bluuebunny/crossref_metadata_2025_split huggingface dataset:
Difference in the potentiating effect of adenosine triphosphate and α,β‐methylene ATP on the biphasic insulin response to glucose
Authors: Bertrand G. , Gross R. , Chapal J. , Loubatières‐Mariani M.M. 
Published: July 2012

The effects of exogenous adenine nucleotides and structural analogues on the biphasic insulin response to an increase of glucose concentration in the physiological range (from 4.2 to 8.3 mm) were studied in the isolated perfused rat pancreas. Purinoceptor agonists were added either simultaneously or 15 min before increasing glucose.
ATP and ADP at 16.5 μm were ineffective per se in the presence of the non stimulatory glucose concentration (4.2 mm) but markedly potentiated the biphasic insulin response to glucose rise in both experimental protocols.
Two more stable analogues of ATP and ADP (adenylylimidodiphosphate and α,β‐methylene ADP (α,β‐MeADP)) at 16.5 μm behaved like the natural compounds: they were ineffective at a glucose concentration of 4.2 mm and potentiated both phases of insulin response to glucose rise.
α,β‐MeATP added simultaneously with the high glucose concentration, markedly potentiated the first phase of insulin response to glucose rise but did not potentiate the second one. When α,β‐MeATP infusion began 15 min before glucose rise, the biphasic response to glucose was not potentiated, in contrast to what occurred with ATP.
In the presence of α,β‐MeATP, the ATP potentiating effect was unaffected.
It is concluded that ATP and ADP, via activation of β cell P2y purinoceptors, potentiates the biphasic insulin response to an increase of glucose concentration. On the other hand, α,β‐MeATP did not behave like natural and other structural analogues of ATP and ADP: this difference appears not to be the consequence of desensitization of β cell P2y purinoceptors by α,β‐MeATP.
Mechanisms of long‐lasting effects of benidipine on Ca current in guinea‐pig ventricular cells
Authors: Yamamoto M. , Gotoh Y. , Imaizumi Y. , Watanabe M. 
Published: July 2012

Benidipine (KW‐3049), a new derivative of 1,4‐dihydropyridine (DHP), showed dose‐dependent inhibition of Ca current (ICa) which was elicited by depolarization from −40 mV to +10 mV at 0.2 Hz in single cardiac cells isolated from guinea‐pig ventricle under whole cell voltage clamp. Half inhibition doses (IC50) of benidipine and nifedipine for the peak ICa at +10 mV were 2.7 nm and 63.1 nm, respectively.
A change in holding potential from −40 to −75 mV partially removed the block induced by both 10 nm benidipine and 100 nm nifedipine. The block of ICa by benidipine strongly depended upon holding potentials as did that induced by nifedipine.
The effect of 100 nm nifedipine was mostly removed when the cells were kept quiescent at holding potentials negative to −75 mV for 5 min after withdrawal of nifedipine. In contrast, hyperpolarization for several minutes did not significantly accelerate the removal of benidipine‐induced block after withdrawal of the drug. Effects of 10 nm benidipine could not be washed out for up to 30 min regardless of the holding potentials.
It is suggested that the dissociation of benidipine from the DHP binding site, like that of nifedipine, is greatly accelerated by hyperpolarization. Benidipine but not nifedipine may have an additional interaction with the channel or lipid membrane and cannot be washed away even after the dissociation. Alternatively, the dissociation of benidipine from the DHP binding site may be too slow to occur substantially during the limited period of hyperpolarization in the present study (<30 min). In that case, however, the Ca channel bound by benidipine must become unblocked and available to be opened during the hyperpolarization.
Mechanisms for cardiac depression induced by phorbol myristate acetate in working rat hearts
Authors: Karmazyn Morris , Watson Joanne E. , Moffat Margaret P. 
Published: July 2012

