bluuebunny/crossref_metadata_2025 huggingface dataset:
BLOOD FLOW, HISTAMINE CONTENT AND HISTIDINE DECARBOXYLASE ACTIVITY IN RAT SKIN GRAFTS AND THEIR MODIFICATION BY CYCLOSPORIN‐A
Authors: FAN T‐P.D. , LEWIS G.P.
Published: July 2012

An attempt has been made to monitor simultaneously the changes in blood flow, histamine content, histidine decarboxylase (HDC) activity and mast cell population in rat skin isografts and allografts.

The histamine content in rat skin allografts during rejection was decreased in contrast with our earlier observation in rabbits.

Although no definite correlation has been found between blood flow changes, histamine content or HDC activity, a reciprocal relationship appeared to exist between histamine content and HDC activity in the skin grafts, which might be a reflection of the immunosuppressive activity of this amine.

The immunosuppressive agent, cyclosporin‐A (20 mg/kg daily) was able to prolong skin allograft survival and prevent the changes in histamine and HDC activity in allografts.

Possible implications of these findings are discussed in relation to current knowledge concerning the interactions between endothelial cells, lymphocytes and mast cells/basophils in graft rejection.
INFLUENCE OF N‐ETHYLMALEIMIDE ON CHOLINOCEPTORS AND RESPONSES IN LONGITUDINAL MUSCLES FROM GUINEA‐PIG ILEUM
Authors: ARONSTAM ROBERT S. , CARRIER GERALD O.
Published: July 2012

The binding of carbamylcholine to membranes prepared from the longitudinal muscle of guinea‐pig ileum was determined from its inhibition of the binding of [3H]‐3‐quinuclidinyl benzilate. Carbamylcholine binding was resolved into high and low affinity components with apparent dissociation constants of 0.11 ± 0.02 and 11 ± 1 μm 42% of the receptors displayed high affinity carbamylcholine binding.

Alkylation of longitudinal muscle membranes with N‐ethylmaleimide increased muscarinic receptor affinity for carbamylcholine in a manner consistent with a conversion of low affinity to high affinity receptors. After exposure the muscle membrane fragments to 1 mm N‐ethylmaleimide for 20 min at 35°C, carbamylcholine binding was resolved into two components with apparent dissociation constants of 0.11 ± 0.01 and 9 ± 2 μm, with 74% of the receptors displaying the higher affinity.

Exposure of longitudinal membranes mounted in an organ chamber to 1 mm N‐ethylmaleimide for 30 s depressed isometric contractions in response to acetylcholine by 80%, while contractions induced by K+ and Ba2+ were reduced by less than 20% and 10%, respectively. Acetylcholine dose‐response curves were shifted to the right while Ba2+ curves were unaffected.

It is suggested that N‐ethylmaleimide has a selective effect on muscarinic responses in the longitudinal muscle by disrupting processes occurring after receptor occupancy but before the induction of phospholipid turnover or calcium influx in the postsynaptic membrane.
INHIBITION OF IONIC CURRENTS IN FROG NODE OF RANVIER TREATED WITH NALOXONE
Authors: CARRATU' MARIA R. , MITOLO‐CHIEPPA DELIA
Published: July 2012

Myelinated nerve fibres of frog sciatic nerve were investigated under current and voltage clamp conditions. In the presence of 68 μM external naloxone, the action potential was completely, though progressively, blocked within 15 min of drug superfusion. The resting potential remained constant.

Under voltage clamp conditions both peak Na+ and steady‐state K+ currents were decreased reversibly by external naloxone. Both currents were reduced in a dose‐dependent manner but, whereas sodium current was affected by the smallest concentrations of naloxone (1.3 up to 12.5 μm), potassium current was decreased only by higher concentrations (25 up to 112 μm).

The time‐course of development of the effect on both Na+ and K+ currents after exposure to 112 μm naloxone (a concentration giving more than 50% of decrease) showed that the effect develops quickly within the first 2 min of exposure to the drug, but afterwards both currents continue to fall more slowly, though progressively.

Experiments with constant test pulses to Em = −10 mV and conditioning prepulses of various amplitudes, showed that the Na inactivation curve, h∞ (Em), was shifted in a negative direction along the potential axis; the shape of the curve was also slightly changed in the presence of naloxone since the shift was larger near the top of the curve. All the observed effects were reversible after returning to the standard Ringer solution.

Internal naloxone (< 0.2 mm) reduced the amplitude of the action potential as well as peak Na+ and steady‐state K+ currents; the sodium inactivation curve, h∞ (Em), was shifted to more negative potentials.

A possible anaesthetic‐like activity of naloxone on the nodal membrane is discussed.
The effect of magnesium deficiency and excess on bovine coronary artery tone and responses to agonists
Authors: Kalsner Stanley
Published: July 2012

The hypothesis that magnesium deficiency, linked to the magnesium content of drinking water, induces major tone increases in coronary arteries and enhances their responses to vasoactive agents to an extent sufficient to explain sudden death associated with ischaemic heart disease was examined in an in vitro preparation.

The spontaneous tone of cattle coronary arteries was not increased during a 30 min exposure to Mg2+‐deficient Krebs until the mineral was omitted entirely from the bathing medium, and even then the observed increase was small. Only in strips maintained under extremely deficient conditions for a prolonged period, namely Mg2+ concentration of 0.2 mm and 0.0 mm for 3h, was tone substantially greater than in controls in standard (1.2 mm) Mg2+‐Krebs.

