bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiological effects of E‐3753, a new antiarrhythmic drug, in guinea‐pig ventricular muscle
Authors: Delpón Eva , Valenzuela Carmen , Tamargo Juan 
Published: July 2012

The electrophysiological effects of E‐3753, a new antiarrhythmic drug, were studied in guinea‐pig papillary muscles.
E‐3753 (10−7‐10−4m) produced a concentration‐dependent decrease in the action potential amplitude and Vmax of the upstroke, shortened the action potential duration (APD) and shifted the resting membrane potential to less negative values. E‐3753 also shortened the effective refractory period (ERP), lengthening the ERP relative to APD.
E‐3753 (10−5m) shifted the membrane responsiveness curve along the voltage axis to more negative potentials.
In the presence of E‐3753 (10−5m) trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax (onset rate at 3 Hz, 0.05 ± 0.009 per action potential), to a new steady‐state level. This use‐dependent Vmax block was augmented at higher rates of stimulation. The time constant for the recovery of Vmax from the use‐dependent block was 41.1 ± 4.8 s.
E‐3753 (10−5‐10−4 m) had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular fibres depolarized by 27 mm KCl.
The slow onset of use‐dependent block during repetitive activity and the slow offset kinetics of use‐dependent Vmax block suggest that E‐3753 exhibits class Ic antiarrhythmic actions in ventricular muscle fibres but does not exhibit class IV (Ca antagonist) antiarrhythmic actions.
A comparison of the effects of a series of anti‐anginal agents in a novel canine model of transient myocardial ischaemia
Authors: Allely M.C. , Alps B.J. 
Published: July 2012

An anaesthetized canine model of transient myocardial ischemia (TMI) has been developed in which reproducible and reversible electrocardiographic (ECG) and haemodynamic responses are exacerbated by electrical pacing.
The model could separate the ECG and haemodynamic effects of compounds with anti‐ischaemic properties.
Compounds known to possess peripheral or coronary vasodilator properties did not necessarily alleviate the ECG consequences of TMI since glyceryl trinitrate was active whereas dipyridamole was not. The effects of verapamil were complicated by its adverse conduction effects while lidoflazine inhibited the ECG changes only during the ischaemic phase and the ‘metabolic modulator’ oxfenicine worsened the ECG response.
In a model considered to lack coronary reserve, improvements observed in the ischaemic ECG and global ventricular function were considered to result from a direct myocardial effect of the drugs examined rather than by a vascular influence. This was provided to the greatest degree by the Ca2+‐entry blockers nifedipine and nicardipine, with flunarizine adopting an intermediate position.
ICI 204448: a κP‐opioid agonist with limited access to the CNS
Authors: Shaw John S. , Carroll Jacqueline A. , Alcock Peter , Main Brian G. 
Published: July 2012

A number of compounds were evaluated in an attempt to identify a κ‐opioid receptor agonist with limited access to the central nervous system.
Quaternary derivatives of the κ‐opioid agonists tifluadom, U‐50488H and ethylketocyclazocine were essentially devoid of opioid activity in a range of isolated tissue preparations.
A novel compound — ICI 204448 — is described which produced a potent and naloxone‐reversible inhibition of electrically‐evoked contraction of the guinea‐pig ileum, mouse vas deferens and rabbit vas deferens preparations. ICI 204448 was shown to displace the binding of the κ‐opioid ligand [3H]‐bremazocine from guinea‐pig cerebellum membranes.
Ex vivo binding studies in mice showed ICI 204448 to be well absorbed following subcutaneous administration. The brain levels achieved by ICI 20448 were substantially lower than those produced by κ‐agonists such as U‐50488H and tifluadom.
A good correlation was found for a range of opioids between lipophilicity and degree of CNS penetration.
Noradrenaline activates a calcium‐activated chloride conductance and increases the voltage‐dependent calcium current in cultured single cells of rat portal vein
Authors: Pacaud P. , Loirand G. , Mironneau C. , Mironneau J. 
Published: July 2012

