bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of a 5‐lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on PAF‐induced airway responses in neonatally immunized rabbits
Authors: Herd Caroline M. , Donigi‐Gale Donna , Shoupe T. Scott , Page Clive P. 
Published: July 2012

Aerosol administration of platelet activating factor (PAF) (80 μg ml−1 for 60 min) to neonatally immunized rabbits caused bronchoconstriction which was far in excess of that produced by a comparable aerosol of bovine serum albumin (BSA), the carrier molecule for PAF. Bronchoconstriction of a similar magnitude was elicited by PAF in immunized, sham‐immunized and normal rabbits.
Aerosol administration of PAF to immunized rabbits induced enhanced airway responsiveness to inhaled histamine in all animals tested, 24 h and 72 h after exposure. In not all cases had airways responsiveness returned to basal levels at 1 week following PAF challenge. In contrast, following exposure of immunized rabbits to BSA, no significant changes in airway responsiveness to histamine were evident at any of the measured time points.
A significant increase in the total number of inflammatory cells recovered in bronchoalveolar lavage (BAL) fluid was determined 24 h and 72 h following PAF exposure in immunized rabbits. This was associated with a significant increase in the number of neutrophils and eosinophils. Similar changes were observed following exposure of PAF to normal and sham‐immunized rabbits. No change in the total number of inflammatory cells was obtained in BAL after BSA challenge to immunized rabbits; however, neutrophil numbers were significantly increased.
PF 5901, a specific inhibitor of the 5‐lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist, at a dose of 10 mg (direct intratracheal administration) significantly inhibited the airway resistance (RL) component of the bronchoconstriction induced by PAF in neonatally‐immunized rabbits. Doses of 10 mg, 3 mg and 1 mg PF 5901 (direct intratracheal administration) were sufficient to inhibit significantly the PAF‐induced increase in airways responsiveness to inhaled histamine in immunized rabbits. PF 5901 however, failed to alter the pulmonary cell infiltration induced by PAF, as assessed by BAL.
We suggest from the results of the present study that PAF induces consistent and long‐lasting increases in airways responsiveness to histamine in immunized rabbits, which is mediated, at least in part, by products of the 5‐lipoxygenase metabolic pathway. Furthermore, the inability of PF5901 to inhibit the influx of inflammatory cells into the airway lumen following PAF challenge may suggest that bronchial hyperresponsiveness and cellular infiltration are not strictly associated events.
Alteration of the L‐type calcium current in guinea‐pig single ventricular myocytes by heptaminol hydrochloride
Authors: Peineau N. , Mongo K.G. , Le Guennec J.‐Y. , Garnier D. , Argibay J.A. 
Published: July 2012

The effects of heptaminol on calcium current amplitude and characteristics were studied in single ventricular myocytes of guinea‐pig by use of the whole cell configuration of the patch clamp technique.
A concentration‐dependent decrease in ICa amplitude was observed. At heptaminol concentration as low as 10−6 m, this effect was observed in only two cells (n = 6). At 10−5 m the reduction of ICa was of 30 ± 15% (n = 11).
The current recovery from inactivation at — 40 mV holding potential (HP) seemed less sensitive to perfusion with heptaminol (> 10−6 m). However, at — 80 mV HP the overshoot of the recovery curve was decreased by heptaminol.
Both at — 40 mV and — 80 mV HP, heptaminol (10−5 m) significantly increased the steady state inactivation of ICa.
As previously proposed by others to explain the effects of membrane active substances, the effects of heptaminol may result from alterations in cell membrane properties and possibly from an increase in intracellular free calcium ion concentration.
Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts
Authors: Bethke Thomas , Meyer Wilfried , Schmitz Wilhelm , Scholz Hasso , Stein Birgitt , Thomas Klaus , Wenzlaff Holger 
Published: July 2012

