontracted mesenteric vasculature were not affected by BQ‐123.
The present study illustrates the presence of ETA receptors which are responsible for vasoconstriction by endothelins in the arterial and venous mesenteric vasculatures. Furthermore, we suggest that the vasodilatations induced by endothelin‐3 in the arterial vasculature uniquely, are ETB receptor‐mediated.
Effect of a calcitonin gene‐related peptide antagonist (CGRP8–37) on skin vasodilatation and oedema induced by stimulation of the rat saphenous nerve
Authors: Escott K. Jane , Brain Susan D. 
Published: July 2012

The effect of the calcitonin gene‐related peptide antagonist (CGRP8–37, 400 nmol kg−1, i.v.) on the increased blood flow induced by calcitonin gene related peptide (CGRP), vasodilator prostaglandins, and topical capsaicin was measured with a laser Doppler blood flow meter in rat abdominal skin.
The saphenous nerve was electrically stimulated and the effect of CGRP8–37 (400 nmol kg−1, i.v.) on the increased blood flow (measured by laser Doppler flowmetry) and oedema formation (measured by the extravascular accumulation of [125I]‐albumin) was investigated in the rat hind paw.
CGRP8–37 (400 nmol kg−1, i.v.) had no effect on basal cutaneous blood flow at uninjected sites and sites injected with Tyrode buffer, but acted selectively to inhibit the increased blood flow induced by intradermal CGRP (10 pmol/site, P < 0.05), but not that induced by prostaglandin E2 (PGE2, 300 pmol/site) or carba‐prostacyclin (cPGI2, 100 pmol/site).
Capsaicin (0.1–33 mm), applied topically, acted in a dose‐related manner to increase blood flow. CGRP8–37 (400 nmol kg−1, i.v.) almost totally inhibited blood flow induced by capsaicin (10 mm; P < 0.05) but did not significantly inhibit blood flow induced by a higher dose of capsaicin (33 mm).
The increased blood flow induced by short stimulation of the saphenous nerve (10 V, 1 ms, 2 Hz for 30 s) was inhibited by 76%, 5 min after i.v. CGRP8–37 (400 nmol kg−1, i.V., P < 0.05).
A longer (5 min) electrical stimulation of the saphenous nerve caused oedema formation, in addition to increased blood flow. The oedema formation was significantly inhibited by CGRP8–37 (400 nmol kg−1, i.v., P < 0.05).
The results suggest that the potent microvascular vasodilator neuropeptide, CGRP, is responsible for the increased blood flow observed after short stimulation of the saphenous nerve and that endogenous CGRP contributes in a pro‐inflammatory manner to neurogenic oedema formation in the rat hind paw.
Structural features important for the biological activity of the potassium channel blocking dendrotoxins
Authors: Hollecker Michelle , Marshall David L. , Harvey Alan L. 
Published: July 2012

Dendrotoxins from mamba snake venoms are small proteins that block neuronal K+ channels. In order to investigate structural features associated with their biological activity, partially folded versions of dendrotoxins I and K from black mamba (Dendroaspis polylepis) were prepared by selectively reducing one or more of their three S‐S bonds.
The modified toxins were tested for ability to compete with 125I‐labelled native toxin I to high affinity binding sites on rat brain synaptosomal membranes and for the ability to increase acetylcholine release in a neuromuscular preparation.
Binding affinity increased progressively as the toxins folded to the native conformation and the most biologically active of the modified species were those in which only the disulphide bond between residues 14 and 38 was not formed. These intermediates had native‐like conformations as determined by circular dichroism but still had about 5–10 times lower affinity than native toxins.
Addition of negatively charged groups to block the free sulphydryls at positions 14 and 38 caused a further, marked loss of activity.
The results are consistent with the existence of two important regions in the dendrotoxin molecules. The region containing two of the disulphide bonds (around Cys5‐Cys55 and Cys30‐Cys51) and much of the secondary structure is essential for the binding affinity of the toxins, while the region around Cys14 and Cys38, equivalent to part of the antiprotease site of the homologous protease inhibitor from bovine pancreas (BPTI), plays an important role in the potency of dendrotoxins.
Muscarinic effect of atrial natriuretic peptide on rabbit airways
Authors: Robichaud A. , Saunier C. , Michoud M.C. , du Souich P. 
Published: July 2012

