bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endplate blocking actions of lophotoxin
Authors: Atchison William D. , Narahashi Toshio , Vogel Stephen M. 
Published: July 2012

Effects of lophotoxin (LTX), a neurotoxin isolated from Pacific sea whips Lophogorgia rigida and Lophogorgia chelensis, on neuromuscular transmission were assessed in the rat phrenic nerve‐hemidiaphragm preparation using conventional microelectrode recording techniques, and in the frog cutaneous pectoris preparation using two microelectode voltage clamp techniques.
LTX (2–25 μm) produced a progressive, irreversible block of miniature endplate potential (m.e.p.p.) and endplate potential (e.p.p.) amplitude. M.e.p.p. amplitude histograms were shifted markedly in the direction of lower amplitude by LTX. These effects occurred following a latency of 25–40 min. The latency to onset of block was decreased with increasing LTX concentrations.
In some preparations, LTX produced a transient increase in m.e.p.p. frequency during the first 5 min of application; however, m.e.p.p. frequency then declined to complete block.
The depressant effect of LTX on m.e.p.p. and e.p.p. amplitude progressed to complete block irrespective of the LTX concentration.
LTX also blocked the endplate depolarization produced by iontophoretic application of acetylcholine (ACh). The resting membrane potential of skeletal muscle fibres was unaffected by LTX.
In voltage clamp experiments, LTX (15 μm) depressed the peak amplitude of the endplate current (e.p.c.) nearly uniformly at potentials between — 120 and ‐I‐ 60 mV. LTX did not affect the e.p.c. reversal potential or the kinetics of e.p.c. decay suggesting that LTX does not block open ACh channels. E.p.c. block by LTX was also progressive and irreversible.
The results indicate that LTX blocks neuromuscular transmission by a postjunctional action. The binding site of LTX may be different from that of ACh.
The control of 86Rb efflux from rat isolated pancreatic islets by the sulphonylureas tolbutamide and glibenclamide
Authors: Matthews E.K. , Shotton P.A. 
Published: July 2012

The efflux of 86Rb from rat isolated pancreatic islets preloaded with the isotope and perifused in vitro, has been used to monitor the effects of sulphonylureas on the potassium permeability, PK, of pancreatic β‐cells.
Tolbutamide (5 μm to 5 mm) had a dual effect, causing initially a decrease in 86Rb efflux (the ‘on’ response) which was rapidly superseded on drug removal by a large phasic increase in 86Rb efflux (the ‘off’ response). Each kinetic response had a different dose‐dependency: the ‘on’ response was half‐maximal at tolbutamide concentrations of 0.02 mm, maximal at 0.2 mm and decreased by concentrations > 0.2 mm whereas the ‘off’ response was half‐maximal at 0.07 mm, maximal at 0.7 mm, with further increases in concentration (up to 5 mm) causing no further change in magnitude.
Analysis of the time‐ and concentration‐dependency of tolbutamide action, by presenting increasing concentrations (0 to 1.4 mm) of tolbutamide as a ramp or step function, established a critical dependence of the kinetics of 86Rb efflux during and after exposure to tolbutamide upon the initial rate of increase of the tolbutamide concentration rather than its final steady state.
In the presence of quinine (10 μm), D600 (50 μm), or tetraethylammonium (20 mm), the secondary increase in 86Rb following tolbutamide (0.7 mm) removal was totally inhibited. Co2+ (2.56 mm) not only blocked the secondary ‘off’ response but also potentiated the initial ‘on’ response of tolbutamide.
Glibenclamide produced a rapid decrease in 86Rb efflux but at a much lower concentration (10 μm) than tolbutamide and with no ‘off’ response apparent over a wide range of concentration (1 to 100 μm); moreover the decrease in 86Rb efflux was sustained and only slowly reversible.
It is concluded that tolbutamide has two opposing actions on islet β‐cell 86Rb efflux, and therefore PK: (i) a tendency to increase a calcium‐sensitive PK by stimulating calcium entry into the cell and (ii) a decrease in PK that may be due to a direct effect on the calcium‐sensitive PK itself. The more sustained pharmacological action of glibenclamide is explained by the longer‐lasting decrease in PK that it produces.
Determination of imidazole acetic acid and its conjugate(s) levels in urine, serum and tissues of rats: studies on changes in their levels under various conditions
Authors: Imamura Ikuo , Maeyama Kazutaka , Wada Hiroshi , Watanabe Takehiko 
Published: July 2012

