bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological studies into cyclo‐oxygenase, lipoxygenase and phospholipase in smooth muscle contraction in the isolated trachea
Authors: Mitchell H.W.
Published: July 2012

Indomethacin (1 μm) enhanced histamine‐induced contractions in pig and guinea‐pig isolated tracheae. Mepacrine (30–50 μm) abolished this effect of indomethacin suggesting that contractile metabolites of arachidonate are involved in the response to indomethacin.

Mepacrine (100 μm) in the absence of indomethacin also markedly reduced histamine‐induced contractions (81.2% inhibition) in the pig trachea, without affecting responses to acetylcholine. Histamine‐induced responses in the guinea‐pig trachea were similarly reduced, but with a higher concentration of mepacrine (300 μm).

BW755c (226 μm) enhanced histamine‐induced contractions in some pig tracheal preparations and caused inhibition in others. These effects of BW755c were negatively correlated to the initial reactivity of the muscle to histamine such that weak contractions were potentiated and strong contractions were inhibited. A similar effect was seen with phenidone (100 μm).

The results with BW755c and phenidone suggest that muscle reactivity (to histamine) may be partly determined by the balance between the release of inhibitory and contractile arachidonate metabolites. Mepacrine exerts a different effect indicating that histamine‐induced contractions are regulated by a mepacrine‐sensitive process which appears to be separate from the metabolism of arachidonate.
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.
Angiotensin II does not inhibit vagally‐induced bradycardia or gastric contractions in the anaesthetized ferret
Authors: Andrews P.L.R. , Dutia M.B. , Harris P.J.
Published: July 2012

The effects of angiotensin II (AII) and the analogue Sar1‐Leu8‐angiotensin II on the changes in heart rate and gastric pressure induced by vagal stimulation were investigated in the urethane‐anaesthetized ferret.

AII at high doses (500 ng kg−1 i.v.) increased blood pressure and decreased gastric pressure whereas Sar1‐Leu8‐AII at the same dose had a much smaller effect on blood pressure and no effect on gastric pressure.

Intravenous injections or infusions of AII or its analogue did not alter the effect of vagal stimulation on heart rate or gastric motility. Our results do not provide support for the proposal that AII modulates parasympathetic activity at peripheral sites (Potter, 1982a, b).
Solubilization and characterization of guanine nucleotide‐sensitive muscarinic agonist binding sites from rat myocardium
Authors: Berrie Christopher P. , Birdsall Nigel J.M. , Hulme Edward C. , Keen Mary , Stockton Jane M.
Published: July 2012

Muscarinic receptors from rat myocardial membranes may be solubilized by digitonin in good yield at low temperatures in the presence of Mg2+.

Under these conditions, up to 60% of the soluble receptors show high affinity binding for the potent agonist [3H]‐oxotremorine‐M (KA = 109M−1), which is inhibited by 5′‐guanylylimido‐diphosphate.

The muscarinic binding site labelled with [3H]‐oxotremorine‐M has a higher sedimentation coefficient (13.4 s) than sites labelled with a 3H antagonist in the presence of guanylylimidodiphosphate (11.6 s) and probably represents a complex between the ligand binding subunit of the receptor and a guanine nucleotide binding protein.
Adenosine deaminase antagonizes inhibitory responses to adenosine and non‐adrenergic, non‐cholinergic inhibitory nerve stimulation in isolated preparations of guinea‐pig trachea
Authors: Satchell D.G.
Published: July 2012

In guinea‐pig isolated tracheal tube preparations treated with dipyridamole, adenosine deaminase antagonized inhibitory responses to adenosine and non‐adrenergic, non‐cholinergic nerve stimulation. Inhibitory responses to vasoactive intestinal peptide (VIP) were unaffected and hyoscine‐sensitive excitatory responses to field stimulation were not reduced. The evidence supports a role of adenosine as an inhibitory neurotransmitter in non‐adrenergic, non‐cholinergic nerves in trachea.
Effects of some depressant drugs on synaptic responses to glutamate at the crayfish neuromuscular junction
Authors: Wachtel Ruth E.
Published: July 2012

Excitatory junction currents produced by glutamate were recorded with an extracellular electrode at the neuromuscular junction of the crayfish.

Pentobarbitone, phenobarbitone, diazepam, chlordiazepoxide and procaine had only minimal effects on current decay at concentrations which are highly effective in other preparations. The glutamate synapse in the crayfish appears relatively resistant to these drugs.

