bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of vasodilator activity of agents activating cyclic nucleotides with those inhibiting their metabolism in rabbit isolated ear artery
Authors: Wood L.M. , Owen D.A.A. 
Published: July 2012

The effects of forskolin, a direct activator of adenylate cyclase and sodium nitroprusside, a direct activator of guanylate cyclase, were studied on rabbit isolated ear arteries preconstricted with 80 mm potassium.
Bolus injection of these two compounds resulted in vasodilatation. They had similar potencies in this tissue but forskolin had a significantly longer duration of action than sodium nitroprusside.
In the same tissue, perfusion with isobutylmethylxanthine (IBMX), a non‐selective phosphodiesterase (PDE) inhibitor, or zaprinast, selective for the PDE primarily responsible for the metabolism of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP), resulted in vasodilatation. However, SK&F 94120 selective for cyclic AMP‐PDE (PDE III), primarily responsible for the metabolism of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP), resulted in vasodilatation only at very high concentrations. The rank order of potency for the compounds was IBMX > zaprinast > SK&F 94120.
The effects of these three PDE inhibitors were studied on the vasoconstriction produced by perivascular sympathetic nerve stimulation in the absence of raised potassium. IBMX and zaprinast, caused a reduction in the response at 50 Hz stimulation frequency and a shift in the frequency‐response curve to the right. SK&F 94120 did not displace the frequency‐response curve but did reduce the response at 50 Hz. The same order of potency for the inhibition of the vasoconstrictor responses to perivascular sympathetic nerve stimulation was found as for vasodilatation i.e. IBMX > zaprinast > SK&F 94120.
These results indicate that in the same tissue direct activation of adenylate and guanylate cyclase results in vasodilatation. Non‐specific PDE and cyclic GMP‐PDE inhibition also resulted in vasodilatation and inhibition of vasoconstrictor responses to sympathetic nerve stimulation. However a selective cyclic AMP‐PDE (PDE III) inhibitor did not result in vasodilatation, except at very high concentrations, or inhibit sympathetic vasoconstrictor responses except to reduce the response at 50 Hz stimulation. These findings provide further support for the ability of PDE inhibitors to be tissue selective.
Inhibition of N‐methyl‐D‐aspartate‐ and kainic acid‐induced neurotransmitter release by ω‐conotoxin GVIA
Authors: Keith Richard A. , Mangano Thomas J. , Salama Andre I. 
Published: July 2012

The role of voltage‐sensitive calcium channels (VSCC) in N‐methyl‐D‐aspartate (NMDA)‐ and kainic acid (KA)‐evoked neurotransmitter release from rat cortical and hippocampal brain slices was evaluated by determining the effects of ω‐conotoxin GVIA, an inhibitor of neuronal L‐ and N‐type VSCC, and PN 200–110, a selective inhibitor of L‐type VSCC.
Selective antagonists of the NMDA receptor ionophore complex, Mg2+, CPP and MK‐801, inhibited NMDA‐ but not KA‐evoked release of [3H]‐noradrenaline from hippocampal and cortical brain slices. This suggests that cortical and hippocampal receptors are similar and that NMDA and KA act at distinct excitatory amino acid receptor subtypes.
[3H]‐noradrenaline release induced by both NMDA and KA was similarly inhibited (approximately 30%) by ω‐conotoxin GVIA. In contrast, PN 200–110 had no significant effect, although there was a tendency towards inhibition.
The results suggest that although NMDA‐ and KA‐receptors are pharmacologically distinct, the N‐type, but not the L‐type, VSCC plays a small but significant role in neurotransmitter release induced by both NMDA and KA. It remains to be determined whether the N‐type VSCC are involved in the physiological and/or pathological manifestations of excitatory amino acid receptor stimulation.
Cromakalim‐induced relaxation of guinea‐pig isolated trachealis: antagonism by glibenclamide and by phentolamine
Authors: Murray M.A. , Boyle J.P. , Small R.C. 
Published: July 2012

