bluuebunny/crossref_metadata_2025_split huggingface dataset:
The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones
Authors: Hales Tim G. , Lambert Jeremy J. 
Published: July 2012

The interaction of the intravenous general anaesthetic propofol (2,6‐diisopropylphenol) with the GABAA receptor has been investigated in voltage‐clamped bovine chromaffin cells and rat cortical neurones in cell culture. Additionally, the effects of propofol on the glycine and GABAA receptors of murine spinal neurones were determined.
Propofol (1.7–16.8 μm) reversibly and dose‐dependently potentiated the amplitude of membrane currents elicited by GABA (100 μm) applied locally to bovine chromaffin cells. Intracellular application of propofol (16.8 μm) was ineffective. In rat cortical neurones and murine spinal neurones, extracellular application of 8.4 μm and 1.7–16.8 μm propofol respectively produced a potentiation of GABA‐evoked currents qualitatively similar to that seen in the bovine chromaffin cell.
The potentiation by propofol (1.7 μm) was not associated with a change in the reversal potential of the GABA‐evoked whole cell current. On outside‐out membrane patches isolated from bovine chromaffin cells, propofol (1.7 μm) had little or no effect on the GABA single channel conductances, but greatly increased the probability of the GABA‐gated channel being in the conducting state.
The potentiation of GABA‐evoked whole cell currents by propofol (1.7 μm) was not influenced by the benzodiazepine antagonist flumazenil (0.3 μm). A concentration of propofol (1.7 μm) that substantially potentiated GABA currents had little effect on currents induced by the activation of the GABAA receptor by pentobarbitone (1 mm).
Bath application of propofol (8.4–252 μm), to bovine chromaffin cells voltage clamped at −60 mV, induced an inward current associated with an increase in membrane current noise on all cells sensitive to GABA. Intracellular application of propofol (16.8 μm) was ineffective in this respect. Local application of propofol (600 μm) induced whole cell currents with a reversal potential dependent upon the Cl− gradient across the cell membrane.
On outside‐out membrane patches formed from bovine chromaffin cells, propofol (30 μm) induced single channels with mean chord conductances of 29 and 12 pS. The frequency of propofol channels was greatly reduced by coapplication of 1 μm bicuculline. Under identical ionic conditions, GABA (1 μm) activated single channels with mean chord conductances of 33, 16 and 10 pS.
Bath applied propofol (0.84–16.8 μm) dose‐dependently potentiated strychnine‐sensitive currents evoked by glycine (100 μm) in murine spinal neurones.
The relevance of the present results to the general anaesthetic action of propofol is discussed.
Nitric oxide from vascular smooth muscle cells: regulation of platelet reactivity and smooth muscle cell guanylate cyclase
Authors: Mollace Vincenzo , Salvemini Daniela , Anggard Erik , Vane John 
Published: July 2012

Incubation of smooth muscle cells (SMC) from bovine aorta for 3 min with human washed platelets treated with indomethacin (10 μm) promoted a cell number‐related inhibition of platelet aggregation induced by thrombin (40 mu ml−1). This inhibition was not attributable to products of the cyclooxygenase pathway for the SMC were also treated with indomethacin (10 μm).
The inhibitory activity of the SMC on platelet aggregation was enhanced by incubating the SMC with E. coli lipopolysaccharide (LPS, 0.5 μg ml−1) for a period of 9 to 24 h. This effect was attenuated when cycloheximide (10 μg ml−1) was incubated together with LPS. Cycloheximide did not prevent the inhibitory activity of the non‐treated cells.
The inhibition of platelet aggregation obtained with non‐treated or LPS‐treated SMC was potentiated by superoxide dismutase (SOD, 60 u ml−1) and ablated by oxyhaemoglobin (OxyHb, 10 μm). Preincubation of the SMC with NG‐monomethyl‐l‐arginine (l‐NMMA, 30–300 μm) for 60 min prevented their antiaggregatory activity. This effect was reversed by concurrent incubation with l‐arginine (l‐Arg, 100 μm) but not with d‐arginine (d‐Arg, 100 μm).
Exposure of the non‐treated SMC (5 × 105 cells) to stirring (1000 r.p.m., 37°C) for 10 min led to a significant increase in their levels of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) but not adenosine 3′:5′‐cyclic monophosphate (cyclic AMP). l‐NMMA (300 μm) attenuated the increase in cyclic GMP induced by stirring but did not affect the basal levels of cyclic GMP in the cells. The inhibitory activity of l‐NMMA was reversed by co‐incubation with l‐Arg (100 μm) but not d‐Arg (100 μm). l‐Arg alone had no effect on the levels of cyclic GMP. In the absence of stirring, a 10 min stimulation of the non‐treated SMC with glyceryl trinitrate (GTN, 200 μm) or atrial natriuretic factor (ANF, 10−7 m) led to an increase in the levels of cyclic GMP but not cyclic AMP. The increase in cyclic GMP promoted by GTN or ANF was not affected by l‐NMMA. The levels of cyclic GMP were higher in the LPS (0.5 μg ml−1, 18 h)‐treated cells (5 × 10−5) and stirring was more effective in increasing the levels of cyclic GMP in these cells.
These findings support the idea that non‐treated or LPS‐treated cultured SMC can produce an NO‐like factor. Production by the latter requires protein synthesis as evidenced by blockade with cycloheximide. This NO‐like factor may play a role in the auto‐regulation of smooth muscle cell reactivity through a cyclic GMP‐dependent mechanism.
Electrophysiological effects of amineptine on neurones of the rat substantia nigra pars compacta: evidence for an inhibition of the dopamine uptake system
Authors: Mercuri N.B. , Stratta F. , Calabresi P. , Bernardi G. 
Published: July 2012

