bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of chronic vitamin E deficiency on vascular function ‐ a study of sympathetic nerves, smooth muscle and endothelium of the mesenteric arterial bed of the rat
Authors: Ralevic Vera , Milla Peter J. , Bumstock Geoffrey 
Published: July 2012

Male rats were deprived as weanlings of dietary vitamin E for 2, 4, 6, 10 and 12 months. Mesenteric arterial beds from these rats and from age‐matched controls were isolated and perfused with Krebs solution at a constant flow rate (5 ml min−1). The function of perivascular sympathetic nerves, smooth muscle and endothelium was assessed.At 12 months vitamin E deficient rats exhibited the characteristic symptoms of vitamin E deficiency, namely poor coat condition, muscle wasting, kyphoscoliosis and impaired gait. In the isolated mesenteric arterial bed electrical field stimulation (EFS) of perivascular nerves (4–32 Hz, 90 V, 1 ms, for 30 s) elicited frequency‐dependent vasoconstrictor responses which were unaffected by vitamin E deficiency except at 12 months, at which age responses were significantly greater than those of the controls at 24 and 32 Hz (P<0.01).Exogenous noradrenaline (NA; 0.15–500 nmol) elicited dose‐dependent vasoconstriction which was similar in vitamin E‐deficient and control preparations at all ages. Potassium chloride (0.15 mmol) also produced similar vasoconstrictor responses in vitamin E‐deficient and control preparations at each age.Tone of the preparations was raised by continuous perfusion with methoxamine (4–70 μm), producing similar increases in perfusion pressure in vitamin E‐deficient and control preparations at each age. Endothelium‐dependent dose‐dependent vasodilatation to adenosine 5′‐triphosphate was significantly impaired in mesenteric arterial beds from 12 month‐old vitamin E‐deficient rats compared with the controls (P<0.05). Relaxation to acetylcholine was not significantly different at any age.Endothelium‐independent vasodilatation to sodium nitroprusside was similar in vitamin E‐deficient rats and age‐matched controls.These results suggest that long term (12 months) deprivation of dietary vitamin E may impair endothelial function in mesenteric arteries of the rat. Sympathetic perivascular nerve constrictor function was increased at 12 months. There were no functionally expressed changes in the vascular smooth muscle, which appears to be more resilient to the effects of oxidative stress in vitamin E deficiency.
Pentobarbitone modulation of NMDA receptors in neurones isolated from the rat olfactory brain
Authors: Charlesworth P. , Jacobson L. , Richards C.D. 
Published: July 2012

The action of pentobarbitone on the N‐methyl‐D‐aspartate (NMDA) receptors of neurones freshly dissociated from the olfactory bulb and olfactory tubercle has been studied using patch‐clamp techniques.
Pentobarbitone produced a concentration‐dependent depression of the currents evoked by NMDA with an IC50 value of c. 250 μm.
Analysis of the NMDA‐evoked noise produced power spectra that could be fitted by the sum of two Lorentzians with comer frequencies of 17 and 82 Hz. Pentobarbitone increased the comer frequency of the high frequency component but did not alter the apparent single channel conductance estimated from the noise.
Single channel recordings in either the cell‐attached or outside‐out patch configurations revealed that NMDA (20 or 50 μm) opened channels with a main conductance level around 55 pS and a principal subconductance around 44 pS. The uncorrected mean open time of the channels was 3.4 ms and mean burst length was 6.0 ms. Mean cluster length was about 12 ms.
Pentobarbitone produced a concentration‐dependent reduction in both mean open time and burst length. Mean cluster length was much less affected. Pentobarbitone did not decrease unitary current amplitude or bias the open‐state current amplitude distribution in favour of a particular substate.
From these data it appears that pentobarbitone depresses the inward current evoked by NMDA by reducing the probability of channel opening and this results from a shortening of the lifetime of the channel open state and by decreasing burst length.
Identification of a prostanoid FP receptor population producing endothelium‐dependent vasorelaxation in the rabbit jugular vein
Authors: Chen J. , Champa‐Rodriguez M.L. , Woodward D.F. 
Published: July 2012

