bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of reported Ca2+ sensitisers on the rates of Ca2+ release from cardiac troponin C and the troponin‐tropomyosin complex
Authors: Smith Susan J. , England Paul J. 
Published: July 2012

The calcium sensitivity of force production of cardiac muscle fibres is altered by certain drugs. The sites of action of three such compounds (pimobendan, sulmazole, isomazole) within the myofibril have been investigated. Calmodulin antagonists, perhexilene and bepridil, which have been shown to alter the calcium dependence of myofibrillar ATPase activity and oxmetidine, an H2‐receptor antagonist which binds to calmodulin, were also studied.
The rates of dissociation of calcium from both the regulatory and high affinity sites on bovine isolated cardiac troponin C (cTnC) were measured in a stopped‐flow fluorimeter. The rates of dissociation were found to be 136.5 ± 16s−1 and 1.3 ± 0.20s−1 (mean ± s.e.mean, n = 11 determinations; conditions: 100 mm KCl, 10 mm MOPS, 3 mm MgCl2, 0.1 mm dithriothreitol, pH 7.0, 15°C). Sulmazole, isomazole and perhexiline (final concentration of 50 μm) had no effect on the rate of Ca2+ dissociation from the regulatory Ca2+ site, indicating that these compounds do not act on cTnC directly.
The rate of dissociation of Ca2+ from the regulatory site was slightly reduced (∼20%) by pimobendan (50 and 100 μm) and was somewhat increased by oxmetidine (28% at 100 μm).
Bepridil (25 μm) reduced the rate of dissociation by 50%, indicating a direct effect of bepridil on TnC.
Sulmazole, isomazole, perhexiline, pimobendan (50 μm) and bepridil (25 μ) were without effect on the rate of dissociation of Ca2+ from the high affinity Ca2+/Mg2+ sites. Oxmetidine caused 24% decrease in the rate of Ca2+ dissociation from these sites.
The rate of dissociation of Ca2+ from the regulatory site on the complex of troponin‐tropomyosin (TnTm) was measured. Sulmazole and pimobendan (50 μm) were without effect on the rate of dissociation of Ca2+ from the regulatory site in the protein complex, and isomazole (50 μm) caused only a slight reduction (23%). Perhexiline (50 μm) or bepridil (10 μm) reduced the rate of Ca2+ dissociation by about 50%. The rate of dissociation of Ca2+ from the high affinity Ca2+/Mg2+ sites was not altered by sulmazole, isomazole, or pimobendan (50 μm), but was decreased ∼35% by perhexiline (50 μm) or bepridil (10 μm).
Differential effects of petit mal anticonvulsants and convulsants on thalamic neurones: GABA current blockade
Authors: Coulter Douglas A. , Huguenard John R. , Prince David A. 
Published: July 2012

Currents evoked by applications of γ‐aminobutyric acid (GABA) to acutely dissociated thalamic neurones were analysed by voltage‐clamp techniques, and the effects of the anticonvulsant succinimides ethosuximide (ES) and α‐methyl‐α‐phenylsuccinimide (MPS) and the convulsants tetramethylsuccinimide (TMS), picrotoxin, pentylenetetrazol (PTZ), and bicuculline methiodide were assessed.
TMS (1 μm‐10 mm) reduced responses to iontophoretically applied GABA, as did picrotoxin (0.1–100 μm), PTZ (1–100 mm) and bicuculline (1–100 μm).
ES, in high concentrations (1–10 mm), reduced GABA responses to a lesser extent, and also occluded the reductions in GABA‐evoked currents produced by TMS, picrotoxin, and PTZ. ES did not occlude the effects of bicuculline on GABA responses. Therefore, we propose that ES acts as a partial agonist at the picrotoxin GABA‐blocking receptor.
MPS had no effect on GABA responses (at a concentration of 1 mm), and, like ES, occluded the GABA‐blocking actions of TMS, apparently acting as a full antagonist.
The anticonvulsant actions of ES and MPS against TMS and PTZ‐induced seizures may thus involve two independent mechanisms: (1) the occlusion of TMS and PTZ GABA‐blocking effects; and (2) the previously described specific effect of ES and MPS on low‐threshold calcium current of thalamic neurones. The latter cellular mechanism may be more closely related to petit mal anticonvulsant activity.
The effects of drugs on Sephadex‐induced eosinophilia and lung hyper‐responsiveness in the rat
Authors: Spicer B.A. , Baker R.C. , Hatt P.A. , Laycock S.M. , Smith H. 
Published: July 2012

