bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function
Authors: Murray Kenneth J. , Eden Roger J. , Dolan John S. , Grimsditch David C. , Stutchbury Catherine A. , Patel Bella , Knowles Aileen , Worby Angela , Lynham James A. , Coates William J. 
Published: July 2012

SK&F 95654 inhibited the guanosine 3′:5′‐cyclic monophosphate (cyclic GMP)‐inhibited phosphodiesterase (cGI‐PDE) with an IC50 value of 0.7 μm. The IC50 values were greater than 100 μm for the other four phosphodiesterase isoenzymes tested. The R‐enantiomer of SK&F 95654 (IC50 = 0.35 μm) was a more potent inhibitor of cGI‐PDE than was the S‐enantiomer (IC50 = 5.3 μm).
In the guinea‐pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate.
Oral administration of SK&F 95654 to conscious dogs caused dose‐dependent increases in left ventricular dp/dtmax in the range 10–50 μg kg−1. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtmax were similar for orally and intravenously administered compound, indicating good oral bioavailability.
SK&F 95654 caused a potent inhibition of U46619‐induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nm) and in human platelet‐rich plasma (PRP) (IC50 = 60 nm), indicating that the compound shows negligible plasma binding.
The R‐enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S‐enantiomer. The similarity of this ratio to that obtained on the cGI‐PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI‐PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP‐dependent protein kinase in human platelets.6 Collagen‐induced aggregation of rat PRP was also inhibited by SK&F 95654 (IC50 = 65 nm). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg−1, SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI‐PDE inhibitors studied (siguazodan and SK&F 94120).7 In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine‐ or U46619‐induced bronchoconstriction in the anaesthetized, ventilated guinea‐pig.8 Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.
Effects of noradrenaline on rat paratracheal neurones and localization of an endogenous source of noradrenaline
Authors: Reekie Fiona M. , Burnstock Geoffrey 
Published: July 2012

Intracellular recording techniques were used to study the actions of exogenous noradrenaline (NA) on rat paratracheal neurones in situ. The receptor subtypes underlying these actions were investigated by application of selective adrenoceptor antagonists.
Application of NA (0.1–10 μm) by superfusion evoked a membrane depolarization in 85% (52 out of 61) of all paratracheal neurones studied. The response consisted of a slow depolarization which was sometimes accompanied by action potential discharge. In 26 out of 31 cells the response was associated with a change in input resistance of the cell membrane. In 22 out of 26 cells there was a 30% increase, whilst in a further 4 cells there was a 15% decrease in input resistance. The amplitude of the NA depolarization was concentration‐dependent.
The depolarization evoked by NA was reversibly antagonized by prazosin (1 μm) but unaffected by yohimbine (1 μm) or propranolol (1–10 μm).
High performance liquid chromatography with electrochemical detection (h.p.l.c.‐e.c.d.) was used to assay for NA and dopamine in samples containing mainly paratracheal ganglia and in samples of tracheal smooth muscle with mucosa. NA was present in all samples assayed at a level of 1.6 μg NA g−1 and 0.5 μg NA g−1 wet weight of the two sample types respectively. Dopamine was not detected in any samples of either ganglia or smooth muscle with mucosa.
It is concluded that NA‐evoked depolarizations of rat paratracheal neurones result from stimulation of α1‐adrenoceptors, and that local levels of NA may be sufficiently high to activate these receptors directly.
Cytosolic calcium increase in coronary endothelial cells after H2O2 exposure and the inhibitory effect of U78517F
Authors: Kimura Masaaki , Maeda Kaori , Hayashi Shigehiro 
Published: July 2012

Cytosolic calcium concentrations ([Ca2+]i were determined with fura‐2 on both resting (unstimulated) and A23187‐stimulated coronary endothelial cells following injury by hydrogen peroxide (H2O2).
Treatment of cells with H2O2 (10−4 m) caused an increase in the resting [Ca2+]i, which reached a maximum of five fold after 3 h.
The increase in resting [Ca2+]i was significantly attenuated by treatment with U78517F, a potent inhibitor of lipid peroxidation, at a concentration of 10−6 m or greater. Catalase (50 u ml−1) also markedly inhibited the H2O2‐induced rise in [Ca2+]i. Pretreatment with verapamil (10−5 m), nifedipine (10−6 m) or diltiazem (10−5 m) had no effect on the increase in [Ca2+]i following addition of H2O2.
A23187 produced a transient increase in [Ca2+]i followed by a sustained plateau. The initial peak and plateau phase responses to A23187 were augmented by H2O2. This augmentation of [Ca2+]i was suppressed by U78517F or catalase but not by Ca‐entry blockers.
Thus, it is likely that lipid peroxidation plays a critical role in the sustained increase in [Ca2+]i that occurs following treatment with H2O2 and that this continues in the presence of agonists which stimulate the endothelium. Voltage‐gated Ca2+ channels do not seem to be involved in the genesis of cellular damage associated with sustained large increases in [Ca2+]i.
Effects of long‐term oral administration of amiodarone on the electromechanical performance of rabbit ventricular muscle
Authors: Kodama Itsuo , Suzuki Ryoko , Kamiya Kaichiro , Iwata Hirokazu , Toyama Junji 
Published: July 2012

