bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of NG‐substituted analogues of l‐arginine on NANC relaxation of the rat anococcygeus and bovine retractor penis muscles and the bovine penile artery
Authors: Liu Xiaorong , Gillespie John S. , Gibson Ian F. , Martin William
Published: July 2012

The effects of two inhibitors of nitric oxide synthase, NG‐monomethyl l‐arginine (l‐NMMA) and NG‐nitro l‐arginine (l‐NOARG), were examined on non‐adrenergic non‐cholinergic (NANC) inhibitory transmission in the rat anococcygeus, bovine retractor penis (BRP) and bovine penile artery.

In the rat anococcygeus, l‐NMMA (10–1000 μm) produced a concentration‐dependent augmentation of guanethidine (30 μm)‐induced tone and inhibited NANC relaxation at all frequencies tested (0.1–20 Hz): the maximum inhibition obtained was 56 ± 6% (n = 6). l‐NOARG (0.3–30 μm) also augmented tone and inhibited NANC relaxation in a concentration‐dependent manner, but unlike l‐NMMA the maximum inhibition was 100%.

In the BRP, l‐NMMA (10–100 μm) had no effect on tone or NANC‐induced relaxation, but at 1000 μm tone was increased and NANC relaxation inhibited by 25 ± 7% (n = 6). l‐NOARG (0.3–30 μm) produced a concentration‐dependent increase in tone and inhibition of NANC relaxation. As in the rat anococcygeus, inhibition of NANC relaxation was complete.

The effects of l‐NMMA and l‐NOARG were stereospecific since d‐NMMA (10–1000 μm) and d‐NOARG (1–1000 μm) had no effect on tone or NANC relaxation of the rat anococcygeus or BRP.

l‐Arginine (10–300 μm) had no effect by itself on NANC‐induced relaxation of the rat anococcygeus or BRP. It did, however, reverse the ability of l‐NMMA (10–1000 μm) to augment tone and inhibit NANC relaxation in the rat anococcygeus and BRP. The actions of low concentrations l‐NOARG (0.3–10 μm) were also reversed by l‐arginine (300 μm), but those of higher concentrations were not. d‐Arginine (1000 μm) had no effect on the ability of l‐NMMA or l‐NOARG to augment tone and inhibit NANC relaxation in the anococcygeus and BRP.

On the bovine penile artery, both l‐NMMA (100μm) and l‐NOARG (30 μm) augmented the tone induced by guanethidine (30 μm) and 5‐hydroxytryptamine (0.2 μm) in an endothelium‐dependent manner. l‐NMMA had no effect on NANC‐induced relaxation, but inhibited acetylcholine‐induced endothelium‐dependent relaxation. l‐NOARG abolished NANC relaxation at all frequencies tested and inhibited acetylcholine‐induced relaxation. d‐NOARG (30 μm) had no effect on NANC or acetylcholine‐induced relaxation.

The ability of l‐NOARG to abolish NANC‐induced relaxation in the rat anococcygeus, BRP and bovine penile artery suggests that the l‐arginine‐nitric oxide pathway mediates neurotransmission in all three tissues. The effectiveness of l‐NMMA in blocking NANC relaxation in the rat anococcygeus but not the BRP and bovine penile artery suggests a species difference in the neuronal nitric oxide synthase. The neuronal and endothelial nitric oxide synthases in the penile artery also appear to differ.
ICI D7114 a novel selective β‐adrenoceptor agonist selectively stimulates brown fat and increases whole‐body oxygen consumption
Authors: Holloway Brian R. , Howe Ralph , Rao Balbir S. , Stribling Donald , Mayers Rachel M. , Briscoe Martyn G. , Jackson Jacqueline M.
Published: July 2012

ICI D7114 is a novel, β‐adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg−1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)‐binding (ED50, 0.15 mg kg−1, p.o.) with no chronotropic effects on the heart at these doses.

Reference β‐adrenoceptor agonists, isoprenaline and clenbuterol, also stimulated oxygen consumption and BAT activity but were less selective because they also produced effects on heart rate at these doses.

Treatment of conscious rats with ICI D7114 did not attenuate the chronotropic effects on the heart of a subsequent isoprenaline challenge.

Administration of ICI D7114 or of its acid metabolite had no effect in a cat soleus muscle model of tremor or on blood potassium levels in the conscious dog, indicating lack of effects at β2‐adrenoceptors.

The results indicate that ICI D7114 may have activity at atypical β‐adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.
Quantitative assessment of increased airway microvascular permeability to 125I‐labelled plasma fibrinogen induced by platelet activating factor and bradykinin
Authors: Pedersen K.E. , Rigby P.J. , Goldie R.G.
Published: July 2012

We have used 125I‐labelled fibrinogen (I‐FN) in experiments monitoring plasma extravasation from vessels within guinea‐pig trachea and peripheral lung tissue in response to platelet activating factor (PAF) and bradykinin (BK). Retained tissue radioactivity derived from I‐FN was detected by direct measurement and by autoradiography.

Both PAF and BK caused concentration‐dependent increases in radioactivity in trachea and peripheral lung, with PAF being approximately 1000 times more potent than BK at both sites. On a wet weight basis, mean tracheal leakage responses to PAF and BK were approximately 6 times and 2 times greater respectively than those in peripheral lung. Furthermore, in trachea, the maximal response to PAF was nearly twice that to BK, although they were approximately equiactive in peripheral lung. The dipeptidyl carboxypeptidase inhibitor, enalapril (1 mg kg−1, i.v.), increased the potency of BK by approximately 40 fold.