The effects of the phorbol ester, phorbol myristate acetate (PMA) were examined on function and energy metabolism in the isolated working heart of the rat.
At a concentration of 10−9 m. PMA produced a rapid loss in cardiac function in terms of aortic flow rate (AFR) and coronary flow rates (CFR) whereas a similar concentration of 4α‐phorbol 12,13‐didecanoate was ineffective. At a concentration of 10−10 m., the PMA‐induced depression was more gradual but nevertheless very pronounced with an almost total loss in AFR after 30 min perfusion. The reduction in CFR was more moderate than that observed with respect to AFR.
The protein kinase C (PKC) inhibitor (±)‐l‐O‐hexadecyl‐2‐O‐acylglycerol significantly attenuated the loss in AFR and CFR following addition of PMA.
Two inhibitors of Na+/H+ exchange, amiloride and quinacrine, totally prevented the reduction in AFR. Although the PMA‐induced depression in CFR was also attenuated by both amiloride and quinacrine, these effects were not significant, probably reflecting the less pronounced effect of PMA on this parameter.
Nifedipine, a dihydropyridine calcium channel blocker reduced PMA toxicity to a similar degree as Na+/H+ exchange inhibition whereas the calcium channel agonist Bay K 8644 was without effect.
Tissue content of energy metabolites including high energy phosphates, total adenine nucleotides or lactate were not significantly affected by PMA perfusion.
We conclude that PKC activation is necessary for phorbol ester‐induced cardiac dysfunction. The consequence of PKC stimulation includes (1) Na+/H+ exchange activation and a subsequent elevation in intracellular calcium [Ca2+]i via Na+/Ca2+ exchange and (2) PKC‐dependent phosphorylation of the calcium channel, both of which would produce toxicity by elevation of [Ca2+]i. Pharmacological manipulation of any of these steps prevents PMA toxicity by virtue of a reduction in the accumulation of [Ca2+]i. PMA effects or their prevention are unrelated to any changes in energy metabolism.
Pharmacological modulation of the contractile response to toluene diisocyanate in the rat isolated urinary bladder
Authors: Mapp Cristina E. , Chitano Pasquale , Fabbri Leonardo M. , Patacchini Riccardo , Maggi Carlo A. 
Published: July 2012

Toluene diisocyanate produced concentration‐dependent contractions of the rat isolated urinary bladder.
The contractions were tetrodotoxin‐resistant and were abolished by previous exposure of the strips to capsaicin.
Indomethacin (5 μm) and ruthenium red (30 μm) inhibited toluene diisocyanate‐induced contractions. Responses expressed as a percentage of the response obtained with substance P, 30 nm, were respectively 141.6 ± 24.8% and 20.1 ± 5.1% in control and indomethacin‐treated strips (P < 0.005); 123.0 ± 30.2% and 14.0 ± 6.5% in control and ruthenium red‐treated strips (0.01 < P < 0.05).
These results suggest that toluene diisocyanate‐induced contractions of the rat isolated bladder are the result of the release of cyclo‐oxygenase products which may act by activating the capsaicin receptor.
Prevention by the NMDA receptor antagonist, MK801 of neuronal loss produced by tetanus toxin in the rat hippocampus
Authors: Bagetta G. , Nisticò G. , Bowery N.G. 
Published: July 2012