Membrane responses were recorded by a patch pipette technique in cultured cells isolated from rat portal vein. Using the whole‐cell mode, pressure ejections of noradrenaline evoked depolarization (current clamp) and inward current (voltage clamp) at membrane potentials of −60 to −70 mV. The noradrenaline‐induced response was reversibly blocked by prazosin indicating that the response was mediated by α1‐adrenoceptors.
The ionic mechanism of the noradrenaline‐induced inward current was investigated in potassium‐free caesium‐containing solutions. Alteration of the chloride equilibrium potential produced similar changes in the reversal potential of the noradrenaline‐induced current, indicating that noradrenaline opened chloride‐selective channels. There was no evidence implicating sodium or calcium as the charge‐carrying ion.
Caffeine applied in the bathing solution also induced a transient increase in chloride conductance but the noradrenaline‐induced response was lost after application of caffeine. This is interpreted to mean that the increase in chloride conductance induced by noradrenaline and caffeine can occur as a consequence of a rise in intracellular calcium concentration depending on release of calcium from the same intracellular stores.
In the presence of caffeine, noradrenaline increased both the voltage‐dependent calcium and chloride membrane conductances during application of repetitive depolarizing pulses. It is concluded that in isolated cells of the rat portal vein the depolarization in response to noradrenaline is mediated by an increase in chloride conductance depending on both the calcium release from intracellular stores and the increase of the voltage‐dependent calcium current.
The effects of infusions of arginine vasopressin or 1‐deamino‐8‐D‐arginine vasopressin on common carotid vascular resistance in conscious, Long Evans rats
Authors: Gardiner S.M. , Compton A.M. , Bennett T. 
Published: July 2012

Intravenous infusions of arginine vasopressin or 1‐deamino‐8‐d‐arginine vasopressin (DDAVP) were given to conscious, Long Evans rats chronically instrumented with bilateral, common carotid, pulsed Doppler probes and intravascular catheters.
During infusion of vasopressin at 0.3 nmol min−1 there was an increase in common carotid vascular resistance with no change in mean blood pressure or heart rate. Following infusion there was a common carotid vasodilatation.
During infusion of vasopressin at 3.0 nmol min−1 there were increases in mean arterial blood pressure and in common carotid vascular resistances, accompanied by bilateral reductions in flow and in heart rate. Administration of (+)−(CH2)5Tyr(Et)DAVP (a V1‐receptor antagonist), during the continued infusion of vasopressin, reversed the effects of the latter on mean blood pressure and heart rate; under these conditions there were increases in common carotid blood flows above baseline, in company with bilateral vasodilatations. The latter effects persisted after cessation of vasopressin infusion.
Infusions of DDAVP were without significant effects on any measured cardiovascular variable.
The results do not provide straightforward support for the claim that vasopressin acts to promote cerebral perfusion, at least when V1‐receptor effects are unopposed. Furthermore, it seems likely that the vasodilator influence of vasopressin on the common carotid vascular bed is not due to stimulation of V2‐receptors.
Characteristics of oedema formation induced by N‐formyl‐methionyl‐leucyl‐phenylalanine in rabbit skin
Authors: Hellewell Paul G. , Yarwood Helen , Williams Timothy J. 
Published: July 2012

The characteristics of N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP)‐induced oedema formation were investigated in vivo in rabbit skin.
FMLP injected intradermally alone induced a small increase in plasma leakage, but marked synergism with prostaglandin E2 (PGE2) in producing oedema responses was observed. In the presence of PGE2, FMLP was equiactive with C5a des Arg and 100–1000 times more active than histamine in terms of permeability‐increasing activity. The response to FMLP was not dependent on endogenous histamine release.
FMLP‐induced responses were of long duration (t1/2 ∼ 40–50 min) when compared with bradykinin (t1/2 ∼ 4–5 min).
The activity of a range of N‐formyl peptides in increasing vascular permeability in skin correlated well with their activity as neutrophil stimulants in vitro.
Intravenous infusion of zymosan‐activated plasma (ZAP) resulted in transient neutropenia and inhibition of oedema formation induced by FMLP and C5a des Arg in the skin. Responses to bradykinin were unaffected by the infusion of ZAP.
Intravenous injection of the non‐steroidal antiinflammatory drug, ibuprofen, resulted in an inhibition of FMLP‐induced, but not histamine‐induced, oedema formation. This effect was independent of cyclo‐oxygenase inhibition and the drug did not induced neutropenia.
Intravenous injection of the microtubule blocking agent colchicine inhibited FMLP‐induced oedema formation. Responses to bradykinin were unaffected. When colchicine was administered after intradermal FMLP, subsequent plasma leakage was abolished.
The inference that receptors have evolved to bacterial secretions (i.e. FMLP) and products of the interaction of bacterial cell walls with tissue fluid (i.e. C5a des Arg), is consistent with the hypothesis that oedema formation is fundamentally a functional process concerned with regulating microbial lysis and opsonisation in an infected tissue.
Characterization of pigment aggregating α2‐adrenoceptors of fish melanophores by use of different agonists after partial irreversible receptor inactivation
Authors: Karlsson Jan Olof G. , Andersson Rolf G.G. , Grundström Nils 
Published: July 2012