In trachea, PAF (50 ng kg−1, i.v.)‐induced leakage was selectively inhibited by the PAF receptor antagonist, WEB 2086 (5–50 μg kg−1), while responses to BK (50 μg kg−1, i.v.) were selectively inhibited by the BK2 receptor antagonist NPC 349 (0.5–1 mg kg−1). Neither PAF nor BK‐induced leakage were significantly altered by pretreatment with the histamine H1‐receptor antagonists mepyramine (10 μg kg−1) or ketotifen (50 μg kg−1) or the leukotriene receptor antagonist SKF 104353. These data indicate that both agonists caused direct, specific receptor operated increases in tracheal vascular permeability to plasma macromolecules. The α/β‐adrenoceptor agonist adrenaline (100 μg kg−1) caused modest inhibition of leakage induced by BK, but not of the leakage response to PAF.

Peripheral airway leakage responses to both PAF and BK were also detected by light microscopic autoradiography in paraffin‐embedded tissue sections. This was possible since a significant amount of extravasated I‐FN was apparently precipitated and fixed in the extravascular space as 125I‐labelled fibrin. Autoradiograms showed that both agonists caused increases in peripheral bronchial circulation microvascular permeability to I‐FN. No evidence for leakage in alveolar wall capillaries or in pulmonary blood vessels was observed. Quantitation of such autoradiographic data will allow a comprehensive evaluation of the effects of putative asthma mediators on microvascular permeability throughout the respiratory tree.
Changes of quantal transmitter release caused by gadolinium ions at the frog neuromuscular junction
Authors: Molgó Jordi , del Pozo Esperanza , Baños Josep E. , Angaut‐Petit Denise
Published: July 2012

The actions of the trivalent cation, gadolinium (Gd3+), were studied on frog isolated neuromuscular preparations by conventional electrophysiological techniques.

Gd3+(450 μm) applied to normal or formamide‐treated cutaneous pectoris nerve‐muscle preparations induced, after a short delay, a complete block of neuromuscular transmission. The reversibility of the effect was dependent on the time of exposure.

Gd3+(5–450 μm) had no consistent effect on the resting membrane potential of the muscle fibres.

Gd3+(5–40 μm) applied to preparations equilibrated in solutions containing high Mg2+and low Ca2+reduced the mean quantal content of endplate potentials (e.p.ps) in a dose‐dependent manner. Under those conditions, 3,4‐diaminopyridine (10 μm) consistently reversed the depression of evoked quantal release.

The calcium current entering motor nerve terminals, revealed after blocking presynaptic potassium currents with tetraethylammonium (10 mm) in the presence of elevated extracellular Ca2+(8 mm), was markedly reduced by Gd3+(0.2–0.5 mm).

Gd3+(40–200 μm) increased the frequency of spontaneous miniature endplate potentials (m.e.p.ps) in junctions bathed either in normal Ringer solution or in a nominally Ca2+‐free medium supplemented with 0.7 μm tetrodotoxin. This effect may be due to Gd3+entry into the nerve endings since it is not reversed upon removal of extracellular Gd3+with chelators (1 mm EGTA or EDTA). Gd3+also enhanced the frequency of me.p.ps appearing after each nerve stimulus in junctions bathed in a medium containing high Mg2+and low Ca2+

Gd3+, in concentrations higher than 100 μm, decreased reversibly the amplitude of m.e.p.ps suggesting a postsynaptic action.

It is concluded that the block of nerve‐impulse evoked quantal release caused by Gd3+is related to its ability to block the calcium current entering the nerve endings, supporting the view that Gd3+blocks N‐type Ca2+channels; while the enhancement of spontaneous quantal release is probably the result of Gd3+entry into motor nerve endings. Besides its dual prejunctional effects on quantal release it is suggested that Gd3+exerts a postsynaptic action on the endplate acetylcholine receptor‐channel complex.
Local intracoronary infusions of bradykinin profoundly reduce the severity of ischaemia‐induced arrhythmias in anaesthetized dogs
Authors: Vegh Agnes , Szekeres Laszlo , Parratt James R.
Published: July 2012

Bradykinin in a dose (25 ng kg−1min−1) which did not alter coronary flow, or saline, were infused into a small branch of the left anterior descending coronary artery in dogs anaesthetized with chloralose and urethane, for 10 min prior to coronary artery occlusion and throughout the 25 min occlusion period. The degree of inhomogeneity of conduction and epicardial ST‐segment changes were measured in the ischaemic zone with a composite electrode. In control dogs, coronary artery occlusion led to severe arrhythmias with an incidence of ventricular fibrillation of 47% and tachycardia of 80% and with a mean of 528 ± 140 ventricular premature beats. In marked contrast, those dogs administered bradykinin had no ventricular fibrillation or tachycardia and the number of premature beats was significantly less (53 ± 19). ST‐segment changes were also much less in these dogs. These results raise the possibility that bradykinin might contribute to the protective effects of preconditioning and acts as an ‘endogenous myocardial protective substance’.
Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil
Authors: Cross Alan J. , Jones Julie A. , Baldwin Helen A. , Green A. Richard
Published: July 2012

The effect of chlormethiazole, and other drugs which potentiate γ‐aminobutyric acid (GABA) function on delayed neuronal death in the hippocampus has been examined in the gerbil.

Chlormethiazole (100 mg kg−1, i.p.) and two other drugs previously reported to be neuroprotective (dizocilpine, 3 mg kg−1, i.p. and ifenprodil, 4 mg kg−1, i.p.) were all found to prevent neurodegeneration of CA1/CA2 neurones in the hippocampus when given 30 min before a 5 min episode of bilateral carotid artery occlusion.

Chlormethiazole (100 mg kg−1) was neuroprotective when given up to 3 h, after the ischaemic episode.

Given 1 h after the cartoid artery occlusion, chlormethiazole produced significant protection against hippocampal neurodegeneration at a dose of 50 mg kg−1, but not at 25 mg kg−1.