The behavioural and neuropathological effects of tetanus toxin, microinjected directly into the hippocampus, were studied in rats.
A single dose (1000 minimum lethal doses, MLDs) of tetanus toxin, injected unilaterally into the hippocampus produced a time‐dependent neuronal loss in the CA1 pyramidal cell layer. In comparison with the contralateral, untreated side these effects became statistically significant (P > 0.05) 7 days (22.0 ± 1.1% reduction) and 10 days (29.2 ± 1.7% reduction) after the injection. No significant changes were observed 7 days after treatment with 500 MLDs whereas a reduction of 37.5 ± 3.1% in the CA1 area cell number was produced 4 days after the injection of 2000 MLDs.
Behavioural stimulatory effects were also induced by tetanus toxin (1000 MLDs) within 48 h of the injection and these culminated in generalized convulsions 5–7 days later. Convulsions were observed after a shorter period of latency in rats receiving 2000 MLDs tetanus toxin whereas 500 MLDs were ineffective.
No behavioural and neuropathological effects were observed in rats treated with neutralized tetanus toxin (1000 MLDs), bovine serum albumin or phosphate buffer.
Pretreatment with MK801 (0.3 mg kg−1, i.p., given 1 h before and after the injection with tetanus toxin and then once daily for 4 or 7 days) prevented the behavioural and neuropathological effects induced by tetanus toxin (1000–2000 MLDs). In addition, such treatment fully protected the animals from the lethal effects induced by 1000 MLDs tetanus toxin. By contrast, pretreatment with diazepam (3.0 mg kg−1, i.p.) using the same schedule as for MK801 did not antagonize the effects of tetanus toxin (1000–2000 MLDs).
In conclusion, the present experiments have demonstrated that the intrahippocampal injection of tetanus toxin produces in rats a dose‐ and time‐dependent behavioural stimulation and neuronal loss in the CA1 pyramidal cell layer which can be prevented by the non‐competitive NMDA antagonist, MK801.
Effects of the cyclo‐oxygenase inhibitor, fenbufen, on clenbuterol‐induced hypertrophy of cardiac and skeletal muscle of rats
Authors: Palmer R.M. , Delday M.I. , McMillan D.N. , Noble B.S. , Bain P. , Maltin C.A. 
Published: July 2012

When rats were fed with clenbuterol for 7 days skeletal muscle mass increased by 21% in the tonic soleus and phasic plantaris muscles and a 16% hypertrophy of the heart was also induced. Fenbufen, fed to rats for the same period, blocked the hypertrophy of the heart but not that of the skeletal muscles.
When feeding of fenbufen commenced 3 days before the administration of clenbuterol, plasma prostaglandin F2α (PGF2α) was reduced by 79%; there was again no effect of fenbufen on clenbuterol‐induced increases in the RNA or protein content of plantaris, nor in the increased area of fast or slow twitch fibres in the soleus. In the heart the clenbuterol‐induced increases in the RNA (+ 21%) and protein content (+ 20%) were totally inhibited.
The effects of clenbuterol on heart muscle appear to be mediated by a cyclo‐oxygenase metabolite of arachidonic acid whilst the effects on skeletal muscle are not.
Functional characterization of neuronal pre and postsynaptic α2‐adrenoceptor subtypes in guinea‐pig submucosal plexus
Authors: Shen K.‐Z. , Barajas‐Lopez C. , Surprenant A. 
Published: July 2012

The α2‐adrenoceptors on cell bodies of submucosal neurones, on presynaptic cholinergic nerve terminals innervating submucosal neurones, and on presynaptic sympathetic fibres innervating submucosal arterioles were characterized in functional studies by use of subtype selective ligands.
Both membrane hyperpolarization and presynaptic inhibition of nicotinic excitatory synaptic potentials (e.p.s.ps) produced by UK 14304 were similarly antagonized by idazoxan, yohimbine, SKF 104078, WB 4101 and ARC‐239. Antagonism was competitive and dissociation equilibrium constants were the same for both effects.
Vasoconstriction of submucosal arterioles in response to stimulation of the sympathetic nerves (20 Hz for 2 s) was inhibited by UK 14304 and clonidine; concentrations producing half‐maximum responses were 6 nm and 10 nm respectively. Idazoxan, yohimbine, WB 4101 and SKF 104078 antagonized this action, with dissociation constants similar to those for antagonism of the postsynaptic membrane hyperpolarization and presynaptic inhibition of nicotinic e.p.s.ps.
Oxymetazoline was a partial agonist when membrane hyperpolarization or presynaptic inhibition of nicotinic e.p.s.ps were measured but a full agonist when presynaptic inhibition of sympathetically‐mediated arteriolar vasoconstriction was measured. As an agonist, oxymetazoline produced half maximum responses at 80–120 nm; the dissociation constant for oxymetazoline as an antagonist was 130 nm.
Neither prazosin nor chlorpromazine (up to 30 μm) altered any of the three responses to α2‐adrenoceptor agonists.
It is concluded that α2‐adrenoceptors present on submucosal neuronal cell bodies, on presynaptic cholinergic nerve terminals and on presynaptic sympathetic nerve terminals are the α2A subtype. However, functional characterization of this subtype differs from that provided by ligand binding studies.
Renal selective N‐acetyl‐γ‐glutamyl prodrugs: a study on the mechanism of activation of the renal vasodilator prodrug CGP 22979
Authors: Drieman J.C. , Thijssen H.H.W. , Zeegers H.H.M. , Smits J.F.M. , Boudier H.A.J. Struyker 
Published: July 2012