Rats given an intravenous injection of Sephadex particles (0.5 mg of G200 in 1 ml of saline) on days 0, 2 and 5 had a blood eosinophilia which was maximal on day 7.
On day 7, broncho‐alveolar lavage (BAL) fluids taken from the rats contained an increased number of eosinophils and fewer mononuclear cells but there was no change in the small number of neutrophils. In addition the rats were hyper‐sensitive to the increase in resistance to artificial respiration produced by 5‐hydroxytryptamine (5‐HT), given intravenously, with a shift to the left of the log dose‐response curve. Lung parenchymal strips, taken from the rats on days 6, 7 and 8, were hyper‐reactive to 5‐HT with an increase in slope of the log dose‐response curve.
Compounds with a wide variety of activities were evaluated for their effects on the blood eosinophilia on day 7 when given before each injection of Sephadex. The eosinophilia was reduced by glucocorticosteroids, β‐adrenoceptor agonists, aminophylline, dapsone and phenidone.
Dexamethasone, isoprenaline, dapsone and phenidone at doses that reduced the blood eosinophilia also reduced the changes in number of leucocytes in the BAL fluids and the hyper‐responsiveness to 5‐HT in vivo and in vitro, except that the effects of dapsone on the hyper‐sensitivity to 5‐HT in vivo did not reach significance. Aminophylline was the least effective of the drugs at reducing the blood eosinophilia and its effects on the other changes did not reach significance. Sodium cromoglycate reduced the BAL eosinophilia but had no effect on the other changes produced by Sephadex.
The correlation coefficients between blood eosinophil numbers and reactivity to 5‐HT in vitro and sensitivity in vivo were r = 0.76, (n = 88; P > 0.001) and r = 0.53, (n = 61; P > 0.001) respectively.
Doses of dexamethasone, isoprenaline, dapsone and phenidone that reduced the blood eosinophilia when given before each injection of Sephadex were inactive when given up to 8 h after the Sephadex.
These data show an association between blood eosinophilia and hyper‐responsiveness of the lung. The blood eosinophilia in the rats was triggered within the first few hours of injecting the Sephadex and drugs have been identified which inhibit this trigger.
Benzodiazepine analogues inhibit arachidonate‐induced aggregation and thromboxane synthesis in human platelets
Authors: Fonlupt P. , Croset M. , Lagarde M. 
Published: July 2012

Benzodiazepine analogues inhibit human platelet aggregation induced by arachidonate with an EC50 value of 0.68 μm for PK 11195, the most potent analogue used.
There was a highly significant correlation between the inhibition of arachidonate‐induced aggregation and the affinity for the peripheral‐type of benzodiazepine binding sites.
There was no significant correlation between the inhibition of the platelet activating factor (PAF)‐induced aggregation and the binding to the peripheral‐type of benzodiazepine binding sites.
The inhibition of platelet aggregation seems to result from the inhibition of arachidonic acid cyclooxygenation, since the synthesis of thromboxane and 12‐hydroxy‐heptadecatrienoic acid, both cyclooxygenase products, was reduced.
Our results suggest that peripheral‐type of benzodiazepine binding sites on human platelets could be linked to cyclo‐oxygenase.
Responses to noradrenaline in human subcutaneous resistance arteries are mediated by both α1‐ and α2‐adrenoceptors
Authors: Nielsen H. , Mortensen F.V. , Mulvany M.J. 
Published: July 2012