The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea‐pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes.
In homogenates of cardiomyocytes and multicellular ventricular tissue, four distinct soluble PDE activities could be separated by DEAE‐sepharose chromatography.
In multicellular cardiac tissue as well as in cardiomyocyte preparations, adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) PDE isoenzymes I‐IV were comparable in terms of substrate affinities, and inhibition or stimulation by guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). However, in cardiomyocytes the Vmax values of PDE I‐IV were lower by a factor of about 2 to 7 and the basal activities were lower by a factor of about 3 to 5 as compared to multicellular cardiac tissue.
To investigate whether the PDE I‐IV activities were similarly inhibited by PDE inhibitors in both preparations, we studied the effects of 3‐isobutyl‐1‐methylxanthine (IBMX), UD‐CG 212 Cl (2‐(4‐hydroxy‐phenyl)‐5‐(5‐methyl‐3‐oxo‐4,5‐dihydro‐2H‐6‐pyridazinyl)benzimidazole HCl) and rolipram. UD‐CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 μmol l−1) and in ventricular tissue (IC50 value 0.1 μmol l−1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 μmol ml−1) and in ventricular tissue (IC50 1.1 μmol l−1) whereas IBMX was a nonselective PDE inhibitor in both preparations.
It is concluded that the PDE isoenzymes I‐IV from multicellular ventricular tissue can be used as a representative system for investigating PDE inhibiting properties of PDE inhibitors in the myocardium since comparable PDE isoenzymes I‐IV exist in guinea‐pig ventricular cardiomyocytes and multicellular ventricular tissue.
Chloride anion concentration as a determinant of renal vascular responsiveness to vasoconstrictor agents
Authors: Quilley Caroline P. , Lin Yu‐Shi R. , McGiff John C. 
Published: July 2012

The role of chloride concentration in modulating vasoconstrictor responses of the rat isolated kidney, perfused with Krebs‐Henseleit solution, to angiotensin II (AII), arginine vasopressin (AVP) and phenylephrine (PE) was investigated.
Reduction of perfusate chloride from a high (117 mm) to low (87 mm) concentration, by substitution of sodium chloride with a mixture of sodium salts of propionate, acetate and methanesulphonate, reduced responsiveness to all three vasoconstrictors, the change for AII being most pronounced.
For AII, reduced vasoactivity with low chloride was evident both in terms of the threshold dose and on the linear part of the dose‐response curve but not for the maximum response. This attenuating effect of low chloride on the vasoconstrictor response to AII was reversed when perfusion with high chloride was reinstituted. Continuous perfusion with high chloride progressively increased the vasoconstrictor effect of low doses of AII for successive dose‐response curves.
In addition to reducing responses on the linear part of the dose‐response curve for both AVP and PE, low chloride also reduced the maximum vasoconstrictor response to PE, whereas the threshold dose for the two agonists was unchanged. In contrast to the enhanced pressor response to AII, during continuous perfusion with high chloride, tachyphylaxis occurred with AVP and PE.
The ability of chloride to modify renal responsiveness to vasoconstrictor agents may contribute to the increase in renal vascular resistance and decrease in glomerular filtration rate (GFR) which occurs during infusion of hyperchloremic solutions into the renal artery and explain the need for chloride as the anion accompanying sodium in salt‐sensitive hypertensive models.
Ionic effects on amiloride block of the mechanosensitive channel in Xenopus oocytes
Authors: Lane John W. , McBride Don W. , Hamill Owen P. 
Published: July 2012

Patch clamp techniques were used to measure the ionic dependence of amiloride block of single mechanosensitive (MS) channels in frog (Xenopus laevis) oocytes.
The primary aim was to determine whether the difference in potency of amiloride block of MS channels in frog oocytes (IC50 = 0.5 mm) and chick auditory hair cells (IC50 = 50 μm) was due to the different ionic recording solutions.
Amiloride block of the oocyte MS channel does not vary significantly with complete substitution of external Na+ (i.e. 100 mm) with K+ in Ca2+‐free recording solution (in both Na+ and K+ the IC50 = 0.5 mm).
A physiological concentration (1.8 mm) of external Ca2+ blocks the oocyte MS channel and reduces the potency of amiloride block (IC50 = 1.1 mm) without altering the voltage‐dependence or the Hill coefficient (n = 1.8) of amiloride block. The reduction in potency can be explained by surface charge screening by Ca2+ which reduces the effective amiloride surface concentration.
The present results indicate that factors other than ionic recording conditions must underlie the difference in potency of amiloride block of MS channels in oocytes and auditory hair cells.
A comparison of the actions of agonists and antagonists at non‐NMDA receptors of C fibres and motoneurones of the immature rat spinal cord in vitro
Authors: Pook P. , Brugger F. , Hawkins N.S. , Clark K.C. , Watkins J.C. , Evans R.H. 
Published: July 2012

