bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of imiloxan as a selective α2B‐adrenoceptor antagonist
Authors: Michel Anton D. , Loury Dana N. , Whiting Roger L. 
Published: July 2012

The α2‐adrenoceptor binding sites of rabbit spleen and rat kidney, labelled with [3H]‐rauwolscine, were characterized using a range of subtype selective ligands.
In rabbit spleen, the α‐2‐adrenoceptor binding sites displayed high affinity for oxymetazoline and WB 4101 and low affinity for prazosin and chlorpromazine suggesting the presence of an α2A subtype.
There was evidence for heterogeneity of the α2‐adrenoceptor binding sites present in rabbit spleen. The results obtained with oxymetazoline and WB 4101 indicated that at least 75% of the [3H]‐rauwolscine binding sites in this preparation displayed a pharmacology consistent with the presence of an α2A subtype.
In rat kidney, the α2‐adrenoceptor binding sites displayed high affinity for prazosin and chlorpromazine and low affinity for oxymetazoline and WB 4101 suggesting the presence of an α2B subtype.
The inclusion of guanylylimidodiphosphate (Gpp(NH)p, 0.1 mm) did not modify the pharmacology of the α2‐adrenoceptor binding sites present in the two preparations. Furthermore, when the two membrane preparations were combined, the resultant pharmacology was still consistent with the presence of two receptors that retained the characteristics of the α2A and α2B subtypes.
Imiloxan was identified as a selective α2B ligand while benoxathian displayed a high degree of selectivity for the α2A‐adrenoceptor binding site. The selectivity of imiloxan for the α2B‐adrenoceptor binding site, coupled with its specificity for α2‐adrenoceptors, should make it a valuable tool in the classification of α2‐adrenoceptor subtypes.
l‐NG‐monomethyl arginine and l‐NG‐nitro arginine inhibit non‐adrenergic, non‐cholinergic relaxation of the mouse anococcygeus muscle
Authors: Gibson A. , Mirzazadeh Shokoufeh , Hobbs A.J. , Moore P.K. 
Published: July 2012

The effects of l‐NG‐monomethyl arginine (l‐NMMA) and l‐NG‐nitro arginine (l‐NOARG) on non‐adrenergic, non‐cholinergic (NANC) relaxations of the mouse anococcygeus were investigated.
l‐NMMA (10–200 μm) produced a concentration‐related inhibition of the NANC response; the inhibitory effect of 50 μm l‐NMMA was completely reversed by l‐arginine but not d‐arginine (both 100 μm).
l‐NOARG (1–50 μm) also produced a concentration‐related inhibition of the NANC response and was some 30–50 times more potent than l‐NMMA; again, the effects of 10 μm l‐NOARG were reversed by 100 μm l‐, but not d‐, arginine. By itself 100 μm l‐arginine did not relax the tissue, but did cause a slight potentiation of the NANC response.
Sodium nitroprusside (0.01–10 μm), hydroxylamine (0.1–100 μm), sodium azide (1–100 μm) and nitric oxide (3–120 μm) all relaxed carbachol‐induced tone; relaxations to submaximal concentrations of these nitrovasodilators were unaffected by either 50 μm l‐NMMA or 10 μm l‐NOARG.
l‐NOARG 10 μm did not inhibit, but rather potentiated, contractions of the mouse anococcygeus due to stimulation of its sympathetic nerves.
The inhibitory effects of 10 μm l‐NOARG on NANC relaxations were reversed by l‐arginine (by 131%), l‐citrulline (by 75%), l‐arginine methyl ester (by 46%) and l‐homoarginine (by 22%), but were unaffected by a variety of other amino acids and their derivatives (all at 100 μm).
The results provide strong evidence that NANC relaxations of the mouse anococcygeus are mediated by an endogenous nitrate material, probably derived from l‐arginine, and confirm that l‐NOARG provides a very useful and potent drug for the investigation of endogenous nitrate function.
Effects on renal sympathetic axons in dog of acute 6‐hydroxydopamine treatment in combination with selective neuronal uptake inhibitors
Authors: Sunn N. , Harris P.J. , Bell C. 
Published: July 2012