A convenient and reproducible method for assay of imidazole acetic acid (ImAA) was developed as a modification of that described previously (Watanabe et al., 1983). ImAA conjugate(s) (ImAA‐C), mainly consisting of imidazole acetic acid riboside, could be measured by this method after its hydrolysis to ImAA.
The ImAA and ImAA‐C levels in various tissues of rats were measured and the effects of various agents on these levels were studied.
The renal clearance values of ImAA‐C in rats and man were similar to the creatinine clearance values, but those of ImAA were 1/40 of those of ImAA‐C, suggesting that the latter is readily excreted in the urine.
Consistent with this idea, the urinary excretion of ImAA‐C was found to increase much more than that of other histamine metabolites during late pregnancy, when the foetus produces much histamine.
Effects of five different organic calcium antagonists on guinea‐pig isolated trachea
Authors: Advenier C. , Cerrina J. , Duroux P. , Floch Anne , Renier Annick 
Published: July 2012

The relaxant effects of five organic calcium antagonists (nicardipine, diltiazem, PY 108068, verapamil and bepridil) on guinea‐pig isolated trachea were tested against contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, potassium chloride (KCl) and tetraethylammonium (TEA) in a medium containing the normal amount of calcium and against calcium dose‐response curves in a calcium‐free, potassium‐enriched medium. These effects were compared with those of spasmolytic or specific acetylcholine or histamine antagonists.
In contrast to the other drugs tested, organic calcium antagonists exerted a specific inhibitory effect on KCl‐ and TEA‐induced contractions. Their degree of activity was in the order: nicardipine > diltiazem > PY 108068 > verapamil > bepridil. All calcium antagonists inhibited calcium dose‐response curves at similar concentrations.
Organic calcium antagonists therefore seem to exert a specific inhibitory effect on depolarizing agents in the guinea‐pig isolated trachea, unlike other tissues, notably some vascular smooth muscles.
Evidence that cyclic nucleotides are not mediators of fever in rabbits
Authors: Dascombe M.J. 
Published: July 2012

The N6‐2′‐0‐dibutyryl derivative of adenosine 3′,5′‐monophosphate (db cyclic AMP) and related compounds have been micro‐injected into the preoptic/anterior hypothalamic nuclei (PO/AH) of the unanaesthetized, restrained rabbit and the effects on deep body temperature observed.
Db cyclic AMP (100–400 μg) produced hypothermia of rapid onset in rabbits at an ambient temperature of 20–23 °C. Hypothermia was also produced by N2‐2′‐0‐dibutyryl guanosine 3′,5′‐monophosphate (db cyclic GMP), but not by saline, sodium n‐butyrate, adenosine 3′,5′‐monophosphate (cyclic AMP), guanosine 3′,5′‐monophosphate, adenosine 5′‐mono‐, di‐ or triphosphate.
The initial hypothermic response to db cyclic AMP and db cyclic GMP was followed by a sustained rise in temperature. However, all compounds injected into the PO/AH produced a similar hyperthermia which was attenuated by paracetamol. Development of this tissue‐damage fever abolished the hypothermic response to db cyclic AMP in some rabbits.
The effects of db cyclic AMP on body temperature and behaviour were not reproduced by the adenylate cyclase activators, cholera toxin (0.125‐5 μg) and guanyl imidodiphosphate (5–400 μg).
It is concluded that hypothermia is the principal effect of db cyclic AMP on body temperature when injected into the PO/AH in rabbits. These data do not support the proposal that endogenous cyclic AMP in the rabbit brain mediates pyrexia.
Effects of bepridil on the electrophysiological properties of guinea‐pig ventricular muscles
Authors: Anno Takafumi , Furuta Tatsuji , Itho Masanori , Kodama Itsuo , Toyama Junji , Yamada Kazuo 
Published: July 2012