The shift in d.c. potential in dorsal roots (EC50 8.0 μm ± 0.9 s.e.mean, n = 5) or depression of the C elevation of the compound action potential (EC50 3.0 μm ± 0.3, n = 7) have been used to measure the depolarizing action of kainate on dorsal root C fibres of immature (3 to 5 day old) rats. Depolarization of motoneurones was measured from the shift in d.c. potential in ventral roots.
6‐Cyano‐7‐nitroquinoxaline,2–3,dione (CNQX) (pA2 5.78 ± 0.06, n = 8) and 6‐nitro‐7‐suplhamobenzo(f)quinoxaline‐2,3‐dione (NBQX) (pA2 5.75 ± 0.04, n = 7) had similar potencies as antagonists of kainate at dorsal root fibres. The potency of NBQX as a kainate antagonist was similar also at motoneurones (pA2 5.72 ± 0.07, n = 3). At motoneurones, NBQX was less potent as an antagonist of domoate (pA2 5.29 ± 0.05) and more potent as an antagonist of S‐α‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) (pA2 6.80 ± 0.09) than as an antagonist of kainate.
Application of l‐glutamate, quisqualate and RS‐AMPA to dorsal roots produced only short lasting depolarizations but kainate concentration‐effect plots were shifted to the right in the presence of these three agonists (pA2 5.08 ± 0.08, (n = 3), 5.59 ± 0.04, (n = 4) and 4.46 ± 0.04 (n = 4) respectively). Slopes of dose‐ratio against concentration were significantly less than one for the latter antagonism.
The amplitude of depolarizations induced by l‐glutamate, AMPA and quisqualate were increased up to ten fold and those induced by kainate up to two fold following treatment of dorsal roots with concanavalin A. The duration of the responses was increased also by the latter treatment. Folowing 85 s applications of glutamate, quisqualate, AMPA and kainate the mean respective times (s ± s.e.mean (n)) taken for responses to decay to half the peak amplitude were increased from 63 ± 7 (10), 86 ± 17 (4), 95 ± 19 (4) and 135 ± 3 (12) to 202 ± 49 (10), 147 ± 7 (4), 160 ± 13 (6) and 163 ± 10 (10). Under similar conditions the mean decay time of γ‐aminobutyric acid‐induced responses was 145 ± 7 (10). This was not significantly altered by concanavalin A treatment.
Application to dorsal roots of l‐aspartate at concentrations up to 5 mm (with or without concanavalin A treatment), the selective metabotropic agonist 1S,3R‐trans‐1‐aminocyclopentane‐1,3‐dicarboxylate (1 mm,) and d‐serine (20 μm) in the presence or absence of N‐methyl‐d‐aspartate (NMDA, 500 μm) neither depolarized the preparations nor shifted the kainate concentration‐effect plot.
It is concluded that primary afferent C fibres possess only one type of non‐NMDA receptor which is activated strongly by domoate or kainate but only weakly by AMPA. This receptor is readily desensitized by glutamate, quisqualate or AMPA and it is less readily desensitized by kainate.
Renal selective N‐acetyl‐l‐γ‐glutamyl prodrugs: studies on the selectivity of some model prodrugs
Authors: Drieman J.C. , Thijssen H.H.W. , Struyker‐Boudier H.A.J. 
Published: July 2012

In this study, a number of structurally different N‐acetyl‐l‐γ‐glutamyl prodrugs were investigated with respect to selective uptake by the kidney in male Wistar rats.
All prodrugs were tested in vitro in rat kidney slices and kidney homogenate to study their uptake and conversion. It was found that the prodrugs of para‐nitroaniline (agPNA), aminophenyl acetic acid (agAFA), sulphamethoxazole (agSM), sulphadimethoxine (agSDM), propranolol (agPP) and metoprolol (agMP) were accumulated by a probenecid‐sensitive carrier. The prodrug of 4′‐aminoantipyrine (agAAP) was not accumulated by a probenecid‐ or buthionine sulphoximine‐sensitive carrier. Unlike all other prodrugs, agAAP and agMP were not, or only a very limited extent converted to the parent compound in vitro.
agPNA, agAFA and agPP were also investigated in vivo. The tissue distribution of the prodrugs and the parent drugs was established, as was their urinary excretion and pharmacokinetic behaviour. agPNA and agAFA showed selective uptake by the kidney, in contrast to agPP which accumulated in the liver. The distribution of the parent compounds following prodrug administration was as follows: agPNA was found in kidney and plasma: agAFA in kidney only; agPP in liver only.
The factors which determine the selectivity of N‐acetyl‐l‐γ‐glutamyl prodrugs are discussed. The main factors are: the transport into the kidney, the conversion rate, the residence time of the prodrug in the kidney and the presence or absence of competition for uptake and conversation by other tissues, e.g. the liver. It is concluded that this prodrug approach offers the possibility of delivering drugs selectively to the kidney, but also that it is not universally applicable.
The effect of cyclic AMP and cyclic GMP phosphodiesterase inhibitors on the superoxide burst of guinea‐pig peritoneal macrophages
Authors: Turner Nicholas C. , Wood Lorna J. , Burns Fiona M. , Gueremy Thomas , Souness John E. 
Published: July 2012