Intracellular recordings were made from substantia nigra pars compacta neurones of the rat maintained in vitro in order to study the effects of the tricyclic antidepressant drug, amineptine.
Amineptine hydrochloride (1–30 μm) decreased spontaneous firing and slightly hyperpolarized the membrane potential. In neurones voltage‐clamped at − 50 or − 60 mV, amineptine produced an outward membrane current. These actions were concentration‐dependent and were completely antagonized by (−)‐sulpiride.
The amineptine‐induced hyperpolarization was resistant to tetrodotoxin (1 μm) but it was abolished in 0 mm Ca2+ (plus 13 mm MgCl2) solutions.
Amineptine (300 nm‐30 μm) and cocaine (10–30 μm) increased the amplitude and duration of responses to exogenously applied dopamine. The effects of dopamine were potentiated about 5 fold by 10 μm amineptine; this potentiation persisted in calcium‐free solutions.
Cocaine (10 μm) had no additional effect on the dopamine‐induced responses in the presence of amineptine (30 μm). Amineptine (10 μm) produced no detectable effects in the presence of cocaine (30 μm).
It is concluded that amineptine acts as a dopamine uptake blocker in slices of rat substantia nigra.
ATP modulates the efferent function of capsaicin‐sensitive neurones in guinea‐pig isolated atria
Authors: Rubino Annalisa , Amerini Sandra , Ledda Fabrizio , Mantelli Laura 
Published: July 2012

The effect of adenosine triphosphate (ATP) and its stable analogues, α,β‐methylene‐ATP and β,γ‐methylene‐ATP, on the efferent function of capsaicin‐sensitive non‐adrenergic, non‐cholinergic (NANC) nerves was tested in guinea‐pig isolated atria.
Transmural nerve stimulation of atria isolated from reserpine‐pretreated guinea‐pigs, in the presence of 1 μm atropine and 0.3 μm CGP 20712A, induced a transient positive inotropic effect attributable to calcitonin gene‐related peptide (CGRP) release from NANC nerve endings.
ATP (1–30 μm) concentration‐dependently reduced the cardiac response to transmural nerve stimulation, without affecting the inotropic response to 10 nm exogenous CGRP. The inhibitory effect of ATP was competitively antagonized by the P1‐purinoceptor antagonist, 8‐phenyltheophylline (8‐PT, 1 μm), but was unaffected by the P2‐purinoceptor antagonist, suramin (100 μm).
β,γ‐Methylene‐ATP in the same concentration range as ATP, inhibited the cardiac response to transmural nerve stimulation. The inhibitory effect of β,γ‐methylene ATP was antagonized by 1 μm 8‐PT. The desensitizing agonist for P2‐purinoceptors, α,β‐methylene ATP did not induce any inhibitory effect either on the cardiac response to transmural nerve stimulation or on the inhibitory effect curve for ATP.
The inhibitory effect of ATP on the NANC neurotransmission was inconsistently modified in the presence of 10 μm α,β‐methylene‐adenosine diphosphate, an inhibitor of the 5′‐ectonucleotidases.
These results demonstrate that ATP modulates the efferent function of cardiac NANC nerve endings through prejunctional inhibitory receptors belonging to the P1 type. The metabolic conversion of ATP to adenosine does not seem to be a pre‐requisite for the ATP agonist activity.
Bovine polymorphonuclear leukocytes increase sensitivity to noradrenaline in isolated mesenteric arteries
Authors: De Kimpe S.J. , Van Heuven‐Nolsen D. , Nijkamp F.P. 
Published: July 2012

