bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of changing extracellular levels of magnesium on spontaneous activity and glutamate release in the mouse neocortical slice
Authors: Smith D.A.S. , Connick J.H. , Stone T.W. 
Published: July 2012

The mouse neocortical slice preparation, maintained in a two compartment, grease gap bath, exhibits spontaneous depolarizing activity (with or without rhythmic after potentials) after perfusion with magnesium‐free artificial cerebrospinal fluid.
If the magnesium concentration is decrementally lowered over an extended time period, then incrementally raised following a similar time course, the spontaneous depolarizing shift activity shows a hysteresis (with regard to both frequency and amplitude), the depolarizing shifts being more resistant to magnesium during the the incremental period.
The amino acid content of the perfusing fluid was analysed by high performance liquid chromatography (h.p.l.c.). Although a basal efflux of 6 amino acids was quantifiable, only glutamate levels increased following superfusion of the preparation with magnesium‐free, artificial cerebrospinal fluid.
Glutamate release increased to 266% of the resting release in the presence of magnesium within the first 12 min of the change into magnesium‐free artificial cerebrospinal fluid. This increase in release preceded the onset of spontaneous depolarising activity. The release of glutamate remained elevated at 182% of control up to 60 min after perfusion with magnesium‐free buffer, when depolarizing activity was well established.
A model is presented and discussed for the genesis and maintenance of the spontaneous depolarizing shifts. It is suggested that the maintenance of this spontaneous activity reflects a long term enhancement of neocortical neurone excitability which may be related to long term potentiation in the hippocampus.
Differential control and calcium‐dependence of production of endothelium‐derived relaxing factor and prostacyclin by pig aortic endothelial cells
Authors: White David G. , Martin William 
Published: July 2012

Production of endothelium‐derived relaxing factor (EDRF) by primary cultures of pig aortic endothelial cells was assessed indirectly by measuring endothelial cyclic GMP content, and prostacyclin production was measured by radioimmunoassay of 6‐keto prostaglandin F1α (6‐keto PGF1α).
The resting level of cyclic GMP fell significantly following removal of extracellular calcium (1 mM EGTA present), but elevations of cyclic GMP content induced by sodium azide (10 μm) or atriopeptin II (10 nm) were similar in the absence and presence of extracellular calcium.
Haemoglobin (10 μm) reduced the resting level of cyclic GMP in the presence, but not the absence of extracellular calcium. M&B 22,948 (100 μm), superoxide dismutase (30 u ml−1), bradykinin (0.1 μm), ATP (10 μm) and ionophore A23187 (0.1 μm) each induced an increase in endothelial cyclic GMP content that was reduced in the absence of extracellular calcium.
In cascade bioassay experiments using endothelial cells on microcarrier beads and perfused in columns, continuous infusion of bradykinin (0.1 μm) induced release of EDRF, assayed on rabbit aortic rings, that was maximal after 2 min and still detectable up to about 16 min.
In the presence of extracellular calcium, the time course of bradykinin (0.1 μm)‐stimulated production of EDRF, assessed as endothelial cyclic GMP content was maximal within 1 min, declined thereafter, but was still significant after 30 min. Production of 6‐keto PGF1α, measured simultaneously, rose rapidly but was complete within 3 min.
In the absence of extracellular calcium the resting endothelial content of cyclic GMP fell, but resting production of 6‐keto PGF1α was unaffected. The rise in cyclic GMP content stimulated by bradykinin (0.1 μm) was lower than when calcium was present and was complete within 3 min, but the magnitude and time course of bradykinin (0.1 μm)‐stimulated production of 6‐keto PGF1α was unaffected.
In the presence of TMB‐8 (100 μm) resting endothelial content of cyclic GMP rose slightly, but production of 6‐keto PGF1α fell. The bradykinin (0.1 μm)‐stimulated increase in cyclic GMP content was augmented, but the stimulation of 6‐keto PGF1α production was blocked. Results from cascade bioassay experiments confirmed that TMB‐8 (100 μm) did not inhibit bradykinin‐induced production of EDRF.
The data suggest that resting production of EDRF but not prostacyclin is dependent upon the presence of extracellular calcium. Bradykinin‐stimulated production of EDRF is sustained and requires the presence of extracellular calcium, but stimulated production of prostacyclin is transient and may result from discharge of an intracellular pool of calcium.
The vascular endothelial cell appears therefore to control differentially production of EDRF and prostacyclin.
Effects of propafenone on electrical and mechanical activities of single ventricular myocytes isolated from guinea‐pig hearts
Authors: Honjo Haruo , Watanabe Toshifumi , Kamiya Kaichiro , Kodama Itsuo , Toyama Junji 
Published: July 2012