In anaesthetized dogs, we have investigated the effect on renal responses to sympathetic nerve stimulation of acute treatment with the catecholaminergic neurotoxin 6‐hydroxydopamine (2 mg kg−1 i.v.), administered alone or after blockade of neuronal catecholamine uptake pathways for noradrenaline (NA) or dopamine with desmethylimipramine or benztropine, respectively.
Under control conditions, renal nerve stimulation caused renal vasoconstriction, reduced glomerular filtration and sodium and water excretion and caused net efflux of NA and dopamine into the renal venous plasma. Two h after administration of 6‐hydroxydopamine alone, there was abolition of both functional responses and catecholamine efflux during nerve stimulation.
In animals pretreated with desmethylimipramine (1 mg kg−1), 6‐hydroxydopamine had no significant effect on functional responses to renal nerve stimulation and nerve‐evoked efflux of NA was only moderately reduced. Efflux of dopamine was still markedly reduced by 6‐hydroxydopamine, but more variably than occurred without desmethylimipramine treatment.
In animals pretreated with benztropine (0.2 mg kg−1), nerve‐evoked efflux of dopamine, but not that of NA, was protected against reduction by 6‐hydroxydopamine. A higher dose of benztropine (1 mg kg−1) protected efflux of both NA and dopamine against 6‐hydroxydopamine.
We conclude that acute treatment with a low dose of 6‐hydroxydopamine is an effective method of inactivating peripheral sympathetic nerves. The differential effects of desmethylimipramine and benztropine in preserving nerve‐evoked efflux of NA and dopamine after 6‐hydroxydopamine support the view that these catecholamines originate predominantly from different intrarenal axons. However, neither uptake blocker appears to be completely specific in its actions.
Influence of two β‐adrenoceptor antagonists, propranolol and pindolol, on cold adaptation in the rat
Authors: Kortelainen Marja‐Leena , Huttunen Pirkko , Lapinlampi Tuomo 
Published: July 2012

Adult male rats were treated with propranolol (2.0 mg kg−1 day−1 i.p.), pindolol (0.2 mg kg−1 May−1 i.p.) or 0.9% NaCl day−1 i.p. and exposed to +4°C for 42 days, or treated with 0.9% NaCl day−1 i.p. and kept at +23°C for 42 days. They were weighed once a week, when a 24 h urine sample was also collected and colon temperature measured.
Urinary noradrenaline (NA), adrenaline (Ad) and dopamine were analysed by high‐performance liquid chromatography with an electrochemical detector. After the acclimatization period the interscapular brown adipose tissue was excised and weighed and the activity of the oxidative enzymes succinate dehydrogenase and cytochrome oxidase measured.
The pindolol‐treated and propranolol‐treated rats gained weight during the cold‐acclimatization period. The amount of interscapular brown adipose tissue increased in the cold, but the increase was lowest in the pindolol‐treated group. No changes were seen in the other brown adipose tissue parameters in cold‐exposed animals. The excretion of catecholamines followed the same pattern in all three cold‐exposed groups, with an initial rise in noradrenaline and adrenaline excretion and a slight rise in dopamine excretion.
The results suggest possible connections between β‐adrenoceptor antagonists, weight gain and cold acclimatization. Pindolol had a slight inhibitory effect on cold‐induced brown adipose tissue hypertrophy in rats.
RS 30026: a potent and effective calcium channel agonist
Authors: Patmore Leslie , Duncan Greig P. , Clarke Brendan , Anderson Amanda J. , Greenhouse Robert , Pfister Jürg R. 
Published: July 2012

A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine‐induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive.
RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2nm.
Compounds were also evaluated for their effects on guinea‐pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10−9 and 10−6 m (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10−6 m (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10−10 and 10−7 m.
Calcium channel currents in single embryonic chick myocytes were recorded by whole‐cell voltage clamp techniques. RS 30026 (100 nm‐500 nm) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nm) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nm) were much less marked.
Analysis of the activation characteristics of currents showed parallel shifts in the activation curve to more negative potentials in the presence of 50 nm Bay K 8644, with a much smaller shift in the presence of 500 nm Bay K 8644. RS 30026 (100 and 500 nm) caused concentration‐dependent shifts in the activation of the calcium channel currents with an increase of the slope of the curve.
RS 30026 appears to be the most potent and effective calcium channel agonist described to date.
Ciguatoxin enhances quantal transmitter release from frog motor nerve terminals
Authors: Molgó Jordi , Cornelia Joan X. , Legrand Anne Marie 
Published: July 2012