The affinity for, and the intrinsic efficacy on, postsynaptic melanosome aggregating α2‐adrenoceptors of fish melanophores was studied for B‐HT 920, clonidine, medetomidine, noradrenaline, phenylephrine and UK‐14,304. Investigations were carried out by evaluating the effects of progressive, irreversible inactivation of the α2‐adrenoceptors by benextramine.
The double reciprocal plots of equieffective concentrations of B‐HT 920, clonidine, noradrenaline and phenylephrine were linear, which indicated that these compounds exerted their effects, mainly, through interaction with one receptor site.
The affinity for the α2‐adrenoceptor selective agonist B‐HT 920, was found to be about 1000 times higher than the affinity for the α1‐adrenoceptor selective agonist phenylephrine.
The corresponding plot of equieffective concentrations of medetomidine was not linear, which may indicate that this imidazole compound exerted its effect through more than one receptor site. However, when phenoxybenzamine was used in place of the more selective benextramine, a linear relationship was obtained.
Lipomobilizing effects of procaterol and yohimbine in the conscious dog: comparison of endocrinological, metabolic and cardiovascular effects
Authors: Valet Philippe , Taouis Mohammed , Tran Marie A. , Montastruc Paul , Lafontan Max , Berlan Michel 
Published: July 2012

Lipid mobilization during a hypocaloric diet may be enhanced by a pharmacological approach using β2‐adrenoceptor agonists or α2‐adrenoceptor antagonists. Studies were undertaken in the dog, an animal model presenting fat cell antilipolytic α2‐ and lipolytic β‐adrenoceptors, in order, firstly, to demonstrate the presence of β2 subtype adrenoceptors on adipocytes and, secondly, to compare the effects of procaterol (β2‐adrenoceptor agonist) and of yohimbine (α2‐adrenoceptor antagonist) on metabolic, endocrinological and cardiovascular parameters.
Procaterol strongly stimulates lipolysis in dog adipocytes in vitro. The utilisation of selective β1‐ and β2‐adrenoceptor antagonists (bisoprolol and ICI 118,551) in both lipolysis and binding studies (displacement of [3H]‐dihydroalprenolol binding) demonstrated the presence of the two β‐adrenoceptor subtypes in dog fat cells.
Infusion of either yohimbine or procaterol (10 and 0.4 nmol min−1 kg−1, respectively for 30min). provoked an equivalent increase in plasma non‐esterified fatty acids (+100%). Procaterol, but not yohimbine, induced hyperglycaemia (+ 120%). Plasma insulin was weakly enhanced by yohimbine (+ 120%) as compared to the increase given by procaterol (+ 500%).
Both drugs stimulated sympathetic nervous system activity, as indicated by the increased plasma noradrenaline concentration, but only yohimbine increased the plasma adrenaline level.
Cardiovascular measurements indicated that procaterol strongly enhances heart rate and transiently decreases mean blood pressure. Yohimbine exhibits a weaker effect on heart rate and slightly increases mean blood pressure.
The present work clearly indicates that lipid mobilization is enhanced during fasting in the dog by selective β2‐adrenoceptor stimulation or by α2‐adrenoceptor blockade. This enhanced lipolytic effect may result either from a direct action of the drugs on the adrenoceptors of fat cells or from an activation of the sympathetic nervous system. Procaterol suffers major limitations since it strongly increases heart rate, immunoreactive insulin and glycaemia. On the other hand, yohimbine induces only minor modifications both in cardiovascular and endocrinological parameters.
Electrophysiological effects of adenosine and adenosine triphosphate on sheep Purkinje fibres under normal and simulated ischaemic conditions
Authors: Boachie‐Ansah G. , Kane K.A. , Parratt J.R. 
Published: July 2012

