bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of selective cyclic GMP phosphodiesterase inhibition in the myorelaxant actions of M&B 22,948, MY‐5445, vinpocetine and 1‐methyl‐3‐isobutyl‐8‐(methylamino)xanthine
Authors: Souness John E. , Brazdil Roman , Diocee Baljeet K. , Jordan Roy 
Published: July 2012

The mechanism by which M&B 22,948, MY‐5445, vinpocetine and 1‐methyl‐3‐isobutyl‐8‐(methylamino)xanthine (MIMAX), which have been described as selective cyclic GMP phosphodiesterase (PDE) inhibitors, relax rat aorta was investigated.
Three cyclic nucleotide PDEs were identified in the soluble fraction of rat aorta; a Ca2+‐insensitive form exhibiting substrate selectivity for cyclic GMP (cGMP PDE), a Ca2+/calmodulin‐stimulated form which also preferentially hydrolyzed cyclic GMP (Ca2+ PDE), and a form demonstrating substrate selectivity for cyclic AMP (cAMP PDE).
M&B 22,948 and MIMAX inhibited cGMP PDE (Ki = 0.16 μm and 0.43 μm, respectively) and Ca2+ PDE (Ki = 9.9 μm and 0.55 μm, respectively), but exhibited weak activity against cAMP PDE (Ki = 249 μm and 42 μm, respectively). MY‐5445 selectivity inhibited cGMP PDE (Ki = 1.3 μm) and vinpocetine selectively inhibited Ca2+ PDE (Ki = 14 μm).
M&B 22,948 and MIMAX induced dose‐dependent increases in the accumulation of cyclic GMP, but not cyclic AMP, in rat aorta pieces. These effects were greatly reduced by endothelial denudation and by methylene blue (5 μm) which blocks the actions of endothelium‐derived relaxant factor. MY‐5445 and vinpocetine had no effect on rat aorta cyclic GMP or cyclic AMP accumulation.
All four compounds caused dose‐related relaxation of 5‐hydroxytryptamine (10 μm) contracted, endothelium‐intact rat aorta, the effects of M&B 22,948 and MIMAX being greatly reduced by methylene blue (5 μm). Methylene blue also caused 10 fold and 100 fold rightward shifts in the dose‐response curves of MY‐5445 and vinpocetine, respectively.
The results are consistent with the smooth muscle relaxant actions of M&B 22,948 and MIMAX, but not vinpocetine and MY‐5445, being mediated through a mechanism involving inhibition of cyclic GMP hydrolysis.
A patch‐clamp study of effects of dihydroavermectin on Ascaris muscle
Authors: Martin R.J. , Pennington A.J. 
Published: July 2012

Effects of bath‐application of the anti‐parasitic agent 22,23 dihydroavermectin B1a (DHAVM 20 fM to 0.2 μm) on outside‐out and inside‐out patches from collagenase‐treated muscle membranes of Ascaris suum were examined.
DHAVM was tested as a γ‐aminobutyric acid (GABA) agonist by application to outside‐out patches. DHAVM failed to open characteristic GABA channels even when high concentrations (20 nm to 0.2 μm) were used. These high concentrations of DHAVM also failed to potentiate opening of channels activated by application of 3–4 μm GABA; instead they acted to depress GABA‐activated channel currents by reducing mean conductances and Popen.
In outside‐out patches, low concentrations of DHAVM (1 pM to 100 pM) produced opening of 0–13 channels, the number depending on the patch. The progressive opening of channels gave rise to a ‘Staircase’ effect. The conductance of these channels was 9–15 pS and open times were long (greater than 100 mS). Ion substitution experiments showed these channels to be permeable to Cl. The channels were not blocked by 20 μm picrotoxin. There was a long delay (greater than 15 s) between DHAVM application and channel opening; this delay and lipophilic nature of DHAVM suggested a site of action in the lipid phase of the membrane.
The effect of bath‐application of low concentrations of DHAVM on inside‐out patches was investigated under low‐Ca conditions (to avoid Ca‐activated Cl channels). DHAVM (20 fM to 1 nm) did not produce opening of Cl channels but produced opening after a long delay (mean 2.5 minutes) of noisy cation‐selective channels which had conductances of 5–30 pS.
The actions of DHAVM are discussed.
Effects of potassium channel toxins from Leiurus quinquestriatus hebraeus venom on responses to cromakalim in rabbit blood vessels
Authors: Strong P.N. , Weir Sheila W. , Beech D.J. , Hiestand P. , Kocher H.P. 
Published: July 2012

