bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of metoprolol and dazmegrel, alone and in combination, on arrhythmias induced by coronary artery occlusion in conscious rats
Authors: Leprán Istvan , Parratt James R. , Szekeres Laszlo , Wainwright Cherry L. 
Published: July 2012

The effects of metoprolol and the thromboxane synthetase inhibitor dazmegrel, alone and in combination, were examined in a model of coronary artery occlusion in conscious rats.
In a dose (2 mg kg−1), intravenously, that resulted in a marked bradycardia (of 50–80 beats min−1) metoprolol did not influence the incidence or severity of the ventricular arrhythmias that occur in the first 20 min following occlusion, nor did it improve survival (assessed at both 20 min and 16 h). In a dose (5 mg kg−1), intravenously, that in another conscious rat model involving tissue hypoperfusion inhibited thromboxane production, dazmegrel also did not modify ischaemic arrhythmias or survival.
In contrast, metoprolol and dazmegrel (2 mg kg−1 and 5 mg kg−1 i.v.) when given together prior to coronary artery occlusion, produced a significant reduction in mortality both at 20 min and 16 h (e.g. from 60–75% in the control, metoprolol alone and dazmegrel alone groups and only 25% in the combined‐treatment group). This was due to a decrease in the incidence of terminal ventricular fibrillation.
The results suggest that a combination of a β‐adrenoceptor blocking drug with a drug that inhibits thromboxane synthesis may offer more protection against ischaemia‐induced ventricular fibrillation than either drug used alone. They suggest a role for both catecholamines and thromboxane in the genesis of ischaemia‐induced ventricular fibrillation.
Electrophysiological effects of propafenone in untreated and propafenone‐pretreated guinea‐pig atrial and ventricular muscle fibres
Authors: Delgado C. , Tamargo J. , Tejerina T. 
Published: July 2012

The electrophysiological effects of propafenone (10−7 to 10−4 M) were studied on guinea‐pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 10 mg kg−1, for 28 days.
In untreated atria propafenone produced a dose‐dependent decrease in the rate and maximum following frequency, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline.
In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and Vmax, reduced the resting membrane potential and prolonged the action potential duration (APD) and the effective refractory period, lengthening the effective refractory period relative to APD.
Propafenone depressed the amplitude and Vmax and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K‐depolarized papillary muscles.
Pretreatment with propafenone reduced atrial rate, but did not modify the action potential characteristics compared to the values obtained in untreated atria. Further addition of propafenone produced similar but more marked changes in untreated atria.
In ventricular muscle fibres pretreated with 3 mg kg−1, action potential characteristics before and after further addition of propafenone were similar to those obtained in untreated fibres. However, muscles pretreated with 10 mg kg−1 exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg−1; further addition of propafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments.
It is concluded that even though the effects of propafenone are similar to those of quinidine (class I antiarrhythmic), it also exhibited class II and class IV actions. In pretreated animals a prolongation of the APD (class III action) could also be involved in the antiarrhythmic effects of the drug.
Electrophysiological mechanisms for the antiarrhythmic action of mexiletine on digitalis‐, reperfusion‐ and reoxygenation‐induced arrhythmias
Authors: Amerini Sandra , Carbonin Pierugo , Cerbai Elisabetta , Giotti Alberto , Mugelli Alessandro , Pahor Marco 
Published: July 2012

The antiarrhythmic potency of mexiletine was evaluated on three groups of guinea‐pig isolated hearts. Arrhythmias were induced (a) with digitalis intoxication, (b) with hypoxia followed by reoxygenation and (c) with ischaemia followed by reperfusion.
Mexiletine 10 μM was found to be very effective against all three types of arrhythmias in all three groups.
The electrophysiological effects of mexiletine were then studied on sheep cardiac Purkinje fibres manifesting oscillatory afterpotentials and triggered automaticity induced by barium or strophanthidin.
Mexiletine 10 μM consistently decreased the amplitude of oscillatory afterpotentials and blocked subsequent triggered activity in sheep Purkinje fibres.
In contrast, mexiletine 10 μM had no significant effect on in normal, barium‐ and strophanthidin‐treated preparations.
The results are discussed in relation to the mechanisms of antiarrhythmic action of mexiletine.
Excitatory neurotensin receptors on the smooth muscle of the rat fundus: possible implications in gastric motility
Authors: Huidobro‐Toro J. Pablo , Kullak Andreas 
Published: July 2012