In contrast, ether and halothane increased the rate of decay of the currents at concentrations which are comparable to those occurring during anaesthesia.
Responses of human, monkey and dog coronary arteries in vitro to carbocyclic thromboxane A2 and vasodilators
Authors: Toda Noboru
Published: July 2012

Carbocyclic thromboxane A2 (cTxA2), a stable analogue of TxA2, and prostaglandin (PG) F2α contracted helical strips of human, monkey and dog coronary arteries in a concentration‐dependent manner. Apparent ED50 values for cTxA2 were markedly less (1/58 in humans, 1/373 in monkeys and 1/397 in dogs) than those for PGF2α; maximum contractions induced by cTxA2 and PGF2α relative to those induced by 30 mM K+ were approximately identical in the human and monkey arteries.

PGI2 caused a concentration‐related relaxation in human and dog coronary arteries maximally precontracted with cTxA2 and in human, monkey and dog coronary arteries partially precontracted with PGF2α. The relaxation response was greatest in the dog arteries and least in the monkey arteries.

Contractions induced by cTxA2 or PGF2α and relaxations induced by PGI2 were selectively antagonized by treatment with diphloretin phosphate.

Human coronary artery strips contracted with cTxA2 responded to nitroglycerine with a rapid, transient relaxation and to verapamil with a slowly‐developing, persistent relaxation, as did monkey and dog coronary artery strips.

Thromboxane (Tx) A2 appears to be one of the most potent endogenous vasoconstrictors in human coronary arteries, if cTxA2 acts on TxA2 receptors. It is suggested that PGI2, nitroglycerine and verapamil are effective vasodilators in human conduit coronary arteries maximally contracted with cTxA2, although the extent and the duration of vasodilatation induced by these agents were quite different.
Cardiovascular studies with SK&F 93319, an antagonist of histamine at both H1‐ and H2‐receptors
Authors: Harvey Carol A. , Owen D.A.A.
Published: July 2012

Cardiovascular studies have been made in anaesthetized cats with SK&F 93319, an antagonist of histamine at both H1‐ and H2‐receptors.

SK&F 93319, 8 × 10−8 and 4 × 10−7 mol kg−1 min−1 antagonized depressor responses to injections of histamine and the maximum displacement of histamine dose‐response curves exceeded that which can be obtained with either an H1‐receptor antagonist or an H2‐receptor antagonist alone.

SK&F 93319, 8 × 10−8 and 4 × 10−7 mol kg−1 min−1, also caused dose‐dependent antagonism of histamine‐induced falls in blood pressure and total peripheral resistance during intravenous infusions of histamine.

SK&F 93319 inhibited depressor responses to intravenous injections of 2‐(2‐aminoethyl)pyridine, dimaprit and impromidine. The displacement of the 2‐(2‐aminoethyl)pyridine dose‐response curve was similar to the displacement of histamine dose‐response curves. SK&F 93319 caused greater displacement of dimaprit or impromidine dose‐response curves than of histamine or 2‐(2‐aminoethyl)pyridine dose‐response curves.

SK&F 93319 was an effective antagonist of histamine, 2‐(2‐aminoethyl)pyridine or dimaprit‐induced vasodilatation in femoral and gastric vasculature.

SK&F 93319 has been shown to be an effective antagonist of vascular responses to histamine in anaesthetized cats. SK&F 93319 appeared to be more effective as an H2‐receptor antagonist than as an H1‐receptor antagonist in these vascular studies.
A new canine model of endotoxin shock
Authors: Evans S.F. , Hinds C.J. , Varley J.G.
Published: July 2012

A new canine model of endotoxin shock has been developed in which spontaneous recovery of cardiovascular function is largely prevented, the haemodynamic effects of anaesthesia are minimized and intravascular volume replacement is given.

This model has been evaluated using two groups of five adult mongrel dogs anaesthetized with α‐chloralose and breathing spontaneously. Animals in one group were anaesthetized, instrumented and given Escherichia coli (E. coli) endotoxin intravenously, whilst those in the control group were subjected only to anaesthesia and instrumentation.