Tested against the spontaneous tone of guinea‐pig isolated trachealis, cromakalim (0.1–100 μm), isoprenaline (1 nm‐1 μm) and theophylline (1 μm‐1 mm) each produced concentration‐dependent relaxation.
Glibenclamide (0.1–10 μm) did not itself alter the spontaneous tone of the trachea nor did it modify the relaxant actions of isoprenaline or theophylline. In contrast, glibenclamide (0.1 and 1 μm) caused a concentration‐dependent rightward shift of the log concentration‐effect curve of cromakalim. Glibenclamide (10 μm) reduced the slope of the log concentration‐effect curve of cromakalim and moved the foot of the curve back towards the control position.
Phentolamine (1, 10 and 100 μm) did not itself alter the spontaneous tone of the trachea nor did it modify the relaxant actions of isoprenaline or theophylline. In contrast phentolamine caused concentration‐dependent depression of the log concentration‐effect curve of cromakalim.
Neither prazosin (1 μm) nor yohimbine (10 μm) modified the spontaneous tone of the trachea. Prazosin and yohimbine each failed to antagonise the effects of cromakalim, isoprenaline and theophylline.
Intracellular electrophysiological recording showed that glibenclamide (1 μm) and phentolamine (100 μm) caused minor change in the resting membrane potential of trachealis cells. Slow wave activity was slightly depressed by these agents. In contrast tetraethylammonium (TEA; 8 mm) caused marked depolarisation, and promoted the conversion of slow waves into regenerative action potentials. These electrical changes were accompanied by tonic tension development.
Phentolamine (100 μm) and glibenclamide (1 μm) reduced and reversed both the relaxation and the hyperpolarisation induced by cromakalim (10 μm).
It is concluded that glibenclamide and phentolamine each provide selective antagonism of the relaxant action of cromakalim in guinea‐pig trachealis. These agents also inhibit the plasmalemmal hyperpolarisation induced by cromakalim. The effect of phentolamine is unrelated to the blockade of α1 or α2‐adrenoceptors. If either glibenclamide or phentolamine act to block the K+ channels opened by cromakalim, then such channels are not identical to those which endow the trachealis plasmalemma with its powerful rectifying behaviour.
Effects of extracellular adenine nucleotides on the electrical, ionic and secretory events in mouse pancreatic β‐cells
Authors: Petit P. , Bertrand G. , Schmeer W. , Henquin J.C. 
Published: July 2012

The mechanisms whereby extracellular adenine nucleotides modulate pancreatic β‐cell function were studied with mouse islets stimulated by 15 mm glucose.
Adenosine 5′‐triphosphate (ATP) and adenosine 5′‐diphosphate (ADP) (100 μm) inhibited insulin release, 45Ca efflux and 86Rb efflux from islet cells, and decreased electrical activity in β‐cells. These changes were rapid but small and transient.
α,β‐Methylene ADP caused a rapid and sustained inhibition of insulin release, 45Ca efflux and 86Rb efflux from islet cells. It also produced a slight hyperpolarization of the β‐cell membrane, with sustained modification of the pattern but only transient decrease of the intensity of the electrical activity. In the absence of extracellular Ca2+, α,β‐methylene ADP increased 45Ca and 86Rb efflux without changing insulin release. Most effects of α,β‐methylene ATP were qualitatively similar but quantitatively smaller than those of the ADP‐analogue.
Adenylylimido‐diphosphate (AMP‐PNP) slightly increased 45Ca and 86Rb efflux and potentiated insulin release in the presence of extracellular Ca2+. However, its effects on electrical activity in β‐cells were qualitatively similar to those of the α,β‐methylene analogues.
The small effects of ATP and ADP could result from their degradation into adenosine. α,β‐Methylene ADP appears to increase K+ permeability of the β‐cell membrane and to produce a second, intracellular, effect which largely contributes to the inhibition of insulin release. Another recognition site, with higher affinity for triphosphate derivatives, could mediate the small stimulatory effects of AMP‐PNP.
Identification of a single α1‐adrenoceptor corresponding to the α1A‐subtype in rat submaxillary gland
Authors: Michel Anton D. , Loury Dana N. , Whiting Roger L. 
Published: July 2012

The α1‐adrenoceptors present in membranes of rat liver, cortex and submaxillary gland were labelled with [3H]‐prazosin and the affinity of 15 ligands for these receptors was determined.
In saturation studies, [3H]‐prazosin bound with high affinity (Kd = 30–39 pM) to a single population of sites in all three preparations.
In competition studies using rat cortex, evidence for heterogeneity of the α1‐adrenoceptor binding sites was obtained. Displacement isotherms for amidephrine, benoxathian, oxymetazoline, phentolamine and WB 4101 were biphasic and were consistent with the presence of both α1A‐ and α1B‐adrenoceptor subtypes as described by Morrow & Creese (1986) and Han et al. (1987).
The rat liver and submaxillary gland membrane preparations both possessed homogeneous populations of α1‐adrenoceptors. However, there were pharmacological differences between the receptors in these two preparations. Rat submaxillary gland α1‐adrenoceptors displayed high affinity for amidephrine, benoxathian, oxymetazoline, phentolamine and WB 4101 and therefore appeared to represent α1A‐adrenoceptors. Rat liver α1‐adrenoceptors possessed lower affinity for these ligands (6–65 fold) suggesting that these receptors were of the α1B‐subtype.
Spiperone exhibited 12.9 fold higher affinity for rat liver α1B‐adrenoceptors than for rat submaxillary gland α1A‐adrenoceptor and may therefore represent the first α1B‐adrenoceptor selective ligand.
Differential cardiovascular and respiratory responses to central administration of selective opioid agonists in conscious rabbits: correlation with receptor distribution
Authors: May C.N. , Dashwood M.R. , Whitehead C.J. , Mathias C.J. 
Published: July 2012