Responses to acetylcholine and to noradrenaline were not increased in Mg2+‐free Krebs but those to potassium and to 5‐hydroxytryptamine were enlarged over the lower parts of their concentration‐response curves. Responses to potassium and to 5‐hydroxytryptamine were also examined in Krebs containing very low concentration of Mg2+ (0.4 and 0.2 mm) and only modest increases in contraction size were detected. Increases in the Mg2+ concentration of the Krebs (to 4.8 mm) depressed responses to potassium and 5‐hydroxytryptamine.

It is concluded that Mg2+ deficiency must be nearly complete (0.4–0.0 mm) to induce even moderate tone increases in coronary vessels, or to sensitize them to agonist responses, and that there is no reason to link marginally subnormal Mg2+ levels, occasionally reported in humans with heart disease, to marked changes in coronary dynamics.
Additional evidence against universal modulation of β‐adrenoceptor responses by excessive thyroxine
Authors: Taylor Samuel E.
Published: July 2012

The effect of prolonged, excessive thyroxine on β‐adrenoceptor‐mediated relaxation of guinea‐pig trachea was studied.

Thyroxine did not significantly affect the potency of the β1‐adrenoceptor agonist, noradrenaline, or the β2‐adrenoceptor agonist, terbutaline.

Thyroxine did not significantly affect the apparent KB values of the selective β1‐adrenoceptor antagonist, practolol, or the selective β2‐adrenoceptor antagonist, butoxamine.

Thyroxine did not significantly affect the maximum response to noradrenaline. The maximum response to terbutaline in tissues from the thyroxine‐treated animals was only slightly lower than the maximum response in tissues from paired control animals.

These results suggest that excessive thyroxine does not significantly affect the β‐adrenoceptor‐mediated relaxation of guinea‐pig trachea and that the reported modulation of β‐adrenoceptor‐mediated responses in other tissues is specific for the given tissue rather than common to all β‐adrenoceptor systems.
Anticonvulsant‐like actions of baclofen in the rat hippocampal slice
Authors: Ault Brian , Nadler J. Victor
Published: July 2012

The effects of baclofen were tested on epileptiform discharge in the rat hippocampal slice. Slices were superfused with bicuculline methiodide (100 μm) and maximal periods of afterdischarge were evoked by stimulating the Schaffer collateral‐commissural pathway in area CA1, mossy fibres in area CA3 or perforant path fibres in the fascia dentata or by antidromic stimulation of CA1 pyramidal cells.

(−)‐Baclofen attenuated the afterdischarge evoked by stimulating all three sets of fibres in areas CA1 and CA3. In each case, a threshold effect was observed at a concentration of 0.25 or 0.5 μm, and complete suppression was usually attained with a concentration of 5 μm. EC50 values ranged between 1 and 2 μm. (−)‐Baclofen attenuated hippocampal afterdischarge with 120 times the potency of (+)‐baclofen. It did not, however, affect the repetitive firing of dentate granule cells in response to stimulation of perforant path fibres.

(−)‐Baclofen also reduced the amplitude of the initial population spike evoked by stimulation of Schaffer collateral‐commissural fibres, but did not affect the antidromic population spike nor the initial population spike evoked by stimulation of the mossy fibres.

Recurrent inhibition in area CA1 was abolished by 1 μm (−)‐baclofen. Thus baclofen, unlike many anticonvulsants, does not suppress afterdischarge by potentiating GABAergic inhibition.

These results suggest that baclofen attenuates hippocampal afterdischarge by a combination of pre‐ and postsynaptic mechanisms.
Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β2‐agonists in rat heart cell culture
Authors: Freyss‐Beguin Marianne , Griffaton Geneviève , Lechat Paul , Picken Douglas , Quennedey Marie Claude , Rouot Bruno , Schwartz Jean
Published: July 2012

The chronotropic response and the variation in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) accumulation induced by isoprenaline and six β2‐selective agonists (fenoterol, salmefamol, soterenol, zinterol, salbutamol and formoterol) were analyzed on cultured heart cells of the rat.

The compounds elicited an enhancement of the frequency, but the time course of the variation of the beating rate was not identical for all of them. A rapid onset was observed for isoprenaline, zinterol and formoterol while it was slower for fenoterol, salmefamol and salbutamol.

In contrast with isoprenaline, the β2‐selective agonists gave concentration‐beating frequency curves which were not sigmoidal. Their effects extended up to a concentration of 5 to 6 orders of magnitude. Nevertheless, the concentration at which the maximal effect occurred and the intrinsic activities of the various compounds agrees better with the responses observed on guinea‐pig atria than with those on trachea.

All the β2‐selective agonists increased the accumulation of cyclic AMP in rat heart cells with a maximal effect at 10−5 m or less. The effects of β2‐agonists on cyclic AMP production showed some analogies with those on beating frequency of the heart cells. The increase in cyclic AMP accumulation induced by β2‐agonists also corresponded to their chronotropic effects on guinea‐pig atria. Thus, the correlation coefficient between the inverse of the log of the concentration producing the half maximal cyclic AMP accumulation in cultured heart cells and the pD2 values on guinea‐pig atria was 0.93.

It is concluded that, in contrast to what was observed in other models, the β2‐selective agonists induce an increase in the production of cyclic AMP in rat heart cells. Furthermore, the effects of the β2‐agonists on cyclic AMP accumulation and on beating rate in the heart cells may correspond with their β1‐adrenoceptor potencies.
Characterization of postsynaptic α‐adrenoceptors in rat aortic strips and portal veins
Authors: Digges K.G. , Summers R.J.
Published: July 2012

Postsynaptic α‐adrenoceptors in rat isolated aortic strips and portal veins have been examined using a number of agonist and antagonist drugs which have varying selectivity for α1‐ and α2‐adrenoceptors.