The effects of propafenone on the transmembrane action potential and sarcomere shortening during twitch contraction were investigated in single ventricular myocytes isolated from guinea‐pig hearts.
Propafenone at low concentrations (3–5 × 10−7 m) slightly lengthened action potential duration (APD), but shortened it at higher concentrations. The shortening of APD was accompanied by an attenuation of sarcomere shortening during twitch contraction.
Propafenone (>10−6 m) caused a concentration‐dependent decrease in the maximum upstroke velocity () of the action potential. In the presence of propafenone (3 × 10−6 m), trains of stimuli led to an exponential decline in A time constant for the recovery of from the use‐dependent block was 4.8 s.
In myocytes treated with propafenone (3 × 10−6 m), the of test action potentials preceded by the conditioning clamp pulses to 0mV was progressively decreased by increasing the duration of single clamp pulse or by increasing the number of multiple brief clamp pulses.
These findings suggest that propafenone has use‐dependent inhibitory action on the sodium channel by binding to the channel during both activated and inactivated states, and that the unbinding rate is comparable to that of Class‐I antiarrhythmic drugs with intermediate kinetics. Propafenone may also have an inhibitory action on calcium and potassium channels.
GR32191, a highly potent and specific thromboxane A2 receptor blocking drug on platelets and vascular and airways smooth muscle in vitro
Authors: Lumley P. , White B.P. , Humphrey P.P.A. 
Published: July 2012

The thromboxane A2 (TP)‐receptor blocking activity and specificity of action of GR32191 ([1R‐[1α(Z),2β,3β,5α]]‐(+)−7‐[5‐([1,1′‐biphenyl]‐4‐ylmethoxy)−3‐hydroxy‐2‐(1‐piperidinyl)cyclopentyl]‐4‐heptonoic acid has been evaluated in human platelets and various smooth muscle preparations, both vascular and non‐vascular, from a range of species including man.
Utilising a platelet counting method to assess aggregation the drug was found to antagonise, in a surmountable manner, human platelet aggregation produced by the TP‐receptor agonists, U‐46619, EP171 and SQ26655, in whole blood and physiological buffer, with pA2 values of approximately 8.3 and 8.7 in the two media respectively. In the presence of GR32191 the rate of aggregation induced by U‐46619 was slowed.
The effect of GR32191 upon U‐46619‐induced platelet shape change and aggregation in plateletrich plasma was evaluated utilising a turbidometric technique. Both shape change and aggregation were antagonised by GR32191. At relatively high concentrations of the drug a slowing of aggregation and shape change to U‐44619 was seen and an unsurmountable antagonism became apparent.
The action of GR32191 upon human platelets was specific with platelet aggregation induced by adenosine 5′‐diphosphate, platelet activating factor, vasopressin and adrenaline and the inhibitory effects of prostacylin (PGI2), prostaglandin D2 (PGD2) and N‐ethylcarboxamide‐adenosine (NECA) being unaffected by concentrations of the drug as high as 10 μm. Furthermore, at concentrations of up to 100 μm, the drug itself produced no shape change or aggregation, of human platelets.
GR32191 also specifically and potently antagonised in a competitive, surmountable manner the contractile actions of U‐46619 upon human vascular smooth muscle and antagonised U‐46619‐induced contractions of vascular and airways smooth muscle preparations from rat, dog, guinea‐pig and rabbit with varying potency. This is discussed in terms of possible heterogeneity of TP‐receptors.
GR32191 therefore represents a highly potent and specific TP‐receptor blocking drug. This profile of action, coupled to its long duration of effect in man described elsewhere, make it an ideal drug tool for elucidating the physiological and pathophysiological role of thromboxane A2.
Investigation of the central sites at which morphine acts to cause hypertension in conscious rabbits
Authors: May C.N. , Whitehead C.J. , Dashwood M.R. , Mathias C.J. 
Published: July 2012