The effects of long‐term administration of oral amiodarone on transmembrane action potential and contraction of ventricular muscle were investigated in rabbits.
ECGs of rabbits that received oral amiodarone 50 mg or 100 mg kg−1 daily for 4 weeks, showed a significant prolongation of RR, QT and corrected QT (QTc) intervals, whereas PQ and QRS were unaffected. Serum and myocardial tissue amiodarone concentrations were 0.14–0.18 μg ml−1 and 1.47–3.63 μg g−1 wet wt. respectively.
Right ventricular papillary muscles isolated from treated rabbits were characterized by a moderate prolongation of action potential duration (APD) compared with controls. A slight decrease of the maximum upstroke velocity was also observed at the higher dose. The APD prolongation by chronic amiodarone, unlike acute effects of sotalol, E‐4031, Cs+ and 4‐aminopyridine, did not show marked reverse use‐dependence.
APD and restitution following slow basic stimuli (0.03 Hz) were unaffected by chronic treatment with amiodarone.
Acute application of amiodarone (10 μm) caused a significant decrease in APD and developed tension, as well as a marked use‐dependent inhibition with fast recovery kinetics.6 These findings suggest that a major and consistent electro‐physiological effect of chronic amiodarone is repolarization delay (Class‐III action) showing minimal frequency‐dependence. However, when amiodarone above a certain concentration is present in the extracellular space, a fast kinetic Class‐I action would be added as an acute effect.
Changes in intrinsic inhibition in isolated hippocampal slices during ethanol withdrawal; lack of correlation with withdrawal hyperexcitability
Authors: Whittington M.A. , Little H.J. , Lambert J.D.C. 
Published: July 2012

Intracellular recordings were made from pyramidal cells in area CA1 in mouse isolated hippocampal slices, after chronic ethanol treatment in vivo.
Fast i.p.s.ps were isolated by injection of the impaled neurones with QX314 (to block fast sodium currents and the slow i.p.s.p.) and stimulating the interneurones in the presence of the glutamatergic blockers, CNQX and APV.
The isolated fast‐inhibitory postsynaptic potential (f.‐i.p.s.p.) was measured at intervals during the 7 h withdrawal period. The reversal potential and sensitivity to bicuculline suggested that the isolated f.‐i.p.s.p. was mediated by activation of the GABAA receptor‐chloride ionophore complex.
Measurement of stimulus‐response relationships for the f.‐i.p.s.ps revealed an initial increase in the maximum size of the i.p.s.p., evoked from a membrane potential of −50 mV, seen at 2 h into ethanol withdrawal. This was attributed to a negative shift in the reversal potential, Ei.p.s.p., with no observed change in conductance, Gi.p.s.p..
No differences in f.‐i.p.s.ps evoked during ethanol withdrawal or in control slices were seen at 4 h or 6 h. At these times, epileptiform activity was seen in previous field potential recordings.6 Paired pulse depression of the f.‐i.p.s.p. was significantly increased at 2 h into withdrawal, when a 150 ms pulse interval was used. No differences were seen at later times in the ethanol withdrawal period.7 The results suggest that ethanol withdrawal hyperexcitability in isolated hippocampal slices is not caused by primary decreases in inhibition mediated by the GABAA receptor‐chloride ionophore complex. The increase in the f.‐i.p.s.p. during the initial stages of the withdrawal might prevent the overt expression of epileptiform activity at this time.
Effect of histamine and histamine analogues on human isolated myometrial strips
Authors: Martínez‐Mir María Inocencia , Estañ Luis , Morales‐Olivas Francisco J. , Rubio Elena 
Published: July 2012