In both tissues (−)‐noradrenaline ((−)‐NA), (−)‐adrenaline ((−) Adr) (−)‐α‐methyl noradrenaline ((−)‐α‐Me‐NA) and (−)‐phenylephrine ((−)‐PE) were full agonists, while clonidine, oxymetazoline and (2‐(2,6‐dichlorophenyl)‐5,6‐dihydroimidazo(2,1,b) thiazole (44,549) were partial agonists. Guanfacine was a full agonist in aortic strips but only a partial agonist in portal veins.

In aortic strips, pA2 values for prazosin and yohimbine were not significantly different using (−)‐NA, (−)‐PE or guanfacine as the agonist, suggesting a single population of α‐adrenoceptors. The order of potency of the antagonists, prazosin = 2‐(β‐(4‐hydroxyphenyl)‐ethylaminomethyl)‐tetralone (BE2254) > phentolamine > yohimbine > rauwolscine, is indicative of an α1‐type of receptor.

In portal veins, the order of potency of the antagonists was prazosin > BE2254 > phentolamine > yohimbine > rauwolscine, again indicating an α1‐type of receptor.

The mean pA2 value for yohimbine was not significantly different in either tissue. However, mean pA2 values for prazosin, BE‐2254 and phentolamine were approximately one order of magnitude lower in portal veins than in aortic strips, suggesting that the receptors in the two tissues may not be identical.
The role of 5‐hydroxytryptamine in the feline response to intravenous infusion of live E. coli
Authors: Arvidsson S. , Falk A. , Haglind E. , Haglund U.
Published: July 2012

A standardized septic shock was induced in cats by intravenous infusion of a live E. coli bacteria strain. The bacterial infusion induced a rapid haemodynamic response characterized mainly by a pulmonary arterial hypertension and a late phase characterized by systemic hypotension and hypodynamic circulation.

Systemic arterial, pulmonary arterial, portal venous, left atrial pressures, max inspiratory‐expiratory pressure difference in the trachea, aortic and intestinal blood flows were monitored. Arterial blood samples were taken for recording the number of circulating platelets and white blood cells and for determining the acid‐base balance.

The effect of pretreatment with ketanserin, a specific 5‐hydroxytryptamine2 (5‐HT2)‐receptor blocker on these haemodynamic reactions was studied.

In short term experiments on non‐bacteriaemic control cats, ketanserin prevented the pulmonary hypertension induced by intravenous 5‐HT infusions but not the increase in intestinal blood flow.

Ketanserin induced a reduction of total peripheral (including intestinal) vascular resistance to blood flow but had no effect on aortic blood flow.

After infusion of bacteria, ketanserin pretreated cats were more hypotensive due to a relative peripheral dilatation of the resistance vessels. Ketanserin pretreatment had no effect on the pulmonary vascular reactions, the tracheal pressure difference or the number of circulating platelets or white blood cells. Thus, except for a more pronounced hypotension early after bacterial infusion, ketanserin pretreatment did not influence the haemodynamic response.

It is concluded that 5‐HT is not of significant importance in the pathogenesis of the haemodynamic reactions following experimental bacteraemia.
Determination of receptors that mediate opiate side effects in the mouse
Authors: Hayes Ann. G. , Tyers MichaelB.
Published: July 2012

The effects of μ and κ‐opiate receptor agonists were studied in a variety of tests in the mouse designed to correspond to clinical side‐effects in man. These included sedation, decrease in pupil diameter, Straub tail, decrease in body temperature, decrease in respiratory rate and inhibition of gut propulsion.

The μ‐receptor agonists tested produced opiate side‐effects in the mouse at doses between 2.4 and 34 times higher than their antinociceptive doses in the abdominal constriction test. Their ranked orders of potency in producing these effects were very similar to their order of antinociceptive potency.

In contrast, the κ‐receptor agonists only produced opiate side‐effects at doses between 29 and >2500 times higher than their antinociceptive doses. There was no correlation between the potency ratios in these tests and in the abdominal constriction test.

It is concluded that μ‐receptor agonists may produce both their antinociceptive effects and opiate side‐effects by interacting with the μ‐receptor. The κ‐receptor agonists have previously been shown to produce antinociception via the κ‐receptor, but the opiate‐like side‐effects which appear with some of the drugs at much higher doses are probably due either to interaction with the μ‐receptor or to some other non‐specific action.
Vascular reactivity in diabetes mellitus: role of the endothelial cell
Authors: Fortes Zuleica B. , Lerne J. Garcia , Scivoletto Regina
Published: July 2012

The response to vasoactive agents of microvessels in situ and large arteries in vitro was compared in normal and alloxan‐diabetic rats.

Noradrenaline was equally effective in evoking a constrictor response of mesenteric microvessels in normal and diabetic animals.

The constrictor response to a standard amount of noradrenaline in such vessels was fully antagonized by acetylcholine or papaverine, the minimum effective doses being equivalent in normal and diabetic animals. In contrast, the minimum doses of histamine or bradykinin, effective in normal animals, had to be increased about 20 fold to be active in diabetic animals.

Increased osmolarity of extracellular fluid caused a significant and equivalent increase in latency of the vasoconstrictor response of microvessels to noradrenaline in normal and diabetic animals.

Concentration‐effect curves, constructed from the response of isolated aortae to noradrenaline, were similar in normal and diabetic animals, provided the endothelium was removed. Diabetes only affected preparations in which the endothelium was left intact. In these, the median effective concentrations of noradrenaline were greatly increased in comparison with normal values.

Precontracted aortae from normal and diabetic animals were equally relaxed by acetylcholine and histamine, provided the endothelium was left intact. Loss of the relaxant response of the preparations in all groups of animals was observed following removal of endothelial cells.