In conscious rabbits intracerebroventricular (i.c.v.) morphine (10 and 50 μg kg−1) caused a dose‐related increase in plasma noradrenaline and adrenaline, respiratory depression and sedation. The increase in sympatho‐adrenal outflow resulted in hypertension accompanied by bradycardia and the increase in adrenaline secretion caused hyperglycaemia. Morphine (1 μg kg−1 i.c.v.) and i.c.v. saline had no effect.
The same doses of morphine given intracisternally (i.c.) caused bradycardia and a similar degree of respiratory depression to i.c.v. morphine, but no significant increase in blood pressure and only a small, gradual rise in plasma adrenaline.
Intravenous naloxone (1 mg kg−1) did not block the hypertension, hyperglycaemia or increase in plasma catecholamines that followed i.c.v. morphine, but prevented the respiratory depression and sedation.
Ganglionic blockade with pentolinium prevented the rise in plasma catecholamines, blood pressure and plasma glucose induced by i.c.v. morphine.
These findings demonstrate that the increased sympathoadrenal outflow following i.c.v. morphine results from an action on periventricular structures. The resultant increase in plasma catecholamines, which is largely naloxone resistant, accounts for the hypertension and hyperglycaemia. The bradycardia is probably partly baroflex mediated and partly due to an increase in vagal tone as a result of stimulation of brainstem opioid receptors. The respiratory depression is probably due to an action of morphine on brainstem opioid receptors.
Effects of adenosine on polymorphonuclear leucocyte function, cyclic 3′:5′‐adenosine monophosphate, and intracellular calcium
Authors: Nielson Christopher P. , Vestal Robert E. 
Published: July 2012

Inhibition of human polymorphonuclear leucocyte (PMN) function by adenosine was studied with respect to effects of adenosine on intracellular cyclic AMP and calcium during the PMN respiratory burst.
The adenosine analogue 5′‐N‐ethylcarboxamide‐adenosine (NECA) and L‐N6‐phenyl‐isopropyladenosine (L‐PIA) inhibited PMN oxygen metabolite generation with relative potencies (NECA > adenosine > L‐PIA) characteristic of an A2 receptor.
The respiratory burst was inhibited by adenosine when PMN were activated by calcium ionophore or chemotactic peptide but not when cells where activated by oleoyl‐acetyl‐glycerol (OAG).
Adenosine increased intracellular cyclic AMP during the PMN respiratory burst regardless of whether cells were stimulated by ionophore, chemotactic peptide or OAG.
To determine whether the differences in cell inhibition by adenosine were related to differences in intracellular calcium mobilization by each activating agent, calcium was evaluated with the fluorescent probe, indo‐1. Adenosine suppressed the increase in intracellular calcium following PMN activation by calcium ionophore or chemotactic peptide. In contrast, calcium did not increase in PMN activated by OAG and adenosine did not affect intracellular calcium changes following this stimulus.
These results demonstrate that physiological concentrations of adenosine inhibit the PMN respiratory burst in association with an increase in intracellular cyclic AMP and reduction of intracellular calcium.
The ability of denbufylline to inhibit cyclic nucleotide phosphodiesterase and its affinity for adenosine receptors and the adenosine re‐uptake site
Authors: Nicholson C.D. , Jackman S.A. , Wilke R. 
Published: July 2012

Denbufylline has been examined for its ability to inhibit cyclic nucleotide phosphodiesterase isoenzymes from rat cardiac ventricle and cerebrum, as well as for its affinity for adenosine A1 and A2 receptors and the re‐uptake site. For comparison, SK&F 94120, theophylline and 3‐isobutyl‐1‐methyl‐xanthine (IBMX) were examined as phosphodiesterase inhibitors whilst N6‐cyclohexyladenosine, R(−)‐N6‐(2‐phenylisopropyl)‐adenosine, 5′‐N‐ethylcarboxamido‐adenosine, 2‐nitrobenzylthioinosine, theophylline and IBMX were examined for their affinity for adenosine binding sites.
This investigation confirmed the presence of four phosphodiesterase activities in rat cardiac ventricle; in rat cerebrum only three were present.
Denbufylline selectively inhibited one form of Ca2+‐independent, low Km cyclic AMP phosphodiesterase. The form inhibited was one of two present in cardiac ventricle and the sole one in cerebrum. This form was not inhibited by cyclic GMP. The inotropic agent SK&F 94120 selectively inhibited the form of cyclic AMP phosphodiesterase which was inhibited by cyclic GMP present in cardiac ventricle. Theophylline and IBMX were relatively non‐selective phosphodiesterase inhibitors.
Denbufylline was a less potent inhibitor of ligand binding to adenosine receptors than of cyclic AMP phosphodiesterase. This contrasted with theophylline, which had a higher affinity for adenosine receptors, and IBMX which showed no marked selectivity. Denbufylline, theophylline and IBMX all had a low affinity for the adenosine re‐uptake site.
Denbufylline is being developed as an agent for the therapy of multi‐infarct dementia. The selective inhibition of a particular low Km cyclic AMP phosphodiesterase may account for the activity of this compound.
Phentolamine and structurally related compounds selectively antagonize the vascular actions of the K+ channel opener, cromakalim
Authors: McPherson Grant A. , Angus James A. 
Published: July 2012