Prostaglandin F2α (PGF2α) and its synthetic analogue, fluprostenol, potently relaxed the precontracted isolated jugular vein of the rabbit (RJuV). The vasorelaxant activity of PGF2α and fluprostenol was dependent upon an intact vascular endothelium. Although removal of the vascular endothelium abolished activity associated with PGF2α‐like agonists, it did not significantly alter the relaxant effects of prostaglandin E2 (PGE2).
The nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine methyl ester (l‐NAME), at 100 μm significantly inhibited the endothelium‐dependent relaxations induced by PGF2α. Lower doses (1 μm, 10 μm) of l‐NAME had little or no effect. The relaxant effects of PGE2 were not affected by l‐NAME (1–100 μm). D‐NAME at 100 μm was without effect on the vasorelaxant responses to either PGF2α or PGE2.
The potassium (K)‐channel blockers tetraethylammonium (TEA, 1 mm), barium (1 mm) and quinine (100 μm), each tested in the presence of the inactive enantiomer D‐NAME (100 μm) did not significantly affect the response to PGF2α. Unexpectedly, both TEA and barium significantly and partially reversed the inhibitory effects of 100 μm l‐NAME, whereas quinine had no effect. In similar studies, none of the three potassium channel blockers had any effect on relaxations elicited by PGE2 when given with D‐NAME or l‐NAME.
These results indicate that the PGF2α‐sensitive prostanoid receptors found in the vascular endothelium of the rabbit jugular vein are of the FP‐receptor subtype. Nitric oxide (NO) appears to be the predominant messenger involved in PGF2α‐induced relaxation of the rabbit jugular vein. Potassium channels may have a minor role in mediating the vasorelaxation response to PGF2α. When both NO synthesis and K‐channels are simultaneously blocked, inhibition of PGF2α‐induced vasorelaxation by l‐NAME is opposed by K‐channel blockers. This diminution of the inhibitory effect of l‐NAME by TEA and barium suggests that K‐channels may possibly serve a compensatory role via the NO pathway.
Discrimination between UTP‐ and P2‐purinoceptor‐mediated depolarization of rat superior cervical ganglia by 4, 4′‐diisothiocyanatostilbene‐2, 2′‐disulphonate (DIDS) and uniblue A
Authors: Connolly G.P. , Harrison P.J. 
Published: July 2012

Using a grease‐gap recording technique we have investigated the effects of some antagonists of P2‐purinoceptors on the depolarization of the rat isolated superior cervical ganglion evoked by 100 μMα, β‐methylene‐adenosine 5′‐triphosphate (α, β‐MeATP) or uridine 5′‐triphosphate (UTP). The effects of the putative P2Z‐purinoceptor antagonist, coomassie brilliant blue G, putative P2X‐purinoceptor antagonist, 4, 4′‐diisothiocyanatostilbene‐2, 2′‐disulphonate (DIDS) and uniblue A (an analogue of the P2Y‐ and P2X‐purinoceptor antagonist reactive blue 2) were investigated.
At the highest concentration examined uniblue A (300 μM) depressed α, β‐MeATP‐induced depolarization and at 100 and 300 μM enhanced UTP‐evoked depolarizations. Coomassie brilliant blue G (1 and 10 μM) did not affect depolarizations evoked by α, β‐MeATP or UTP. Depolarizations evoked by potassium (5 mM) or muscarine (100 nM) were unaltered by either coomassie brilliant blue G or uniblue A. Uniblue A (100 and 300 μM) produced a concentration‐dependent depression of hyperpolarizations evoked by adenosine (100 μM) whereas coomassie brilliant blue G at up to 10 μM, did not alter adenosine‐induced hyperpolarizations.
DIDS (30 and 100 μM) did not alter adenosine‐evoked hyperpolarizations, or depolarizations evoked by potassium or UTP. DIDS at 100 μM did not alter depolarizations evoked by muscarine. In contrast DIDS produced a concentration‐dependent depression of α, β‐MeATP‐evoked depolarizations.
These results are consistent with the proposal that uniblue A and DIDS but not coomassie brilliant blue G are antagonists of P2‐purinoceptors and that uniblue A is also an antagonist at P1 ‐purinoceptors present on the rat superior cervical ganglion.
The ability of uniblue A and DIDS to distinguish between depolarizations evoked by UTP and α, β‐MeATP provides further justification for the proposal that these nucleotides activate separate receptors present on the rat superior cervical ganglion, i.e. pyrimidinoceptors and P2‐purinoceptors respectively.
Attenuation by nitrosothiol NO donors of acute intestinal microvascular dysfunction in the rat
Authors: László F. , Whittle B.J.R. , Moncada S. 
Published: July 2012