The aim of the present work was to investigate under which circumstances atrial natriuretic peptide (ANP) modulates airway resistance.
Of the six groups of rabbits (n = 5) studied, three received an infusion of ANP (80 ng min−1 kg−1 i.v.) for a period of 100 min, while the other three were infused with the vehicle. Before receiving the infusion of ANP or the vehicle, the animals were pretreated with atropine (0.5 mg kg−1 i.v.), propranolol (2 mg kg−1 i.v.) or not pretreated. After 75 min of infusion of ANP, bronchoconstriction was induced by inhalation of histamine. Respiratory resistance (Rrs) was measured before and 3, 5, 10, 15 and 20 min post‐histamine challenge.
Following 75 min of ANP infusion, plasma ANP concentration increased from 153 ± 52 (mean ± s.e.mean) to 1441 ± 203 pg ml−1 (P < 0.05) without affecting baseline Rrs. Control Rrs values (12.5–20.4 cmH2O l−1 s) were significantly increased following the inhalation of histamine (P < 0.001). By themselves, atropine, propranolol or ANP did not modify the histamine‐induced increase in Rrs. However, when the animals were pretreated with atropine, ANP infusion significantly reduced the increase in Rrs induced by histamine (30 ± 2 vs 51 ± 6 cmH2O l−1 s; P < 0.05).
These data suggest that ANP has an indirect modulating effect on the airway smooth muscle and will decrease Rrs when muscarinic receptors are blocked.
Effects of antidepressants on the inward current mediated by 5‐HT3 receptors in rat nodose ganglion neurones
Authors: Fan Ping 
Published: July 2012

Effects of three different categories of antidepressants, imipramine (tricyclic), fluoxetine (selective 5‐hydroxytryptamine (5‐HT) uptake inhibitor), phenelzine and iproniazid (monoamine oxidase (MAO) inhibitor) on the inward current mediated by 5‐HT3 receptors were investigated in rat nodose ganglion neurones. The whole‐cell patch‐clamp technique was used for recording the 5‐HT current.
All the antidepressants tested inhibited the peak 5‐HT current. The inhibition gradually reached a steady level and the recovery was incomplete when antidepressants were removed. IC50 values for imipramine, fluoxetine and phenelzine were 0.54 μm, 1.3 μm and 4.2 μm respectively. The correspondent Hill coefficients were 0.9, 0.87 and 0.92.
The antidepressants examined increased the rate of 5‐HT current desensitization. IC50 values for imipramine, fluoxetine and phenelzine on the decrease in desensitization time constant were 0.11 μm, 0.18 μm and 2.4 μm respectively. The correspondent Hill coefficients were 0.9, 1.14 and 1.06.
Intracellular applications of the protein kinase inhibitor, H‐7 (100 μm), GDP‐β‐S (2 mm) and the calcium chelator BAPTA (20 mm) did not affect the 5‐HT current and the actions of antidepressants on 5‐HT current.
These results suggest that the 5‐HT3 receptor is an acting site for the therapeutic use of antidepressants. The present observation is also helpful in explaining the analgesic effect of antidepressants seen in pain clinics.
Typical and atypical NK1 tachykinin receptor characteristics in the rabbit isolated iris sphincter
Authors: Hall Judith M. , Mitchell Debra , Morton Ian K.M. 
Published: July 2012