Effects of bepridil, a new antianginal and potential antiarrhythimic agent, on transmembrane action potentials of ventricular muscles were examined in isolated right ventricular papillary muscles of guinea‐pig.
Bepridil at concentrations above 5 × 10−6m caused a dose‐dependent decrease in both the maximum upstroke velocity (Vmax) and the action potential duration from the upstroke to 30% repolarization (APD30). On the other hand, the resting potential (RP), the amplitude of action potential (AMP), and the action potential duration from the upstroke to 90% repolarization (APD90) were not affected even at the highest concentration applied (10−5m).
The curves relating membrane potential and Vmax were shifted by bepridil at 5 × 10−6m along the voltage axis in the direction of more negative potentials.
The recovery kinetics of Vmax assessed by premature stimuli were definitely slowed by bepridil at above 10−6m. This effect was more pronounced with higher [K+]o(10 mm) than normal [K+]o(5 mm).
Bepridil at 5 × 10−6m caused a rate‐dependent decrease of Vmax (use‐dependent block) with rapid onset and offset, as did lidocaine.
Slow responses, which had been induced by isoproenaline (5 × 10−6m) in K+‐depolarized preparations, were suppressed significantly by additional application of bepridil at 10−5m.
These findings suggest that bepridil has electrophysiological characteristics similar to those both of Class Ib and Class IV antiarrhythmic drugs.
Morphine augments calcium‐dependent potassium conductance in guinea‐pig myenteric neurones
Authors: Cherubini E. , Morita K. , North R.A. 
Published: July 2012

Intracellular recordings were made from myenteric neurones removed from guinea‐pig ileum and maintained in vitro.
Action potentials were elicited by passing brief depolarizing currents through the recording electrode. In AH cells they were followed by afterhyperpolarizations resulting from an increase in potassium conductance (GK.ca).
Morphine (1 nm − 1 μ m), applied by superfusion, increased the duration of the afterhyperpolarization (and the underlying GK.Ca) which followed from 1 to 30 action potentials. Morphine did not change the peak amplitude of the afterhyperpolarization.
This action of morphine occurred both in cells which showed no change in resting membrane potential or resistance and in cells which were hyperpolarized. It was prevented by naloxone (10 nm − 1 μm).
The possibility is proposed that morphine inhibits one of the mechanisms by which myenteric neurones control their free intracellular calcium concentration close to the plasma membrane.
The classification of β‐adrenoceptors in isolated ring preparations of canine coronary arteries
Authors: O'Donnell Stella R. , Wanstall Janet C. 
Published: July 2012

Relaxant responses to the β‐adrenoceptor agonists isoprenaline, fenoterol, noradrenaline or procaterol were obtained on isolated ring preparations of canine coronary arteries contracted with KCl (20 mm) or 5‐hydroxytryptamine (3 μm).
On left circumflex arterial preparations, Schild plots for the selective antagonists atenolol (β1‐selective) or ICI 118,551 (β2‐selective), when using noradrenaline or fenoterol as agonist, were superimposed. This suggested that only one subtype of β‐adrenoceptor was involved in the responses.
The pA2 values on left circumflex artery preparations were: atenolol, noradrenaline as agonist 6.98, fenoterol as agonist 6.71; ICI 118,551, noradrenaline as agonist 6.66, fenoterol as agonist 7.04. These data indicated that the β‐adrenoceptor subtype was β1.
The relative potencies of isoprenaline: noradrenaline: fenoterol were left circumflex 100: 10.0: 2.3, left ventricular branch 100: 9.7: 2.0, septal branch 100: 10.9: 2.5. These data confirmed that β1‐adrenoceptors were involved in the responses of all three arterial preparations.
On preparations of left circumflex artery, left ventricular branch and septal branch, responses were obtained to high concentrations (1 to 100 μm) but not to low concentrations (0.001 to 0.1 μm) of procaterol. This observation confirmed the absence of β2‐adrenoceptors in these arteries.
Responses of left circumflex artery to isoprenaline were potentiated by the extraneuronal uptake inhibitor drugs, corticosterone and metanephrine.
It is concluded (a) that responses of canine left circumflex artery, left ventricular branch and septal branch are mediated by a homogeneous population of β1‐adrenoceptors, and (b) that modulation of responses to isoprenaline by extraneuronal uptake is not confined to responses mediated by β2‐adrenoceptors.
The effects of timolol on arrhythmias and prostanoid release during canine myocardial ischaemia and reperfusion
Authors: Coker Susan J. , Parratt James R. 
Published: July 2012