The effect of histamine and histamine H1 and H2‐receptor agonists on isolated myometrium strips of premenopausal women has been examined. The effect of acetylcholine was also determined.
Histamine, 2‐pyridylethylamine, 4‐methylhistamine and acetylcholine, but not dimaprit, produced a concentration‐related contractile response in human isolated myometrial strips. Histamine also produced a further contraction in human isolated myometrial strips precontracted with KCl (55 mm).
The contractile response to histamine was antagonized by the histamine H1‐receptor angatonist, clemizole (0.1 μm) but was potentiated by the histamine H2‐receptor antagonist, ranitidine (10 μm). Clemizole (0.1 nm to 10 nm) competitively antagonized the contractile effect of 2‐pyridylethylamine (– log KB = 10.5 ± 0.5). The concentration‐response curve for acetylcholine was displaced to the right by atropine 0.1 μm.
Atropine (0.1 μm), propranolol (0.1 μm), prazosin (0.1 μm) and indomethacin (1 μm) failed to modify the contractile response to histamine.
In human isolated myometrial strips precontracted with KCl (55 mm), clemizole at 1 μm completely abolished the contractile response to histamine and revealed a concentration‐dependent relaxation. Dimaprit alone and 4‐methylhistamine (in the presence of clemizole), produced concentration‐related relaxation with a magnitude similar to that in response to histamine. The relaxant response to dimaprit was antagonized by ranitidine.6 It is concluded that human isolated uterine strips possess histamine H1‐ and H2‐receptors: the former mediating contraction and the latter relaxation. The predominant response to histamine in this tissue is contraction.
Millimolar amiloride concentrations block K conductance in proximal tubular cells
Authors: Discala Françoise , Hulin Philippe , Belachgar Fouzia , Planelles Gabrielle , Edelman Aleksander , Anagnostopoulos Takis 
Published: July 2012

Amiloride, applied at millimolar concentrations, results in the blockade of K+ conductance in amphibian proximal convoluted cells (PCT), fused into giant cells.
Amiloride results directly in a blockade of K+ conductance that is not related to inhibition of the Na+‐H+ antiport, which would lower intracellular pH, adversely affecting K+ conductance. On the contrary, high amiloride concentrations promote entry of this lipophilic base in the cell, leading to higher cell pH.
Under voltage clamp conditions, control vs. amiloride, current‐voltage curves from PCT fused giant cells intersect at −86.2 ± 3.4 mV, a value close to the equilibrium potential for potassium.
Hexamethylene amiloride, 10−5 m, irreversibly depolarizes the membrane potential.
Barium decreased by 50% the initial slope of realkalinization, following removal of a solution containing NH4Cl, as did amiloride. In addition, these blockers reduced membrane conductance by 40%, suggesting that a fraction of the amiloride‐suppressible NH4+ efflux may be conductive.6 Amiloride does not directly inhibit the Na+‐K+, ATPase in our preparation, contrary to the prevalent belief.7 In vivo studies show that amiloride interferes with an apical K+ conductance but it does not alter basolateral K+ conductance.
5‐Hydroxytryptamine (5‐HT) mediates potent relaxation in the sheep isolated pulmonary vein via activation of 5‐HT4 receptors
Authors: Cocks T.M. , Arnold P.J. 
Published: July 2012