In vitro experiments in a microvascular myograph were designed to characterize postjunctional α‐adrenoceptors of human subcutaneous resistance arteries (normalised internal diameter 143–313 μm).
Both the α1‐selective agonist phenylephrine in the presence of 0.3 μm yohimbine and the α2‐selective agonist B‐HT 933 in the presence of 0.3 μm prazosin elicited prominent and concentration‐dependent contractions. The maximum response to phenylephrine and B‐HT 933 was not different from the response to high K physiological salt solution (125 mm K+), and the pD2 values (−log EC50) were 5.90 and 6.11, respectively.
In the presence of the α2‐selective antagonist yohimbine (0.3 μm), the α1‐selective antagonist prazosin competitively antagonised the responses to phenylephrine; the pA2 of prazosin for the receptor which mediated the response to phenylephrine was 8.41.
Blockade of either α2‐adrenoceptors with 0.1 μm yohimbine or α1‐adrenoceptors with 0.1 μm prazosin caused shifts to the right of the noradrenaline concentration‐response curves and the shifts in pD2 were 0.69 and 0.61, respectively. The combination of the two antagonists at the above‐mentioned concentrations caused a marked, parallel shift to the right of the noradrenaline concentration‐response curve, the shift of the pD2 was 2.68.
These results suggest that activation of both α1‐ and α2‐adrenoceptors produces contractions in human subcutaneous resistance arteries, and that responses to noradrenaline in these vessels are mediated by both α‐adrenoceptor subtypes.
Action of calcitonin gene‐related peptide upon bovine vascular endothelial and smooth muscle cells grown in isolation and co‐culture
Authors: Crossman D.C. , Dashwood M.R. , Brain S.D. , McEwan J. , Pearson J.D. 
Published: July 2012

Bovine aortic endothelial cells (BAE) and smooth muscle cells (BASM) were grown separately and in co‐culture.
Calcitonin gene‐related peptide (CGRP) caused dose‐dependent activation of adenylate cyclase in each cell type when grown in isolation. The concentration of CGRP causing half‐maximal activation in BAE and BASM was 200 nm and 310 nm, respectively.
In cells grown in co‐culture exposure to bradykinin produced dose‐dependent elevations in cyclic GMP content which were maximal 1 min after application of the agonist.
CGRP (1 nm−1 μm) did not stimulate a rise in cyclic GMP in co‐cultures.
Displaceable CGRP binding was identified throughout the wall of the bovine aorta.
We conclude that CGRP receptors coupled to adenylate cyclase are present on BAE and BASM, but there is no coupling of these receptors to the release of any agent (such as endothelium‐derived relaxing factor) that activates guanylate cyclase.
Protective effect of beraprost sodium, a new chemically stable prostacyclin analogue, against the deterioration of baroreceptor reflex following transient global cerebral ischaemia in dogs
Authors: Kurihara Junichi , Sahara Tatsuhiro , Kato Hitoshi 
Published: July 2012

A possible cerebroprotective effect of a chemically stable prostacyclin analogue, beraprost sodium, was investigated in a canine model of cerebral ischaemia. Cerebral ischaemia was produced by the combined occlusions of the left subclavian and the brachiocephalic arteries with preceding ligations of the intercostal arteries.
The decrease in baroreceptor reflex sensitivity (BRS), measured by phenylephrine‐induced reflex bradycardia, following 5 min ischaemia was used to assess the cerebroprotective effect.
Beraprost (1 μg kg−1 min−1 i.v., infused for 15 min just before ischaemia) completely prevented the decrease in BRS. Although the lower dose of beraprost (0.1 μg kg−1 min−1 i.v.) failed to show such a protective effect, its inhibitory effect on ADP‐induced platelet aggregation was as potent as that of the higher dose.
The extent of decrease in BRS was inversely correlated with the extent of the residual blood flow in the medulla oblongata during ischaemia. Since beraprost did not affect the extent of the residual blood flow during ischaemia, its cerebroprotective effect could not be ascribed to the reduction of the degree of ischaemia by increasing collateral blood flow to the brain.
Post‐ischaemic reduction of the regional blood flow in the medulla and the cerebral cortex was completely prevented by the higher dose of beraprost.
The present study suggests that the cerebroprotective effect of beraprost may be independent of its anti‐aggregatory and vasodilator effects. It is possible that the protection may be due to a prostacyclin‐like cytoprotective effect through membrane stabilization.
The effect of two lipophilic γ‐aminobutyric acid uptake blockers in CA1 of the rat hippocampal slice
Authors: Rekling Jens C. , Jahnsen Henrik , Laursen Arne Mosfeldt 
Published: July 2012