The electrophysiological effects of adenosine and adenosine triphosphate (ATP) were examined in sheep Purkinje fibres, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). The ability of adenosine to modify the effects of noradrenaline on action potential characteristics was also investigated.
The only statistically significant effects of adenosine (10−6‐10−4 m) and of ATP (10−6‐10−4 m) on normal action potential characteristics were a slight dose‐dependent shortening of the action potential by adenosine and a depolarization by ATP, 10−4 m.
Superfusion with a hypoxic, hyperkalaemic and acidotic PSS caused marked reductions in resting membrane potential, upstroke and duration of the action potential.
Both adenosine and ATP attenuated the reduction in the rate of rise of the upstroke and the amplitude of the action potential caused by the modified PSS.
Adenosine did not alter the noradrenaline‐induced effects on automaticity or on action potentials of normal or depressed Purkinje fibres.
Adenosine and ATP had electrophysiological effects on Purkinje fibres, exposed to conditions in vitro that mimic mild myocardial ischaemia, that were different from those observed on normally polarized fibres.
The effect of cromakalim on the smooth muscle of the guinea‐pig urinary bladder
Authors: Foster C.D. , Fujii K. , Kingdon J. , Brading A.F. 
Published: July 2012

The actions of cromakalim were studied on the detrusor muscle from guinea‐pig urinary bladder. Cromakalim reduced the frequency and amplitude of spontaneous contractile activity of the smooth muscle of the guinea‐pig urinary bladder at 5 × 10−8 m and abolished the activity at concentrations above 5 × 10−7 m.
Electrophysiological experiments demonstrated that cromakalim increased membrane conductance, caused a dose‐dependent hyperpolarization of the cell membrane and loss of spike activity. These events are consistent with the opening of K+ channels.
The effects of 10−6 m and 10−5 m cromakalim on the contractile responses to carbachol, potassium and transmural nerve stimulation were studied. Cromakalim did not prevent the detrusor from responding to these agents, although it significantly reduced the contractile response to K+ at concentrations below 70 mm.
Uptake and efflux experiments using 86Rb+ were unable to demonstrate any significant effect on transmembrane movement produced by cromakalim (10−5 m).
43K+ efflux showed a dose‐dependent increase in the rate constant on addition of cromakalim. The difference in the selectivity for K+ over Rb+ was confirmed in dual label uptake experiments.
Substitution experiments in which the K+ ions in the tissue were gradually replaced by Rb+ demonstrated that cromakalim had a progressively decreasing effect on spontaneous activity as internal K+ was lowered. When all the K+ was replaced by Rb+, cromakalim no longer inhibited spontaneous activity, confirming that the channel opened by cromakalim appears relatively impermeant to Rb+.
Dissipation mechanisms for 5‐hydroxytryptamine in the coronary circulation of the isolated perfused heart of the rat
Authors: Bryan Lesley J. , O'Donnell Stella R. , Williams Adrienne M. 
Published: July 2012

The contribution of uptake into vascular endothelial cells, of neuronal uptake and of extraneuronal uptake in the dissipation of 5‐hydroxytryptamine (5‐HT) perfused through the coronary circulation of the rat heart was examined.
Hearts from reserpine‐pretreated rats were isolated and perfused in vitro with 5‐HT, in the absence or presence of inhibitors, and rates of appearance of the deaminated metabolite, 5‐hydroxyindoleacetic acid (5‐HIAA), in the venous effluent were measured using an h.p.l.c. assay.
The steady‐state rates of 5‐HIAA appearance in the venous effluent in hearts perfused with 1 μm 5‐HT (422 ± 8.48 pmol g−1 min−1, n = 12) were reduced by pretreatment of the rats with 6‐hydroxydopamine (22% inhibition), and by inclusion in the perfusion solution of 30 μm cocaine (28% inhibition), 100 μm 3‐O‐methylisoprenaline (64% inhibition), 100 μm corticosterone (58% inhibition), or 30 μm cocaine and 100 μm 3‐O‐methylisoprenaline (87% inhibition).
The extraneuronal deamination of 5‐HT in the heart was saturable (Km = 101 μm, Vmax = 31.2 nmol g−1 min−1). The neuronal deamination of 5‐HT was saturated by about 50 fold lower concentrations of 5‐HT than was extraneuronal deamination, but Km and Vmax values could not be determined.
In the coronary circulation of the rat heart, 5‐HT was dissipated by the uptake processes for catecholamines, extraneuronal uptake (predominantly) and neuronal uptake, and subsequent metabolism by monoamine oxidase. There was no evidence that a cocaine‐sensitive uptake of 5‐HT into vascular endothelial cells made any significant contribution to 5‐HT dissipation in the heart.
Effects of oxodipine on 45Ca movements and contractile responses in vascular smooth muscle
Authors: Tamargo J. , Tejerina T. 
Published: July 2012