The effects of the nitric oxide (NO) donors, S‐nitroso‐glutathione (SNG) and S‐nitroso‐N‐acetyl‐penicillamine (SNAP), on the acute intestinal microvascular dysfunction induced by NG‐nitro‐L‐arginine methyl ester (L‐NAME) in combination with low doses of endotoxin were investigated in the anaesthetized rat.
Administration of L‐NAME (5mg kg−1, s.c.) concurrently with E. coli lipopolysaccharide (LPS, 3 mg kg−1, i.v.) provoked the leakage of radiolabelled albumin in the ileum and colon, as a measure of microvascular damage, determined 1 h after challenge.
Intravenous infusion of SNOG or SNAP (1–10 μg kg−1 min−1) dose‐dependently attenuated the microvascular leakage induced by L‐NAME and LPS.
Infusion of the lowest doses of SNOG or SNAP (1 μg kg−1 min−1, i.v.) that significantly reduced the albumin leakage, did not affect the increase in blood pressure in response to L‐NAME in LPS‐treated rats. Higher doses of SNOG or SNAP (5–10 μg kg−1 min−1, i.v.) dose‐dependently reduced this increase in blood pressure.
In control studies, intravenous infusion of glutathione (10 μg kg−1 min−1) or N‐acetyl‐penicillamine (10 μg kg−1 min−1) had no effect on microvascular leakage in the ileum and colon induced by LPS and L‐NAME.
Pretreatment with rabbit anti‐rat neutrophil serum (0.4 ml kg−1, i.p., 4h before challenge), which reduced the neutrophil count in peripheral arterial blood, also inhibited the microvascular leakage in the ileum and colon.
The protective effects of the nitrosothiol NO donors in this model may reflect, in part, modulation of neutrophil interactions within the microcirculation or actions on endothelial cell integrity, in addition to any local vasodilator action.
The use of microdialysis for the study of drug kinetics: some methodological considerations illustrated with antipyrine in rat frontal cortex
Authors: Patsalos P.N. , Abed W.T. , Alavijeh M.S. , O'Connell M.T. 
Published: July 2012

The neuropharmacokinetics of antipyrine, a readily dialysable drug, in rat frontal cortex were studied and the effect of sampling time and contribution of period sampling and dialysate dead volume investigated in relation to tmax, Cmax, AUC and t1/2 values.
After i.p. administration, antipyrine (35 mg kg−1, n = 5) concentrations rose rapidly in rat frontal cortex (tmax, 12 min) and then declined exponentially. tmax, Cmax, AUC and t1/2 values were determined after 2 min dialysate sampling and compared to values obtained from simulated sampling times of 4, 6, 8, 10 and 20 min.
Antipyrine tmax and Cmax values were directly dependent on sampling frequency. Thus, mean 2 min sampling tmax and Cmax values were 63% lower and 27% higher, respectively, compared to 20 min sampling values. AUC and t1/2 values were unaffected.
Adjustment for dialysate dead volume (the volume of dialysate within the dialysis probe and sampling tube) reduced tmax values significantly but did not affect the other neuropharmacokinetic parameters.
Contribution of period sampling on neuropharmacokinetic parameters were investigated by comparing plots of antipyrine concentration data at midpoint and at endpoint of sampling time interval. Only tmax values were affected with values decreasing with increasing sampling time interval.
In conclusion, although microdialysis is a useful method for monitoring events at the extracellular level and for kinetic studies, it is important to understand its inherent characteristics so that data can be interpreted appropriately. Sampling frequency, particularly during monitoring of periods of rapid change, is very important since Cmax and tmax values will be significantly underestimated and overestimated respectively, if sampling time is longer rather than shorter. These considerations are particularly important in relation to microdialysis studies of pharmacokinetic‐pharmacodynamic interrelationships and modelling.
Potentiation of P1075‐induced K+ channel opening by stimulation of adenylate cyclase in rat isolated aorta
Authors: Linde Claudia , Quast Ulrich 
Published: July 2012

