bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiological effects of OPC‐88117, a new antiarrhythmic agent on papillary muscles and single ventricular myocytes isolated from guinea‐pig hearts
Authors: Toyama Junji , Kodama Itsuo , Honjo Haruo , Kamiya Kaichiro 
Published: July 2012

The effects of OPC‐88117, a new antiarrhythmic agent, on transmembrane action potentials were examined in right ventricular papillary muscles and in single ventricular myocytes isolated from guinea‐pig hearts.
In papillary muscles, OPC‐88117 above 3 × 10−6 m caused a dose‐dependent prolongation of action potential duration (APD).
OPC‐88117 above 3 × 10−5 m caused a significant decrease in the maximum upstroke velocity () of the action potential without affecting the resting membrane potential. The inhibition of was enhanced at higher stimulation frequencies.
In the presence of OPC‐88117, trains of stimuli at rates ≥ 1.0 Hz led to a use‐dependent inhibition of with rapid onset. The time constant for the recovery of from the use‐dependent block was 456 ms.
The curves relating membrane potential and were shifted by OPC‐88117 to the direction of more negative potentials (9mV at 10−4 M).
In single ventricular myocytes treated with OPC‐88117 (1–3 × 10−4 M), the of test action potentials preceded by conditioning clamp pulses to 0mV was decreased progressively as the clamp pulse duration was prolonged.
These findings suggest that the primary electrophysiological effect of OPC‐88117 on the cardiac muscle cell is prolongation of APD (Class III action) and that at high concentrations, it may also possess a lignocaine‐like sodium channel inhibitory effect (Class I action).
Effects of OPC‐88117, a new antiarrhythmic agent, on the electrophysiological properties of rabbit isolated hearts
Authors: Nezasa Yasuko , Kodama Itsuo , Toyama Junji 
Published: July 2012

Effects of a new antiarrhythmic agent, OPC‐88117, on the conduction properties and excitability of Langendorff‐perfused rabbit hearts were compared with those of lignocaine.
OPC‐88117 above 10−5 m caused a significant prolongation of atrio‐His bundle conduction time (A‐H interval) as well as His bundle‐ventricular conduction time (H‐V interval). Lignocaine above 10−5 m caused a similar prolongation of H‐V interval with a minimum change of A‐H interval. The conduction time from His bundle stimulus to the left ventricle (St‐LV) at a low frequency (1 Hz) was also prolonged by these drugs around 10−4 M.
OPC‐88117 above 3 × 10−6 m prolonged the effective and functional refractory periods of His bundle (ERPHB, FRPHB) as well as the effective refractory period of left ventricular muscle (ERPVM) in a dose‐dependent manner. ERPHB, FRPHB and ERPVM were, shortened by low concentrations of lignocaine (3 × 10−6‐10−5 M), but were prolonged by high concentrations (3 × 10−5‐10−4 M).
Lignocaine (3 × 10−6‐10−4 M) induced an upward displacement of the His bundle refractory curve, indicating a greater intraventricular conduction delay for premature excitation. In experiments with OPC‐88117, such an upward displacement was observed only at 10−4 M.
These results suggest that the primary electrophysiological effect of OPC‐88117 is a lengthening of ventricular refractoriness, and that at high concentrations it may also exert lignocaine‐like inhibition of ventricular conduction.
2‐Chloroadenosine attenuates kainic acid‐induced toxicity within the rat striatum: relationship to release of glutamate and Ca2+ influx
Authors: Arvin B. , Neville L.F. , Pan J. , Roberts P.J. 
Published: July 2012

The mechanism by which 2‐chloroadenosine (2‐chloroado) exerts a neuroprotective action against the excitotoxic effect of kainic acid (KA) when injected into the rat striatum was investigated.
Histological examination two weeks after a single injection of KA (2.2 nmol) into rat striatum revealed widespread neuronal damage. Co‐injection of 2‐chloroado (6–25 nmol) with the neurotoxin afforded dose‐dependent neuroprotection. This effect was reversed by administration of an equimolar concentration of the adenosine receptor antagonist theophylline.
Both K+ (30 mM) and KA (1 mM) enhanced the release of endogenous glutamate from guinea‐pig purified cerebrocortical synaptosomes in a predominantly (approximately 70%) Ca2+‐dependent manner. 2‐Chloroado (10 nM‐1 μm) inhibited the release of glutamate evoked by both KA and K+. These effects were partially reversed by the selective A1‐adenosine receptor antagonist 8‐cyclopentyltheophylline (CPT) (1 μm).
Crude rat cortical synaptosomes were loaded with the fluorescent calcium indicator quin‐2 and Ca2+ influx monitored following two successive depolarising stimuli (30 mM K+; ′S1′ and ′S2′). 2‐Chloroado (10 nM‐1 μm) produced a dose‐dependent reduction in the S2:S1 ratio when added before the S2 period of stimulation. This effect was reversed by 1 μm theophylline. However, KA (1 mM) failed to enhance Ca2+ influx in the same preparation.
These results suggest that the anti‐excitotoxic action of 2‐chloroado is mediated primarily through a specific presynaptic receptor mechanism involving reduction of transmitter glutamate release, possibly occurring through an inhibition of Ca2+ influx.
A dual model for cardiac arrhythmias: coexistence of re‐entry and abnormal automaticity and effects of antiarrhythmic agents
Authors: Wu Kuei‐Meng , Hunter Thomas , Proakis Anthony 
Published: July 2012