The effects of fractionated Leiurus quinquestriatus hebraeus venom on cromakalim‐induced 86Rb+ efflux in rabbit aortic smooth muscle were examined.
Crude venom (0.1–30 μg ml−1) produced a concentration‐dependent decrease of 1 μm cromakalim‐induced 86Rb+ response. The maximum blocking activity attainable was approximately 60%.
Fractionation of crude venom by gel permeation chromatography and subsequent chromatography on a cation ion‐exchange column, produced two fractions (X and XI), active in the 86Rb+ blocking assay.
Fraction XII contained charybdotoxin (∼85% pure). After a final high performance liquid chromatography (h.p.l.c.) purification step, the purified toxin failed to inhibit the cromakalim‐stimulated 86Rb+ efflux although it was a potent inhibitor of A23187‐induced K+ flux in human erythrocytes and the large conductance calcium‐activated potassium channel in rabbit portal vein smooth muscle.
Subsequent purification of fraction X by h.p.l.c. yielded a minor peak which contained 86Rb+ blocking activity. This subfraction was also capable of inhibiting apamin‐sensitive, angiotensin II‐stimulated K+ flux in guinea‐pig hepatocytes.
It is concluded that the potassium channel opened by cromakalim in rabbit aortic smooth muscle is not blocked by charybdotoxin but by another distinct toxin in the venom of Leiurus quinquestriatus hebraeus.
An electrophysiological comparison of a novel class Ic antiarrhythmic agent, NIK‐244 (ethacizin) and flecainide in canine ventricular muscle
Authors: Satoh Hiroyasu , Ishii Masaaki , Hashimoto Keitaro 
Published: July 2012

Electrophysiological effects of NIK‐244 (ethacizin), a novel class I antiarrhythmic drug, were compared with flecainide in canine ventricular muscle by use of conventional microelectrode techniques.
At concentrations of 10−6 m. or higher, NIK‐244 depressed the maximum rate of rise of depolarization () significantly in a concentration‐dependent manner. Also, the resting potential was depolarized at 10−5 m. NIK‐244 did not have any effect on the other action potential parameters or on the effective refractory period.
Flecainide significantly decreased at 3 × 10−6 m. or higher and the resting potential was depolarized at 10−5 m. Like NIK‐244, flecainide did not affect other action potential parameters.
NIK‐244 and flecainide caused a use‐dependent block of , and the rates of onset of inhibition at 3 Hz stimulation were 0.014 ± 0.002 AP−1 at 2 × 10−6 m. NIK‐244 and 0.021 ± 0.012 AP−1 at 10−5 m. flecainide. Under the same conditions, the time constants of the recovery from use‐dependent block were 27.1 ± 13.3 s and 12.2 ± 2.5 s for NIK‐244 and flecainide, respectively.
These results suggest that NIK‐244, like flecainide, should be classified as a slow kinetic drug and as Ic.
Differences between the α2‐adrenoceptor in rat submaxillary gland and the α2A‐ and α2B‐adrenoceptor subtypes
Authors: Michel Anton D. , Loury Dana N. , Whiting Roger L. 
Published: July 2012