We investigated the potent 5‐hydroxytryptamine (5‐HT)‐mediated vasorelaxation of the sheep pulmonary vein. Here we present evidence that this response is due to activation of 5‐HT4 receptors.
5‐HT (1–1000 nm) caused concentration‐dependent, maintained relaxations (pEC50 = 8.4 ± 0.1) of isolated rings of sheep pulmonary vein pre‐contracted with endothelin‐1 (3 nm).
The relaxation response to 5‐HT was unaffected by either removal of the endothelium or by inhibition of NO‐synthase by NG‐nitro‐l‐arginine (100 μm).
Ketanserin, methiothepin, methysergide and MDL 72222 at concentrations that selectively block 5‐HT2, 5‐HT1‐like and 5‐HT3 receptors respectively, had no effect on the concentration‐relaxation curve to 5‐HT.
ICS 205–930 (1–10 μm) competitively antagonized the concentration‐relaxation curve to 5‐HT with a pA2 of approximately 6.7.6 Increasing the concentration of ICS 205–930 from 10 to 30 μm did not cause a further rightward shift of the 5‐HT concentration‐relaxation curve. The pEC50 of 6.50 for 5‐HT in the presence of ICS 205–930 (30 μm) was taken as an estimate of the affinity of 5‐HT for 5‐HT1‐like receptors since methiothepin (10 nm) unmasked further competitive inhibition of 5‐HT in the presence of this concentration of ICS 205–930.7 Other 5‐HT agonists including 5‐carboxamidotryptamine (5‐CT), α‐methyl‐5‐HT and BIMU 8 (but not 2‐methyl‐5‐HT) also relaxed the pulmonary vein. The response to 5‐CT was inhibited by methiothepin (10 nm) and methysergide (100 nm) but unaffected by ICS 205–930 (30 μm), whilst that to α‐methyl‐5‐HT and BIMU 8 was unaffected by methiothepin (10 nm) but blocked by ICS 205–930 (estimated pKB values of 6.4 and 6.9 respectively). Relaxation curves to both 5‐HT and BIMU 8 were unaffected by cocaine (6 μm).8 In conclusion, these results indicate that the sheep pulmonary vein possesses 5‐HT4 receptors that mediate potent endothelium‐independent relaxation. 5‐HT1‐like relaxant receptors are also present in this tissue but 5‐HT has a lower affinity at these receptors. This preparation may thus provide a robust and sensitive bioassay for future development of selective 5‐HT4 receptor agonists and antagonists.
Differential potentiation of GABAA receptor function by two stereoisomers of diimidazoquinazoline analogues
Authors: Im Haesook K. , Im Wha Bin , Pregenzer Jeff F. , Petke James D. , Hamilton Beverly J. , Carter Donald B. , VonVoigtlander Philip F. , Hansen Holger C. , Kristiansen Marit 
Published: July 2012

U‐84935, diimidazo[1,5‐a;1′,2′‐C]quinazoline,5‐(5‐cyclopropyl‐1,2,4‐oxidiazol‐3yl)‐2,3‐dihydro, is a ligand of high affinity for the benzodiazepine site of the GABAA receptor composed of α1β2γ2 subunits.
The efficacy of its analogues was measured with their ability to potentiate GABA‐mediated Cl− currents in the whole cell configuration of the patch clamp techniques in human kidney cells (A293 cells) expressing the subtype of the GABAA receptor.
The analogues displayed various levels of efficacy including agonists, partial agonists and antagonists without marked changes in their affinity for the receptors.
The major determinant of their efficacy was the spacial configuration of a methyl substituent of the C2 atom of the rigid and planar diimidazoquinazoline ring: U‐90167, containing the methyl substituent projected below the plane of the ring, markedly enhanced the GABA current with a maximal potentiation of 220 ± 25%, while its stereoisomer, U‐90168, marginally increased the GABA response with a maximal potentiation of 45 ± 10%, to which its methyl group appeared to contribute very little.
U‐90167 potentiated the GABA response with an EC50 of 8.1 nm and a Hill coefficient of 1.1 and did not alter the reversal potential for the Cl− current.6 From computational modelling, the sensitive methyl group of U‐90167 could be assigned to the general region for the 5‐phenyl group of diazepam. The diimidazoquinazoline, because of its rigid and plantar ring structure, may be useful to define further the out‐of‐plane region responsible for agonistic activity and to pinpoint other areas pivotal to the functionality of benzodiazepine ligands.
Increase in vascular permeability produced in rat airways by PAF: potentiation by adrenalectomy
Authors: Boschetto Piera , Musajo Francesco G. , Tognetto Laura , Boscaro Marco , Mapp Cristina E. , Barnes Peter J. , Fabbri Leonardo M. 
Published: July 2012

The effect of bilateral adrenalectomy on the sensitivity of blood vessels in rat airways to mediators that increase vascular permeability was examined.
An increase in vascular permeability was induced by intravenous platelet activating factor (PAF, 50, 100, 500, 1000 ng kg−1) and measured by quantifying the extravasation of Evans blue dye.
PAF consistently increased the amount of Evans blue extravasation in the larynx, trachea, main bronchi and intrapulmonary airways in sham‐operated rats.
The magnitude of this extravasation was significantly greater in the larynx (P < 0.05), trachea (P < 0.05) and main bronchi (P < 0.05) of the adrenalectomized rats than it was in these tissues of the sham‐operated rats.
When adrenalectomized rats were given subcutaneous dexamethasone (0.2 mg kg−1 4 h before PAF) the amount of plasma extravasation produced by PAF was decreased to the level of the sham‐operated rats.
We conclude that adrenalectomy potentiates the increase in airway vascular permeability induced by PAF in rats and that this effect may be due to the depletion of endogenous corticosteroids.
Extracellular ATP and UTP exert similar effects on rat isolated hepatocytes
Authors: Keppens Stefaan , Vandekerckhove Ann , DE Wulf Henri 
Published: July 2012