The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of a range of doses (0.01, 0.1 and 1.0 nmol kg−1) of specific μ‐ δ‐ and κ‐opioid agonists on cardiovascular and respiratory function and on plasma catecholamines have been studied in conscious rabbits. The distribution of μ‐ δ‐ and κ‐opioid receptors was localized in rabbit brain by in vitro autoradiography.
The μ‐agonist [D‐Ala2, MePhe4‐Gly5‐ol]enkephalin (DAGOL) given i.c.v. caused a large rise in plasma noradrenaline and adrenaline, hypertension accompanied by an initial bradycardia followed by tachycardia, respiratory depression and sedation. After i.c. administration there were similar changes in heart rate (HR) and respiration, but no significant changes in mean arterial pressure (MAP) or plasma catecholamines.
The δ‐agonist [D‐Pen2,5]enkephalin (DPDPE) increased MAP and HR after both i.c.v. and i.c. administration, caused a small increase in noradrenaline but had no effect on adrenaline and did not alter respiration rate or blood gases. After i.c.v. DPDPE the rabbits became more alert and active.
The κ‐agonist U69593 given i.c.v. or i.c. had no effect on MAP or HR. After i.c.v. U69593, Paco2 fell, but there were no other respiratory effects. The responses to dynorphin 1–13, an endogenous κ‐agonist, were similar to those of U69593.
The opioid antagonist naloxone (30 nmol kg−1) given intravenously (i.v.) blocked the effects of i.c.v. DAGOL (1 nmol kg−1). A 100 fold higher dose of i.v. naloxone (3 μmol kg−1) was required to abolish the effects of i.c.v. DPDPE (1 nmol kg−1).
Autoradiographic studies demonstrated a high density of μ‐ and δ‐opioid receptors in hypothalamic sites. In the brainstem μ‐receptors were demonstrated in the nucleus tractus solitarius (NTS) and δ‐receptors in the dorsal motor nucleus of the vagus. κ‐Receptors were not detected in either the hypothalamus or brainstem.
These findings demonstrate that DAGOL increases sympatho‐adrenal outflow, probably by stimulation of hypothalamic μ‐receptors. The effects on HR are probably partly through a baroreflex and partly through an action of DAGOL on μ‐receptors in the dorsal motor nucleus of the vagus. DPDPE probably acts on δ‐receptors in the NTS to increase MAP and HR. Respiratory depression resulted from stimulation of μ‐receptors in the brainstem with no evidence of δ‐ or κ‐receptors being involved.
Capsaicin evokes secretion of nasal fluid and depletes substance P and calcitonin gene‐related peptide from the nasal mucosa in the rat
Authors: Petersson G. , Malm L. , Ekman R. , Håkanson R. 
Published: July 2012

The secretion of nasal fluid was studied in anaesthetized rats after topical application of capsaicin, and of calcitonin gene‐related peptide (CGRP) alone or CGRP in combination with substance P (SP). The flow of nasal fluid was stimulated and the secretions collected by a filter paper technique. The concentrations of SP and CGRP in nasal biopsies were determined after topical or systemic administration of capsaicin.
Capsaicin (single dose administration) stimulated nasal secretion in a dose‐dependent manner. The effect was inhibited by hexamethonium, lignocaine, or by the tachykinin antagonist (D‐Pro2, D‐Trp7,9)‐SP, but not by atropine, or by a combination of the histamine H1‐receptor antagonist chlorpheniramine and the H2‐receptor antagonist ranitidine.
When applied cumulatively, capsaicin rapidly produced desensitization. The concentrations of SP and CGRP in the nasal mucosa were reduced by capsaicin 6 days after topical or s.c. administration but not 15 min after topical application of desensitizing doses.
CGRP did not stimulate the secretion of nasal fluid and did not alter SP‐evoked nasal secretion.
The inhibition by hexamethonium of the capsaicin‐evoked nasal secretion suggests the involvement of ganglionic reflexes. In addition, the inhibition of the response to capsaicin by (D‐Pro2,D‐Trp7,9)‐SP and lidocaine and the depletion of SP and CGRP after capsaicin indicate the involvement of tachykinin‐mediated axon reflexes.
Amelioration of glycerol‐induced acute renal failure in the rat with 8‐cyclopentyl‐1,3‐dipropylxanthine
Authors: Kellett R. , Bowmer C.J. , Collis †M.G. , Yates M.S. 
Published: July 2012