It is suggested that different mechanisms may be involved in the effects of vasodilator agents on large arteries in vitro or small vessels in situ. Histamine and bradykinin which are potent permeability‐increasing factors, may antagonize the vasoconstrictor response of microvessels to noradrenaline through an action on endothelial cells with increased vascular permeability and temporary changes in composition of extracellular fluid. The reactive process of endothelial cells to permeability factors was affected by diabetes mellitus. However, the response of microvessels to acetylcholine and papaverine which are devoid of permeability‐increasing properties, was not influenced by diabetes.
Neurotensin and antinatriuresis in the conscious rabbit
Authors: Bloom Stephen R. , Peart William S. , Unwin Robert J.
Published: July 2012

The mechanism of alteration in renal sodium excretion in response to dietary changes is complex and poorly understood. A gut ‘sensor’ might exist which regulates the renal response and this may involve one or more of the now ubiquitous gastrointestinal peptides. Several of these gut peptides, including neurotensin, have been found within the kidney. Plasma levels of neurotensin, which is both a circulating hormone and putative neurotransmitter, rise promptly on feeding. When infused into the conscious rabbit, neurotensin produces a dose‐related fall in renal sodium excretion.
Antinociceptive properties of thyrotropin releasing hormone in mice: comparison with morphine
Authors: Boschi Gabrielle , Desiles Marguerite , Reny Veronique , Rips Richard , Wrigglesworth Susan
Published: July 2012

To investigate the antinociceptive activity of thyrotropin releasing hormone (TRH) in mice, different nociceptive stimuli were used. TRH (i.p.) was active in the phenyl‐p‐benzoquinone or acetic acid‐induced writhing tests (chemical stimuli) and in Haffner's test (mechanical stimulus); its action decreased rapidly 15 min after intraperitoneal injection.

To determine whether the activity of TRH has a peripheral or central origin, we administered TRH intracerebroventricularly via cannulae previously implanted in mice. The results provide evidence that a central mechanism is involved in the analgesic effect of TRH since when given intracerebroventricularly it was 10,000 and 1,000 times more active against chemical and mechanical stimuli respectively than intraperitoneally. The action of TRH decreased rapidly 5 min after i.c.v. injection. Morphine was studied in these tests and it was found that at the peak effect TRH analgesia (i.c.v.) was greater than that of morphine (i.c.v.) on a molar basis.

To investigate the mechanisms involved in the antinociceptive action of TRH, the effects of pre treatment with either agonists or antagonists of noradrenaline (NA), dopamine and 5‐hydroxytryptamine (5‐HT), or with naloxone were studied. TRH activity was generally resistant to modifications of NA, dopamine and 5‐HT systems. The TRH effect was not antagonized by naloxone, but TRH at a non‐analgesic dose prevented the hyperalgesia induced by naloxone.

In conclusion, TRH i.c.v. possessed a short, strong antinociceptive activity against chemical and mechanical stimuli. This analgesia was at least equipotent to that of morphine i.c.v.
Studies on the antinociceptive action of α‐agonist drugs and their interactions with opioid mechanisms
Authors: Bentley G.A. , Newton S.H. , Starr Jennifer
Published: July 2012

A modified abdominal constriction test, whereby the drugs used are injected intraperitoneally when the writhing response is maximal, has been used to study the antinociceptive activity of various sympathomimetic drugs. Of those tested, clonidine was the most potent, with an ID50 value in the nanomolar range. (—)‐Isoprenaline, (—)‐adrenaline and (—)‐noradrenaline were only a little less potent. Phenylephrine, the least potent, had only about one‐sixtieth of the activity of clonidine.

The antinociceptive action appears to occur within the peritoneum, since it was apparent almost immediately after the drugs were injected and was produced by doses far smaller than were effective by the subcutaneous route.

α‐Adrenoceptors appear to be involved in the reaction, since noradrenaline showed stereos‐pecificity, and the α‐adrenoceptor antagonists phentolamine and piperoxan both shifted the dose‐response curves of the α‐adrenoceptor agonist drugs to the right, usually parallel to the control curves.

The high antinociceptive potency of clonidine and oxymetazoline, indicate the importance of α2‐adrenoceptors and this was supported by the finding that piperoxan was a more effective antagonist than phentolamine. The moderate potency of phenylephrine suggests that α1‐adrenoceptors may also be involved, although the selective α1‐antagonist, prazosin, did not antagonize noradrenaline and had antinociceptive activity of its own.

β‐Adrenoceptors also appear to be involved in the antinociceptive response, since propranalol antagonized the effect of isoprenaline, but not that of clonidine.

Piperoxan was a very effective antagonist of morphine, while phentolamine had a weaker action. Naloxone had little action against the α‐adrenoceptor agonists.

Mice pretreated with clonidine or oxymetazoline but not noradrenaline showed a very great cross‐tolerance to morphine. Morphine pretreatment caused marked desensitization of itself, but little cross‐tolerance to clonidine or oxymetazoline.

It is suggested that sensory nerves in the mouse peritoneum have α2‐ and β‐adrenoceptors on their terminals, and possibly α1‐receptors also. It is possible that when activated by the appropriate agonists they depress the generation of pain impulses. There is an interaction between the α‐adrenoceptors and opioid receptors in the mouse peritoneum.
Electrophysiological effects of imipramine in non‐treated and in imipramine‐pretreated rat atrial fibres
Authors: Manzanares J. , Tamargo J.
Published: July 2012

The effect of imipramine (Imip) in concentrations between 10−7M and 5 × 10−5M has been studied on rat atrial transmembrane potentials. In another group of experiments the effect of Imip was studied in atrial fibres from rats pretreated for 24 days with twice daily intraperitoneal injections of Imip 7.5 mg/kg or saline.