Phenobarbitone (100 mg kg−1, i.p.) and Saffan (alphaxalone, 45 mg kg−1plus alphadalone, 15 mg kg−1, i.p.) were not protective when given 1 h after the ischaemic episode while pentobarbitone (30 mg kg−1, i.p.) had a modest protective effect.

Evidence is presented to show that neither the operating procedure nor the chlormethiazole administration lowered rectal or cerebral temperature.

The data suggest that chlormethiazole may be a useful treatment in the prevention of neurodegeneration following stroke or cardiac arrest.
Discrepancy between the short and long term effects of ouabain on the sodium pumps of human cells grown in culture
Authors: Griffiths Nina M. , Ogden Patricia H. , Cormack Richard , Lamb J.F.
Published: July 2012

Human cells (HeLa) were cultured for periods up to 48 h in growth medium in the absence or presence of a range of concentrations of cardiac glycosides. In some experiments the potassium concentration of the medium was varied between 0.3 mm and the usual 5 mm.

For periods up to 2 h in ouabain the association and dissociation rate constants were measured and the equilibrium binding constant (KD) calculated; the apparent equilibrium binding constant (K′D) was measured after 1–2 days growth in ouabain.

Ouabain had a K′D after 2 days of 2–6 nm in 5 mm K+growth medium, a 4 fold greater blocking effect on sodium pumps after 2 days than expected from the association and dissociation rate constants measured in untreated or previously ouabain‐treated cells.

This effect was: (a) approximately the same over a range of external potassium concentrations from 0.3 to 5 mm, although the absolute effect of ouabain over this range of potassium was much different; (b) probably not due to different isoforms of pumps in cells grown in ouabain compared to untreated cells; (c) apparently not a consequence of internalisation of pump‐glycoside complexes.

We conclude that ouabain has only a limited access to sodium pumps in whole cells; this could be because sodium pumps cycle continuously through an inaccessible region of the plasma membrane. This effect needs to be considered both in the assessment of the magnitude of the long term effects of cardiac glycosides on cells, and in the measurement of the glycoside affinities of various isoforms of the pump.
Noradrenaline release in the rat vena cava is inhibited by γ‐aminobutyric acid via GABAB receptors but not affected by histamine
Authors: Schneider Dörthe , Schlicker Eberhard , Malinowska Barbara , Molderings Gerhard
Published: July 2012

Segments of the rat vena cava preincubated with [3H]‐noradrenaline were superfused with [3H]‐noradrenaline‐free solution containing desipramine and corticosterone and the effects of γ‐aminobutyric acid (GABA) receptor ligands and of histamine on tritium overflow evoked by transmural electrical stimulation were studied.

GABA inhibited, and histamine failed to affect, the electrically (0.66 Hz) evoked tritium overflow both in the absence and presence of rauwolscine (which was present in the superfusion medium in the subsequent experiments). The effect of GABA was less pronounced at a stimulation frequency of 2 Hz.

The inhibitory effect of GABA (pIC35 5.83) on the electrically (0.66 Hz) evoked overflow was mimicked by the GABAB receptor agonist, R‐(−)‐baclofen (6.07) and less potently by S‐(+)‐baclofen (3.30) and the GABAA receptor agonist, muscimol (3.70). The concentration‐response curve of GABA was shifted to the right by the GABAB receptor antagonist, CGP 35348 (P‐(3‐aminopropyl)‐P‐diethoxymethyl‐phosphinic acid; apparent pA2 4.76), but not affected by the GABAA receptor antagonist, (−)‐bicuculline methiodide 100 μmol1−1. Given alone, (−)‐bicuculline methiodide slightly increased, and CGP 35348 did not affect, the evoked overflow.

The effect of GABA in veins from rats treated for 14 days with RS‐baclofen (10 mg kg−1, i.p. once daily) did not differ from that in veins from rats which received the vehicle instead. The effect of GABA also did not differ in veins from rats treated once either with RS‐baclofen or with its vehicle.

The results suggest that the postganglionic sympathetic nerve fibres in the rat vena cava are endowed with presynaptic GABAB receptors, but not with receptors for histamine. (−)‐Bicuculline methiodide increases noradrenaline release by a mechanism not related to GABAA, GABAB, α2‐receptors or noradrenaline uptake.
Inhibition of the myocardial Ca2+‐current (ICa) by the enantiomers of DPI 201–106 and BDF 8784
Authors: Ravens Ursula , Pfeifer Thomas , Wettwer Erich , Grundke Martin
Published: July 2012

We studied the stereoselectivity of the effects of the enantiomers of the cardiotonic agent DPI 201–106 (4‐[3′‐(4″‐benzhydryl‐1″‐piperazinyl)‐2′‐hydroxypropoxy]‐1H‐indole‐2‐carbonitrile, DPI) and its methyl‐for‐carbonitrile analogue BDF 8784 on cardiac calcium currents (ICa) of guinea‐pig ventricular myocytes. The actions of the S‐ and R‐enantiomers were compared with those of the racemate.

Racemic, S‐ and R‐DPI depressed ICa in a concentration‐dependent manner, the IC50 values were 1.1 μmol 1−1for racemic and S‐DPI, and 1.2 μmol 1−1for R‐DPI, respectively. Racemic, S‐ and R‐BDF 8784 also reduced ICa, the respective IC50 values were 3.6 μmol 1−1for racemic BDF 8784, 1.3 μmol 1−1for S‐BDF 8784 and 1.1 μmol 1−1for R‐BDF 8784.

Neither the DPI nor the BDF 8784 enantiomers alter the time course of inactivation of ICa. The steady‐state inactivation curve for ICa was shifted along the voltage axis to negative membrane potentials. The block of ICa was dependent on the membrane potential and increased with membrane depolarization.