The effects of cromakalim, a novel vasodilator agent believed to open K+ channels, were studied in a range of large and small arteries in vitro. In dog isolated coronary artery, precontracted with U46619 (a thromboxane A2‐mimetic), cromakalim caused concentration‐dependent relaxation which could be inhibited by phentolamine (10–100 μm).
The ability of phentolamine to antagonize cromakalim was selective since it did not affect responses to a number of other vasodilators including isoprenaline, nitroprusside or nicorandil.
The effect of phentolamine was not related to its α‐adrenoceptor blocking actions since other α‐adrenoceptor antagonists (prazosin 10 μm, rauwolscine 10 μm and phenoxybenzamine 1 μm) failed to influence the action of cromakalim.
A number of compounds structurally related to phentolamine were also able to block the vasorelaxant response to cromakalim in the dog isolated coronary artery. The rank order of potency was alinidine = phentolamine = ST91 > tramazoline = naphazoline. Clonidine and tolazoline were inactive. The most potent compounds (alinidine and phentolamine) were effective only at concentrations above 1 μm.
Electrophysiological studies, in which resting membrane potential and tension were measured simultaneously, were carried out on rat isolated femoral artery. Phentolamine (30 μm) antagonized both the vasorelaxation and hyperpolarization caused by cromakalim.
These results suggest that phentolamine and some structurally related compounds, may inhibit K+ channel opening, an action which would account for their ability to antagonize the actions of cromakalim. Such compounds may prove useful in determining the role of K+ channels in regulating vascular smooth muscle tone in vivo and in vitro.
The dihydropyridine niguldipine modulates calcium and potassium currents in vascular smooth muscle cells
Authors: Klöckner U. , Isenberg G. 
Published: July 2012

Vascular smooth muscle cells were isolated from the portal vein and from pial vessels of the cow. They were voltage‐clamped with a single patch electrode technique (whole cell recording) in order to analyse the effects of niguldipine on ionic membrane currents. Due to adsorption of niguldipine to plastic and glass, the effective concentrations are lower than the nominal concentrations by a factor of about 3.
Niguldipine reduced Ca‐currents (ICa of the L‐type, voltage operated) at nominal concentrations > 0.1 μm up to a complete block at 1 μm (50% block at 0.4 μm). Nominal concentrations between 50 and 200 nm facilitated ICa (‘Ca‐agonistic effect’). The Ca‐agonistic effects of niguldipine showed modest use‐ but strong voltage‐dependence.
Niguldipine increased the outward currents at nominal concentrations >10nM. The extra outward currents reversed at −85 mV, the result suggesting that niguldipine had increased potassium currents, IK. Maximal facilitation of IK by niguldipine was about 400% and was obtained at 1 μm, half‐maximal facilitation was obtained with a nominal concentration of 20 nm.
Both reduction of ICa and facilitation of IK may contribute to vasodilatation by niguldipine. Due to its greater sensitivity, the effects on IK may dominate.
Classification of tachykinin receptors in muscularis mucosae of opossum oesophagus
Authors: Daniel E.E. , Cipris S. , Manaka Y. , Bowker P. , Regoli D. 
Published: July 2012