In non‐treated atria Imip depressed action potential amplitude and Vmax, reduced the resting membrane potential and shifted the membrane responsiveness and recovery time curves downward and to the right.

Imip also prolonged the action potential duration and the effective refractory period, lengthening the effective refractory period relative to action potential duration.

Pretreatment with Imip decreased the resting membrane potential, amplitude and Vmax of the action potential and prolonged the effective refractory period. Further addition of Imip produced similar but more marked changes than in non‐treated animals.

Imip suppressed the spontaneous atrial automaticity as well as the abnormal automaticity induced by BaCl2, aconitine, ouabain or isoprenaline.

The drug produced a negative inotropic effect and depressed the amplitude of the slow contractions elicited by isoprenaline in K‐depolarized atria.

It is concluded that even when the effects of Imip are similar to those of quinidine (group I of antiarrythmics), it also produces a reduction in Ca and K conductances.
The antinociceptive activity of meptazinol depends on both opiate and cholinergic mechanisms
Authors: Bill D.J. , Hartley J.E. , Stephens R.J. , Thompson A.M.
Published: July 2012

Antinociceptive responses to meptazinol, morphine and oxotremorine and the effects of pretreatment with naloxone or scopolamine on these responses in mice and rats, were examined.

Meptazinol evoked larger increases in nociceptive thresholds in the mouse than in the rat, whereas morphine induced large increases in both species. Oxotremorine was both a more potent and a more effective antinociceptive agent in the mouse than in the rat.

Antinociceptive responses to meptazinol were consistently inhibited in animals pretreated with naloxone, whereas scopolamine attenuated the effects of meptazinol in some, particularly the mouse tail immersion test, but not in all of the procedures used.

Naloxone inhibited all antinociceptive responses to morphine, and scopolamine inhibited all responses to oxotremorine. However, there was no significant interaction between naloxone and oxotremorine or between scopolamine and various opioid analgesic agents.

These results indicate that meptazinol, unlike established opioid drugs, may induce antinociception by a dual action on opiate and cholinergic mechanisms.
Membrane potential responses to ionophoretically applied α‐adrenoceptor agonists in the mouse anococcygeus muscle
Authors: Large W. A.
Published: July 2012

Noradrenaline, phenylephrine, naphazoline and oxymetazoline were applied by ionophoresis to the mouse anococcygeus muscle and the membrane potential was recorded with an intracellular microelectrode.

The ionophoretic application of noradrenaline and phenylephrine produced dose‐related depolarizations in 96% of the cells tested; in contrast, naphazoline and oxymetazoline depolarized only 62% of the cells although contraction was always seen.

The depolarizations produced by all four drugs had similar characteristics in shape and time course except that the latency of responses induced by the imidazoline‐related drugs was significantly longer than the value obtained with the phenylethanolamines. This discrepancy was not due to the difference in susceptibility to neuronal uptake of the two groups of drugs.

The time to peak depolarization for naphazoline and oxymetazoline was longer than that for noradrenaline and phenylephrine but was not sufficient to account for the considerably slower contraction produced by the former drugs.

At room temperature the sensitivity of the mouse anococcygeus to ionophoretically applied naphazoline and oxymetazoline was significantly lower than that to noradrenaline and phenylephrine but at 35°C the sensitivity was similar for all drugs.

These results suggest that there might be two subclasses of α1‐adrenoceptor in the mouse anococcygeus; stimulation of one type leads to depolarization and contraction and activation of the other class produces contraction with no change in membrane potential.
Effects of pancuronium and hexamethonium on paraoxon‐induced twitch potentiation and antidromic firing in rat phrenic nerve diaphragm preparations
Authors: Clark Amanda L. , Hobbiger F. , Terrar D.A.
Published: July 2012

The actions of pancuronium, a selective antagonist of acetylcholine (ACh) at nicotinic cholinoceptors at motor endplates, and hexamethonium, a selective antagonist of ACh at nicotinic cholinoceptors in autonomic ganglia, have been studied in rat phrenic nerve diaphragm preparations. The effects on paraoxon‐induced twitch potentiation and antidromic firing (ADF) in the phrenic nerve, were compared with the effects on normal twitch tension and intracellularly recorded miniature endplate potentials (m.e.p.ps) and endplate potentials (e.p.ps.)

In preparations exposed to paraoxon, pancuronium was found to be approximately 10 times more effective in reducing the potentiated component of the twitch than the component which corresponded to the pre‐paraoxon twitch. A similar result was obtained with hexamethonium.

Pancuronium and hexamethonium, in concentrations which reduced paraoxon‐induced twitch potentiation but had no effect on the twitch tension of preparations not treated with paraoxon, reduced paraoxon‐induced ADF. The lowest concentrations of pancuronium and hexamethonium required for this also reduced the amplitude of m.e.p.ps and e.p.ps.

Dithiothreitol, a disulphide bond reducing agent which reduces the affinity of ACh for nicotinic cholinoceptors, enhanced the potency of pancuronium 2 to 3 fold. The same also applied for hexamethonium.

It is concluded that the experiments failed to provide evidence for an action of ACh on prejunctional nicotinic cholinoceptors of the ganglionic‐type being involved in the initiation by paraoxon of twitch potentiation and ADF. Furthermore, the results obtained can be explained by pancuronium and hexamethonium reducing the action of ACh at the postjunctional membrane.
Effects of apamin on α‐adrenoceptor‐mediated changes in plasma potassium in guinea‐pigs
Authors: Coats Rachel A.
Published: July 2012

An intravenous K+‐sensitive electrode has been used to monitor plasma [K+] changes induced by adrenaline (1.4–6.8 μg kg−1) and amidephrine (14–340 μg kg−1) in anaesthetized guinea‐pigs.