Our findings indicate that DPI and BDF 8784 inhibit ICa in a non‐stereoselective manner, which contrasts the opposite effects of the DPI enantiomers on Na+channels.
Supersensitivity to tetrodotoxin and lignocaine of sea anemone toxin II‐treated sodium channel in guinea‐pig ventricular muscle
Authors: Nishio Matomo , Ohmura Tsuyoshi , Kigoshi Shigeru , Muramatsu Ikunobu
Published: July 2012

Sea anemone toxin II (ATX II, 20–30 nm) doubled the action potential duration in guinea‐pig papillary muscles without affecting the maximum rate of rise of the action potential () and the resting potential.

Tetrodotoxin and lignocaine shortened the prolonged action potential in the ATX II‐treated papillary muscles in concentrations (30 nm − 3 μm) at which these drugs did not suppress the .

Whole‐cell voltage‐clamp experiments with single ventricular cells showed that ATX II produced a slowly decaying inward sodium current following a transient sodium current upon depolarization.

The ATX II‐induced slowly decaying current was reduced by tetrodotoxin or lignocaine in concentrations (300 nm–1 μm for tetrodotoxin, 3–10 μm for lignocaine) at which these drugs failed to affect the in cells not treated with ATX II.

These results suggest that sodium channel modification by ATX II not only changes its kinetics but also increases the susceptibility of the channel to block by tetrodotoxin and lignocaine.
The agonist properties of m‐chlorophenylbiguanide and 2‐methyl‐5‐hydroxytryptamine on 5‐HT3 receptors in N1E‐115 neuroblastoma cells
Authors: Sepúlveda María‐Isabel , Lummis Sarah C.R. , Martin Ian L.
Published: July 2012

The effects of 5‐HT3 selective agonists have been studied in whole‐cell voltage‐clamped N1E‐115 neuroblastoma cells.

Application of 5‐hydroxytryptamine (5‐HT) results in the rapid development of a transient inward current at quasiphysiological membrane potentials. This current can be blocked by the 5‐HT3 specific antagonists BRL 43694 and GR67330.

Application of 2‐methyl‐5‐HT (2‐Me5‐HT), a 5‐HT3 selective agonist, produced a qualitatively similar inward current, but with a maximum response only 20% of that produced by 5‐HT.

In the presence of 100 μm 2‐Me5‐HT, the upper part of the 5‐HT dose‐response curve was shifted to the right but reached the same maximum value as in the absence of 2‐Me5‐HT. 2‐Me5‐HT appears therefore to be a partial agonist under these conditions.

The novel 5‐HT3 agonist, meta‐chlorophenylbiguanide (mCPBG) is a full agonist, but has a Hill coefficient (1.5) significantly less than that of 5‐HT (2.3).

Comparison with radioligand binding data show that mCBPG is 100 times less potent than expected; it may therefore exhibit a high affinity for a desensitized state.
Transepithelial water movement in response to carbamazepine, chlorpropamide and demeclocycline in toad urinary bladder
Authors: Hirji M.R. , Mucklow J.C.
Published: July 2012

Osmotic water movement across toad isolated hemibladders was measured by a gravimetric method.

The influence of carbamazepine, chlorpropamide and demeclocycline on the antidiuretic hormone (ADH)‐induced water flow rate was examined.

No antidiuretic activity due to carbamazepine alone was observed but a slight inhibition due to ADH‐induced water flow was observed in the presence of carbamazepine over a selected dose‐range. This was unexpected and is inconsistent with data from in vivo studies in man.

Chlorpropamide potentiated ADH‐induced water flow, in keeping with the hypothesis that chlorpropamide sensitizes the renal tubules to ADH‐induced water flow.

Demeclocycline inhibited ADH‐induced water flow. The mechanism of action remains unclear.
The non‐peptide tachykinin antagonist, CP‐96,345, is a potent inhibitor of neurogenic inflammation
Authors: Lembeck Fred , Donnerer Josef , Tsuchiya Megumi , Nagahisa Atsushi
Published: July 2012

Release of the tachykinin, substance P, from the peripheral terminals of polymodal afferent C‐fibres is thought to be largely responsible for the vasodilatation and plasma protein extravasation described as neurogenic inflammation. The effects of CP‐96,345, a non‐peptide antagonist at the substance P (NK1) receptor, on these vascular reactions were investigated in the rat.

Intravenously (i.v.) injected CP‐96,345 (0.4–3.0 μmol kg−1) prevented the drop in blood pressure, a measure of the peripheral vasodilatation, evoked by substance P and neurokinin A in a dose‐ and time‐dependent manner, but did not affect that elicited by the non‐tachykinin peptides calcitonin gene‐related peptide and vasoactive intestinal polypeptide.

Plasma protein extravasation evoked by i.a. infusion of substance P, antidromic stimulation of the saphenous or the vagus nerve, and stimulation of cutaneous afferent nerves with mustard oil, were each significantly inhibited by CP‐96,345 (3.0–9.0 μmol kg−1, i.v.). Furthermore, CP‐96,345 was orally active in blocking mustard oil‐induced plasma extravasation with an ED50 of 10 μmol kg−1.

The inhibition of substance P‐induced vasodilatation and of neurogenic plasma extravasation by CP‐96,345 was stereospecific as the inactive isomer CP‐96,344 (2R, 3R enantiomer of CP‐96,345) had no effect.

Thus CP‐96,345 is a specific, highly potent, long‐acting and orally active inhibitor of tachykinin‐mediated neurogenic inflammation.
Different in vivo properties of three new inhibitors of catechol O‐methyltransferase in the rat
Authors: Männistö Pekka T. , Tuomainen Päivi , Tuominen Raimo K.
Published: July 2012

We compared three new catechol O‐methyltransferase (COMT) inhibitors (OR‐611, Ro 40–7592 and CGP 28014; 10 and 30 mg kg−1, i.p.) in male rats given levodopa (l‐DOPA, 50 mg kg−1, i.p.) and carbidopa ((−)‐l‐α‐methyl dopa, 50 mg kg−1, i.p.). In some studies pretreatment with pargyline (80 mg kg−1, i.p.) was used to block the function of monoamine oxidase (MAO).