The effects of analogues and stimulators of cyclic AMP on the 86Rb+efflux‐stimulating and binding properties of P1075, an opener of ATP‐dependent potassium channels, were studied in rat aortic rings. The increase in 86Rb+efflux stimulated by P1075 was taken as a qualitative measure of K+ channel opening.
Forskolin, a direct activator of adenylate cyclase, isobutylmethylxanthine (IBMX), a phosphodiesterase inhibitor, and dibutyryl‐cyclic AMP (db‐cyclic AMP), a membrane permeant cyclic AMP‐analogue, relaxed rat aortic rings contracted by noradrenaline with EC50 values of 0.06, 2 and 10 μM, respectively.
Forskolin, IBMX and db‐cyclic AMP produced concentration‐dependent increases of the 86Rb+efflux induced by P1075 (50 nM) by up to twofold with EC50 values of about 0.1, 1.7 and 81 μM. At these concentrations the agents had little effect on the basal rate of 86Rb+efflux.
The 86Rb+efflux produced by P1075 in the presence of the cyclic AMP stimulators was inhibited by glibenclamide, a blocker of ATP‐sensitive potassium channels.
IBMX (100 μM) induced a leftward shift of the concentration ‐ 86Rb+efflux curve of P1075 without increasing the maximum. The enhancements of P1075‐stimulated 86Rb+efflux produced by combinations of forskolin and IBMX were either additive or less than additive.
The protein kinase A inhibitor, H‐89, inhibited P1075‐stimulated 86Rb+efflux in the presence of IBMX significantly more than in the absence of IBMX, suggesting that the effect of increased cyclic AMP levels is mediated by protein kinase A.
At high concentrations, forskolin and IBMX slightly increased basal 86Rb+efflux and inhibited the tracer efflux induced by P1075.
Binding of [3H]‐P1075 to rat aortic rings was either unaffected or inhibited by forskolin, IBMX and db‐cyclic AMP.
This study shows that moderate stimulation of the cyclic AMP system potentiates the K+ channel opening effect of P1075 by activation of protein kinase A. The fact that binding of [3H]‐P1075 remains unchanged or is diminished favours the hypothesis that the K+ channel openers activate ATP‐dependent K+ channels by an indirect mechanism.
Effect of platelet‐derived growth factor on voltage‐operated calcium channels in rabbit isolated ear artery cells
Authors: Wijetunge S. , Hughes A.D. 
Published: July 2012

Platelet derived growth factor (PDGF), AB and BB isoforms (100 μM) increased calcium channel currents measured by whole cell voltage clamp technique in single vascular smooth muscle cells isolated from rabbit ear arteries.
Tyrphostin‐23 (100 μM) a selective inhibitor of protein tyrosine kinases, reduced calcium channel currents. Pre‐incubation with tyrphostin‐23 prevented PDGF‐AB induced increase in calcium channel currents. However, in these same cells 10 nM (+)‐202791, a dihydropyridine calcium channel agonist, did increase calcium channel currents.
Bistyrphostin (10 μM), a selective inhibitor of epidermal growth factor (EGF)‐kinase also reduced calcium channel currents and inhibited PDGF‐AB‐induced increases in calcium channel currents.
Genistein (100 μM) a selective inhibitor of tyrosine kinases, structurally unrelated to the tryphostins, also inhibited calcium channel currents and pre‐incubation with genistein prevented the PDGF‐AB‐induced rise in calcium channel currents.
These results indicate that PDGF increases calcium channel currents in vascular smooth muscle. This action of PDGF probably involves a tyrosine kinase.
5‐HT3 receptor agonist induced carrier‐mediated release of dopamine in rat striatum in vivo
Authors: Santiago Marti , Machado Alberto , Cano Josefina 
Published: July 2012