In this study the processes underlying the renal selectivity of the vasodilator prodrug CGP 22979 (N‐acetyl‐l‐glutamic acid‐N‐[N2‐(5‐n‐butyl‐2‐pyridyl) hydrazide]) were studied in rats.
The active drug CGP 18137 (2‐hydrazino‐5‐n‐butyl pyridine) selectively accumulated in the renal tissue following administration of the prodrug.
The kidney concentrations of active drug following prodrug administration were significantly lower than control values when either buthionine sulphoximine, glutathione or probenecid was coadministered (29 ± 11; 33 ± 14 and 61 ± 20% of control values, respectively). Inhibition of γ‐glutamyl transpeptidase by AT‐125 did not cause a significant decrease of renal CGP 18137 levels.
In order to correlate tissue drug concentrations with pharmacological effect, the renal haemodynamic responses to CGP 22979 were measured and the effect of buthionine sulphoximine, glutathione and AT‐125 on these responses evaluated. All three of the compounds attenuated the renal response to the prodrug: an approximately 50% lesser decrease in renal resistance was found. The compounds had no effect on the haemodynamic actions of CGP 18137 itself.
In vitro, it was found that kidney cytosol was able to convert the prodrug, whereas microsomes were not, unless acylase was added.
The results indicate that, upon prodrug administration, γ‐glutamyl transpeptidase is not involved in the renal accumulation of CGP 18137 but is partly responsible for the renal haemodynamic responses to CGP 22979. Active transport of the prodrug into the tubular cells appears to be the major reason for the renal selectivity. A model is proposed for the renal action of CGP 22979, in which the important parts are the uptake of the prodrug via a transport system followed by an intracellular conversion to the active drug.
Comparison of the effects of xamoterol and isoprenaline on rat cardiac β‐adrenoceptors: studies of function and regulation
Authors: Kowalski M.T. , Haworth D. , Lu X. , Thomson D.S. , Barnett D.B. 
Published: July 2012

The effects of the β1‐selective partial agonist xamoterol and the full agonist isoprenaline on rat cardiac β‐adrenoceptors were compared in functional studies of heart rate response in vivo and in vitro. In addition, the ability of both agents to cause receptor down‐regulation in the rat heart following chronic (6 days) subcutaneous infusions was assessed by radioligand binding with [125I]‐pindolol.
In the functional studies, xamoterol produced a maximal effect equivalent to approximately 65% of that of isoprenaline and was overall less potent than the full agonist.
Compared to saline control, the density of β‐adrenoceptors was reduced approximately 39% in ventricular membranes prepared from animals after 6 days of isoprenaline infusion but was unaffected by xamoterol. The relative proportions of the β‐adrenoceptor subtypes were unchanged by either active treatment.
Plasma xamoterol level at the end of the infusion period was equivalent to that associated with maximum tachycardia in vivo and to the concentration producing maximal stimulation of the rat isolated atrium in vitro. Thus suggesting 100% β‐adrenoceptor occupancy during the period of xamoterol infusion.
These results indicate that in this animal model xamoterol does not induce cardiac β‐adrenoceptor down‐regulation during chronic treatment, with doses that produce a maximal functional response both in vitro and in vivo.
Effects of selective phosphodiesterase inhibition on cyclic AMP hydrolysis in rat cerebral cortical slices
Authors: Challiss R.A. John , Nicholson C. David 
Published: July 2012