We have developed a dual model for arrhythmia in anaesthetized dogs. The model consists of an inducible re‐entrant atrial tachycardia and spontaneous ventricular ectopies in the same heart.
The model for re‐entrant atrial tachycardia was created by crushing the right atrium longitudinally in the intercaval region and transversely in the front free wall parallel to the atrioventricular groove. Ventricular abnormal automaticity was produced by prior (20 ∼ 24 h) left anterior descending coronary artery occlusion. The ventricular arrhythmia was partially suppressed during rapid pacing‐induced atrial tachycardia and resumed after atrial re‐entry was terminated.
Mapping experiments indicate that the atrial tachycardia was due to circus movement occurring in the tissue around the tricuspid ring. This re‐entrant circuit was identical to that induced in the model created by the incision method.
Clofilium (0.75 mg kg−1, n = 5) increased the cycle length of atrial re‐entry by 14 ± 4% from 139 ± 12 to 159 ± 18 ms (P < 0.05). Flecainide (1.8 ± 0.9 mg kg−1, n = 5) prolonged the cycle length of the tachycardia by 114 ± 57% from 158 ± 11 to 332 ± 66 ms (P < 0.05).
Both drugs terminated the atrial arrhythmia, but re‐entry could be reinduced only in flecainide‐treated dogs. Flecainide reduced ventricular ectopies by 89 ± 19%, whereas clofilium did not change ventricular abnormal automaticity or maximum pacing cycle length that is necessary to overdrive the ventricle fully.
These data indicate that the dual model provides coexisting arrhythmias of different mechanisms in the same heart and that Class I and Class III anti‐arrhythmic drugs may be differentiated from each other by the distinct patterns of pharmacological activities produced in this test system.
Vasopressin and the pathogenesis of chronic renal failure
Authors: Brooks David P. , Solleveld Henk A. , Contino Lisa C. 
Published: July 2012

Partial (5/6) renal ablation was performed in Long Evans rats treated with vehicle or a vasopressin V1‐receptor antagonist, in control Long Evans rats, and in homozygous Brattleboro rats which lack endogenous vasopressin.
In control and vasopressin‐blocked Long Evans rats, 3 weeks following partial renal ablation, systolic blood pressure was 215 ± 5 and 199 ± 9 mmHg and, urinary protein excretion was 54 ± 4 and 50 ± 3mg day−1, respectively.
The pressor response to exogenous vasopressin was significantly (P < 0.05) reduced in rats treated with the V1‐receptor antagonist (ED50mmHg 5.0 ± 1.6 vs. 0.09 ± 0.01 μg kg−1).
In control Long Evans and in Brattleboro rats, 3 weeks following renal ablation, systolic blood pressure was 204 ± 10 and 191 ± 7 mmHg, and urinary protein excretion was 97 ± 27 and 71 ± 5 mg day−1, respectively.
Histological examination of the remaining kidney tissue demonstrated significant glomerular hyalinization following renal ablation but no differences between any of the groups.
The data indicate that neither vasopressin nor the urinary concentrating mechanism is likely to be involved in the hypertension and proteinuria associated with partial renal ablation.
Time‐dependent effects of theophylline on myocardial reactive hyperaemias in the anaesthetized dog
Authors: Gidday Jeffrey M. , Esther John W. , Ely Stephen W. , Rubio Rafael , Berne Robert M. 
Published: July 2012