Timolol (50 μg kg−1), administered intravenously to chloralose‐anaesthetized open‐chest greyhounds 30 min prior to occlusion of the left anterior descending coronary artery, reduced heart rate and mean arterial blood pressure. This dose caused a 20 fold increase in the dose of isoprenaline required to increase heart rate by 25 beats min−1.During the first 30 min of myocardial ischaemia the number of extrasystoles in the timolol‐treated dogs (327 ± 179) was less than in the control group (888 ± 168) and none of the dogs that received timolol fibrillated.The haemodynamic changes induced by coronary artery occlusion (decreased cardiac output and stroke volume, increased peripheral vascular resistance) were similar in both control and timolol‐treated dogs as were the increases inPco2and decreases inPO2and pH in blood draining from the ischaemic myocardium.Timolol did not alter the release during myocardial ischaemia, of either thromboxane B2or prostacyclin (measured as 6‐keto PGF1α).Reperfusion‐induced venticular fibrillation occurred in 7 out of 8 control dogs and in 5 out of 10 timolol‐treated dogs. The overall survival following occlusion and reperfusion was improved by 10% to 50% by timolol.
The roles of stored calcium in contractions of cat tracheal smooth muscle produced by electrical stimulation, acetylcholine and high K+
Authors: Ito Yushi , Itoh Takeo 
Published: July 2012

Effects of direct or indirect (nerve‐mediated) muscle stimulation, acetylcholine (ACh), caffeine and procaine on the membrane and mechanical properties of smooth muscle cells of the cat trachea were investigated by means of double sucrose‐gap and isometric tension recording methods.
Outward current pulses (2 s in duration) applied to the muscle tissue in the presence of tetrodotoxin (10−7m), atropine (10−6m) and propranolol (10−6m) evoked no action potential (spike); however, when the depolarization exceeded 9 mV, a contraction was evoked.
The spike and contraction evoked by outward current pulses in the presence of tetraethylam‐monium (TEA, 10 mm) were suppressed by treatment of the tissue with either Ca2+‐free EGTA (2 mm) containing solution or Mn2+ (5 mm). In the presence of procaine (10 mm), outward current pulses evoked an action potential but no contraction.
Field stimulation of short duration (50 μs) applied to the whole tissue produced an excitation of the intrinsic nerves and evoked excitatory junction potentials (e.j.ps), and when the amplitude of e.j.ps exceeded 4 mV, a twitch contraction occurred. E.j.p. was more effective in producing a contraction than was the membrane depolarization evoked by outward current pulses.
Amplitudes of contractions evoked by exogenous ACh (10−5m) were much larger than those evoked by 128 mm‐[K]o or caffeine (10 mm), in normal Krebs solution. When the amplitudes of the contractions produced by 128 mm [K]o were defined as a relative amplitude of 1.0, the mean amplitudes of contraction produced by ACh (10−5m) or caffeine were 2.5 ± 0.20 or 1.2 ± 0.26, respectively.
In Ca2+‐free EGTA (2 mm)‐containing solution, the contraction induced by 128 mm‐[K]o was rapidly abolished, whereas the contractions evoked by caffeine (10 mm) or the initial phasic contraction produced by ACh (10−5m) were largely unaffected.
When the amount of Ca2+ stored in the muscle cell was estimated from the amplitude of caffeine‐induced contraction evoked in Ca2+‐free solution, procaine (10 mm) applied simultaneously with Ca2+, after depletion of Ca2+ from the cells by means of caffeine, increased the amount of Ca2+ stored to 1.31±0.14 (n = 6) times the control value. However, ACh (10−7m) or excess concentrations of [K]o applied with Ca2+ did not increase the amount of Ca2+ stored in the caffeine‐sensitive intracellular compartment.
These results indicate that the amount of Ca2+ stored in the smooth muscle cells of the cat trachea may be larger than other visceral smooth muscle and plays an important role in the initiation of contraction, in response to endogenous or exogenous ACh.
Differential effects of prostaglandin E2 and cyclic AMP on release of arachidonic acid metabolites from resting and lipopolysaccharide‐stimulated macrophages
Authors: Feuerstein Nili , Ramwell Peter W. 
Published: July 2012