The effects of selective inhibition of phosphodiesterase activities on the concentration and rate of hydrolysis of adenosine 3′: 5′ cyclic‐monophosphate (cyclic AMP) in rat cerebral cortical slices has been studied.
Isoprenaline caused a rapid, concentration‐dependent increase in cyclic AMP concentration to new steady‐state levels (basal: 7.1 ± 0.7; 10 μm isoprenaline: 14.3 ± 1.4 pmol mg−1 protein). Addition of a β‐adrenoceptor antagonist to isoprenaline‐stimulated cerebral cortical slices caused a rapid decrease in cyclic AMP concentration to basal levels (t1/2: 58 ± 18 s).
Preincubation of slices for 30 min with the phosphodiesterase inhibitors 1‐methyl‐3‐isobutylxanthine, denbufylline, rolipram or Ro20 1724 caused concentration‐dependent increases in basal and isoprenaline‐stimulated cyclic AMP concentrations and decreased the rate of cyclic AMP hydrolysis measured after addition of a β‐adrenoceptor antagonist. However, SKF 94120 and zaprinast had none of these effects.
The results are discussed with respect to previous studies of phosphodiesterase isozymic activities isolated from cerebrum and it is suggested that the Ca2+/calmodulin‐independent, low Km cyclic AMP phosphodiesterase isozyme, which is selectively inhibited by denbufylline, rolipram and Ro20 1724, and is present in cerebrum is of critical importance to the regulation of cyclic AMP concentration in this tissue.
Evidence against an involvement of the haloperidol‐sensitive σ recognition site in the discriminative stimulus properties of (+)‐N‐allylnormetazocine ((+)‐SKF 10,047)
Authors: Singh L. , Wong E.H.F. , Kesingland A.C. , Tricklebank M.D. 
Published: July 2012

The involvement of the haloperidol‐sensitive, σ recognition site and the N‐methyl‐d‐aspartic acid (NMDA) receptor in the mediation of the discriminative stimulus properties of (+)‐N‐allylnormetazocine ((+)‐NANM, (+)‐SKF 10,047), has been investigated in the rat by use of a two‐lever, operant drug discrimination paradigm.
Six compounds with nanamolar affinity for the σ recognition site ((±)‐pentazocine, (+)‐3‐(hydroxyphenyl)‐N‐propylpiperidine ((+)‐3‐PPP), ditolylguanidine (DTG), haloperidol, (−)‐butaclamol and BMY 14802) were investigated for their ability to generalise or antagonise the (+)‐NANM discriminative stimulus. Each drug was tested at doses found in an ex vivo radioligand binding assay to displace [3H]‐DTG from the central σ recognition site by more than 40%.
While (±)‐pentazocine (in the presence of naloxone) generalised and (+)‐3‐PPP partially antagonised the (+)‐NANM cue, the other putative σ ligands were ineffective either as agonists or antagonists at doses clearly occupying the σ site in vivo.
Dose‐dependent generalisation to the (+)‐NANM cue was seen with the selective non‐competitive NMDA receptor antagonist, MK‐801, a compound devoid of significant affinity for the σ recognition site.
(±)‐Pentazocine was found to antagonise seizures induced in the mouse by NMDLA, a model reflecting antagonism of central NMDA receptors, and a strong correlation was found between the rank order of potency of compounds to generalise to the (+)‐NANM discriminative stimulus and their potencies as anticonvulsants.
In conclusion, no evidence was found to substantiate the contention that the discriminative stimulus properties of (+)‐NANM are mediated by the haloperidol‐sensitive σ recognition site. On the other hand, the results are consistent with the interoceptive stimulus being mechanistically based in the NMDA receptor complex.
Agmatine acts as an antagonist of neuronal nicotinic receptors
Authors: Loring Ralph H. 
Published: July 2012