Previous studies have shown that 8‐phenyltheophylline (8‐PT), a non‐selective antagonist at adenosine A1‐ and A2‐receptors, can ameliorate the severity of glycerol‐induced acute renal failure (ARF) in the rat. In the present study we have examined the effects of an antagonist with selectivity for adenosine A1‐receptors (8‐cyclopentyl‐1,3‐dipropylxanthine, CPX) on the development of ARF.
In the anaesthetised rat 8‐PT (4 mg kg−1, i.v.) and CPX (0.1 mg kg−1, i.v.) antagonised adenosine‐evoked responses which are thought to be mediated via A1‐receptors (bradycardia and decrease in renal blood flow). The agonist dose‐ratio produced by CPX was equal to or greater than that found with 8‐PT (heart rate and renal blood flow respectively). The hypotensive response to adenosine which is predominantly due to A2‐receptor activation was also antagonised by 8‐PT, whereas CPX was a much less effective antagonist of this response.
Administration of CPX (0.1 mg kg−1, i.v.; twice daily for two days) significantly attenuated the increase in plasma levels of urea and creatinine, the increased kidney weight and the renal tubule damage observed in rats 2 days following induction of ARF with intramuscular glycerol injection. In addition treatment with CPX significantly enhanced the clearances of inulin and p‐aminohippurate.
After glycerol injection, the mortality rate over 7 days in untreated and vehicle‐treated rats was 43% and 21% respectively. In contrast, all animals treated with CPX survived over the 7 day observation period.
These results support the suggestion that adenosine is an important factor in the development of ARF and indicate that this effect of the purine is likely to be mediated via an adenosine A1‐receptor.
The relationship between neutrophils and increased microvascular permeability in a model of myocardial ischaemia and reperfusion in the rabbit
Authors: Williams Frances M. , Collins Paul D. , Tannière‐Zeller Marianne , Williams Timothy J. 
Published: July 2012

111In‐labelled neutrophils and 125I‐labelled albumin were used to measure neutrophil accumulation and microvascular plasma protein leakage in the ischaemic/reperfused myocardium of anaesthetized rabbits.
A period of 30 min coronary artery occlusion followed by 3h reperfusion resulted in an increase in both 111In and 125I counts in the area at risk (AR) of the myocardium.
Pretreatment of 111In‐neutrophils in vitro with monoclonal antibody 60.3 directed against the CD18 antigen on neutrophils, followed by intravenous administration, significantly suppressed their accumulation into the AR myocardium.
Depletion of circulating neutrophils by use of anti‐neutrophil serum or mustine hydrochloride did not affect plasma protein leakage into the AR myocardium.
Administration of the platelet activating factor (PAF) antagonist WEB 2086 (10 mg kg−1, i.v.) had no effect on the accumulation of 111In‐neutrophils or on plasma protein leakage in the AR myocardium.
The effect of benserazide on the peripheral and central distribution and metabolism of levodopa after acute and chronic administration in the rat
Authors: Kent A.P. , Stern G.M. , Webster R.A. 
Published: July 2012

The effects of levodopa alone (50 mg kg−1) and levodopa (10 mg kg−1) plus benserazide (50 mg kg−1) were tested on the levels of dopa, dopamine, 3‐methoxytyrosine (3‐MT), 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), measured by h.p.l.c with electrochemical detection, in samples of plasma, CSF, urine, striatum and hypothalamus of rats taken 30 min after injection. Levodopa plus benserazide produced significantly higher levels of dopa in plasma and brain than levodopa alone and reduced the peripheral synthesis and metabolism of dopamine.
When given chronically over 6 weeks the advantages of adding benserazide (50 mg kg−1 day−1) to levodopa (40 mg kg−1 day−1) were less marked and although more dopamine was present in the striatum than with levodopa given alone (200 mg kg−1 day−1) there was no evidence of any increase in its metabolites (HVA and DOPAC) and therefore of its turnover and utilisation.
The most striking effect of chronic treatment with levodopa plus benserazide was the appearance of large quantities of 3‐MT in plasma, CSF and brain.
When levodopa alone, or levodopa plus benserazide, was given as an acute challenge to animals receiving the same treatment chronically, it was found that levodopa alone still produced increases in striatal dopamine, DOPAC and HVA in those animals dosed chronically on levodopa, but it was less effective in this respect when given with benserazide to the animals dosed with levadopa plus benserazide.
It is concluded that this difference in levodopa distribution may depend on the persistence in benserazide‐treated animals of 3‐MT, which has a long half‐life and may compete with dopa for transport into the blood and brain.
The implication of these findings to the treatment of Parkinsonism is discussed.
Effect of neuropeptide Y on α2‐adrenoceptor‐mediated cardiovascular responses in the pithed rat
Authors: Vila E. , Macrae I.M. 
Published: July 2012