Decreases of hypothalamic and striatal 3‐O‐methyl‐dopa (3‐OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3‐methoxytyramine (3‐MT; after pargyline) levels.

The three COMT inhibitors studied had different individual characteristics. OR‐611 was primarily a peripherally acting COMT inhibitor, decreasing 3‐OMD levels in the striatum (to 31–52%) and in the hypothalamus (to 16–27%) both in the control and pargyline‐treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3‐MT.

Ro 40–7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3‐OMD (always to < 30%), HVA (to < 50%) and 3‐MT levels (to < 23%) significantly both at 1 and 3 h. It was more potent than OR‐611.

CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3‐OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3‐MT levels at 1 h (to 37–22% and 42–35% in the striatum, and to 57–33% and 64–35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR‐611 and Ro 40–7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor.
Inhibitory effect of morphine on yawning induced by cholinoceptor and dopamine D2 receptor activation in rats
Authors: Zarrindast M.R. , Jamshidzadeh A.
Published: July 2012

Bromocriptine (2, 4 and 8 mg kg−1, i.p.), physostigmine (0.05, 0.1 and 0.2 mg kg−1, i.p.) and pilocarpine (1, 3 and 5 mg kg−1, i.p.) induced dose‐dependent yawning in rats.

These responses were reduced in a dose‐dependent manner by pretreatment with morphine.

The inhibitory effect of morphine was reversed by naloxone.

Naloxone alone induced slight but significant yawning.

The present results suggest that morphine inhibits yawning in rats at an opiate receptor downstream from the sites at which cholinoceptor and dopamine D2 activation induce yawning. The anatomical location of these sites remains to be established.
Positive inotropic and negative chronotropic effects of (−)‐cis‐diltiazem in rat isolated atria
Authors: Nasa Yoshihisa , Ichihara Kazuo , Yoshida Rei , Abiko Yasushi
Published: July 2012

The cardiovascular effects of (−)‐cis‐diltiazem, an optical isomer of diltiazem, were studied in the isolated atrium and aortic strip. (−)‐cis‐Diltiazem (30 μm or more) increased the developed tension of the rat left atrium, while (+)‐cis‐diltiazem (1 μm or more) decreased it.

(−)‐cis‐Diltiazem (1 to 100 μm) decreased the rate of spontaneous beating in the right atrium as did (+)‐cis‐diltiazem.

The potency of the positive inotropic action of (−)‐cis‐diltiazem was almost the same as that of ouabain in the rat left atrium, but in the guinea‐pig left atrium it was considerably weaker than that of ouabain.

In both endothelium‐intact and endothelium‐denuded aortic strips, (−)‐cis‐diltiazem relaxed the Ca2+‐induced contraction. In the endothelium‐intact rat aortic strip depolarized by 15 mm KCl, Bay K 8644, a calcium channel agonist, increased the contractile force, whereas (−)‐cis‐diltiazem did not.

These results indicate that (−)‐cis‐diltiazem has a positive inotropic action in isolated atria in rats and guinea‐pigs, but the mode of positive inotropic action of (−)‐cis‐diltiazem is different from that of ouabain or Bay K 8644.
Effects of lignocaine and quinidine on the persistent sodium current in rat ventricular myocytes
Authors: Ju Yue‐Kun , Saint David A. , Gage Peter W.
Published: July 2012

The effects of the Class 1 antiarrhythmic agents lignocaine and quinidine on action potentials, and on sodium currents and potassium currents activated by depolarization, were examined in rat isolated ventricular myocytes by the whole cell, tight seal recording technique.

Tetrodotoxin and lignocaine shortened, whereas quinidine prolonged, the duration of the plateau phase of action potentials.

At low concentrations, lignocaine and quinidine blocked a persistent sodium current that was resistant to inactivation but they had only a small effect on the transient sodium current. At higher concentrations, they also blocked the transient sodium current.

Quinidine, but not tetrodotoxin or lignocaine, depressed potassium currents activated by depolarization and this could account for the prolongation of the plateau phase caused by quinidine.

It is suggested that block of the persistent sodium current may be responsible, at least in part, for the antiarrhythmic action of lignocaine and quinidine.
Effect of adenosine and adenosine analogues on cyclic AMP accumulation in cultured mesangial cells and isolated glomeruli of the rat
Authors: Olivera Ana , Lopez‐Novoa Jose M.
Published: July 2012

Changes in intracellular levels of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) were studied in rat isolated glomeruli and cultured glomerular mesangial cells exposed to adenosine and to the preferential A1 receptor agonist N6‐R‐1‐methyl‐2‐phenylethyl adenosine (R‐PIA), or the potent A2 adenosine receptor agonist 5‐(N‐ethylcarboxamide)adenosine (NECA).

Whereas NECA and adenosine triggered a dose‐dependent increase in cyclic AMP values with EC50 values of approximately 10−6 m and 3 × 10−5 m respectively, R‐PIA lowered cyclic AMP levels at concentrations of 10−6 m or less and increased them at higher concentrations.

The time‐course of the increase induced by 10−6 m NECA was slower than that induced by 10−4 m adenosine. Adenosine produced a maximal stimulation within the first minute, whereas the effect of NECA in both glomeruli and mesangial cells was noticeable only from the second minute of incubation.