In vivo microdialysis was used to study the effect of phenylbiguanide (PBG), a 5‐hydroxytryptamine3 receptor agonist, on the extracellular output of dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5‐hydroxyindoleacetic acid (5‐HIAA) in the corpus striatum.
PBG produced a dose‐related (10‐500 μM) increase in the release of dopamine (280‐2000%). DOPAC and HVA output decreased with the perfusion of PBG. This decrease was similar with 50–500 μM PBG. 5‐HIAA output was not affected by any PBG concentration used.
When nomifensine (500 μM) was included in the Ringer solution, the effect of PBG on the release of dopamine was ameliorated or inhibited. However, the effect of PBG (50‐500 μ) on the extracellular output of DOPAC and HVA was similar in the absence and in the presence of nomifensine (500 μM).
Perfusion of MDL 72222, a 5‐hydroxytryptamine3 receptor antagonist, at doses of 50 and 100 μM produced similar decreases (50% of controls) and increases (120% of controls) in the extracellular output of dopamine and DOPAC, respectively. HVA and 5‐HIAA output levels were not affected by either concentration of MDL 72222. MDL 72222 (10 μm) produced a slight ard transient increase in the release of dopamine and a decrease in the extracellular output of DOPAC. HVA and 5‐HIAA extracellular output was not affected by MDL 72222 (10 μM) perfusion.
Co‐perfusion of MDL 72222 (10 and 100 μ) or tetrodotoxin (1 μM) with PBG (50 μM) did not modify the effect produced by PBG (50 μM) alone on the release of dopamine.
These results suggest that the effect of PBG on the release of dopamine is mainly carrier‐mediated.
The effects of formoterol on plasma exudation produced by a localized acute inflammatory response to bradykinin in the tracheal mucosa of rats in vivo
Authors: O'Donnell Stella R. , Anderson Gary P. 
Published: July 2012

The effects of formoterol, a β2‐adrenoceptor agonist, on plasma protein exudation and microvascular permeability induced by topical, i.e. applied onto the tracheal mucosal surface, bradykinin (10 nmol; 20 μM, 5 min, 0.1 min‐1) were studied in a perfused segment of trachea prepared in situ in anaesthetized rats.
Bradykinin increased the amount of plasma (fluorimetric assay for protein) in the perfusate (response; 10.98 ± 0.357 μ, n = 69; total increase in plasma over basal during 45 min after start of bradykinin application) and 2 responses at a 90 min interval were reproducible. Carbon labelling was seen in tracheal sections from animals that received i.v. colloidal carbon, indicating that bradykinin caused tracheal microvessels to leak (increase in microvascular permeability).
Five minutes after topical formoterol, 5 or 30 nmol (10 or 60 μ perfused for 5 min), the bradykinin response was significantly reduced. The effects of formoterol were not dose‐related, i.e. were maximal at 5 nmol. The bradykinin response was at control levels 30 min after 5 nmol formoterol. After 30 nmol formoterol, the response was still reduced 120 min later. The bradykinin response was significantly reduced 60 min after systemic formoterol (i.p., 0.029 to 870 nmol kg‐1) and, for 290 nmol kg‐1 i.p. formoterol, this reduction was shown to last at least 150 min.
The bradykinin response was not prevented by supramaximal doses of topical (30 nmol) or i.p. (870 nmol kg‐1) formoterol and carbon‐labelled microvessels were seen in tracheal sections from all animals that received formoterol, although these were less in number and less densely labelled than in the absence of formoterol. There was a correlation between the plasma exudation response (μ1) and the number of carbon‐labelled vessels (Spearman's correlation coefficient 0.415, P < 0.001).
In animals pretreated with propranolol (3 μmol kg−1, i.V.), 29 nmol kg−1 formoterol, i.p., did not reduce the bradykinin response. However, propranolol itself markedly potentiated the bradykinin response which confounded the interpretation of its effects on formoterol.
The study has shown, in a preparation of rat trachea in situ, that supramaximal doses of the β 2‐adrenoceptor agonist, formoterol (a) produced a sustained, but incomplete, inhibition of plasma exudation (induced by topical bradykinin), and (b) did not prevent bradykinin‐induced leaky microvessels. The data support the view that, at least in rodent airways, β‐adrenoceptor agonists attenuate, but do not abolish, the microvascular permeability effects of bradykinin, a putative asthma mediator.
Relaxin‐induced increased coronary flow through stimulation of nitric oxide production
Authors: Bani‐Sacchi Tatiana , Bigazzi Mario , Bani Daniele , Mannaioni Pier Francesco , Masini Emanuela 
Published: July 2012