The present study investigated the effect of cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) and prostaglandin E2 (PGE2) on arachidonic acid metabolism in rat peritoneal macrophages.
Dibutyryl cyclic AMP (db‐cyclic AMP) caused differential effects on the synthesis of PGE2 and thromboxane. Although db cyclic AMP enhanced the release of PGE2, it inhibited the release of thromboxane. This suggests that cyclic AMP may regulate cellular functions via induction of a shift in the proportion of arachidonic acid metabolites.
PGE2, at low concentrations, markedly inhibited thromboxane release in nontreated macrophages, but it had virtually no effect on thromboxane release in cells treated with lipopolysac‐charide (LPS). By contrast, db‐cyclic AMP inhibited thromboxane release also in LPS‐stimulated cells.
The interrelationships between PGE2, thromboxane and cyclic AMP, and possible interference of LPS in these interactions are discussed.
Pharmacokinetics and biliary excretion of bromosulphophthalein, [3H]‐ouabain and [3H]‐taurocholic acid in rats with glycerol‐induced acute renal failure
Authors: Bowmer C.J. , Yates M.S. 
Published: July 2012

The pharmacokinetics and biliary excretion of bromosulphophthalein (BSP), ouabain and taurocholic acid (TChA) have been studied in rats with glycerol‐induced acute renal failure (ARF).
In rats with ARF, the hepatic uptake and initial biliary excretion of BSP were decreased. In addition, the rate of BSP conjugation with glutathione by rat liver homogenates was also decreased. This latter change may contribute to the initial decrease in the biliary excretion of BSP.
No change was found in the hepatic uptake and biliary excretion of ouabain, but the area under the concentration‐time curve was increased and the plasma clearance (Clp) decreased in rats with ARF. This decrease in Clp was not due to reduced renal excretion.
The decreased Clp of ouabain in rats with ARF may come from reduced tissue binding and a concomitant decrease in its volume of distribution (Vd).
The hepatic handling of TChA appeared unaltered in ARF, but the rate constant for the terminal part of the concentration‐time curve (β) was decreased. This change probably resulted from a large increase in Vd in rats with ARF.
It is concluded that the decreased uptake of BSP was not due to a non‐specific disturbance of hepatocyte function in ARF because the hepatic handling of ouabain and TChA were unaltered.
Benzodiazepines modulate the A2 adenosine binding sites on 108CC15 neuroblastoma × glioma hybrid cells
Authors: Snell C.R. , Snell P.H. 
Published: July 2012