Ciguatoxin (CTX), a marine toxin produced by the benthic dinoflagellate Gambierdiscus toxicus, is responsible for a complex endemic disease in man known as ciguatera fish poisoning. In the present study we have investigated the effects of purified CTX extracted for Gymnothorax javanicus moray‐eel liver on frog isolated neuromuscular preparations with conventional electrophysiological techniques.
CTX (1–2.5 nm) applied to cutaneous pectoris nerve‐muscle preparations induced, after a short delay, spontaneous fibrillations of the muscle fibres that could be suppressed with 1 μm tetrodotoxin (TTX) or by formamide to uncouple excitation‐contraction.
In preparations treated with formamide, CTX (1–2.5 nm) caused either spontaneous or repetitive muscle action potentials (up to frequencies of 60–100 Hz) in response to a single nerve stimulus. Recordings performed at extrajunctional regions of the muscle membrane revealed that during the repetitive firing a prolongation of the repolarizing phase of the action potential occurred. At junctional sites the repetitive action potentials were triggered by repetitive endplate potentials (e.p.ps).
CTX (2.5 nm) caused a TTX‐sensitive depolarization of the muscle membrane.
In junctions equilibrated in solutions containing high Mg2+ + low Ca2+, addition of CTX (1.5 nm) first induced an average increase of 239 ± 36% in the mean quantal content of e.p.ps. Subsequently CTX reduced and finally blocked nerve‐evoked transmitter release irreversibly.
CTX (1.5–2.5 nm) increased the frequency of miniature endplate potentials (m.e.p.ps) in junctions bathed either in normal Ringer, low Ca2+‐high Mg2+ medium or in a nominally Ca2+‐free solution containing EGTA. Extensive washing with toxin‐free solutions did not reverse the effect. Furthermore, Cd2+ (0.1 mm), a potent calcium channel blocker, neither antagonized nor abolished the increase in transmitter release caused by CTX.
TTX (1 μm) completely prevented the effect of CTX (2.5 nm) on m.e.p.p. frequency. This effect was independent of the presence of extracellular Ca2+. TTX, when added after CTX (2.5 nm) exposure, antagonized the increase in m.e.p.p. frequency. The antagonism was complete in Ca2+‐free medium. These results strongly suggest that increased permeability of the nerve terminal to Na+ is responsible for the increase in m.e.p.p. frequency caused by CTX. It is likely that CTX may trigger calcium release from internal stores due to an increase of intraterminal Na+ concentration.
It is concluded that CTX exerts, in the nanomolar concentration range, a selective action on sodium channels of the neuromuscular junction causing both pre‐ and postsynaptic effects.
Different effects of prostaglandins on adrenergic neurotransmission in atrial and ventricular preparations
Authors: Mantelli Laura , Amerini Sandra , Ledda Fabrizio 
Published: July 2012

The effects of prostaglandin E2 (PGE2) and iloprost on the cardiac response to adrenergic nerve stimulation in guinea‐pig atrial and ventricular preparations have been studied.
In guinea‐pig isolated atria both PGE2 (0.1–10 nm) and iloprost (0.1–3 μm) concentration‐dependently reduced the cardiac response to adrenergic nerve stimulation.
The inhibition of cyclo‐oxygenase by indomethacin and acetylsalicylic acid potentiated the response to nerve stimulation in the atrial preparations.
Arachidonic acid (1–10 μm) reduced the response to nerve stimulation in atria. This effect was prevented by indomethacin and acetylsalicylic acid.
In guinea‐pig ventricles PGE2 and iloprost were found to be effective at higher concentrations than in atrial preparations: arachidonic acid, indomethacin or acetylsalicylic acid did not modify the cardiac response to adrenergic nerve stimulation.
These results suggest a different modulator role for endogenous prostaglandins in atrial and ventricular tissue.
(+)‐Hydrastine, a potent competitive antagonist at mammalian GABAA receptors
Authors: Huang Jun‐Hua , Johnston Graham A.R. 
Published: July 2012

(+)‐Hydrastine is a phthalide isoquinoline alkaloid, isolated from Corydalis stricta. It has the same 1S,9R configuration as the competitive GABAA receptor antagonist bicuculline and is the enantiomer of the commercially available (−)‐hydrastine.
(+)‐Hydrastine (CD50 0.16 mg kg−1, i.v.) was twice as potent as bicuculline (CD50 0.32 mg kg−1, i.v.) as a convulsant in mice. This action was stereoselective in that (+)‐hydrastine was 180 times as potent as (−)‐hydrastine.
(+)‐Hydrastine was a selective antagonist at bicuculline‐sensitive GABAA receptors in the guinea‐pig isolated ileum. It did not influence phaclofen‐sensitive GABAB receptors or acetylcholine receptors in this tissue. (+)‐Hydrastine was a competitive antagonist of GABAA responses (pA2 6.5) more potent than bicuculline (pA2 6.1).
When tested against the binding of [3H]‐muscimol to high affinity GABAA binding sites in rat brain membranes, (+)‐hydrastine (IC50 2.37 μm) was 8 times more potent than bicuculline (IC50 19.7 μm).
As an antagonist of the activation of low affinity GABAA receptors as measured by the stimulation by GABA of [3H]‐diazepam binding to rat brain membranes, (+)‐hydrastine (IC50 0.4 μm) was more potent than bicuculline (IC50 2.3 μm).
(+)‐Hydrastine, 10 nm to 1 mm, did not inhibit the binding of [3H]‐(−)‐baclofen to GABAB binding sites in rat brain membranes.
Actions of cocaine on rat nucleus accumbens neurones in vitro
Authors: Uchimura N. , North R.A. 
Published: July 2012