Relaxin (RLX) is a multifunctional hormone which, besides its role in pregnancy and parturition, has also been shown to influence the cardiovascular system. In this study, we investigated the effect of RLX on coronary flow of rat and guinea‐pig hearts, isolated and perfused in a Langendorff apparatus. RLX was either added to the perfusion fluid at a concentration of 5 × 10−9 M for a 20‐min perfusion, or given as a bolus into the aortic cannula at concentrations of 10−9 M, 5 × 10−9 M and 10−8 M dissolved in 1 ml of perfusion fluid.
RLX, given either for a 20‐min perfusion or as a bolus in the aortic cannula to guinea‐pig and rat isolated hearts, increased the coronary flow and the amount of nitrite, a stable end‐product of nitric oxide (NO) metabolism, that appeared in the perfusates in a concentration‐dependent fashion.
The increase in coronary flow and in nitrite in the perfusates induced by RLX was significantly reduced by pretreatment with the nitric oxide synthase (NOS) inhibitor, NG‐monomethyl‐L‐arginine (L‐NMMA, 10−4 M).
The effects of RLX on coronary flow and nitrite amounts in the perfusates were compared with those induced by the endothelium‐dependent vasodilator agent, acetylcholine (ACh, 10−8 − 10−7 M), and by the endothelium‐independent vasodilator agent, sodium nitroprusside (SNP, 10−7‐10−6M). The results obtained show that RLX is more effective than ACh and SNP in increasing coronary flow.
The results of this study show that RLX increases coronary flow through stimulation of NO production; hence this hormone should be regarded as a novel agent capable of improving myocardial perfusion.
Pharmacological selectivity of the cloned human P2U‐purinoceptor: potent activation by diadenosine tetraphosphate
Authors: Lazarowski Eduardo R. , Watt William C. , Stutts M. Jackson , Boucher Richard C. , Harden T. Kendall 
Published: July 2012

The human P2U‐purinoceptor was stably expressed in 1321N1 human astrocytoma cells and the pharmacological selectivity of the expressed receptor was studied by measurement of inositol lipid hydrolysis.
High basal levels of inositol phosphates occurred in P2U‐purinoceptor‐expressing cells. This phenomenon was shown to be due to release of large amounts of ATP from 1321N1 cells, and could be circumvented by adoption of an assay protocol that did not involve medium changes.
UTP, ATP and ATPγS were full and potent agonists for activation of phospholipase C with EC50 values of 140 nM, 230 nM, and 1.72 μM, respectively. 5BrUTP, 2C1ATP and 8BrATP were also full agonists although less potent than their natural congeners. Little or no effect was observed with the selective P2Y‐, P2X‐, and P2T‐purinoceptor agonists, 2MeSATP, α,β‐MeATP, and 2MeSADP, respectively.
Diadenosine tetraphosphate, Ap4A, was a surprisingly potent agonist at the expressed P2U‐purinoceptor with an EC50 (720 nM) in the range of the most potent P2U‐purinoceptor agonists. AP4A may be a physiologically important activator of P2U‐purinoceptors.