Drugs that increase inhibitory synaptic transmission in the central nervous system may be valuable tools in the treatment of seizures. Theoretically, substances that block the uptake of inhibitory transmitters such as γ‐aminobutyric acid (GABA) into intracellular compartments should also increase inhibition and therefore have potential value as antiepileptic drugs. However, most of these substances penetrate the blood‐brain barrier poorly and have therefore until now had limited value. NO‐05–0328 and NO‐05–0329 are two new lipophilic GABA uptake inhibitors that readily enter the CNS from the blood.
We have investigated the effect of these two uptake inhibitors on the responses to exogenous GABA and on GABA‐mediated inhibitory synaptic potentials in pyramidal neurones of the CA1 region in the rat hippocampal slice.
We found that both drugs increased the amplitude and duration of responses to exogenous GABA. Furthermore, the inhibitory synaptic potentials increased in amplitude. This increase was seen in both early and late phases of the synaptic potentials. We conclude that NO‐05–0328 and NO‐05–0329, at least in vitro, are more effective than older GABA uptake inhibitors such as nipecotic acid and they therefore deserve consideration for clinical use.
2‐Substituted indazolinones: orally active and selective 5‐lipoxygenase inhibitors with anti‐inflammatory activity
Authors: Foster S.J. , Bruneau P. , Walker E.R.H. , McMillan R.M. 
Published: July 2012

This paper describes the pharmacological profile of ICI207968, a novel, orally‐active and selective inhibitor of 5‐lipoxygenase.
Inhibition of leukotriene B4 (LTB4) synthesis by 2‐substituted indazolinones was not directly related to redox potential but was critically dependent on the nature of the N2 substituent. 2‐(3‐Pyridylmethyl)‐indazolinone (ICI207968) combined selectivity and oral potency.
In several in vitro systems ICI207968 exhibited similar lipoxygenase inhibitory potency (IC50 values from 1.5 μm to 6.0 μm) and was approximately 300 times less potent against cyclo‐oxygenase, as measured by inhibition of prostaglandin E2 (PGE2) synthesis.
ICI207968 also produced selective lipoxygenase inhibition following oral administration in the rat. ED50 values of 2.5, 10 and 25 mg kg−1 p.o. for inhibition of LTB4 release from A23187‐stimulated blood were obtained 1, 3 and 5 h after dosing. The compound did not inhibit PGE2 synthesis at oral doses up to 300 mg kg−1.
Co‐administration of ICI207968 with arachidonic acid, into rabbit dermis, potently inhibited both plasma extravasation and polymorphonuclear leucocyte (PMNL) infiltration induced by this inflammatory fatty acid. The anti‐inflammatory potency of a number of intradermally administered indazolinones, with similar redox potentials, was related to their inhibitory potency against leukotriene generation in blood. Oral administration of ICI207968 (100 mg kg−1) in the rabbit inhibited ex vivo leukotriene generation in blood and arachidonic acid‐induced skin inflammation.
These data demonstrate that ICI207968 is an orally active and selective inhibitor of 5‐lipoxygenase which has anti‐inflammatory properties. ICI207968 will be a valuable agent for clarifying the biological roles of leukotrienes and the therapeutic potential of 5‐lipoxygenase inhibitors.
Action of an irreversible acetylcholine esterase inhibitor, soman, on muscarinic hyperpolarization in cat bladder parasympathetic ganglia
Authors: Kumamoto Eiichi , Shinnick‐Gallagher Patricia 
Published: July 2012