The effects of polymorphonuclear leukocytes (PMN) on vascular function to (−)‐noradrenaline were examined in vitro. Purified bovine PMN were incubated in siliconized organ baths containing rings of bovine mesenteric arteries, after which a concentration‐effect curve in response to (−)‐noradrenaline was obtained.
PMN‐derived products induced a long lasting concentration‐dependent contraction of the blood vessels generating 24.4 ± 6.8% of the maximal tension to (−)‐noradrenaline at a cell concentration of 2.5 × 106 ml−1. The contractile response was also found in endothelium‐denuded vascular rings.
PMN present in the organ bath caused an increase in the sensitivity of vascular rings to (−)‐noradrenaline. At a cell number of 2.5 × 106 PMN ml−1 the pD2‐value for (−)‐noradrenaline was augmented 0.40 ± 0.05 (P < 0.001), while total contraction at the highest concentration (−)‐noradrenaline was not affected. This increase in sensitivity was dependent on an intact endothelium.
The increase in sensitivity to (−)‐noradrenaline by PMN was inhibited by superoxide dismutase, but not by catalase, dimethylthiourea, indomethacin or nordihydroguaiaretic acid. The non‐stimulated bovine PMN produced oxygen radicals as measured by chemiluminescence.
Simultaneous incubation of PMN and (−)‐noradrenaline with arterial rings induced an increase in the release of prostacyclin, measured by an elevated concentration of 6‐keto‐prostaglandin Fα in the supernatant.
It is concluded that PMN can increase vascular tone directly or indirectly probably via the interaction of PMN‐derived superoxide anions with endothelium‐derived relaxing factor.
Mechanism of action of MY‐1250, an active metabolite of Repirinast, in inhibiting histamine release from rat mast cells
Authors: Takei Masao , Endo Koichi , Takahashi Kazuo 
Published: July 2012

When MY‐1250 (3.6 × 10−5 m) was added to mast cells, it caused a rapid increase in adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and decrease in adenosine 5′‐triphosphate (ATP), both of which recovered to their original levels within 2 min. The accumulation of cyclic AMP was maximal at 20 s after challenge with MY‐1250. The minimum level of ATP was observed at 20 s after addition of MY‐1250.
The initial rise in [Ca2+]i and the histamine release induced by DNP‐AS antigen (40 μg ml−1) was most strongly inhibited at 20 s after incubation of the mast cells with MY‐1250.
MY‐1250 strongly and dose‐dependently inhibited the histamine release from rat mast cells induced by antigen. Moreover, MY‐1250 strongly inhibited calcium ion mobilization from the intracellular Ca2+‐store.
These results suggested that the inhibitory mechanism of MY‐1250 on the initial rise in [Ca2+]i and histamine release induced by antigen was due to the inhibition of ATP‐dependent Ca2+‐release from the intracellular Ca2+‐stores.
Comparisons of the effects of ryanodine on catecholamine secretion evoked by caffeine and acetylcholine in perfused adrenal glands of the guinea‐pig
Authors: Nakazato Yoshikazu , Hayashi Hirotaka , Teraoka Hiroki 
Published: July 2012