A biphasic response consisting of an initial increase in [K+] followed, within 1 min, by a fall below baseline was observed with both agonists.

Apamin (0.4–40 μg kg−1) reduced the hyperkalaemic phase of the response to amidephrine in a dose‐related, non‐competitive manner. The response to adrenaline was also reduced but to a lesser extent.

Apamin caused little or no reduction of the hypokalemic phase of the response to either agonist.
Effects of various antipsychotic drugs upon the striatal concentrations of para‐hydroxyphenylacetic acid and meta‐hydroxyphenylacetic acid in the mouse
Authors: Juorio A.V. , McQuade P.S.
Published: July 2012

The endogenous concentrations of p‐ and m‐hydroxyphenylacetic acid in the mouse caudate nucleus were determined by a gas chromatographic or a gas chromatographic‐mass spectrometry technique and the concentrations were about 30 and 11 ng g−1 respectively.

The subcutaneous administration of (+)‐butaclamol (1 mg kg−1), haloperidol (5 mg kg−1), molindone (100 mg kg−1), sulpiride (50 mg kg−1) or chlorpromazine (20 mg kg−1) increased the concentration of mouse striatal p‐ and m‐hydroxyphenylacetic acid; the effects were observed at 2 h after drug administration.

Lower doses of chlorpromazine (2 mg kg−1), haloperidol (0.2 mg kg−1) and molindone (2 mg kg−1) did not affect p‐ or m‐hydroxyphenylacetic acid concentrations.

The time course for the concentration changes produced by chlorpromazine (20 mg kg−1) revealed that the formation of the metabolites occurred within 30 min after its administration and that their efflux from the caudate nucleus took at least 4 h for p‐hydroxyphenylacetic acid and more than 8 h for m‐hydroxyphenylacetic acid.

Promethazine and (‐)‐butaclamol which have chemical structures related to chlorpromazine or (+)‐butaclamol respectively but which lack antipsychotic activity, produced no effect on striatal p‐ or m‐hydroxyphenylacetic acid concentrations.

The results suggest that antipsychotic drugs increase the utilization of mouse striatal p‐ and m‐tyramine and that after use the amines are metabolized by monoamine oxidase to form p‐ or m‐hydroxyphenylacetic acid. The synthesis of the acid metabolites occurs within 30 min after chlorpromazine administration and their efflux from the caudate nucleus takes from 4–8 h.
Characterization of the locomotor stimulant action of nicotine in tolerant rats
Authors: Clarke P.B.S. , Kumar R.
Published: July 2012

Tests of locomotor activity (photocell cages) were used to investigate the development of tolerance to nicotine in rats. Repeated exposure to the apparatus did not influence the rate at which tolerance was acquired.

Comparisons of (+)‐nicotine (0.4–1.6 mg kg−1, s.c.) and (‐)‐nicotine (0.1–0.4 mg kg−1, s.c.) in tolerant rats showed that the (‐)‐isomer Was at least ten times more potent in stimulating motor activity.

Subcutaneous pretreatment with mecamylamine (1.0 mg kg−1) completely prevented the locomotor stimulant action of nicotine in tolerant rats, whereas chlorisondamine (0.01 or 0.1 mg kg−1 s.c.) only partially reduced it. When mecamylamine was given after an injection of nicotine, the locomotor stimulant action of nicotine was blocked, and nicotine actually reduced activity.

A single intraventricular dose of chlorisondamine (2 μg) blocked the stimulant actions of nicotine for the duration of the experiment (23–24 days).
Haemodynamic factors influencing myocardial ischaemia in a canine model of coronary artery stenosis: the effects of nitroglycerine
Authors: Szekeres L. , Udvary Éva
Published: July 2012

At a critical degree of coronary stenosis (allowing a just adequate blood supply to the poststenotic area only at the expense of maximal hypoxic coronary vasodilatation), an additional loading of the heart induced marked local myocardial ischaemia, as indicated by appropriate biochemical, electrophysiological and haemodynamic changes.

In this model myocardial oxygen demand was increased in three different ways: (i) increasing heart rate by atrial pacing; (ii) increasing afterload by aortic occlusion and (iii) increasing preload by blood infusion. These procedures were compared in their ability to produce local myocardial ischaemia and characterized by ST‐segment elevation recorded from the endocardium and epicardium.

Increasing afterload evoked the mildest degree of ischaemia since the resulting increase in coronary perfusion pressure and coronary flow almost met the augmented myocardial oxygen demand evoked by the elevated peripheral resistance and by the simultaneously increased preload. A rather more pronounced ischaemia was produced by increasing the preload. The most serious ischaemia of all was induced by atrial pacing. This reduced coronary flow and perfusion pressure and increased left ventricular end diastolic pressure (LVEDP).

Nitroglycerine transiently reduced blood pressure and coronary blood flow and increased epicardial and endocardial ST‐segment elevation; the changes had disappeared 10 min after terminating the infusion. However, at this time a prolonged protective action against pacing‐induced ST‐segment elevation was observed. This protection was also seen after intracoronary injections of nitroglycerine. This indicated that part of the beneficial effect of nitroglycerine in ischaemia is due to direct coronary and/or myocardial actions.
The effects of calcium channel inhibitors and other procedures affecting calcium translocation on drug‐induced rhythmic contractions in the rat vas deferens
Authors: Hay D.W.P. , Wadsworth R.M.
Published: July 2012

In the rat isolated vas deferens, methoxamine 8.1 μm produced an initial phasic response that declined towards baseline and was followed by rhythmic contractions that continued until wash‐out. These responses were predominant in the epididymal half. BaCl2 1 mm produced a similar type of response which was not mediated by noradrenaline release or activation of α‐adrenoceptors. The barium responses were similar in the epididymal and prostatic halves.