The cyclic nucleotide phosphodiesterase (PDE) activity of guinea‐pig peritoneal macrophages was partially characterized and the effects of selective and non‐selective inhibitors of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP PDE) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP PDE) phosphodiesterases on superoxide generation were investigated using peritoneal macrophages from horse‐serum pretreated guinea‐pigs.
The non‐selective PDE inhibitor, 3‐isobutyl‐1‐methylxanthine (IBMX) and the PDE I/V selective inhibitor, zaprinast, inhibited spontaneous superoxide generation with IC50s of 30.7 ± 11.3 μm and 145 ± 17 μm respectively (n = 6 and 5). The concentration‐response curves for the PDE IV selective inhibitors rolipram and Ro20–1724 were biphasic; mean maximum inhibitions were 56.9 ± 5.9% and 66.8 ± 10.5% respectively at 300 μm, but in 2 out of 6 (rolipram) and 2 out of 5 (Ro20–1724) experiments inhibition was < 50%. The PDE III inhibitor SK&F 94120 was without effect. Spontaneous superoxide generation was reduced 57 ± 10% by 1 μm prostaglandin E2 (PGE2) and 62.6 ± 3.76% by 1 μm salbutamol.
The increase in superoxide generation elicited by FMLP (10−9−10−5 m) was unaffected by any of the PDE inhibitors studied. Inhibition of FMLP‐stimulated superoxide generation by PGE2 was enhanced in the presence of 10 μm IBMX.
Macrophages were found to contain a predominantly membrane bound cyclic AMP PDE (90% of total activity) which was unaffected by cyclic GMP or calcium/calmodulin. The cyclic AMP PDE activity in the cytosolic fraction was enhanced in the presence of calcium/calmodulin. Selective inhibitors of PDE IV inhibited the particulate cyclic AMP PDE activity (IC50s rolipram 1.5 ± 0.3 μm, Ro 20–1724 4.1 ± 0.6 μm) as did the non‐selective inhibitor IBMX (IC50 22 ± 8 μm). The macrophage particulate PDE activity was resistant to inhibition by the PDE III inhibitor SK&F 94836 and the PDE I/V inhibitor, zaprinast. The cytosolic calcium/calmodulin stimulated cyclic AMP hydrolytic activity was inhibited by zaprinast (IC50 ‐ calcium/calmodulin 123 ± 39 μm; + calcium/calmodulin IC50 17.7 ± 6.3 μm).
The results indicate that guinea‐pig peritoneal macrophages contain a type IV cyclic AMP PDE which is predominantly membrane associated and a predominantly cytosolic calcium/calmodulin stimulated cyclic AMP PDE. Functional studies suggest that both of these PDE activities contribute to cyclic AMP hydrolysis and regulation of superoxide generation in these cells. Inhibition of spontaneous superoxide generation, but not that stimulated by FMLP, suggests that the activity of PDE inhibitors is subject to functional antagonism but that this can be overcome by enhancing cyclic AMP formation.
Effects of the immunosuppressants cyclosporin A and FK 506 on exocytosis in the rat exocrine pancreas in vitro
Authors: Waschulewski Ingo H. , Hall Diane V. , Kern Horst F. , Edwardson J. Michael 
Published: July 2012

We have examined the effects of the immunosuppressive drugs cyclosporin A (CsA) and FK 506 on exocytosis in two in vitro preparations of the exocrine pancreas—lobules and dispersed acini.
In lobules taken from starved rats and stimulated with the secretagogue caerulein, both CsA and FK 506, given shortly before stimulation, caused a dose‐dependent inhibition of amylase secretion. In lobules from rats that had been pretreated in vivo with the protease inhibitor FOY‐305 to stimulate secretion maximally, both CsA and FK 506 inhibited secretion of newly synthesized proteins, whereas only FK 506 inhibited caerulein‐stimulated amylase release.
These different effects of the immunosuppressants on amylase release were reflected in their effects on degranulation, as revealed by electron microscopy. Control acinar cells in lobules from FOY‐305‐treated rats were almost completely degranulated, whereas treatment with FK 506, but not CsA, caused the accumulation of zymogen granules close to the apical plasma membrane.
In dispersed acini, stimulated with the cholinomimetic secretagogue bethanechol, both CsA and FK 506 reduced the secretory response, to about 45% of control; IC50 values were 50 nm and 3 nm, respectively. A similar partial inhibition of exocytosis was seen in acini permeabilized with the bacterial toxin streptolysin O and stimulated with 10 μm Ca2+.
These results demonstrate that the immunosuppressants cause an inhibition of exocytosis in the exocrine pancreas that is both rapid in onset and potent. The loss of the inhibitory effect of CsA on amylase release in lobules taken from FOY‐305‐treated rats may reveal a change in the characteristics of exocytosis as a consequence of the high level of stimulation, and also indicates that CsA and FK 506 have subtly different effects on secretion. We suggest that these drugs might be useful tools in the dissection of the molecular mechanisms of exocytosis.
α2‐Adrenoceptor antagonist potencies of two hydroxylated metabolites of yohimbine
Authors: Berlan Michel , Verge Roger Le , Galitzky Jean , Corre Pascal Le 
Published: July 2012