Muscularis mucosae of the distal oesophagus of the opossum contracts in response to substance P and to a variety of tachykinins. To delineate the nature of the receptors present in this tissue, we evaluated contractile responses to substance P, neurokinin A, neurokinin B, eledoisin and analogues believed to be highly selective for NK‐1, NK‐2 and NK‐3 receptors. In addition, the effects of prolonged exposure to each of these agents (10−6 m or 10−5m) on contractile responses to substance P and to itself were evaluated. Similarly effects of prolonged exposure to the various tachykinins and their analogues on the field‐stimulated responses of this muscle were studied.
All naturally occurring tachykinins were full agonists and differed in potency (comparing ED50 values) by less than ten fold. In nearly all cases there was cross tachyphylaxis between substance P and the other tachykinins and each reduced tonic responses to field stimulation, a response previously shown to be mediated by a substance P like agent. Eledoisin failed to cause tachyphylaxis under the conditions of these experiments.
When highly selective tachykinin analogues were used, only that believed to activate NK‐1 receptors was a full agonist. [β‐Ala4,Sar9,MetO211]SP(4–11) was also only slightly less potent than substance P. In contrast, an agonist selective for NK‐2 (NK‐A) receptors, [Nle10]NKA(4–10), and one selective for NK‐3 (NK‐B) receptors, [β‐Asp4,MePhe7]NKB(4–10) were unable to produce a response equal to 50% of the maximum even at 10−5m. However, all three selective tachykinin analogues reduced responses to substance P but not to carbachol. They usually reduced both phasic and tonic responses to field stimulation.
We conclude, based on this and earlier study, that the tachykinin receptors of opossum oesophagus muscularis mucosae recognize all naturally occurring tachykinins but may represent only NK‐1 receptors. The ability of analogues selective for other types of tachykinin receptors to reduce responses to substance P raises the possibility that their selectivity depends in part on diminished efficacy rather than totally on diminished affinity at some classes of receptor.
Effects of capsaicin pretreatment on neuropeptides and salivary secretion of rat parotid glands
Authors: Ekström Jörgen , Ekman Rolf , Håkanson Rolf , Luts Anders , Sundler Frank , Tobin Gunnar 
Published: July 2012

‘Atropine‐resistant’ secretion of saliva in response to parasympathetic stimulation may reflect antidromic activation of sensory nerve fibres. In this investigation, the effect of pretreatment in the rat with capsaicin (total dose of 125 mg kg−1, s.c.), was determined.
In the parotid glands substance P (SP)/calcitonin gene‐related peptide (CGRP)‐containing nerve fibres around ducts and blood vessels disappeared after capsaicin, while periacinar SP‐containing fibres (devoid of CGRP) and CGRP‐containing fibres (devoid of SP) remained. Vasoactive intestinal peptide (VIP)‐containing nerve fibres seemed to be unaffected. The parotid content of SP and CGRP was reduced by 11 and 36% respectively, while that of VIP remained unchanged.
The weights of the parotid glands and their sensitivity to the secretagogues methacholine and SP, injected intravenously, were unchanged as was the response to stimulation of the auriculo‐temporal nerve in the presence and absence of atropine.
In contrast to capsaicin pretreatment, parasympathetic denervation of the parotid gland reduced the weight of the gland and produced an increase in the response to methacholine and SP.
For comparison, the effectiveness of the capsaicin treatment on neuropeptide content was determined in the urinary bladder. The bladder of capsaicin‐pretreated rats increased in weight (21%) and in VIP content (31%), while the content of SP and CGRP was reduced by 86 and 94%, respectively. SP‐ and CGRP‐containing nerve fibres were virtually eliminated, while VIP‐containing nerve fibres seemed unaffected.
In conclusion, antidromic activation of primary afferent (capsaicin‐sensitive) C‐fibres does not contribute significantly to the ‘atropine‐resistant’ secretory response of the parotid gland to stimulation of the parasympathetic nerve.
Dual effects of diazoxide on ATP‐K+ currents recorded from an insulin‐secreting cell line
Authors: Kozlowski R.Z. , Hales C.N. , Ashford M.L.J. 
Published: July 2012

The effects of diazoxide on ATP‐K+ channel currents, recorded from the insulin‐secreting cell line, CRI‐G1, were studied using patch‐clamp techniques.
Under current‐clamp recording conditions diazoxide (0.6 mm), inhibited action potential activity and hyperpolarized CRI‐G1 cells with a concomitant increase in membrane conductance. Recordings from voltage‐clamped whole‐cells and isolated patches indicate that activation of ATP‐K+ channel currents underlie these effects.
Diazoxide elicited an activation of ATP‐K+ channels which had been partially inhibited by ATP, on application to either surface of the plasma membrane, although it was more effective when applied directly to the cytoplasmic side. Activation of the ATP‐K+ currents involves an increase in the single channel open‐state probability and an apparent increase in the number of functional channels.
Activation was observed only when Mg‐ATP was present in the cytoplasmic bathing solution. There was no activation of currents by diazoxide when ATP, in the absence of Mg2+ ions, or Mg‐AMP‐PNP was present to inhibit the ATP‐K+ channels.
In the absence of ATP and Mg2+ ions in the cytoplasmic bathing solution, diazoxide (0.6 mm) produced an inhibition of ATP‐K+ currents.
Cromakalim (BRL 34915) at 10 μm and 100 μm had no significant effects on ATP‐K+ currents.
It is concluded that diazoxide‐induced activation of ATP‐K+ channel currents probably involves phosphorylation of the channel or some closely associated membrane protein.