Intracellular recording techniques were used to examine the action of an irreversible acetylcholine esterase (AChE) inhibitor, soman, on the hyperpolarizations mediated through muscarinic cholinoceptors in cat bladder parasympathetic neurones.
Soman (0.1–10 μm) depressed the amplitude and prolonged the duration of the muscarinic slow inhibitory postsynaptic potential (s‐i.p.s.p.) elicited by a preganglionic tetanus (40 Hz for 1 s) in the presence of mecamylamine (20 μm), phentolamine (1 μm) and caffeine (1 mm), in a dose‐dependent manner. The effect of soman on the amplitude of the s‐i.p.s.p. was partially reversible, while the effect on the duration was irreversible.
Soman hyperpolarized the membrane and decreased input resistance, but this effect could not account for soman‐induced inhibition of the s‐i.p.s.p.
Soman depressed the amplitude and prolonged the duration of a muscarinic hyperpolarization induced by pressure application of acetylcholine (ACh) in the presence of mecamylamine, phentolamine and caffeine. The time course of this effect paralleled that on the synaptically‐evoked muscarinic s‐i.p.s.p.
A reversible AChE inhibitor, pyridostigmine (10–100 μm), also depressed the amplitude and prolonged the duration of a muscarinic hyperpolarization induced by either preganglionic stimulation or ACh pressure application. These actions were reversible, and not accompanied by a significant change in membrane potential or input resistance.
The inhibitory action of soman (1 μm) on the muscarinic hyperpolarization was prevented by pyridostigmine (10 μm), but not by atropine (1 μm).
These results demonstrate that soman prolongs not only the muscarinic hyperpolarization, but also inhibits its amplitude through a postsynaptic action, probably through AChE inhibition, in cat bladder parasympathetic neurones.
Presynaptic α2‐autoinhibition in a vascular neuroeffector junction where ATP and noradrenaline act as co‐transmitters
Authors: Bulloch J.M. , Starke K. 
Published: July 2012

α2‐Autoinhibition of transmitter release was investigated in the largest rami caecales of the rabbit ileocolic artery. Vasoconstriction, elicited by electrical field stimulation or by exogenous agonists, was measured as an increase in perfusion pressure.
Short periods of electrical stimulation elicited monophasic vasoconstriction, whereas longer periods (>10s) produced biphasic vasoconstriction. Prazosin had no significant effect on the first component of the biphasic vasoconstriction elicited by electrical stimulation, but did reduce the second component at higher frequencies. α,β‐Methylene ATP significantly attenuated the first component whilst the second component was relatively resistant.
The α2‐adrenoceptor antagonist yohimbine did not change responses evoked by very short pulse trains (< 2 s) but enhanced responses to longer pulse trains. When vasoconstriction was biphasic, both phases were potentiated by yohimbine.
The results indicate that the vasoconstriction elicited by brief trains of sympathetic nerve impulses is mainly or exclusively mediated by ATP, whereas at longer pulse trains a noradrenergic component comes into play. The potentiation produced by yohimbine is due to interruption of presynaptic α2‐adrenoceptor‐mediated autoinhibition of transmitter release. The autoinhibition affects both purinergic and adrenergic components of sympathetic neurotransmission.
Modification of the ischaemic‐induced contraction in the sheep circumflex coronary artery by various pharmacological antagonists
Authors: Kwan Y.W. , Wadsworth R.M. , Kane K.A. 
Published: July 2012