Incubation in nominally Ca2+‐free solution caused abolition or near abolition of rhythmic contractions produced by barium or methoxamine. The initial phasic response to methoxamine was abolished in Ca2+‐free solution, whereas that produced by barium persisted.

Rhythmic contractions produced by methoxamine or barium were inhibited by Mg2+ (2.4–20 mm) and by La3+ (1–5 mm). Mg2+ had selectivity for inhibition of the frequency of methoxamine‐ but not barium‐induced rhythmic contractions.

Despite their dependence on [Ca2+]o, barium‐ and methoxamine‐induced rhythmic contractions were resistant to inhibition by calcium channel inhibitors. Verapamil, nifedipine and flunarazine inhibited the amplitude of rhythmic contractions more readily than the frequency (methoxamine IC50 for verapamil: amplitude = 29.8 ± 5.40 μm, n = 6, frequency = 96.7 ± 31.0 μm, n = 5, for nifedipine: amplitude = 2.42 ± 0.34 μm, n = 7, frequency = 3.24 ± 0.75 μm, n = 7, and for flunarizine: amplitude = 15.9 ± 5.95 μm, n = 7, frequency = 153 ± 28.6 μm, n = 7). There was no differentiation between inhibition of methoxamine and barium‐induced responses.

Like Mg2+, methoxyverapamil selectively inhibited the frequency of methoxamine‐induced contractions (IC50: amplitude = 16.8 ± 2.86 μm, n = 5, frequency = 2.07 ± 0.81 μm, n = 5) but not barium‐induced contractions (IC50: amplitude = 13.9 ± 1.95 μm, n = 5, frequency = 48.5 ± 8.98 μm, n = 5).

Diazoxide (43.3–2167 μm) and nitroprusside (3.36–6712 μm) had only a small effect on barium contractions, but produced a dose‐related reduction in the amplitude of methoxamine‐induced responses. Diazoxide and nitroprusside caused methoxamine contractions to occur in groups, although they had no effect on their overall frequency.

It is concluded that barium‐ and methoxamine‐induced rhythmic contractions in the rat vas deferens are mediated by the entry of [Ca2+]o via membrane calcium channels that have a lower affinity (10–100 ×) for calcium channel inhibitors than those mediating the KCl response. Channels activated by methoxamine are concentrated in the epididymal half, whereas those opened by barium are evenly distributed. However, although responses to methoxamine and barium are similar in form, differences in the effects of some of the drugs tested, together with the results of previous studies, indicate that they produce contractions by different mechanisms.
The myotoxicity of bupivacaine, a 31P n.m.r. investigation
Authors: Newman Raymond J. , Radda George K.
Published: July 2012

Phosphorus nuclear magnetic resonance (n.m.r.) spectroscopy is a recently introduced method for the non‐invasive study of muscle biochemistry.

It was shown in the rat that an intramuscular injection of the drug resulted in degeneration that was reflected spectroscopically in a progressive decrease in the intracellular concentrations of phosphocreatine and adenosine triphosphate without a corresponding rise in that of inorganic phosphate. Furthermore, ATP was depleted in the presence of significant levels of phosphocreatine. As regeneration occurred spectra returned to normal and this was complete by day 10.

No such spectroscopic effects were demonstrated in man following the use of bupivacaine in an intravenous regional anaesthetic.

It is suggested that further studies in man are required before this drug can be administered intramuscularly with confidence.
Etomidate‐anaesthesia, with and without fentanyl, compared with urethane‐anaesthesia in the rat
Authors: De Wildt D.J. , Hillen F.C. , Rauws A.G. , Sangster B.
Published: July 2012

In spontaneously breathing rats, continuous infusion of etomidate with and without fentanyl caused a slight decrease in blood pressure and heart rate. Coadministration of fentanyl and etomidate in order to obtain full anaesthesia and analgesia resulted in respiratory depression.

In artificially ventilated rats both etomidate as well as the anaesthetic combination caused a strong reduction in aortic flow and an increase in total peripheral resistance. A single infusion of etomidate did not change blood pressure. Etomidate combined with fentanyl reduced blood pressure. Under adjusted ventilation blood pressure, aortic flow, max(dF/dt) and heart rate were progressively reduced during a 4 h period.

In contrast, urethane anaesthesia reduced aortic flow to a minor extent. Total peripheral resistance and max(dF/dt) were hardly affected. The slightly reduced blood pressure and blood gas variables remained stable during the experiment.

From pharmacokinetic studies it was established that effective etomidate plasma levels were maintained constant during the experimental period. Pharmacokinetic interaction between etomidate and fentanyl did not occur.

It is concluded that for anaesthesia of longer duration during cardiovascular experiments in rats, urethane is preferable to etomidate/fentanyl because it does not cause serious changes in basal haemodynamic variables.
Cardiovascular responses in rats with glycerol‐induced acute renal failure
Authors: Bowmer C.J. , Nichols A.J. , Warren Maxine , Yates M.S.
Published: July 2012

Autonomic and cardiovascular function were assessed in rats with glycerol‐induced acute renal failure (ARF).

Rats with ARF had significantly lower mean arterial blood pressures and heart rates and significantly elevated plasma noradrenaline concentrations.