The α2‐adrenoceptor antagonist capacities of two hydroxylated metabolites of yohimbine in man (10‐OH‐yohimbine and 11‐OH‐yohimbine) were investigated on the α2‐adrenoceptors of human platelets and adipocytes and compared to those of yohimbine.
Yohimbine and 11‐OH‐yohimbine exhibited similar α2‐adrenoceptor affinity in biological studies i.e. inhibition of adrenaline‐induced platelet aggregation and inhibition of UK14304‐induced antilipolysis in adipocytes.
Yohimbine and the two metabolites displaced [3H]‐RX 821002 binding with equivalent affinities in platelet and adipocyte membranes with the following order of potency: yohimbine > 11‐OH‐yohimbine > 10‐OH‐yohimbine. However, when binding studies were carried out in binding buffer supplemented with 5% albumin, the apparent affinity of yohimbine was reduced about 10 fold and was similar to that of 11‐OH‐yohimbine.
Yohimbine and its metabolites were bound to different extents to plasma proteins, the bound fraction being 82%, 43% and 32% respectively for yohimbine, 11‐OH‐yohimbine and 10‐OH‐yohimbine.
These results show that the main hydroxylated metabolite of yohimbine in man (11‐OH‐yohimbine) possesses α2‐adrenoceptor antagonist properties. The discrepancies found in binding studies (i.e. 10 fold lower affinity of 11‐OH‐yohimbine than yohimbine for α2‐adrenoceptors but similar capacities in blocking biological α2‐adrenoceptor effects in cells) are attributable to the higher degree of binding of yohimbine to plasma protein.
Effect of dexamethasone on neutrophil accumulation and oedema formation in rabbit skin: an investigation of site of action
Authors: Yarwood Helen , Nourshargh Sussan , Brain Susan , Williams Timothy J. 
Published: July 2012

The anti‐inflammatory actions of dexamethasone on vascular and leukocyte responses in rabbit skin were investigated.
Neutrophil accumulation and oedema formation were simultaneously measured as the local accumulation of i.v. administered 111In‐labelled neutrophils and 125I‐labelled albumin. Systemically administered dexamethasone (3 mg kg−1) inhibited neutrophil accumulation induced by i.d. zymosan activated plasma (ZAP), N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) and leukotriene B4 (LTB4) when co‐injected with prostaglandin E2 (PGE2). Dexamethasone also inhibited oedema formation elicited by these stimuli and the responses induced by i.d. platelet activating factor (PAF) + PGE2 and bradykinin (BK) + PGE2.
Intradermal dexamethasone (2 × 10−10 mol per site) but not indomethacin (10−8 mol per site) inhibited oedema formation induced by i.d. ZAP + PGE2 and BK + PGE2. This inhibitory effect of dexamethasone was significant only with pretreatment periods of 4 h, shorter pretreatment periods resulting in greatly reduced effects. Intradermal dexamethasone had no effect on neutrophil accumulation induced by ZAP + PGE2.
Intradermal dexamethasone (2 × 10−10 mol per site) had no effect on increase in blood flow induced by PGE2 as measured by 133Xenon clearance.
The accumulation of neutrophils isolated from donor rabbits pretreated with i.v. saline or dexamethasone (3 mg kg−1) was investigated in untreated recipient rabbits. The accumulation of neutrophils, induced by ZAP + PGE2, FMLP + PGE2 and LTB4 + PGE2, from dexamethasone‐pretreated donors was significantly smaller than the accumulation of neutrophils from saline‐pretreated donors.
The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedema formation.
Neutrophil accumulation can be inhibited by an effect of dexamethasone on the neutrophil itself or on the vascular endothelium. These results indicate that at least part of the inhibitory effect is on the circulating neutrophil induced by dexamethasone or a dexamethasone‐induced product.