The α2‐adrenoceptors of rat submaxillary gland, labelled with [3H]‐rauwolscine, were characterized by use of a range of subtype selective ligands and were compared to rabbit spleen α2A‐adrenoceptors and rat kidney α2B‐adrenoceptors.
In rat submaxillary gland, [3H]‐rauwolscine labelled an apparently homogeneous population of binding sites with relatively low affinity (Kd = 11.65 nm) compared to the affinity in rat kidney (Kd = 2.18 nm) and rabbit spleen (Kd = 4.64 nm).
In competition studies using 16 ligands the α2‐adrenoceptors in rat submaxillary gland appeared to differ from both the α2A‐adrenoceptor of rabbit spleen (r = 0.62) and also the α2B‐adrenoceptor of rat kidney (r = 0.28).
The affinity data obtained with benoxathian, imiloxan and WB 4101 indicated the presence of an α2B‐adrenoceptor in rat submaxillary gland. However, data for chlorpromazine, oxymetazoline, spiroxatrine and xylometazoline indicated that submaxillary gland α2‐adrenoceptors were of the α2A subtype. The affinity estimate for prazosin in rat submaxillary gland was intermediate between its affinity at the α2A‐ and α2B‐adrenoceptors while affinity estimates for idazoxan and phentolamine in rat submaxillary gland were greater than those obtained at either the α2A‐ or α2B‐adrenoceptor.
These data indicate that rat submaxillary gland α2‐adrenoceptors differ from the α2A‐ and α2B‐adrenoceptors found in rabbit spleen and rat kidney, respectively.
Cycloleucine blocks NMDA responses in cultured hippocampal neurones under voltage clamp: antagonism at the strychnine‐insensitive glycine receptor
Authors: Hershkowitz Norman , Rogawski Michael A. 
Published: July 2012

Radioligand binding studies have demonstrated that the neutral amino acid cycloleucine may act as a competitive antagonist at the glycine modulatory site on the N‐methyl‐D‐aspartate (NMDA) receptor complex. In the present study, we examined the effects of cycloleucine on NMDA‐evoked inward current responses in dissociated hippocampal neuronal cultures using the whole cell voltage‐clamp technique.
In the presence of 1 μm glycine, cycloleucine caused a reversible, dose‐dependent inhibition of NMDA responses with an IC50 of 24 μm. An increase in glycine to 100 μm resulted in a shift to the right of the cycloleucine concentration‐effect curve (IC50, 1.4 mm). However, with cycloleucine concentrations ≤ 100 μm, a fraction of the block could not be overcome by glycine even at concentrations as high as 1 mm.
The cycloleucine block was unaffected by shifts in the holding potential (‐60 to +60mV), and there was no effect of cycloleucine on the reversal potential of the NMDA‐evoked current.
Cycloleucine failed to effect kainic acid‐ and quisqualic acid‐evoked currents at concentrations which inhibited NMDA responses.
We conclude that cycloleucine is a potent and selective antagonist of NMDA‐receptor mediated responses. Although this effect occurs in part via competitive antagonism at the glycine modulatory site, the cycloleucine block cannot be completely reversed by glycine indicating an interaction with an additional site on the receptor‐channel complex.
Convulsions induced by centrally administered NMDA in mice: effects of NMDA antagonists, benzodiazepines, minor tranquilizers and anticonvulsants
Authors: Moreau Jean‐Luc , Pieri Lorenzo , Prud'hon Bernadette 
Published: July 2012