The effects of the agonists R‐PIA and NECA on the cyclic AMP system were blocked respectively by the A1 adenosine receptor antagonist, 8‐cyclopentyl‐1, 3‐dipropylxanthihe (DPCPX) at 10−6 m and the A2 antagonist N‐(2‐dimethylaminoethyl)‐N‐methyl‐4‐(2, 3, 6, 7‐tetrahydro‐2,b‐dioxo‐1, 3‐dipropyl‐1H‐purin‐8‐yl) benzene sulphonamide (PD115,199) at 10−6 m. Theophylline, a known antagonist of adenosine receptors, inhibited the action of adenosine on cyclic AMP in mesangial cells. Dipyridamole, an inhibitor of the uptake of adenosine by the cells, enhanced the response to adenosine.

These results suggest the existence of A1 and A2 adenosine receptors with opposite actions on intracellular levels of cyclic AMP in both glomeruli and mesangial cells. Adenosine seems to increase cyclic AMP through the activation of a surface adenosine receptor with pharmacological properties distinct from those exhibited by the A2 adenosine receptor.
Inhibition of noradrenaline release in the rat vena cava via prostanoid receptors of the EP3‐subtype
Authors: Molderings Gerhard , Malinowska Barbara , Schlicker Eberhard
Published: July 2012

In segments of the rat vena cava preincubated with [3H]‐noradrenaline and superfused with physiological salt solution (containing desipramine and corticosterone), we studied the effects of prostaglandins of the D, E and F series, of a prostacyclin analogue and a thromboxane‐mimetic and of subtype‐selective prostaglandin E‐receptor (EP‐receptor) ligands on the electrically (0.66 Hz)‐evoked tritium overflow.

The electrically‐evoked tritium overflow was inhibited by prostaglandin E2 (maximum inhibition by about 80%; pIC40 7.49). The effect of prostaglandin E2 was not affected by rauwolscine, which, by itself, increased the evoked overflow; the α2‐adrenoceptor antagonist was added to the superfusion medium in all subsequent experiments. Indomethacin failed to affect either the evoked tritium overflow or its inhibition by prostaglandin E2.

The inhibitory effect of prostaglandin E2 on the electrically‐evoked tritium overflow was not altered by the EP1‐receptor antagonist, AH 6809 (6‐isopropoxy‐9‐oxoxanthene‐2‐carboxylic acid) at a concentration at least 30 fold higher than its pA2 value at EP1‐receptors. The following compounds mimicked the effect of prostaglandin E2 showing the following rank order of potencies: misoprostol (EP2‐/EP3‐receptor agonist) ≃ sulprostone (EP1/EP3‐receptor agonist) ≃ prostaglandin E1 = prostaglandin E2 ≫ iloprost (EP1‐/IP‐receptor agonist) = prostaglandin F2α. The evoked overflow was not affected by high concentrations of prostaglandin D2 or the thromboxane‐mimetic U46619 (9,11‐dideoxy‐11α, 9α‐epoxymethano‐prostaglandin F2α).

The present results suggest that the postganglionic sympathetic nerve fibres innervating the rat vena cava are endowed with presynaptic EP3‐receptors. They are not tonically activated by endogenously formed products of cyclo‐oxygenase and do not interact with the presynaptic α2‐adrenoceptors.
Nitric oxide synthase responsible for l‐arginine‐induced relaxation of rat aortic rings in vitro may be an inducible type
Authors: Moritoki Hideki , Takeuchi Shougo , Hisayama Tetsuhiro , Kondoh Wataru
Published: July 2012

Characteristics of l‐arginine‐induced non‐endothelial nitric oxide (NO) formation in rat isolated thoracic aorta were investigated.

Relaxation to l‐arginine in arterial rings devoid of endothelium developed about 2 h after the first challenge with l‐arginine and reached a maximum after a further 4 h of incubation.

After the arteries had relaxed in response to l‐arginine, guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) production was stimulated. In fresh arteries that had not yet relaxed in response to l‐arginine, l‐arginine failed to elevate cyclic GMP levels.

Glucocorticoids, actinomycin D and polymyxin B prevented the development of l‐arginine‐induced relaxation and l‐arginine‐stimulated increase in cyclic GMP formation.

Once l‐arginine‐induced relaxation developed, these agents no longer suppressed the relaxation and increase in cyclic GMP formation to l‐arginine.

6 From these results, it is suggested that in the isolated thoracic aorta of the rat, endotoxin in the medium triggers induction of a non‐endothelial NO synthase during prolonged incubation, which accelerates production of NO from added l‐arginine to cause relaxation of the arteries via cyclic GMP. Glucocorticoids and protein synthesis inhibitors may prevent induction of NO synthase. It is suggested that the NO synthase mediating the production of muscle‐derived NO from l‐arginine is an inducible type.
Activation of P1‐ and P2Y‐purinoceptors by ADP‐ribose in the guinea‐pig taenia coli, but not of P2X‐purinoceptors in the vas deferens
Authors: Hoyle Charles H.V. , Edwards Gareth A.
Published: July 2012

The activity of adenosine 5′‐diphosphoribose (ADP‐ribose), a ribosylated purine nucleotide, was investigated on the carbachol‐contracted taenia coli, a tissue possessing P1‐ (A2) and P2Y‐purinoceptors and on the guinea‐pig vas deferens which possesses P2X‐purinoceptors.

In the vas deferens, where ATP (1 μm‐1 mm) produced concentration‐dependent contractions, ADP‐ribose was without effect at concentrations up to 1 mm.

In the taenia coli, ADP‐ribose (0.1 μm‐1 mm) produced concentration‐dependent relaxations with a potency similar to that of adenosine, but less than that of ATP. The pD2 values for ADP‐ribose, adenosine and ATP were 4.5 ± 0.07 (27), 4.4 ± 0.10 (9) and 5.5 ± 0.14 (21), respectively. The time‐course of the relaxations elicited by ADP‐ribose was found to be significantly longer than that for ATP and significantly shorter than that for adenosine.