The chronotropic responses to right cervical sympathetic and vagal stimulation were diminished in rats with ARF.

The pressor and depressor responses to noradrenaline and nitroprusside respectively when expressed as a change in mmHg pressure were significantly reduced in rats with ARF when compared to controls. However, when the depressor responses to nitroprusside were expressed as a percentage fall in basal mean arterial pressure, with the exception of the response to a dose of 10 μg kg−1, there were no significant differences between control and uraemic rats.

The present findings show that in the rat, changes in cardiovascular responsiveness occur after a brief period of uraemia which are similar to those observed in patients and rats with chronic renal failure.
Metabolism and uptake of adenosine in rat isolated lung and its inhibition
Authors: Bakhle Y.S. , Chelliah R.
Published: July 2012

The metabolism of adenosine perfused through the pulmonary circulation of isolated lungs from rats was investigated radiochemically.

Following a 10 s infusion of radioactive [14C]‐ or [3H]‐adenosine, the recovery of radioactivity in effluent from the lung after 1 min increased from 30% at 0.5 μm to 80% at 1 mm adenosine.

Unchanged adenosine comprised the major radioactive species in effluent, being about a third of the total up to 100 μm.

Uptake of radioactivity was saturable at high concentrations with an apparent Km of 215 μm.

Radioactivity retained in lung comprised over 80% as ATP and about 2% as adenosine at all concentrations.

Perfusion of lungs with Krebs solution containing dipyridamole (1–100 μm) or adenine (10 μm) increased the rate of radioactive efflux, decreased uptake of radioactivity by lung and decreased metabolites of adenosine (inosine and hypoxanthine) in the effluent.

Dipyridamole (10 UM) was more potent in decreasing uptake in guinea‐pig lungs than in rat lungs.

From these results we conclude that the pulmonary circulation in rat lung exhibits a significant inactivation process for adenosine. The isolated lung provides a convenient preparation for studying in situ pharmacological or pathological modifications of this vascular inactivation process.
Phenolphthalein stimulates the formation of histamine, 5‐hydroxytryptamine and prostaglandin‐like material by rat jejunum, ileum and colon
Authors: Autore G. , Capasso F. , Mascolo N.
Published: July 2012

The effects of Phenolphthalein on the formation of histamine, 5‐hydroxytryptamine (5‐HT) and prostaglandin‐like material by rat intestine were examined in vivo.

Phenolphthalein, in a dose that causes laxation increased the formation of histamine, 5‐HT and prostaglandin‐like material, and indomethacin reduced these increases.

The data support the idea that the laxative effect of Phenolphthalein is due to increased intestinal production of prostaglandin, histamine and 5‐HT.
Effects of noradrenaline and acetylcholine on electro‐mechanical properties of the guinea‐pig portal vein
Authors: Nanjo Tamaki
Published: July 2012

Effects of acetylcholine (ACh) and noradrenaline (NA) on mechanical properties of smooth muscle cells of the guinea‐pig portal vein were investigated using intact and skinned muscle preparations. In some preparations, the electrical activity was also recorded. In addition to ACh and NA, the effects of caffeine, procaine, excess concentrations of [K]o and MnCl2 were investigated.

NA enhanced the mechanical response due to increase in the spike generation, receptor activated depolarization and release of Ca stored in the cell.

ACh also enhanced the mechanical response, but this agent had little effect on the Ca release from the storage sites.

Caffeine and procaine (10 mm) depolarized the membrane and enhanced the electrical activity. Caffeine enhanced the mechanical activity due to an increase in the membrane activity and the release of Ca stored in the cell, while procaine inhibited the contraction. Procaine inhibited and caffeine accelerated the Ca‐induced Ca‐release mechanism in the cell. NA released the Ca from the storage sites to a greater extent than did caffeine or ACh.

MnCl2 inhibited the spontaneous membrane activity and contraction; however, low concentrations of MnCl2 increased the caffeine‐ or NA‐induced contraction in Ca‐free solution.

When the Ca‐tension relationship was observed in saponin‐treated skinned muscles, the minimum concentration of Ca required to produce the contraction was 10−7 m, as observed in other vascular tissues. Caffeine released the stored Ca, NA and ACh had no effect on the Ca release and procaine inhibited the caffeine‐induced Ca release in skinned muscles.

It was concluded that the membrane properties of smooth muscle cells in the portal vein are much the same as observed in other spontaneously active visceral muscles. Differences observed in the actions of NA and ACh on mechanical properties seems to be mainly due to different receptor‐operated Ca release mechanisms.
Strontium, nifedipine and 4‐aminopyridine modify the time course of the action potential in cells from rat ventricular muscle
Authors: Mitchell Mary R. , Powell T. , Terrar D. A. , Twist V.W.
Published: July 2012

Action potentials, initiated by brief depolarizing pulses, were recorded from single cells isolated from rat ventricular muscle. These action potentials showed a rapid upstroke to about + 30 mV, followed by two phases of repolarization referred to as the early and late phases of the action potential.

Nifedipine (1 μm), which blocks the second inward current (Isi) carried by Ca in these cells, shortened the early phase.

Substitution of strontium for calcium in the solution bathing the cells, a procedure which prolongs Isi, prolonged the early phase.

4‐Aminopyridine (1 mm), which inhibits transient outward current, prolonged the early phase with either calcium or strontium in the external solution.

It is concluded that both Isi and transient outward current contribute to the early phase of the action potential in rat ventricular muscle. It is also suggested that Isi does not directly contribute to the late phase, since the characteristics of the late phase are not compatible with such a role, and the possibility of additional inward current is investigated in the accompanying paper (Mitchell et al., 1984).