Convulsions were induced reproducibly by intracerebroventricular injection of N‐methyl‐D‐aspartic acid (NMDA) to conscious mice.
Competitive (carboxypiperazine‐propylphosphonic acid, CPP; 2‐amino‐7‐phosphonoheptanoic acid, AP7) and non‐competitive (MK801; phencyclidine, PCP; thienylcyclohexylpiperidine, TCP; dextrorphan; dextromethorphan) NMDA antagonists prevented NMDA‐induced convulsions.
Benzodiazepine receptor agonists and partial agonists (triazolam, diazepam, clonazepam, Ro 16–6028), classical anticonvulsants (diphenylhydantoin, phenobarbitone, sodium valproate) and meprobamate were also found to prevent NMDA‐induced convulsions.
Flumazenil (a benzodiazepine receptor antagonist) and the GABA agonists THIP and muscimol (up to subtoxic doses) were without effect.
Flumazenil reversed the anticonvulsant action of diazepam, but not that of MK801.
Results obtained in this model differ somewhat from those described in a seizure model with systemic administration of NMDA. An explanation for this discrepancy is offered.
This model is a simple test for assessing the in vivo activity of NMDA antagonists and also expands the battery of chemically‐induced seizure models for characterizing anticonvulsants not acting at NMDA receptors.
GABAB‐related activity involved in synaptic processing of somatosensory information in S1 cortex of the anaesthetized cat
Authors: Kaneko T. , Hicks T.P. 
Published: July 2012

The possible role of GABAB receptor mechanisms in information processing in primary somatosensory (S1) cortex was assessed by use of extracellular recording combined with microiontophoretic methods from 161 neurones in anaesthetized, paralysed cats.
Baclofen‐induced suppressions of cell responses were reversible and stereoselective, the (+)‐isomer being inactive and the (−)−isomer having two to three times the apparent potency of γ‐aminobutyric acid (GABA). The responses measured were threshold to natural stimulation of receptive fields (RFs), responsiveness to thalamic electrical stimulation, change in RF size and magnitude of firing elicited by iontophoretic glutamate.
The action of GABA always was mimicked by muscimol or 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP) but not always by (−)−baclofen; in certain cases (−)−baclofen enhanced neuronal responses while the opposite occurred with GABA or with the other GABAA agonists. The elevation of response thresholds by (−)−baclofen was relatively stronger in peripheral than in central subregions of cutaneous RFs, by contrast with the action of muscimol which was relatively non‐selective as to the area in which it was effective.
Glutamate‐induced and thalamically‐evoked cortical responses as well as spontaneous activity were differentially sensitive to the suppressant effects of muscimol and (−)−baclofen.
Bicuculline methiodide reversibly blocked THIP‐ and muscimol‐induced suppressions of tactile‐ (air puffer)‐induced S1 responses but spared those produced by (−)−baclofen. Phaclofen and δ‐amino‐n‐valeric acid were essentially inactive as blockers of (−)−baclofen‐induced effects and in fact often acted as (−)−baclofen‐like agonists, phaclofen being considerably weaker than δ‐amino‐n‐valeric acid in this respect.
The range of suppressant effects produced by GABA as well as by muscimol and THIP, considered in conjunction with the actions of bicuculline methiodide, suggest that the effects observed by ejected GABA are likely to be due principally to GABAA processes, those mediated by GABAB receptors largely being masked. However, GABAB mechanisms are extant and do appear to be active, probably presynaptically and probably at sites distal to the soma.
The role of α‐ and β‐adrenoceptor subtypes in mediating the effects of catecholamines on fasting glucose and insulin concentrations in the rat
Authors: John G.W. , Doxey J.‐C. , Walter D.S. , Reid J.L. 
Published: July 2012