Extracellular UTP and ATP show obvious similarities in their control of several metabolic functions of rat isolated hepatocytes.
They have a similar time‐course and concentration‐dependency for the activation of glycogen phosphorylase, the generation of inositol trisphosphate (IP3), the inhibition of glycogen synthase and the lowering of adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) levels.
There is a similar synergism of the nucleotides with glucagon in activating phosphorylase.
They undergo a similar inhibition by phorbol myristic acid of their glycogenolytic effect.
The ATP and UTP effect on IP3 levels are not additive.
It is tentatively concluded that UTP and ATP use a common receptor.
The actions of endothelins−1 and −3 on the vascular and capsular smooth muscle of the isolated blood perfused spleen of the dog
Authors: Withrington P.G. , Ansari N. , Croxton R. , DE Nucci G. , Vane J.R. 
Published: July 2012

Endothelin‐1 (ET‐1), endothelin‐3 (ET‐3) and noradrenaline (NA) were administered as intra‐arterial bolus injections into the isolated, blood‐perfused spleen of the dog to assess agonist properties and relative molar potencies on the vascular and capsular smooth muscle.
An initial small vasodilatation was observed occasionally at low doses (1.0–10 pmol) of ET‐1.
ET‐1, ET‐3 and NA all caused graded increases in splenic arterial vascular resistance. The molar ED50 for the splenic vasoconstrictor response to ET‐1 was significantly less (P < 0.001) than that to ET‐3; both peptides were significantly more potent as vasoconstrictor agents than NA. The maximum increase in splenic arterial vascular resistance was not significantly different for either ET‐1, ET‐3 or NA.
The time course of the splenic vasoconstrictor response to ET‐1 was significantly (P < 0.01) longer than that to equieffective doses of ET‐3 or NA.
The splenic vasoconstrictor responses to ET‐1 and ET‐3 were accompanied by reductions in spleen volume. The rank order of molar potency in causing splenic capsular contraction was ET‐1 > ET‐3 > NA. The maximum reduction in splenic volume was significantly greater for NA than for either ET‐1 or ET‐3. The two peptides (ET‐1, ET‐3) were equiefficacious in contracting splenic capsular smooth muscle.
The high molar potency of ET‐1 as a splenic arterial vasoconstrictor, over 1,700 times more potent than NA, suggests that it may play an important local role in the control of splenic haemodynamics.
Comparison of the actions of acetylcholine and BRL 38227 in the guinea‐pig coronary artery
Authors: Eckman D.M. , Frankovich J.D. , Keef K.D. 
Published: July 2012

The contractile and electrical responses to acetylcholine (ACh) in isolated segments of guinea‐pig and rabbit coronary arteries were compared to those of the putative adenosine 5′‐triphosphate (ATP)‐dependent K+ channel opener, BRL 38227.
Both ACh and BRL 38227 produced concentration‐dependent relaxation of vessel segments contracted with the H1‐receptor agonist, 2‐(2‐aminoethyl)pyridine.
An IC90 of either vasodilator also produced 17–20 mV of hyperpolarization of the guinea‐pig coronary artery.
Glibenclamide (1–35 μm) depolarized the guinea‐pig coronary artery by 8–12 mV and antagonized BRL 38227‐ but not ACh‐induced relaxation and hyperpolarization.
In the guinea‐pig coronary artery, the K+ channel blockers phencyclidine (PCP, 100 μm), tetraethylammonium (TEA, 10 mm) and scorpion venom (8.7 μg ml−1) all significantly reduced ACh‐induced relaxation and hyperpolarization whereas only PCP was an effective antagonist of both relaxation and hyperpolarization with BRL 38227.
Similar effects of glibenclamide and scorpion venom on ACh‐ and BRL 38227‐induced relaxation were observed in the rabbit coronary artery.
Apamin (3.5 μm) was without effect on either the ACh‐ or BRL 38227‐induced relaxation in the guinea‐pig coronary artery.
In conclusion, the actions of BRL 38227 in coronary artery are compatible with its proposed effects on ATP‐dependent K+ channels. In contrast, the results with ACh suggest that some step between the initial binding of ACh to endothelial muscarinic receptors and the final relaxation of the smooth muscle depends upon the opening of Ca2+‐activated K+ channels.