The P1‐purinoceptor antagonist, 8‐phenyltheophylline (5 μm), produced parallel rightward shifts in the concentration‐response curves of the relaxations of the taenia coli elicited by ADP‐ribose and adenosine but not ATP.

Dipyridamole (0.3 μm), a purine nucleoside uptake inhibitor, potentiated the responses to adenosine and ADP‐ribose in the taenia coli. These potentiations were sensitive to 8‐phenyltheophylline (5 μm).

6 Reactive blue 2, a P2Y‐purinoceptor antagonist, antagonized the inhibitory responses of ADP‐ribose and ATP in the taenia coli, without significantly altering the inhibitory responses of either adenosine or noradrenaline.

7 In the presence of the potassium channel blocker, apamin (0.3 μm), the inhibitory responses of ADP‐ribose were severely attenuated, and the inhibitory responses of ATP in the taenia coli were converted to transient contractions. Further addition of 8‐PT blocked the residual responses of ADP‐ribose.

8 The P2‐purinoceptor antagonist, suramin (500 μm), antagonized responses to ATP and ADP‐ribose, but not adenosine. Further addition of 8‐PT antagonized the residual responses to ADP‐ribose, but not to ATP.

9 It is concluded that ADP‐ribose has a mixed pharmacological profile, evoking both P1 (A2)‐purinoceptor‐mediated responses and P2Y‐purinoceptor‐mediated responses, while being inert at P2X‐purinoceptors. It is suggested that ADP‐ribose may provide a useful starting point for the generation of structural analogues which have specific activity at the P2Y‐purinoceptor.
Tachykinin receptors in rabbit airways — characterization by functional, autoradiographic and binding studies
Authors: Black J.L. , Diment L.M. , Alouan L.A. , Johnson P.R.A. , Armour C.L. , Badgery‐Parker T. , Burcher E.
Published: July 2012

In many species, both NK1 and NK2 tachykinin receptors appear to be important in mediating the contraction of airway smooth muscle. We have examined the distribution and characterization of receptors for tachykinins in rabbit airways using functional length tension studies, autoradiography and radioligand binding studies.

Contractile responses to tachykinins were elicited in four different areas of the respiratory tree — trachea, and three progressively more distal areas of the right bronchus. The NK2 receptor‐preferring agonists, neurokinin A (NKA), neuropeptide gamma (NPγ) and the NK2‐selective [Lys5 MeLeu9, Nle10]‐NKA(4–10) [NKA (4–10) analogue] produced similar contraction in all four areas. Substance P (SP) and the NK1‐selective [Sar9,Met(O2)11]‐SP (Sar‐SP) exhibited a marked location‐dependence in the magnitude of contraction, producing minimal contraction in the trachea and more proximal bronchi with contractions becoming progressively larger in the more distal airways. Senktide (which is selective for the NK3 receptor) produced negligible contraction in all areas.

The NK2‐selective antagonist, MDL29,913, was a weak antagonist of NKA and NKA(4–10) analogue. At a concentration of 2 μm, it produced a small but significant shift in the response curve to NKA and a greater shift (8 fold) in the curve to NKA(4–10) analogue, but it had no effect on responses to Sar‐SP. The non peptide NK, receptor antagonist, CP‐96,345, was also unexpectedly weak in this preparation. The pD2 value for Sar‐SP was decreased 27 fold by CP‐96,345 at a concentration of 1 μm, without alteration in the maximum response.

Autoradiographic binding sites to [125I]‐NKA were sparse over smooth muscle in proximal airway preparations and markedly increased in density in the more distal airways. There was negligible binding over vascular smooth muscle and epithelium.

Radioligand binding studies revealed binding to [125I]‐NKA which was 82% specific. The order of potency for inhibition of [125I]‐NKA binding was SP >= Sar‐SP > NKA = NPγ>CP‐96,345 > NKA (4–10) analogue > NKB ⋙ MEN 10207 (the NK2 subtype selective antagonist) > MDL 29,913 > senktide. This profile indicates binding predominantly to NK1 receptors.

6 These results suggest that there are at least two types of tachykinin receptors in rabbit airways, a population of NK1 receptors, the density of which is greatest in the periphery and, in addition, NK2 receptors which are uniformly distributed throughout the airways. These receptors have unusual characteristics in that the NK1 antagonist, CP‐96,345 and the NK2 antagonist, MDL 29,913 respectively exhibited only weak potency.
Long‐term changes in gerbil brain neurotransmitter receptors following transient cerebral ischaemia
Authors: Araki Tsutomu , Kato Hiroyuki , Kogure Kyuya , Kanai Yasuo
Published: July 2012

Receptor autoradiographic and histological techniques were used to investigate long‐term changes in the gerbil brain following transient cerebral ischaemia.

Transient ischaemia was induced for 3 min and 10 min, and the animals were allowed to survive for 8 months.

Histological examination revealed that 3 min ischaemia caused neuronal damage and mild shrinkage only in the hippocampal CA1 sector. Ten minutes of ischaemia produced severe neuronal damage in the striatum and the hippocampal CA1 and CA3 sectors. Considerable shrinkage was seen in the hippocampus; the dentate gyrus, however, was not damaged.

Three minutes of ischaemia produced changes in the binding of [3H]‐quinuclidinylbenzilate ([3H]‐QNB), [3H]‐muscimol, and [3H]‐MK‐801 in various brain regions, as determined autoradiographically. In contrast, [3H]‐cyclohexyladenosine ([3H]‐CHA) and [3H]‐PN200‐110 ([3H]‐isradipine) binding in the brain was unaltered.

Ten minutes of ischaemia resulted in a major loss of neurotransmitter receptors, especially in the hippocampus. The substantia nigra showed a significant reduction in [3H]‐CHA binding, whereas the striatum, which was morphologically damaged, showed no significant changes in any of the neurotransmitter receptors examined.