E. coli endotoxin was given to dogs in the shock group as a bolus dose of 5 mg kg−1 followed by a continuous infusion at 2 mg kg−1 h−1. This produced immediate, severe, cardiovascular depression, with precipitous falls in mean arterial pressure (MAP), cardiac index (CI), stroke index (SI) and left ventricular (LV) dp/dt max. There were associated increases in systemic and pulmonary vascular resistances. Arterio‐venous oxygen content difference (C(a‐v)O2) increased after induction of shock, and animals developed a progressive metabolic acidosis. Increasing haemoconcentration occurred, as evidenced by a rising haematocrit (PCV). Hypovolemia was reflected by a concurrent fall in pulmonary capillary wedge pressure (PCWP).

One hour after induction of shock, intravascular volume replacement was given in the form of a colloidal gelatin solution, as a bolus dose of 10 ml kg−1, followed by a continuous infusion at 10 ml kg−1 h−1. Volume replacement reversed haemoconcentration, restored PCWP and produced some haemodynamic improvement, although in general, severe cardiovascular depression persisted throughout a three hour observation period.

This severe endotoxin shock model has proved to be stable, reproducible and economical. It provides a useful preliminary test for new methods of treatment in hypodynamic endotoxin shock, as well as allowing investigation of acute metabolic and physiological changes.
Effects of intravascular volume expansion on the cardiovascular response to naloxone in a canine model of severe endotoxin shock
Authors: Evans S. F. , Hinds C.J. , Varley J.G.
Published: July 2012

The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement.

Animals were anaesthetized with α‐chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion, and treatment was instituted one hour after the endotoxin bolus.

In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone‐treated dogs.

In volume‐replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall.

These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.
α2‐Adrenoceptor agonists potentiate responses mediated by α1‐adrenoceptors in the cat nictitating membrane
Authors: Shepperson N.B.
Published: July 2012

α1 but not α2‐adrenoceptors mediate contractions of the cat nictitating membrane.

The contractions of this tissue evoked by α1‐adrenoceptor agonists, but not those evoked by angiotensin II, are potentiated by pre‐dosing with α2‐adrenoceptor agonists.

This potentiation is reversed by the α2‐adrenoceptor antagonist, WY 2639.

Pressor responses evoked by α1‐adrenoceptor agonists or angiotensin II were not affected by α2‐adrenoceptor agonists.

Contractions of the nictitating membrane evoked by noradrenaline were reduced by pretreatment with WY 2639.

These results suggest that in some tissues the role of α2‐ adrenoceptors may be to modulate responses to α1‐adrenoceptors, rather than to evoke a discrete response themselves.
Hydrostatic pressure modifies the action of octanol and atropine on frog endplate conductance
Authors: Ashford M.L.J. , Macdonald A.G. , Wann K.T.
Published: July 2012

The effects of octanol, ethanol and atropine were examined on the time course of decay (τD) of miniature endplate currents (m.e.p.cs) in the frog neuromuscular junction at normal and high pressure.

Octanol (25–100 μM) decreased reversibly the τD of m.e.p.cs in a dose‐dependent manner, 100 μM reducing τD to 0.39 of the control value. Higher concentrations (200–500 μM) additionally depressed the amplitude of m.e.p.cs.

Hydrostatic pressure (3.19 and 5.25 MPa) reduced the τD of octanol (25–100 μM)‐shortened m.e.p.cs. Thus 3.19 MPa and 5.25 MPa reduced the τD in the presence of 100 μM octanol to 0.75 and 0.78 of the octanol treated values. This effect was not completely reversed on decompression. The m.e.p.c. amplitude is reversibly decreased by pressure in the presence of octanol.

Hydrostatic pressure (3.19–15.55 MPa) did not modify the effect of ethanol on τD. At 10.40 and 15.55 MPa the τD was increased equally in the absence or presence of ethanol.

Atropine (60 μM) reduced the τD and amplitude of m.e.p.cs to 0.33 and 0.63 of the control values. These effects were compeletely reversible. Hydrostatic pressure (3.19 and 5.25 MPa) reduced the τD of atropine‐shortened m.e.p.cs to 0.82 and 0.77 of the atropine‐treated values respectively. This effect was not completely reversed on decompression. Hydrostatic pressure also reversibly depressed the amplitude of atropine‐treated m.e.p.cs.

The implications of these drug‐hydrostatic pressure interactions are discussed.
Lack of effect of leukotriene D4 on Ca‐uptake in airway smooth muscle
Authors: Raeburn David , Rodger Ian W.
Published: July 2012

The effects of verapamil on leukotriene D4 (LTD4)‐ and KCl‐induced contractions and 45Ca‐uptake were examined in guinea‐pig isolated tracheal smooth muscle.