Intracellular recordings were made from 103 neurones of the rat nucleus accumbens in vitro.
Dopamine (3–100 μm; in sulpiride, 1 μm) hyperpolarized neurones (79%) by acting at D1 receptors: dopamine (3–100 μm; in SCH23390, 1 μm) depolarized neurones (55%) by acting at D2 receptors. 5‐Hydroxytryptamine (1–100 μm) depolarized 86% neurones.
Both actions of dopamine as well as the effect of 5‐hydroxytryptamine were potentiated by cocaine (0.3–30 μm), which had no effect of its own on membrane potential.
Dose‐ratio was computed as [(concentration of agonist causing a 4 mV potential change in cocaine)/(concentration of agonist causing a 4 mV potential change without cocaine)]. Cocaine (1–30 μm) caused the same dose‐ratio whether dopamine depolarizations (D2) or hyperpolarizations (D1) were measured; the dose‐ratio ranged from 2 (1 μm) to 50 (30 μm).
Responses to 5‐hydroxytryptamine were increased more than responses to dopamine; cocaine 1 μm gave a dose‐ratio of 13.4 and at 30 μm gave a dose‐ratio of 118.
It is concluded that cocaine acts to inhibit the uptake of dopamine and 5‐hydroxytryptamine in slices of rat nucleus accumbens; lower concentrations of cocaine (0.3 to 1 μm) are particularly effective in potentiating the action of 5‐hydroxytryptamine.
Effect of cyclo‐oxygenase blockade on the renal actions of vasopressin and SK&F 105494 in the rhesus monkey
Authors: Brooks David P. , Caldwell Nancy C. , Koster Paul F. , Albrightson‐Winslow Christine R. , Kinter Lewis B. 
Published: July 2012

Vasopressin administration to pentobarbitone‐anaesthetized, hydrated female rhesus monkeys resulted in dose‐dependent increases in urine osmolality and decreases in urine flow. Treatment with indomethacin at a dose (5 mg kg−1, i.v.) that reduced urinary prostaglandin E2 (PGE2) excretion by at least 70% did not alter these responses.
The vasopressin antagonist, SK&F 105494 (Pas1,6d‐Tyr(Et)2Val4Arg7d‐Arg8desGly9 arginine vasopressin; 10 μg kg−1), caused significant rightward shifts (P < 0.05) of both the vasopressin‐urine osmolality and the vasopressin‐urine flow dose‐response curves. Treatment with indomethacin did not alter these responses.
SK&F 105494 alone or after indomethacin treatment had minimal effects on urine osmolality and urine flow.
The data indicate that indomethacin does not alter the antidiuretic activity of vasopressin in the rhesus monkey and that SK&F 105494 is a potent antagonist of exogenous vasopressin with minimal agonist activity.
Rat hippocampal muscarinic autoreceptors are similar to the M2 (cardiac) subtype: comparison with hippocampal M1, atrial M2 and ileal M3 receptors
Authors: Richards M.H. 
Published: July 2012