We have demonstrated high affinity diazepam binding sites of the Ro5–4864 benzodiazepine receptor subtype on 108CC15 neuroblastoma × glioma hybrid cells. These cells were previously shown to have purinoceptors of the A2 adenosine subtype and we have now found that [3H]‐adenosine can be displaced from this binding site by the benzodiazepines and related compounds that can also bind to the Ro5–4864 site.
Diazepam was found to have no intrinsic activity at the A2‐receptor as measured by the stimulation of adenosine 3′: 5′‐cyclic monophosphate (cylic AMP) production in this cell line.
At concentrations sufficient to compete for the A2‐receptor, diazepam was shown to facilitate, by approximately 2 fold, the stimulation of cyclic AMP by adenosine.
These effects are not due to inhibition of adenosine uptake or phosphodiesterase activity, but are probably a consequence of modulation of the coupling of the A2‐receptor to cyclic AMP production in this hybrid cell line.
Effects of caroverine and diltiazem on synaptic responses, L‐glutamate‐induced depolarization and potassium efflux in the frog spinal cord
Authors: Kudo Yoshihisa , Shibata Shoji 
Published: July 2012

The frog spinal cord was used to determine the characteristics of the actions of caroverine and diltiazem, two organic Ca2+‐antagonists, on synaptic responses and l‐glutamate‐induced depolarization.
Caroverine and diltiazem (10−4m) depressed the dorsal root potential (DR‐DRP) induced by electrical stimulation of an adjacent dorsal root. Diltiazem also depressed the ventral root potential (DR‐VRP), whereas caroverine augmented both the polysynaptic component in the ventral root reflex and the size of the DR‐VRP.
The root potentials induced by high frequency stimulation (20 Hz, for 1 s) were markedly depressed by these Ca2+‐antagonists at a concentration of 10−4m.
When the preparation was perfused with normal medium, the compounds depressed L‐glutamate‐induced depolarizations in ventral and dorsal roots.
In preparations treated with tetrodotoxin (TTX) (2 × 10−7m), the antagonizing actions of the drugs against l‐glutamate‐induced depolarizations in the ventral root were markedly reduced or abolished, while significant antagonizing actions on the depolarization in the dorsal root were still observed.
The increase in extracellular K+ activity induced by l‐glutamate in the TTX‐treated preparation was significantly reduced by the compounds.
Caroverine and diltiazem had no effect on the presynaptic nerve spike and on the focal synaptic potential induced by a single stimulation of a dorsal root; however, the focal synaptic potential induced by high frequency stimulation (20 Hz, 1 s) was attenuated.
Motoneuronal action potentials were abolished by the drugs, while the excitatory postsynaptic potential remained unaffected.
The present results suggest that caroverine and diltiazem are not specific l‐glutamate antagonists in the frog spinal cord, but that they block the initiation of an action potential without affecting presynaptic nerve conduction, transmitter release or transmitter‐receptor interactions. The inhibitory effects of these compounds on L‐glutamate‐induced K+‐efflux are discussed with reference to their Ca2+‐antagonizing actions.
α‐Adrenoceptor antagonism by apoyohimbine and some observations on the pharmacology of α‐adrenoceptors in the rat anococcygeus and vas deferens
Authors: McGrath J.C. 
Published: July 2012

α‐Adrenoceptor antagonism of several test drugs was assessed against adrenergic contractile responses to field stimulation in rat vas deferens and anococcygeus, the prejunctional inhibitory effect of xylazine in vas deferens and the contractile effects of α‐adrenoceptor agonists in anococcygeus.
Against the adrenergic nerve‐induced contraction in vas deferens, the potency series was WB 4101> prazosin > apoyohimbine > corynanthine > yohimbine > rauwolscine.
Against the inhibitory effect of xylazine in vas deferens the potency series was apoyohimbine > rauwolscine = yohimbine > WB 4101 > prazosin and corynanthine.
In anococcygeus, against the contractile responses to adrenergic nerve stimulation or to the agonists amidephrine, noradrenaline and xylazine, the potency series was apoyohimbine > corynanthine > rauwolscine.
These results show that apoyohimbine is more potent than the yohimbine sterioisomers as an antagonist at α1− and α2‐adrenoceptors but is no more selective.
The assay methods employed confirm the current classification of ‘α’‐receptors and drugs.