Both LTD4 (0.1 to 200 nmol l−1) and KCl (8 to 125 mmol l−1) produced concentration‐dependent increases in tension in the tracheal preparations.

Verapamil (1 μmol l−1) inhibited the tension responses induced by both LTD4 and KCl.

LTD4 failed to increase the lanthanum‐resistant Ca content of tracheal smooth muscle at either low (EC25; 3 nmol l−1) or high (EC90; 50 nmol l−1) concentrations. Verapamil did not modify this result.

KCl (90 mmol l−1) increased the lanthanum‐resistant Ca content of the smooth muscle by approximately 60% over basal levels. This effect was completely inhibited by verapamil (1 μmol l1).

It is concluded that in this tissue, LTD4 utilizes principally an intracellular source of Ca2+ to initiate contraction whereas KCl is dependent upon the uptake of Ca2+ from the extracellular compartment. It is suggested that the inhibitory effects of verapamil may reflect an intracellular mechanism of action directed against Ca2+ release initiated by LTD4.
Transmitter release modulated by α‐adrenoceptor antagonists in the rabbit mesenteric artery: a comparison between noradrenaline outflow and electrical activity
Authors: Mishima Shuichi , Miyahara Hiroko , Suzuki Hikaru
Published: July 2012

Effects of α‐adrenoceptor blockers (prazosin, yohimbine, phentolamine and phenoxybenzamine) on the outflow of noradrenaline (NA) and 3,4‐dihydroxyphenylglycol (DOPEG) during perivascular nerve stimulation were observed in relation to electrical events in the rabbit mesenteric artery.

Cocaine or imipramine increased the NA outflow and reduced the DOPEG outflow induced by nerve stimulation. In the absence of stimulation, cocaine and imipramine did not significantly modify the NA and DOPEG outflows.

The α‐adrenoceptor blockers we used enhanced the NA and DOPEG outflow during nerve stimulation, in a dose‐dependent manner; the potency of the enhancement was higher for phentolamine and phenoxybenzamine than for prazosin and yohimbine. Higher concentrations (10−5 M) of yohimbine reduced the NA and DOPEG outflows induced by nerve stimulation.

Prazosin increased the DOPEG outflow in the absence of stimulation, and this effect was not inhibited by pretreatment with cocaine.

Guanethidine increased the NA and DOPEG outflow in the absence of stimulation, and the NA outflow was reduced during nerve stimulation. These effects of guanethidine were prevented by pretreatment with cocaine or imipramine.

Perivascular nerve stimulation evoked excitatory junction potentials (e.j.ps) and with high frequency stimulation, slow depolarization and spike potentials.

Application of phentolamine, phenoxybenzamine or yohimbine enhanced, and of prazosin had no effect, on the amplitude of the e.j.p. Spike potentials were not affected by these α‐adrenoceptor blockers. Slow depolarization ceased in the presence of prazosin, phentolamine or phenoxybenzamine, and was slightly inhibited by yohimbine. Guanethidine blocked all of these electrical responses induced by perivascular nerve stimulation.

Application of prazosin, phentolamine or phenoxybenzamine did not alter the resting membrane potential of the smooth muscle cells. Depolarizations of smooth muscle membrane produced by exogenously applied NA were inhibited by prazosin, phentolamine or phenoxybenzamine. Yohimbine itself depolarized the membrane and the inhibitory effects on the NA‐induced depolarization were weaker.

We conclude that the smooth muscle membrane of the rabbit mesenteric artery possesses α1‐adrenoceptors. Increase in NA outflow by α‐adrenoceptor antagonists during nerve stimulation was not always consistent with increase in e.j.p. amplitude, presumably due to involvement of actions other than α‐adrenoceptor blockade with each of these antagonists.
Photodynamic effects of erythrosine on the smooth muscle cells of guinea‐pig taenia coli
Authors: Matthews E.K. , Mesler D.E.
Published: July 2012

Photon activation of the halogenated fluorescein derivative erythrosine caused a marked calcium‐dependent contraction of the smooth muscle cells of the guinea‐pig taenia coli superfused in vitro. Neither high intensity illumination alone (up to 5 × 104 lux) nor erythrosine alone (up to 2 × 10−4 M) altered the tone of the taenia or its ability to respond to carbachol (5 × 10−5M); photo‐irradiation of erythrosine before tissue contact was also ineffective.