Tritiated agmatine has been used by others in ion flux methods to measure nicotinic receptor function in neurones. However, as shown here, agmatine blocks nicotinic receptor function in both the chick retina and the rat superior cervical ganglion at high concentrations.
In intact chick retina, agmatine 1 mm decreases dimethylphenylpiperazinium (DMPP)‐induced depolarizations measured in the optic nerve by approximately 70%, while having little effect on responses induced by glutamate analogues. DMPP dose‐response curves are reduced in a manner consistent with a non‐competitive effect of agmatine, and agmatine at 1 mm does not prevent binding of 125I‐labelled neuronal bungarotoxin, a snake venom neurotoxin that competitively binds and blocks functional nicotinic receptors in chick retinal homogenates.
Agmatine (10 μm) substantially blocks both DMPP‐induced depolarizations of rat superior cervical ganglion and synaptic transmission through the ganglion. Others have established that [3H]‐agmatine will pass through nicotinic receptor channels in the rat ganglion. These data suggest that agmatine acts both as a cation and as a weak channel blocker at neuronal nicotinic receptors.
Characterization of presynaptic vascular muscarinic receptors inhibiting endogenous noradrenaline overflow in the portal vein of the freely moving rat
Authors: Remie R. , Coppes R. P. , Meurs H. , Roffel A.F. , Zaagsma J. 
Published: July 2012

In the portal vein of permanently cannulated, freely moving, unanaesthetized rats, methacholine (MCh) is able to inhibit the electrically‐evoked endogenous noradrenaline (NA) overflow. This inhibition is mediated by presynaptic inhibitory muscarinic heteroreceptors.
By use of pirenzepine, 4‐diphenylacetoxy‐N‐methylpiperidine methobromide (4‐DAMP) and AF‐DX 116 as M1‐, M3‐, and M2‐selective antagonists respectively, the MCh (0.1 μm)‐induced inhibition of the electrically‐evoked NA overflow could be reversed to the control stimulation value dose‐dependently.
The potency order of the antagonists was: 4‐DAMP > AF‐DX 116 > pirenzepine, pIC50 values being 8.50, 7.96 and 7.01, respectively.
From these results it was concluded that the inhibitory presynaptic heteroreceptors in the portal vein of concious unrestrained rats are of the cardiac M2‐subtype.
Eosinophil accumulation in pulmonary airways of guinea‐pigs induced by exposure to an aerosol of platelet‐activating factor: effect of anti‐asthma drugs
Authors: Sanjar S. , Aoki S. , Boubekeur K. , Chapman I.D. , Smith D. , Kings M.A. , Morley J. 
Published: July 2012

Exposure of guinea‐pigs to aerosols of platelet activating factor (PAF) (0.01 to 100 μg ml−1) induced a dose‐dependent increased incidence of eosinophils in bronchoalveolar lavage fluid (BAL) at 48 h. Total leucocyte numbers and the percentages of lymphocytes and neutrophils were unchanged in BAL fluid.
Increased numbers of eosinophils were detected in BAL 1 h after exposure to PAF but eosinophilia was not maximal until 48 h. One week after exposure to PAF, the percentage of eosinophils in BAL was within the normal range.
Depletion of circulating platelets or neutrophils by intravenous injection of specific antisera did not modify accumulation of eosinophils in the airway lumen following inhalation of PAF (10 μg ml−1).
PAF‐induced pulmonary airway eosinophil accumulation was inhibited by treatment with SDZ 64–412, a selective PAF‐antagonist, whether the compound was administered before, or 30 min after, inhalation of PAF.
Pulmonary airway eosinophil accumulation due to inhaled PAF (10 μg ml−1) was inhibited by prior treatment with aminophylline, cromoglycate, ketotifen, dexamethasone and AH 21–132.
Pulmonary airway eosinophil accumulation due to inhaled PAF (10 μg ml−1) was not inhibited by prior treatment with indomethacin, salbutamol or mepyramine.