bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction between atrial natriuretic peptides and angiotensin II in controlling sodium and water excretion in the rat
Authors: Chamienia Andrzej L. , Johns Edward J. 
Published: July 2012

The present study was designed to determine how the natriuretic and diuretic actions of atrial natriuretic peptides were modulated by circulating angiotensin II.In sodium pentobarbitone‐anaesthetized rats, administration of bolus doses of atriopeptin III (1000 ng kg−1) had no effect on blood pressure, renal blood flow, or glomerular filtration rate but caused reversible increases (allP< 0.001) in urine flow, of 53.9 ± 14.4 μl kg−1min−1, absolute sodium excretion, of 13.4 ± 2.9 μmol kg−1min−1and fractional sodium excretion of 3.26 ± 0.74%. Similar effects were seen following a second dose of the atriopeptin III.Following blockade of the renin‐angiotensin system with captopril (900 μg kg−1h−1), control levels of blood pressure and haemodynamics were unchanged but there were significant (allP< 0.001) increases in urine flow, from 39.96 ± 5.05 to 88.70 ± 8.41 μl kg−1min−1, absolute sodium excretion, from 8.35 ± 1.08 to 21.62 ± 1.62 μmol kg−1min−1and fractional sodium excretion, from 3.82 ± 0.23 to 5.34 ± 0.32%. Under these conditions, atriopeptin III‐induced increases in urine flow (110.2 ± 8.7 versus 43.9 ± 6.2 μl kg−1min−1) absolute (24.0 ± 1.8 versus 9.3 ± 1.2 μmol kg−1min−1) and fractional (5.16 ± 0.24 versus 2.08 ± 0.33%) sodium excretions were significantly (P< 0.001) greater.In another group of rats given captopril, angiotensin II at 10 ng kg−1min−1was also infused; this had no effect on blood pressure or renal haemodynamics, but partially restored basal levels of sodium and water excretion to those obtained before captopril. Atriopeptin III reversibly increased urine flow and absolute sodium excretion to the same degree as that obtained without captopril, but fractional sodium excretion was significantly larger than that obtained in the absence of captopril. In rats infused with angiotensin II at 15 ng kg−1min−1together with the captopril the basal levels of fluid output were unchanged, while the magnitudes of the urine flow and sodium excretory responses to atriopeptin III were identical to those obtained before captopril and angiotensin II.In animals subjected to two weeks of a low‐sodium diet, atriopeptin III reversibly increased urine flow, absolute and fractional sodium excretions by between 53% and 74%; these responses were significantly (P< 0.001) smaller than those obtained in sodium replete rats. Administration of atriopeptin III, to low sodium diet rats given captopril, induced excretory responses which were significantly larger than those obtained in the absence of captopril.The findings of this investigation demonstrate that in acute situations, angiotensin II exerts an important modulatory influence on the natriuretic potency of the atrial peptides by attenuating their action on the kidney. Long‐term activation of the renin‐angiotensin system depresses the renal excretory responses to atrial natriuretic peptides but suppression of angiotensin II production only partially restores the responsiveness of the kidney.
The effect of TYB‐3823, a new antiarrhythmic drug, on sodium current in isolated cardiac cells
Authors: Miyamoto Jiro , Hisatome Ichiro , Matsuoka Satoshi , Kosaka Hiromoto , Kurata Yasutaka , Tanaka Yasunori , Nawada Takahiro , Kotake Hiroshi , Mashiba Hiroto , Sato Ryoichi 
Published: July 2012

Sodium current (INa) blockade by TYB‐3823, a newly synthesized antiarrhythmic agent, was investigated in isolated single ventricular myocytes by use of the whole cell patch‐clamp technique.
TYB‐3823 blocked INa under steady‐state conditions (Kd, rest = 500 μm, Kd, i = 4.9 μm), findings consistent with a shift in the steady state INa availability curve to more negative potentials.
TYB‐3823 produced use‐dependent block at 2 Hz in conjunction with increase in pulse duration (5–300 ms), that was markedly enhanced at less negative holding potentials.
The time course of the onset of block was accelerated and the degree of use‐dependent block was decreased at more negative holding potential. The time course of the onset of block was accentuated with enhancing block at more positive holding potentials.
The time course of recovery from use‐dependent block was accelerated at more negative holding potentials but was accentuated at more positive holding potentials.
These results suggest that both tonic block and use‐dependent block of sodium channels in cardiac tissue might result from an interaction of TYB‐3832 with sodium channels mainly in the inactivated channel states and the kinetics of the interaction between drug and receptor may be modulated by the inactivation gate.
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.
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.