The magnitude of the photodynamic contraction was dependent upon the concentration of erythrosine, the intensity and wavelength of the incident light, and the presence of oxygen; indirect effects via neurotransmitter release or cyclo‐oxygenase activation were specifically excluded.

The photodynamic response was blocked by zero‐[Ca]o and addition of EGTA (1 mM) but not by omission of [Mg]o or a decrease in [Cl]o or [Na]o. D600 (methoxyverapamil) 10−5 M, or a ten fold increase in [Mg]o, to 11.3 mM, partly inhibited the photodynamic contraction at low, but not high, light intensities.

These observations are consistent with the following sequence of events: (i) photo‐activation of the erythrosine molecule, (ii) the generation of highly reactive singlet oxygen, (iii) local peroxidation of cell membrane proteolipid, (iv) increased membrane permeability to Ca2+, (v) the influx of Ca2+ and, (vi) muscle contraction.

It is concluded that the photodynamic action of erythrosine presents a novel method for modulation of membrane calcium permeability, and hence [Ca]i, not only in smooth muscle but possibly in other cells as well, e.g., secretory, epithelial and myocardial cells.
Opioid receptor types on adrenergic nerve terminals of rabbit ear artery
Authors: Fukuda Hiroshi , Hosoki Eiji , Ishida Yukio , Moritoki Hideki
Published: July 2012

Methionine enkephalin, leucine enkephalin, [D‐Ala2, D‐Leu5] enkephalin, α‐neoendorphin, β‐endorphin, dynorphin (1–13) and ethylketocyclazocine inhibited the contractions of rabbit ear artery ring segments elicited by transmural nerve stimulation at 8 Hz.

Ethylketocyclazocine, dynorphin (1–13) and leucine enkephalin produced partial inhibition, their apparent intrinsic activities (α) being 0.57, 0.75 and 0.66, respectively.

Morphine and normorphine, which are agonists at μ‐receptors, did not inhibit the response of the artery.

Naloxone antagonized the actions of opioids and ethylketocyclazocine, and was more effective against methionine enkephalin, leucine enkephalin and [D‐Ala2, D‐Leu5] enkephalin than against α‐neoendorphin, ethylketocyclazocine and dynorphin (1–13). The pA2 values of naloxone against so‐called δ‐agonists were approx. 8.5, and against so‐called k‐agonists were approx. 7.7.

The supposed k‐antagonist, Mr 2266, was more effective than naloxone in antagonizing the actions of α‐neoendorphin, and the k‐agonists dynorphin (1–13) and ethylketocyclazocine. The pA2 values of Mr 2266 against k‐agonists were 8.5–9.0, and against δ‐agonists were 7.8 or less.

The opioid peptides and opioids tested did not cause dilatation of the artery previously contracted with histamine.

These results suggest that the opioid peptides and ethylketocyclazocine acted on opioid receptors at adrenergic nerve terminals in the ear artery.

The opioid receptors appear to be of the δ‐ and k‐types, not the μ‐type.
Further analysis of anomalous pKB values for histamine H2‐receptor antagonists on the mouse isolated stomach assay
Authors: Black J.W. , Leff P. , Shankley N.P.
Published: July 2012

Agonist‐antagonist interactions at histamine receptors have been re‐examined using improved techniques, on the mouse isolated, lumen‐perfused, stomach gastric acid assay.

Using histamine as agonist, pKB values have been estimated for burimamide, metiamide, cimetidine, ranitidine, oxmetidine and famotidine on both the gastric and guinea‐pig isolated right atrium assays. With the exception of oxmetidine on the atrial assay, these compounds behaved as competitive antagonists on both assays.

Oxmetidine significantly depressed basal rate on the atrial assay and the Schild plot slope parameter (0.81) was significantly less than one.

The pKB values estimated on the gastric assay were lower than those on the atrial assay. However, the difference between the values on the gastric and atrial assays was not constant. The difference between the two assays for famotidine was not significant.

We conclude that the apparent varying selectivity of the antagonists for gastric and atrial histamine H2‐receptors may be explained by the differential loss of antagonists into the gastric secretion from the receptor compartment and that there is no need to postulate heterogeneity of histamine H2‐receptors.