The effects of a loading dose of theophylline (5 mg kg−1 i.v.) on the hyperaemias resulting from short‐term (15 and 30 s) interruptions in coronary blood flow and intracoronary adenosine were studied at given intervals over a 2 h period in the anaesthetized dog.
These hyperaemic responses were affected differently by theophylline and each effect was time‐dependent. The reactive hyperaemic response progressively decreased after drug delivery, reaching 46% of control at 2 h. In contrast, after a maximal attenuation to 23% of control 5 min after theophylline, the hyperaemia resulting from intracoronary adenosine progressively increased over the same period, reaching 64% of control 2 h after the loading dose.
Two‐compartment model results based on plasma theophylline measurements and the time course of theophylline accumulation in pericardial infusates, suggested that complete drug distribution throughout the heart may require at least 20 min following a single intravenous dose.
If it is assumed that theophylline blocks coronary vascular adenosine receptors, these pharmacokinetics are consistent with the time‐dependent pattern of response attenuation we observed for the adenosine‐induced hyperaemias, but they cannot entirely explain the pattern of response attenuation observed for the occlusion‐induced hyperaemias. The continued increase in attenuation of this response after complete drug distribution suggests an additional pharmacodynamic action of theophylline.
We conclude that a single therapeutic dose of theophylline results in distinct time‐dependent pharmacological effects with respect to the ability of the coronary vasculature to dilate in response to temporary interruptions in oxygen supply and in response to exogenously administered adenosine. These effects deserve consideration in both experimental studies in which adenosine antagonists are used to assess adenosine action in vivo, and in clinical practice where theophylline pharmacotherapy for pulmonary disorders is commonplace.
Effects of various neuropeptide Y/peptide YY fragments on electrically‐evoked contractions of the rat vas deferens
Authors: Grundemar Lars , Håkanson Rolf 
Published: July 2012

The effects of various neuropeptide Y (NPY) and peptide YY (PYY) fragments on electrically‐evoked twitches in the rat isolated vas deferens were studied and compared with the effects of full length NPY and PYY. The aim was to identify the shortest NPY/PYY fragments that are capable of suppressing the contractions.
NPY (1–36) and C‐terminal fragments of NPY (from 11–36 to 22–36) suppressed the electrically‐evoked twitches in a concentration‐dependent manner. On the whole there seemed to be a gradual lowering of the pIC50 values with progressive shortening of the NPY fragments (except for fragments 16–36 and 22–36 that had rather high pIC50 values). NPY 23–36, 24–36 and 25–36 suppressed the twitches at high concentrations (3 μm). NPY 26–36 was without effect as were C‐terminal carboxy‐deaminated NPY and glycine extended NPY (NPY‐Gly‐Lys‐Arg).
PYY (1–36) and C‐terminal fragments of PYY (from 11–36 to 23–36) suppressed the electrically‐evoked twitches in a concentration‐dependent manner. PYY 1–36 was more potent than any of the fragments. There was a tendency for shorter fragments to have lower pIC50 values. PYY 24–36 and 25–36 suppressed the twitches at high concentrations (3 μm). PYY 26–36 was without effect.
The findings suggest that the 12 C‐terminal amino acid residues of NPY and PYY are the minimum length required to activate the Y2‐receptor.
The effects of acute and chronic lithium treatment on pilocarpine‐stimulated phosphoinositide hydrolysis in mouse brain in vivo
Authors: Whitworth P. , Heal D.J. , Kendall D.A. 
Published: July 2012

Measurements were made of the in vivo formation of inositol phosphates in the brains of C57/B1/601a mice treated acutely or chronically with lithium chloride (LiCl).
A single injection of LiCl (10 m Equiv kg−1, s.c.) 18 h before death increased the accumulation of [3H]‐inositol phosphates ([3H]‐Ins P's) in the brains of mice injected i.c.v. with [3H]‐myo‐inositol 24 h previously.
Pilocarpine (200 mg kg−1, i.p.) injected 15 min before death further enhanced the formation of [3H]‐Ins P's in the brains of LiCl‐treated, but not saline‐treated, mice. The enhancement due to pilocarpine was abolished by injection of atropine sulphate (10 mg kg−1, i.p.) 10 min earlier.
Chronic (14 days) LiCl feeding produced an accumulation of [3H]‐Ins P's significantly less than that due to a single injection of LiCl, but the response to pilocarpine was markedly greater in mice chronically fed with LiCl when compared with mice acutely injected with LiCl.
Mass measurements of endogenous inositol 1,4,5 triphosphate revealed increases due to pilocarpine and chronic LiCl feeding alone. A combination of the two treatments produced levels greater than either alone.
These results demonstrate that LiCl treatment enhances both basal and pilocarpine‐stimulated inositol phospholipid hydrolysis in vivo and this might be relevant to its therapeutic effects.
CI‐977, a novel and selective agonist for the κ‐opioid receptor
Authors: Hunter J.C. , Leighton G.E. , Meecham K.G. , Boyle S.J. , Horwell D.C. , Rees D.C. , Hughes J. 
Published: July 2012