6 The results demonstrated that long‐term survival after transient cerebral ischaemia produced alterations in neurotransmitter receptors, especially in the hippocampal formation, where considerable shrinkage was noted. These results also suggest that the hippocampal damage was not static, but progressive.
Effects of propofol and enflurane on action potentials, membrane currents and contraction of guinea‐pig isolated ventricular myocytes
Authors: Puttick R.M. , Terrar D.A.
Published: July 2012

The effects of two general anaesthetics, propofol and enflurane, on electrical activity and contractions were investigated in single myocytes isolated from guinea‐pig ventricles.

Propofol and enflurane depressed the plateau and shortened the duration of action potentials.

Under voltage‐clamp conditions, propofol and enflurane reduced the amplitude of inward calcium current and of additional inward current activated by cytosolic calcium.

Contractions (measured with an optical technique) accompanying either action potentials or second inward currents (in response to depolarizations to 0 mV) were reduced by both anaesthetics. The mechanisms for calcium entry during contractions accompanying pulses to positive potentials such as + 60 mV are thought to differ from those accompanying second inward currents which are evoked by pulses from −40 to 0 mV. Enflurane enhanced the amplitudes of contractions accompanying pulses to positive potentials; in contrast these contractions were depressed by propofol.

In experiments where recovery processes were investigated by use of pairs of voltage‐clamp pulses with a variable interval between them, enflurane but not propofol slowed the recovery of contractions and calcium‐activated ‘tail’ currents. These observations are consistent with the hypothesis that enflurane may impair calcium handling by the sarcoplasmic reticulum whereas propofol has little, if any, effect at this site.

6 In conclusion, the actions of propofol and enflurane on second inward currents contribute to their effects on action potentials and contraction. The negative inotropic effect of both anaesthetics may result partly from reduced calcium influx to trigger contraction, and for enflurane, partly from an impairment of calcium handling by the sarcoplasmic reticulum.
Effects of the δ‐opioid receptor antagonist naltrindole on antinociceptive responses to selective δ‐agonists in post‐weanling rats
Authors: Crook T.J. , Kitchen I. , Hill R.G.
Published: July 2012

Antagonism, by the selective δ‐opioid receptor antagonist naltrindole, of the antinociceptive effects of [d‐Pen2, d‐Pen5] enkephalin (DPDPE), [d‐Ser2, Leu5, Thr6] enkephalin (DSLET) and d‐Ala2 deltorphin I (DELT I) has been studied in 25 day old rats.

Antinociception was measured by the 50°C tail immersion test following i.p. administration of agonists and/or antagonists.

Dose‐related antinociception was observed with DPDPE, DSLET and DELT I and ED75 doses were computed (0.66 mg kg−1, 0.65 mg kg−1, 0.032 mg kg−1 respectively) and used for antagonism studies.

Naltrindole (0.01 mg kg−1) significantly attenuated the antinociceptive effects of DPDPE and DSLET with 0.1 mg kg−1 producing complete reversal of the effects of the ED75 dose. In contrast, naltrindole at 0.01 and 0.1 mg kg−1 did not alter antinociceptive responses to DELT I. Naltrindole at 1 mg kg−1 significantly attenuated DELT I antinociception.

Naloxone (1 mg kg−1) produced equivalent degrees of antagonism of the antinociceptive effects of DPDPE, DSLET and DELT I. ICI 174,864 (1 mg kg−1) also antagonized antinociception with a differential degree of attenuation (DSLET > DPDPE > DELT I).

6 Naltrindole (1 mg kg−1) had no effect on the antinociception induced by the selective μ‐agonist alfentanil (60 μgkg−1). Naltrindole, naloxone or ICI 174,864 had no effect on nociceptive latencies.

7 The differential antagonism by naltrindole of the effects of three selective δ‐agonists suggests δ‐receptor heterogeneity. Further, the lower sensitivity of response to DELT I suggests that this agent may exert its antinociceptive effects at a different δ receptor subtype from DPDPE or DSLET.
Inhibition by phosphoramidon of the regional haemodynamic effects of proendothelin−2 and −3 in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Bennett T.
Published: July 2012

Regional haemodynamic studies were carried out in conscious, Long Evans rats, chronically‐instrumented with pulsed Doppler flow probes and intravascular catheters.

In the first experiment, proendothelin‐2 and −3 (0.1 and 1.0 nmol kg−1, i.v. boluses) were found to cause dose‐dependent pressor, bradycardic, and renal and, particularly, mesenteric vasoconstrictor effects. The hindquarters showed an initial vasodilatation (which was not dose‐dependent) followed by a vasoconstriction (which was dose‐related). The pressor and renal and mesenteric vasoconstrictor effects of proendothelin‐3 were greater than those of proendothelin‐2.

In the second experiment, it was demonstrated that phosphoramidon (10 μmol kg−1, i.v. bolus) abolished the pressor, bradycardic, and hindquarters vasoconstrictor effects of proendothelin‐2 (1.0 nmol kg−1), and inhibited significantly the renal and mesenteric vasoconstrictor actions of this peptide. Phosphoramidon had similar effects on the responses to proendothelin‐3 (1.0 nmol kg−1), although a slight pressor effect of this peptide remained in the presence of phosphoramidon.

In the third experiment, it was found that phosphoramidon had no significant effect on the pressor or vasoconstrictor responses to endothelin‐2 or −3 (0.1 nmol kg−1).

Collectively, the results indicate that the haemodynamic effects of proendothelin‐2 and −3 in vivo in conscious rats are probably due to their conversion to endothelin‐2 and −3, respectively, by an enzyme(s) that is inhibited by phosphoramidon. There appears to be no obvious difference between proendothelin‐2, proendothelin‐3 and proendothelin‐1 in this respect.