The effect of ryanodine on catecholamine secretion induced by caffeine and muscarinic receptor activation was investigated in perfused adrenal glands of the guinea‐pig.
Caffeine (40 mm) caused only a small increase in catecholamine secretion during perfusion with standard Locke solution. Caffeine‐induced catecholamine secretion was markedly enhanced after removal of CaCl2 together with replacement of NaCl with sucrose.
In the absence of CaCl2 and NaCl, 50 μm ryanodine had no effect on the resting catecholamine secretion. Caffeine (40 mm) administered 15 min after treatment with ryanodine caused an increase in catecholamine secretion similar to that prior to application of ryanodine, but failed to have any effect thereafter. Combined application of ryanodine and caffeine also prevented catecholamine secretion induced by caffeine applied subsequently.
Catecholamine secretion induced by 100 μm acetylcholine (ACh) was only partially inhibited after treatment with ryanodine plus caffeine under Ca2+‐free, Na+‐deficient conditions.
Preferential influence of ryanodine on the response to caffeine was also confirmed in catecholamine secretion evoked by paired stimuli with caffeine and ACh alternately, during perfusion with either Ca2+‐free Locke or sucrose‐substituted solutions.
These results indicate that caffeine increases catecholamine secretion by mobilizing Ca2+ from intracellular Ca2+ stores through ryanodine‐sensitive mechanisms in guinea‐pig adrenal chromaffin cells. Ca2+ stores sensitive to caffeine and muscarinic receptor activation may not overlap entirely.
The role of cyclic AMP in non‐adrenergic non‐cholinergic contraction in guinea‐pig bronchi
Authors: Aikawa Takashi , Sekizawa Kiyohisa , Morikawa Masatoshi , Itabashi Shigeru , Sasaki Hidetada , Takishima Tamotsu 
Published: July 2012

We investigated the role of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) in non‐adrenergic non‐cholinergic (NANC) contraction in guinea‐pig bronchial strips.
Forskolin (3 nm to 1 μm) reduced NANC contraction induced by electrical field stimulation (EFS) in a concentration‐dependent fashion (–log EC50 was 7.22 ± 0.12 m and maximum inhibition was 100 ± 0.01%). However, forskolin (< 1 μm) did not alter the contraction induced by substance P (SP, 1 μm).
Dibutyryl cyclic AMP (1 mm) also reduced NANC contractions induced by EFS (100 ± 0.01%) without significant effect on SP (1 μm)‐induced contractions. In contrast, dibutyryl cyclic GMP (1 mm) was without effect against either NANC or SP‐induced contractions.
Both the β2‐adrenoceptor agonist, procaterol (0.1 nm to 3 nm) and theophylline (100 nm to 1 mm) concentration‐dependently reduced EFS‐induced NANC contractions without significant effect on SP (1 μm)‐induced contractions.
In contrast to forskolin, procaterol and theophylline, both sodium nitroprusside and cromakalim inhibited the EFS‐induced contractions only at those concentrations that similarly reduced the contractions induced by SP (1 μm).
These results suggest that cyclic AMP may mediate pre‐junctional inhibition of NANC contractions in guinea‐pig bronchi.
Okadaic acid inhibits activation of phospholipase C in human platelets by mimicking the actions of protein kinases A and C
Authors: Walker Trevor R. , Watson Steve P. 
Published: July 2012

The effect of okadaic acid, a potent inhibitor of protein phosphatases 1 and 2A (PP1 and PP2A), on human platelets has been investigated.
Okadaic acid exerts a general increase in phosphorylation of platelet proteins but did not induce aggregation or secretion of 5‐hydroxytryptamine (5‐HT). Okadaic acid, however, did inhibit thrombin‐induced functional responses.
Maximally effective concentrations of prostacyclin, to elevate adenosine 3′:5′‐cyclic monophosphate (cyclic AMP), or phorbol dibutyrate, to activate protein kinase C, inhibited the formation of inositol phosphates by thrombin by approximately 60%. When used in combination, prostacyclin and phorbol dibutyrate reduced the levels of inositol phosphates induced by thrombin to 11%.
Okadaic acid (1 μm) decreased thrombin‐induced formation of inositol phosphates by approximately 55% and increased the inhibitory action of prostacyclin or phorbol dibutyrate. Okadaic acid had no further effect when prostacyclin and phorbol dibutyrate were used in combination.
These results suggest that protein kinases A and C act to inhibit phospholipase C by distinct mechanisms and that their action is reversed by PP1 and/or PP2A.
Characterization of P1‐purinoceptors on rat duodenum and urinary bladder
Authors: Nicholls J. , Hourani S.M.O. , Kitchen I. 
Published: July 2012