Sheep isolated circumflex coronary artery rings were exposed to simulated ischaemia (increased K+ reduced pH, hypoxia, reduced glucose and addition of lactate). Simulated ischaemia caused a transient relaxation lasting approximately 5 min followed by a sustained contraction that was reversible on washing with oxygenated Krebs solution.
Haemolysate caused a rise in baseline tension and augmented the ischaemic contraction.
The ischaemic contraction was abolished by BW 755C 5 μm and reduced by indomethacin 1 μm, quinacrine 50 μm or the thromboxane A2 antagonist BM 13177 10 μm. The leukotriene D4 antagonist, ICI 198615, had no effect.
The ischaemic‐induced contraction was enhanced by propranolol 1 μm, methiothepin 1 μm and reduced by ketanserin 1 μm.
The ischaemic contraction was markedly inhibited by trypsin (1 u ml−1) and by verapamil, cromakalim or sodium nitroprusside.
The following had no or little effect on the ischaemic contraction: Sar1‐Thr8‐angiotensin II, mepyramine, atropine, the spin trapping agent PBN or the free radical scavenger dimethylsulphoxide. Superoxide dismutase caused a slight enhancement.
The ischaemic‐induced contraction was abolished by the simultaneous administration, at subthreshold concentrations, either of two vasodilators (iloprost and adenosine) or of a vasodilator and a vasoconstrictor (iloprost and U46619).
The ischaemic relaxation phase was reduced by propranolol and indomethacin, abolished by haemolysate and enhanced by quinacrine or cromakalim.
It is concluded that the ischaemic‐induced contraction is caused by mediators released from the endothelium including a product of the lipoxygenase pathway. There is also evidence that simulated ischaemia causes the release of noradrenaline and 5‐hydroxytryptamine.
Endothelium‐dependent and BRL 34915‐induced vasodilatation in rat isolated perfused mesenteric arteries: role of G‐proteins, K+ and calcium channels
Authors: Adeagbo Ayotunde S.O. , Malik Kafait U. 
Published: July 2012

In the isolated perfused, noradrenaline (NA)‐constricted mesenteric arteries of the rat, acetylcholine (0.003‐1 nmol), histamine (0.01–10 nmol) and the calcium ionophore A23187 (0.01‐1 nmol), caused endothelium‐dependent vasodilatation while the vasodilatation by the K+ channel activator BRL 34915 (0.1‐1 nmol) was independent of endothelium.
The guanylate cyclase inhibitor, methylene blue at 10 μm did not inhibit the action of any of the vasodilators but at 50 μm reduced the vasodilator effect of acetylcholine (ACh), histamine and A23187.
Infusion of ouabain or perfusion with K+‐free or excess K+ (50 mm) Krebs solution reduced the vasodilator effect of ACh, histamine and A23187, suggesting the action of these agents involves, at least in part, activation of Na+/K+‐ATPase. The vasodilator effect of BRL 34915 was not affected by ouabain, but abolished during perfusion with Krebs solution containing excess K+ or depleted of K+.
Five structurally distinct K+ channel blockers (apamin, crude scorpion venom, procaine, quinidine and tetraethylammonium) attenuated the vasodilator effect of ACh, histamine and A23187. The K+ channel blockers, except apamin and crude scorpion venom, also inhibited the vasodilatation produced by BRL 34915.
The vasodilator effect of ACh, histamine or A23187 was not altered in mesenteric vessels of pertussis toxin‐treated rats, suggesting that the K+ channels associated with the endothelium‐dependent vasodilator effect of these agents are either not coupled to G‐proteins or are coupled to G‐proteins that are insensitive to pertussis toxin.
The calcium channel blockers, diltiazem (0.1 or 1 μm), nifedipine (0.01 or 0.1 μm) or nitrendipine (1 nm) attenuated the vasodilatation produced by ACh, histamine, A23187 and also that by BRL 34915.
We conclude that endothelium‐dependent vasodilatation induced by ACh, histamine and A23187 is mediated via activation of membrane K+ channels and Na+/K+‐ATPase. The K+ channels involved in the vasodilator action of these agents are not coupled to pertussis toxin‐sensitive G‐proteins and appear to be regulated by Ca2+.