The inhibitory effects of oxodipine, a new dihydropyridine, were compared with those of nifedipine on contractile responses in rat isolated aortic strips and on spontaneous mechanical activity in portal vein segments.
In rat isolated aorta oxodipine (IC50 = 7.8 ± 1.8 × 10−9 m) and nifedipine (IC50 = 8.5 ± 2.5 × 10−9 m) dose‐dependently inhibited the contractile responses induced by high K (80 mm), whereas responses to noradrenaline (NA, 10−6 m) were only slightly affected (IC50 > 10−7 m). These inhibitory actions were observed with both drugs added either before or after the induced contractions.
Contractile responses induced by addition of Ca to 0 Ca high‐K solution were also dose‐dependently inhibited by oxodipine (IC50 = 4.5 ± 2.5 × 10−9 m). However, oxodipine up to 10−6 m did not modify the contractile responses obtained in strips incubated in 0 Ca when Ca was added in the presence of NA.
Oxodipine and nifedipine also inhibited the development of spontaneous mechanical activity in portal vein segments.
Oxodipine inhibited 45Ca uptake stimulated by high K (I50 = 8.7 ± 2.5 × 10−9 m) or by NA (I50 > 10−7 m). However, it did not modify 45Ca uptake and 45Ca efflux in resting strips or 45Ca efflux stimulated by NA.
These results indicate that the effects of oxodipine on vascular smooth muscle may be due to the blockade of Ca entry through potential‐ and receptor‐operated channels; it was at least 10 times more selective for potential‐operated channels. Oxodipine did not modify Ca entry through passive leak channels and NA‐induced intracellular Ca release.
Arachidonic acid‐induced mobilization of calcium in human neutrophils: evidence for a multicomponent mechanism of action
Authors: Naccache Paul H. , McColl Shaun R. , Caon Adriana C. , Borgeat Pierre 
Published: July 2012

The mechanism(s) involved in the mobilization of calcium induced by arachidonic acid in human neutrophils was investigated.
The addition of arachidonic acid to a suspension of human neutrophils led to a time‐ and concentration‐dependent mobilization of calcium which was the result of two separate and experimentally differentiable processes. The latter consisted of a rapid and transient phase followed by a slower and more sustained response.
The initial phase of calcium mobilization elicited by arachidonic acid was decreased in the presence of EGTA, inhibited by pertussis toxin as well as by nordihydroguaiaretic acid (NDGA), and diminished following a pre‐incubation with leukotriene B4, but not platelet‐activating factor.
The characteristics of the first phase of the mobilization of calcium were consistent with an interaction of the fatty acid with the leukotriene B4 receptors, either directly or indirectly following the synthesis of leukotriene B4, as well as with a release of internal calcium.
The second, slower and more sustained phase of calcium mobilization was more apparent at high concentrations (≥8–16 μm) of arachidonic acid, and was relatively insensitive to pertussis toxin, EGTA or NDGA.
The characteristics of the ‘slow’ phase of calcium mobilization by arachidonic acid are consistent with its being associated primarily with a release of calcium from internal storage pools.
The data presented indicate that the mechanism of mobilization of calcium by arachidonic acid in human neutrophils is complex and involves specific activation pathways employed, in part at least, by other neutrophil agonists. These findings may have relevance to various inflammatory situations in which the elevated levels of extracellular arachidonic acid known to be present could modulate the functional responsiveness of the neutrophils to other stimuli.