CI‐977 is a new, nonpeptide κ‐opioid compound that has been synthesized and its pharmacological properties determined in a series of in vitro and in vivo rodent models.
In radioligand binding studies, with guinea‐pig forebrain homogenates, CI‐977 bound with high affinity to [3H]‐U69593‐labelled κ‐sites (Ki = 0.11 nm) but with low affinity to [3H]‐[d‐Ala2, MePhe4, Glyol5] enkephalin (DAMGO) labelled μ‐sites (Ki = 99nm) and [3H]‐[d‐Pen2,5]enkephalin (DPDPE) labelled δ‐sites (Ki = 1.04 μm). CI‐977 also bound with negligible affinity to [3H]‐(+)‐3‐(1‐propyl‐3‐piperidinyl)phenol (3‐PPP) labelled σ‐sites (Ki = 1.9 μm) and [3H]‐1‐(1‐[2‐thienyl]cyclohexyl)piperidine (TCP) labelled PCP sites (Ki > 10 μm).
CI‐977 produced a potent inhibition of the electrically‐evoked contractions of the guinea‐pig ileum and rabbit vas deferens with IC50 values of 0.087 nM and 3.3 nM, respectively. The pKB values for the opioid antagonists naloxone (7.6) and norbinaltorphimine (10.5) supported the κ nature of the CI‐977‐mediated effects in the smooth muscle assays.
CI‐977 was a potent antinociceptive agent against a mechanical noxious stimulus in rats following intravenous, intramuscular, subcutaneous and oral administration. CI‐977 was also effective against mechanical and chemical noxious stimuli in the mouse but ineffective against a thermal stimulus. The antinociceptive effects produced by CI‐977 were completely reversed by naloxone (1 mg kg−1, s.c.).
At doses close to those required to produce antinociception, CI‐977 also caused a naloxone‐reversible diuresis and inhibition of locomotor activity.
The in vitro and in vivo pharmacological profile of CI‐977 demonstrates that it is a potent and selective agonist at the κ‐opioid receptor.
Kinins and peritoneal exudates induced by carrageenin and zymosan in rats
Authors: Damas Jacques , Bourdon Victor , Remacle‐Volon Gaby , Adam Albert 
Published: July 2012

Kinins were measured by a radioimmunoassay in the inflammatory exudates induced by carrageenin or zymosan in the peritoneal cavity of normal Wistar rats and of kininogen‐deficient Brown Norway rats.
After administration of carrageenin to normal rats, levels of immunoreactive kinins showed a single peak during the first two hours and then decreased. The presence of kinins preceded and accompanied the exudation of 125I‐labelled albumin. Kinins were identified as bradykinin by chromatography.
Captopril, an inhibitor of kininase 2, increased the level of kinins and the volume of the exudates after carrageenin treatment. In Brown Norway rats, the volume of the exudates was small and contained little or undetectable amounts of immunoreactive kinins.
During zymosan‐induced peritonitis, the exudates were devoid of immunoreactive kinins in both species. The volume of the exudates was larger in kininogen‐deficient rats than in normal rats.
We conclude that in rats, the kinin system is a major factor responsible for the development of the inflammatory reactions induced by carrageenin, but is not involved in the reactions induced by zymosan.
5‐HT1A agonists increase and 5‐HT3 agonists decrease acetylcholine efflux from the cerebral cortex of freely‐moving guinea‐pigs
Authors: Bianchi Clementina , Siniscalchi Anna , Beani Lorenzo 
Published: July 2012

The influence of 5‐hydroxytryptamine1A (5‐HT1A), 5‐HT2 and 5‐HT3 agonists and antagonists on acetylcholine (ACh) release from the cerebral cortex was studied in freely moving guinea‐pigs.
8‐Hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT, 0.01–1 mg kg−1, s.c.) caused the 5‐HT syndrome and dose‐dependently increased ACh release. Ru 24969 (1–10 mg kg−1, s.c.) shared the same effects, but it was less potent. (−)‐Propranolol (5 mg kg−1) and metitepine (2 mg kg−1) prevented these behavioural and neurochemical responses.
(±)‐1(4‐Iodo‐2,5‐dimethoxyphenyl)2‐aminopropane (DOI) up to 2 mg kg−1 did not modify ACh release and ketanserin (0.5 mg kg−1) was ineffective on 5‐HT‐induced changes of ACh outflow.
2‐Methyl‐5‐HT (500 μg, i.c.v.) and 5‐HT (500 μg, i.c.v.) plus metitepine (2 mg kg−1, s.c.) inhibited the gross behaviour and ACh release. ICS 205–930 (0.5 mg kg−1) prevented these responses.
2‐Methyl‐5‐HT, up to 10 μmoll−1, and 8‐OH‐DPAT, up to 0.1 μmoll−1, (like 5‐HT) did not change [3H]‐choline efflux from cerebral cortex slices.
These results suggest that exogenous 5‐HT and related selective agonists modulate guinea‐pig cortical cholinergic structures through 5‐HT1A and 5‐HT3 receptors. The stimulation of 5‐HT1A autoreceptors may lead to disinhibition of the cholinergic cells, tonically inhibited by the tryptaminergic control. Conversely, the stimulation of 5‐HT3 receptors inhibits ACh release, possibly through an interneurone. No direct 5‐HT modulation of the cholinergic nerve endings was found.
Inhibition of nicotine‐induced relaxation of the bovine retractor penis muscle by compounds known to have ganglion‐blocking properties
Authors: Alaranta Sakari , Klinge Erik , Pätsi Tuomo , Sjöstrand Nils O. 
Published: July 2012