The role of α‐ and β‐adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists.
Adrenaline (0.2 mg kg−1)‐induced hyperglycaemia was abolished by the selective α2‐adrenoceptor antagonist idazoxan (1.0 mg kg−1), unaltered by non‐selective β‐adrenoceptor blockade (propranolol, 1.0 mg kg−1) and potentiated by the selective α1‐adrenoceptor antagonist prazosin (0.3 mg kg−1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol.
The selective α2‐adrenoceptor agonists UK 14304 (0.1 and 0.3 mgkg−1) and BHT‐920 (0.2 and 0.5 mg kg−1) elicited dose‐dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg−1)‐evoked hyperglycaemia was blocked by idazoxan but not by prazosin.
The selective α1‐adrenoceptor agonists methoxamine (0.3 mg kg−1) and phenylephrine (0.3 mg kg−1) failed to modify either plasma glucose or IRI levels.
Isoprenaline (0.2 mg kg−1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg−1) and the selective β2‐adrenoceptor antagonist ICI 118551 (1.0 mg kg−1), but not by the β1‐selective antagonists atenolol (1.0 mg kg−1) and betaxolol (1.0 mg kg−1).
None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg−1).
The results indicate that adrenoceptors do not appear to be involved in regulating basal plasma glucose and IRI concentrations in the fasted rat. However, the effects of catecholamines on these parameters are mediated by α2‐ and β2‐adrenoceptors, whereas α1‐ or β1‐adrenoceptors do not appear to be involved.
The role of prostanoid TP‐ and DP‐receptors in the bronchoconstrictor effect of inhaled PGD2 in anaesthetized guinea‐pigs: effect of the DP‐antagonist BW A868C
Authors: Hamid‐Bloomfield S. , Payne A.N. , Petrovic A.A. , Whittle B.J.R. 
Published: July 2012

In anaesthetized, pump‐ventilated guinea‐pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5–160 μg kg−1) caused a dose‐dependent rise in both heart rate and systemic mean arterial blood pressure with only a small monophasic rise in pulmonary inflation pressure (PIP).
In contrast, inhaled PGD2 (0.1–1 mg ml−1, 30s) provoked a substantial concentration‐dependent Diphasic rise in PIP. The bronchoconstrictor action of inhaled PGD2 was accompanied by minimal cardiovascular effects.
The 3‐benzyl substituted hydantoin BW A868C (0.1–1 mg kg−1 i.v.) a novel prostanoid DP‐receptor antagonist, had no significant effect on the cardiovascular or bronchoconstrictor effects of intravenously administered or inhaled PGD2.
However, BW A868C (0.1–1 mg kg−1 i.v.) did inhibit the hypotensive actions of the DP‐receptor agonist, BW 245C (1–3 μg kg−1 i.v.).
The prostanoid TP‐receptor antagonist BM 13.177 (2.5 mg kg−1 i.v.) strongly inhibited the bronchoconstrictor effect of inhaled PGD2, abolishing the first phase of this response and reducing the peak increase in PIP provoked by PGD2 (0.1 or 1 mg ml−1 for 30s), by 67 ± 16% and 44 ± 5% respectively.
A combination of BW A868C (0.1 or 1 mg kg−1 i.v.) with BM 13.177 (2.5 mg kg−1 i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg−1 i.v.) alone.
Neither bilateral vagotomy, nor selective inhibition of arachidonate cyclo‐oxygenase with indomethacin or 5‐lipoxygenase with the novel acetohydroxamic acid BW A4C, significantly reduced the bronchoconstrictor effect of inhaled PGD2.
These findings indicate that the bronchoconstrictor effect of inhaled PGD2 in guinea‐pigs in vivo is mediated primarily through direct TP‐receptor activation and not through actions on DP‐receptors.
Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: calcium current reduction
Authors: Coulter Douglas A. , Huguenard John R. , Prince David A. 
Published: July 2012