The effects of neuropeptide Y (NPY) on the cardiovascular responses induced by stimulation of pre‐ and postjunctional α2‐adrenoceptors were studied in the pithed normotensive rat.
The increase in diastolic blood pressure induced by cumulative injection of xylazine (1–1000 μgkg−1, i.v.) were potentiated by NPY (5 μg kg−1) but not affected by a lower dose (0.75 μg kg−1) of this peptide.
Xylazine (1–100 μg kg−1) inhibited in a dose‐dependent manner the tachycardia induced by continuous electrical stimulation (0.2 Hz, 2 ms, 60 V) of the spinal cord (C7‐Thl).
NPY (5 μg kg−1 but not 0.75 μg kg−1) enhanced the inhibitory effect of xylazine on the tachycardia induced by electrical stimulation without having any direct effect on heart rate.
These results suggest that there may be a positive interaction between NPY receptors, postjunctional α2‐adrenoceptors and between NPY receptors and prejunctional α2‐adrenoceptors in the cardiovascular system of the rat.
Identification of human platelet a2‐adrenoceptors with a new antagonist [3H]‐RX821002, a 2‐methoxy derivative of idazoxan
Authors: Galitzky Jean , Senard Jean Michel , Lafontan Max , Stillings Mike , Montastruc Jean Louis , Berlan Michel 
Published: July 2012

The binding of a new α2‐adrenoceptor antagonist, [3H]‐RX821002 (2‐(2‐methoxy‐l,4‐benzodioxan‐2‐yl)‐2‐imidazoline), was investigated in human platelet membranes and compared with [3H]‐yohimbine binding parameters.
Analysis of kinetic data revealed association and dissociation time courses consistent with a simple bimolecular reaction. Saturation isotherms showed that [3H]‐RX821002 labelled a higher total number of α2‐binding sites (224 ± 31 vs 168 ± 24 fmol mg−1 protein) than [3H]‐yohimbine and with higher affinity (Kd: 0.92 ± 0.06 vs 1.51 ± 0.08nm). Moreover [3H]‐RX821002 exhibited a lower percentage of nonspecific binding.
The difference in total binding is due to a better labelling of the α2‐adrenoceptors in the low affinity state by [3H]‐RX821002 since the labelled receptors number in high affinity state was identical with the two radioligands.
[3H]‐RX821002 binding displayed a specificity similar to that obtained with [3H]‐yohimbine. The potency of various compounds acting on adrenoceptors was: yohimbine > oxymetazoline > UK 14304 > (−)−adrenaline > prazosin ≥ (+)‐adrenaline > isoprenaline. This order of potency is classical for an α2A‐adrenoceptor.
RX821002 is a more potent α2‐adrenoceptor antagonist than yohimbine on adrenaline‐induced platelet aggregation.
These results indicate that [3H]‐RX821002 is a suitable ligand for the identification of human platelet α2‐adrenoceptors.
Enhancement of the endothelial production of prostacyclin by inhibitors of protein synthesis
Authors: Boeynaems J.‐M. , Boutherin‐Falson O. , Lagneau C. , Galand N. 
Published: July 2012

Pretreatment of bovine aortic endothelial cells with cycloheximide enhanced their capacity to release prostacyclin in response to adenosine 5′‐triphosphate (ATP) and bradykinin.
The action of cycloheximide was time‐dependent; it became detectable after a 1 h exposure to the cells and was maximal after 3 h.
Puromycin mimicked the effect of cycloheximide. For these two agents, the enhancement of prostacyclin release was obtained at concentrations producing a partial inhibition of protein synthesis.
Cycloheximide increased the mobilization of free arachidonic acid induced by ATP in bovine aortic endothelial cells.
In conclusion, the synthesis of new proteins is not involved in the stimulatory action of ATP and bradykinin on prostacyclin production by bovine aortic endothelial cells. Despite the short half‐life of prostaglandin H synthase in endothelial cells, cycloheximide and puromycin enhanced the release of prostacyclin induced by agonists. Our data suggest that this release might be under the control of rapidly turning‐over phospholipase inhibitory proteins.