The relative potency in blocking the nicotine‐induced relaxation of the bovine retractor penis muscle (BRP) was estimated for 12 drugs known to have ganglion‐blocking properties.
The order of potency of the drugs studied was mecamylamine > chlorisondamine > pentolinium > propantheline > (+)‐tubocurarine > hexamethonium > emepronium > tetraethylammonium > glycopyrrolate > decamethonium > butylscopolamine > scopolamine.
The results conform well to those obtained with other pharmacological methods used for the estimation of ganglion‐blocking activity.
It is concluded that blockade of the nicotinic relaxation of the BRP can be used as an alternative method for quantitative assessment of ganglion‐blocking activity.
Advantages of this technique are that it discriminates well between antinicotinic and antimuscarinic activity and that it satisfies most or all ethical and economical demands.
It is also possible that this method has certain value in predicting whether a drug has enough ganglion‐blocking activity to be likely to cause impotence.
The effects of Bay K 8644 and nifedipine on the responses of rat urinary bladder to electrical field stimulation, β,γ‐methylene ATP and acetylcholine
Authors: Bo Xuenong , Burnstock Geoffrey 
Published: July 2012

Bay K 8644 (0.33 nm to 1 μm) greatly increased the contractions of rat urinary bladder detrusor muscle induced by β,γ‐methylene ATP (β,γ‐MeATP, 10 μm) and by electrical field stimulation of the purinergic component (the cholinergic response was blocked by atropine).
The contractions induced by acetylcholine (ACh, 10 μm) and by electrical field stimulation of the cholinergic component (the purinergic response was blocked following desensitization by α,β‐MeATP) were also potentiated by Bay K 8644, although to a lesser extent than the purinergic responses.
Nifedipine (1 nm to 3.3 μm) inhibited all the contractions induced by β,γ‐MeATP, ACh and electrical field stimulation. However, while the responses to β,γ‐MeATP and electrical field stimulation of the purinergic component were almost abolished, a substantial proportion of the responses to ACh and electrical field stimulation of the cholinergic component were nifedipine resistant.
The concentration‐effect curves for the potentiation by Bay K 8644 of the responses to β,γ‐MeATP, ACh and electrical field stimulation were shifted to the right by nifedipine (10 nm). At concentrations greater than 1 μm, Bay K 8644 inhibited contraction.
It is concluded that voltage‐sensitive calcium channels play an important role in the excitatory mechanical action of P2x‐purinoceptor‐mediated purinergic responses in the rat urinary bladder, while cholinergic‐mediated responses are less dependent on such channels.
Effects of antiarrhythmic agents classified as class III group on ischaemia‐induced myocardial damage in canine hearts
Authors: Sano T. , Sugiyama S. , Taki K. , Hanaki Y. , Shimada Y. , Ozawa T. 
Published: July 2012

The cardioprotective effects of antiarrhythmic agents classified as class III, amiodarone, sotalol and E‐4031, were investigated in anaesthetized dogs.
The left anterior descending coronary artery was occluded for 2 h.
Heart mitochondria were prepared from both the ischaemic and non‐ischaemic areas, and their function was estimated polarographically.
Activities of the lysosmal enzymes, N‐acetyl‐β‐glucosaminidase and β‐glucuronidase, were measured in each fraction.
Two hour occlusion induced ventricular arrhythmias, and amiodarone, sotalol and E‐4031 greatly suppressed the development of arrhythmias.
Amiodarone, sotalol and E‐4031 significantly protected mitochondria against ischaemia, and prevented ischaemia‐induced leakage of lysosomal enzymes.
Antiarrhythmic agents classified as class III show cardioprotective effects, which might participate in their antiarrhythmic effect.