Succinimide derivatives can be either convulsant (tetramethylsuccinimide (TMS)), or anticonvulsant (ethosuximide (ES); α‐methyl‐α‐phenylsuccinimide (MPS)). ES, an anticonvulsant succinimide, has previously been shown to block calcium currents of thalamic neurones, while the convulsant succinimide TMS blocks γ‐aminobutyric acid (GABA) responses in a similar fashion to the convulsant pentylenetetrazol (PTZ).
Using voltage‐clamp techniques, we analysed the effects of the anticonvulsant succinimides ES and MPS and the convulsants TMS and PTZ on calcium currents of acutely isolated thalamic relay neurones of the rat.
MPS and ES reduced low‐threshold calcium current (LTCC) in a voltage‐dependent manner, without affecting steady‐state inactivation. MPS was less potent than ES (IC50 of 1100 vs 200 μm) but greater in efficacy (100% maximal reduction vs 40% for ES).
PTZ had no effect on calcium currents, and TMS only reduced LTCC at very high concentrations, and did not occlude MPS effects when applied concurrently.
These results, which demonstrate that anticonvulsant, but not convulsant, succinimides block LTCC, provide additional support for the hypothesis that LTCC reduction is a mechanism of action of the anticonvulsant succinimides related to their effects in petit mal epilepsy.
Effect of propentofylline (HWA 285) on extracellular purines and excitatory amino acids in CA1 of rat hippocampus during transient ischaemia
Authors: Andiné Peter , Rudolphi Karl A. , Fredholm Bertil B. , Hagberg Henrik 
Published: July 2012

The adenosine uptake blocker propentofylline (HWA 285) has previously been shown to protect hippocampal CA1 pyramidal cells from ischaemia‐induced delayed neuronal death. The influence of propentofylline, on the extracellular concentrations of purines, aspartate and glutamate in the CA1 of the rat hippocampus during transient forebrain ischaemia was investigated.
Twenty min of ischaemia was induced by four‐vessel occlusion in Wistar rats, extracellular compounds were sampled by use of microdialysis and EEG was recorded by a tungsten electrode attached to the dialysis probe.
Propentofylline (10 mgkg−1 i.p.) did not influence the basal levels of any of the compounds in the hippocampal dialysates.
The EEG became isoelectric within 20 s after induction of ischaemia.
Extracellular adenosine, inosine, hypoxanthine, aspartate and glutamate increased several fold during ischaemia and remained elevated during early reflow. Within 2 h of reperfusion the concentration of all compounds was normalized. Xanthine increased upon reperfusion and remained elevated after 2 h.
Propentofylline (10 mg kg−1 i.p.) administered 15 min before ischaemia significantly enhanced the ischaemia‐evoked increase of adenosine but attenuated the increases of the other purine catabolites and of glutamate.
In separate in vitro experiments, propentofylline did not inhibit adenosine deaminase activity.
The present data show that propentofylline enhances extracellular adenosine and lowers extracellular glutamate in vivo during ischaemia. These findings may be important in relation to the neuroprotective properties of propentofylline.
Aging differentially affects direct and indirect actions of endothelin‐1 in perfused mesenteric arteries of the rat
Authors: Dohi Yasuaki , Lüscher Thomas F. 
Published: July 2012

The effects of age on the vascular action of endothelin‐1 were studied in mesenteric resistance arteries of 4,9 and 27 month old Fischer 344 rats.
Third order branches (about 200 μm in diameter) of mesenteric resistance arteries were dissected free and mounted on glass cannulae in organ chambers. Changes in intraluminal diameter of the perfused and pressurized vessels were continuously measured with a video dimension analyzer.
Endothelin‐1 (10−14−3 × 10−8 m.) caused contractions that were augmented after removal of the endothelium. The inhibitory effects of the endothelium were greater in young than in old rats.
The sensitivity of vascular smooth muscle to endothelin‐1 decreased with age, while the maximal response was maintained. In contrast, the contractions to noradrenaline were unaffected by aging.
Threshold concentrations of endothelin‐1 potentiated the contractions evoked by low and moderate concentrations of noradrenaline (10−7−10−6m) in old, but not in young, rats.
Endothelium‐dependent relaxations to acetylcholine inhibited maximal contractions to endothelin‐1 and this effect decreased with age. In contrast, the relaxations to the nitric oxide donor, 3‐morpholinosydnonimine (SIN‐1; the active metabolite of molsidomine), did not differ in the three age groups.
Aging specifically decreases the direct contractile effects of endothelin‐1 and the inhibitory effects of the endothelium against these contractions, while the indirect (potentiating) effects of the peptide become more pronounced.