The P1‐purinoceptors mediating relaxation of the rat duodenum and inhibition of contraction of the rat urinary bladder were characterized by use of adenosine and its analogues 5′‐N‐ethylcarboxamidoadenosine (NECA), N6‐cyclopentyladenosine (CPA) and 2‐p‐((carboxyethyl)phenethylamino)‐5′‐carboxamidoadenosine (CGS 21680), as well as the A1‐selective antagonist 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX). The stable analogue of adenosine 5′‐triphosphate (ATP), adenylyl 5′‐(β,γ‐methylene)diphosphonate (AMPPCP), was also used as previous work had indicated that it has a direct action on some P1 receptors in addition to its P2‐purinoceptor activity.
In the rat duodenum, the order of potency of the adenosine agonists was NECA ≥ CPA > AMPPCP = adenosine > CGS 21680, and DPCPX antagonized CPA and AMPPCP at a concentration of 1 nm whereas equivalent antagonism of NECA and adenosine required a concentration of 1 μm. This suggests the presence of a mixture of A1 and A2 receptors in this tissue, with CPA and AMPPCP acting on the A1 and NECA and adenosine acting on the A2 receptors.
In the rat bladder, the order of potency of the adenosine agonists for inhibition of carbachol‐induced contractions was NECA ≫ adenosine > CPA = CGS 21680, and a concentration of DPCPX of 1 μm was required to antagonize responses to NECA and adenosine. This suggests the presence of A2 receptors in this tissue. ATP and AMPPCP each caused contractions which were not enhanced by DPCPX (1 μm) which suggests that in this tissue AMPPCP was acting only via P2 receptors and had no P1 agonist activity. That AMPPCP was active on the A1 receptors in the duodenum but inactive on the A2 receptors in the bladder implies that it has selectivity for the A1 subtype.
That CGS 21680, which has been reported to bind selectively to the high affinity A2a subclass of A2 receptors, had a very low potency on the A2 receptors in the duodenum and in the bladder suggests that these receptors are of the low affinity A2b subclass.
Dopamine release and metabolism in the rat frontal cortex, nucleus accumbens, and striatum: a comparison of acute clozapine and haloperidol
Authors: Karoum F. , Egan M.F. 
Published: July 2012

The effects of the typical and typical neuroleptic agents clozapine (CLZ) (2.5–20 mg kg−1, i.p.) and haloperidol (Hal) (0.05–1.0 mg kg−1), were compared on dopamine release and metabolism in the rat prefrontal cortex (PFC), nucleus accumbens (ACC) and striatum (ST). Dopamine release was estimated by measuring the steady‐state concentration of 3‐methoxytyramine (3‐MT) and the level of 3‐MT 10 min after pargyline (3‐MT accumulation); dopamine metabolism was evaluated from the steady‐state concentrations of its acidic metabolites.
Both drugs increased 3‐MT accumulation in the PFC in a dose‐dependent manner. In contrast to Hal, CLZ failed to increase 3‐MT accumulation in the ACC or ST. The ST was the region most sensitive to Hal in terms of 3‐MT accumulation and, by inference, dopamine release.
Both CLZ and Hal dose‐dependently elevated the concentrations of 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in all 3 brain regions studied. The ACC appears to be the region most sensitive to these drugs in terms of changes in the levels of HVA.
The result of the present investigations suggest measurements of 3‐MT production in the 3 brain regions analysed might be a useful and simple pharmacological tool in the search for atypical neuroleptic drugs with a selectivity of action for the cortical systems.
Effects of pinacidil on guinea‐pig isolated perfused heart with particular reference to the proarrhythmic effect
Authors: Padrini Roberto , Bova Sergio , Cargnelli Gabriella , Piovan Donatella , Ferrari Mariano 
Published: July 2012

The effects of pinacidil (10, 30, 50 μm) on contractility (+ dP/dtmax), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant‐flow perfused guinea‐pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz).
Pinacidil decreased +dP/dtmax, cP and the QT interval in a dose‐dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q‐wave to T‐wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation.
In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon).
In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 10 μm to 100 μm (8 experiments for each concentration). In control conditions and at the lowest concentration of pinacidil tested (10 μm) VF could never be induced; in the presence of 30 μm pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher that 50 μm permitted the induction of VF in every case.
Although the concentrations of pinacidil producing ventricular fibrillation are 30–40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.