A contraction of the rabbit isolated iris sphincter smooth muscle follows activation of either tachykinin NK1 or NK3 receptors. We have here characterized the pharmacological activity profiles of various tachykinin receptor agonists considered to have NK1‐receptor‐preferring activity in this preparation.
Two groups of NK1‐receptor‐preferring agonists could be distinguished in terms of a common pharmacological profile. The first group (Group 1) included [Glp6,l‐Pro9]‐SP(6–11) (septide), [Glp6]‐SP (6–11), substance P methyl ester, δ‐aminovaleryl‐[l‐Pro9, N‐MeLeu10]‐SP(7–11) (GR73632), and [Apa9–10]‐SP. The second group (Group 2) included [Pro9]‐SP, substance P, physalaemin and ranamargarin.
Under control conditions, the responses to Group 1 agonists were relatively fast in offset (time for reversal of maximal responses, 11.2–18.2 min), and were antagonized by NK1‐receptor‐selective antagonists (range of pKB estimates vs various agonists; GR82334, 7.1–8.2; (±)‐CP‐96,345, 8.9–9.5; RP67580, 7.0–7.4). Following incubation of the tissue with phenoxybenzamine (20 μm, 10 min), the affinity of GR82334, tested against the Group 1 agonists, substance P methyl ester and septide, was not significantly different (P < 0.05; n = 7–18) to that determined in untreated tissues (substance P methyl ester pKB 7.5 ± 0.1 and 7.2 ± 0.2, respectively; septide 7.7 ± 0.2 and 7.9 ± 0.2, respectively). Further, response offset times (5.0–8.5 min) were little reduced as compared to those observed in untreated tissues.
Under control conditions, the response to Group 2 agonists was markedly slow in offset (times for reversal of maximal responses, 51.4–70.4 min), and was not attenuated significantly by the NK1‐receptor‐selective antagonists GR82334 (1 μm), (±)‐CP‐96,345 (0.1 μm) or RP67580 (1 μm). In contrast, after phenoxybenzamine pretreatment, responses to Group 2 agonists reversed rapidly (times for reversal of maximal responses, 13.1–24.2 min), and were now antagonized by GR82334 (pKB estimates, 6.4–7.1).
The responses to the NK3‐receptor‐selective agonist Succ‐[Asp6,Me‐Phe8]‐SP(6–11) (senktide) were relatively fast in offset (time for reversal of maximal response was 18.6 ± 1.7 min) and were not inhibited by GR82334 (10 μm; n = 5). The contractile response resulting from co‐application of the Group 1 agonist, septide together with senktide, did not exhibit prolonged response offset kinetics.
Assuming simple competition at equilibrium, these data from the rabbit iris smooth muscle could be explained either by interaction of the various ligands with two separately‐existing NK1 receptor‐subtypes or ‐isoforms; or alternatively by a preferential interaction of the two agonist groups with different binding domains on a common NK1 receptor.
Relaxation of guinea‐pig trachea by cyclic AMP phosphodiesterase inhibitors and their enhancement by sodium nitroprusside
Authors: Turner Nicholas C. , Lamb Janine , Worby Angela , Murray Kenneth J. 
Published: July 2012

The effects of agents that elevate either cyclic AMP (the phosphodiesterase (PDE) III inhibitor siguazodan, salbutamol) or cyclic GMP (sodium nitroprusside (SNP)) on the relaxant activity of the PDE IV inhibitor, rolipram, were investigated in carbachol (0.1 μm) precontracted guinea‐pig tracheal sheets.
Rolipram, siguazodan and SNP caused concentration‐related reductions in tone of tissues precontracted with 0.1 μm carbachol (EC50 values 12.5; 2.73 and 0.35 μm respectively). Whilst the concentration‐response relationship for the PDE III inhibitor, siguazodan, was monophasic that of the PDE IV inhibitor, rolipram, was biphasic.
The relaxant activity of rolipram was markedly enhanced in the presence of 10 μm siguazodan (EC50 < 0.01 μm), 0.1 μm salbutamol (EC50 0.03 μm) and 0.3 μm SNP (EC50 0.03 μm). In contrast, the relaxant activity of siguazodan was unaffected by SNP and only modestly enhanced by rolipram (10 μm) and salbutamol (0.1 μm).
The relaxant activity of SNP was enhanced by the PDE V inhibitor SK&F 96231 (30 μm: EC50 0.06 μm) and rolipram (30 μm, EC50 0.08 μm) but was unaffected by 30 μm siguazodan.
At concentrations up to 10 μm, neither siguazodan nor rolipram elevated tracheal cyclic AMP levels. However, the combination of 10 μm rolipram and siguazodan caused a two fold increase in the cyclic AMP content (from 2.19 to 4.36 pmol cyclic AMP mg−1protein). SNP (0.1–10 μm) failed to produce a significant increase in tracheal cyclic AMP levels. At 0.1 μm the effect of SNP on tracheal cyclic AMP levels was significantly (P < 0.05) increased in the presence of rolipram but not siguadozan.
The results indicate that the relaxant effects of rolipram are markedly enhanced by agents that inhibit PDE III activity or elevate cyclic GMP. They support the hypothesis that SNP potentiates the effects of rolipram via the inhibitory action of cyclic GMP on hydrolysis of cyclic AMP by PDE III. The findings also suggest that whilst PDE III may be more significant in regulating basal smooth muscle tone in the absence of any exogenous stimulus to cyclic AMP accumulation, PDE IV activity may be more tightly coupled to the pool of adenylyl cyclase stimulated by β2‐adrenoceptor agonists.