Affinity constants for 15 non‐selective or putatively selective muscarinic antagonists were determined at muscarinic autoreceptors and postsynaptic receptors (linked to phosphatidylinositol (PI) hydrolysis) in rat hippocampal slices, at muscarinic receptors mediating contractility in guinea‐pig atria or ileal smooth muscle and at binding sites in rat cerebral cortical membranes labelled with [3H]‐1‐quinuclidinyl benzilate or [3H]‐pirenzepine.
Comparison of the affinities of these antagonists at central M1 receptors (inositol‐monophosphate formation in rat hippocampal slices) with their affinities at peripheral M1 receptors (inhibition by McN‐A‐343 of electrically stimulated twitches in rabbit vas deferens) provides support for the suggestion that these receptors may differ pharmacologically.
Comparison of affinity constants obtained by displacement of specifically bound [3H]‐pirenzepine from rat cerebral cortical membranes with those obtained in functional tests showed poor correlations between affinities for binding sites and for functional atrial receptors or for hippocampal autoreceptors. A significant correlation was found between affinities for [3H]‐pirenzepine binding and those determined at muscarinic receptors linked to PI turnover in rat hippocampus. A significant correlation was also obtained between the affinities for specific [3H]‐pirenzepine binding sites in cortical membranes and the affinities at ileal receptors.
Comparison of the affinity values for muscarinic autoreceptors in rat hippocampus with affinity values obtained from in vitro models of muscarinic receptor subtypes showed no significant correlations between these autoreceptors and either M1 or M3 receptors. A significant correlation was found between antagonist affinities for hippocampal autoreceptors and muscarinic receptors in the heart. Therefore, muscarinic autoreceptors in rat hippocampus are pharmacologically similar to the M2 (cardiac) muscarinic receptor subtype.
The role of the epithelium in modulating the responses of guinea‐pig trachea induced by bradykinin in vitro
Authors: Bramley Andrew M. , Samhoun Marwa N. , Piper Priscilla J. 
Published: July 2012

The effect of removing the epithelium on the responses of the guinea‐pig isolated trachea (GPT) to bradykinin (BK) and prostaglandin E2 (PGE2) was investigated.
BK (3 pmol–10 nmol) induced dose‐related relaxations of the intact (with epithelium), and contracted the rubbed (without epithelium) preparation of GPT. Similar responses were also obtained with PGE2 (0.3–3.0 nmol).
Indomethacin (1.4 μm) modified the BK‐induced response of intact GPT, from a relaxation to a contraction, but inhibited the BK‐induced contraction of the rubbed GPT.
There was a significant increase in PGE2 release from the intact GPT following stimulation with BK.
Removal of the epithelium from the GPT significantly reduced both basal and BK‐induced generation of PGE2.
The induction of tone in the rubbed GPT by addition of acetylcholine (ACh) caused BK and PGE2 (0.3 nmol–3 nmol) to produce relaxations of the tissue.
Salbutamol (10−8 m‐10−6 m) reduced the relaxations induced by BK on intact GPT, in a concentration‐dependent manner.
These results suggest that both tone and an epithelial‐dependent cyclo‐oxygenase mechanism are important in modulating BK‐induced responses of GPT.
Pharmacological analysis of [3H]‐senktide binding to NK3 tachykinin receptors in guinea‐pig ileum longitudinal muscle‐myenteric plexus and cerebral cortex membranes
Authors: Guard Steven , Watson Stephen P. , Maggio John E. , Too H. Phon , Watling Keith J. 
Published: July 2012

The binding properties and pharmacological specificity of the selective NK3 tachykinin receptor agonist [3H]‐senktide ([3H]‐succinyl[Asp6,MePhe8] substance P (6–11)) have been examined in homogenates of guinea‐pig ileum longitudinal muscle‐myenteric plexus (LM/MP) and cerebral cortex.
Scatchard analysis of saturation binding studies in guinea‐pig ileum LM/MP and cerebral cortex membranes indicated that [3H]‐senktide bound to a single site with apparent high affinity, KD = 2.21 ± 0.65 nm; Bmax = 13.49 ± 0.04 fmol mg−1 protein in ileum and KD = 8.52 ± 0.45 nm; Bmax = 76.3 ± 1.6 fmol mg−1 protein in cortex (values are means ± ranges; n = 2).
The pharmacological profile for tachykinins and analogues in displacing [3H]‐senktide from ileum membranes was: [MePhe7] neurokinin B > neurokinin B (NKB) ≃ senktide > eledoisin > substance P (SP) > neurokinin A(NKA) > physalaemin > [Sar9,Met(O2)11]SP > [Nle10]NKA(4–10) = [Glp6,L‐Pro9]‐SP(6–11) > substance P methyl ester, consistent with [3H]‐senktide binding to an NK3 subtype of tachykinin receptor. A similar rank order of affinity was obtained for these peptides in displacing [3H]‐senktide from cortex membranes
Several tachykinin receptor agonists were tested for their ability to displace [3H]‐senktide from ileal and cortical NK3 binding sites and were found to be either weak displacers (pIC50 < 5.00) or inactive.
The binding of [3H]‐senktide to cortex membranes was inhibited by GTP (pIC50 = 6.49)and GTP‐γ‐S (pIC50 = 6.67) with ATP being at least three orders of magnitude less potent (pIC50 = 3.55).
These results indicate that both central and peripheral NK3 receptors share a similar pharmacological specificity and that they may be labelled selectively with the NK3 receptor agonist [3H]‐senktide.