Picomolar concentrations of neurotensin caused concentration‐dependent contractions of the longitudinal musculature of the fundus of the rat stomach. The EC50 of neurotensin was approximately 1.5 nm. On a molar basis neurotensin was about 5–10 times more potent than 5‐hydroxytryptamine (5‐HT) and approximately 80 times as active as acetylcholine in producing similar contractions.
Studies with structurally related peptides indicated that whereas the carboxy terminal portion of neurotensin was essential for biological activity, a substantial part of its amino terminus end could be removed without affecting its potency. The EC50 for the neurotensin fragment 8–13 was identical to that of neurotensin, however its 1–8 or 1–11 fragments were completely inactive.
Tetrodotoxin did not modify the potency of neurotensin or structurally related analogues suggesting that the neurotensin receptor is probably located on the smooth muscle membrane. In addition, the potency of neurotensin in contracting the fundus was not modified by pretreatment with atropine, methysergide or diphenhydramine.
Fade to the contractile response of neurotensin was followed by the development of tachyphylaxis; desensitization was concentration‐dependent and characterized by a shift in the agonist concentration‐response curve to the right and downwards. Desensitization with a priming concentration of neurotensin (approx. EC50) caused a substantial blockade of its excitability.
There was cross‐desensitization between neurotensin and the contractile activity of neurotensin 8–13 or xenopsin, but not with angiotensin II, bradykinin, substance P, acetylcholine, 5‐HT or histamine.
Pretreatment of the fundus strip with verapamil 0.3–1 μm antagonized in a concentration‐dependent fashion the neurotensin‐induced contractions but not the muscular contractions caused by acetylcholine.
It is concluded that neurotensin activates a specific excitatory receptor probably located on the cell membrane of the smooth muscles of the rat fundus. In addition, we suggest that this receptor is somehow related to a voltage‐dependent calcium channel, sensitive to verapamil.
Modulation of [3H]‐dopamine released by different frequencies of stimulation from rabbit retina
Authors: Dubocovich Margarita L. , Hensler Julie G. 
Published: July 2012

Rabbit retinal pieces were incubated with [3H]‐dopamine and superfused with Krebs solution. Calcium‐dependent tritium release was elicited twice within each experiment by electrical field stimulation (360 pulses, 2 ms, 20 mA) at frequencies of 1 Hz, 3 Hz, and 6 Hz. The evoked release of [3H]‐dopamine for the first period of stimulation (S1) was 2.09 ± 0.23% (n = 5) at 1 Hz and was of similar magnitude at all other frequencies of stimulation employed.
The D2‐dopamine receptor agonist, LY 171555 (quinpirole HCl; 0.01‐1 μM) added to the superfusion medium before the second period of stimulation, inhibited the calcium‐dependent release of [3H]‐dopamine in a concentration‐dependent manner, and was more potent the lower the stimulation frequency. The isomer of quinpirole, LY 181990 (0.01‐1 μM) did not inhibit the stimulation‐evoked overflow of tritium, regardless of concentration or stimulation frequency.
The stereoisomers of the D2‐dopamine receptor antagonist sulpiride (0.01–3 μM) increased the calcium‐dependent release of [3H]‐dopamine in a concentration‐dependent manner, being more potent the higher the frequency of stimulation. S‐sulpiride was more potent than R‐sulpiride at all stimulation frequencies. The inhibitory effect of quinpirole was stereoselectively antagonized by sulpiride, but not by LY 181990. The α‐adrenoceptor antagonist phentolamine (1 μM) did not modify the quinpirole‐induced inhibition of [3H]‐dopamine release.
When the synaptic concentration of dopamine was increased by the presence of the dopamine uptake inhibitor nomifensine (3 μM), the potency of the agonist quinpirole in inhibiting the release of [3H]‐dopamine elicited by field stimulation at 1 Hz (180 pulses) was decreased. In contrast, the potency of S‐sulpiride in enhancing the evoked release of [3H]‐dopamine was increased when nomifensine was present in the superfusion medium.
Picomolar concentrations of the hormone melatonin (0.1–10 nM) inhibited the calcium‐dependent release of [3H]‐dopamine from rabbit retina with the same potency regardless of the frequency of stimulation applied (1 Hz, 3 Hz or 6 Hz).
The potency of D2‐dopamine receptor agonists and antagonists in modifying [3H]‐dopamine release from rabbit retina appears to depend on the synaptic concentration of dopamine which is altered by the frequency of stimulation, and by the dopamine uptake inhibitor nomifensine. At lower synaptic concentrations of the transmitter dopamine the receptor agonist quinpirole was more potent in inhibiting [3H]‐dopamine release, while the receptor antagonist sulpiride was more potent in enhancing [3H]‐dopamine release the higher the synaptic concentration of dopamine. In contrast, the potency of melatonin in inhibiting [3H]‐dopamine release was not altered by the frequency of stimulation, or by frequency‐dependent changes in the biophase concentration cf the transmitter dopamine.
The effects of BRL 34915 and nicorandil on electrical and mechanical activity and on 86Rb efflux in rat blood vessels
Authors: Weir Sheila W. , Weston A.H. 
Published: July 2012

The effects of the antihypertensive agent BRL 34915 on a variety of responses of the aorta and portal vein of the rat have been compared with those of nicorandil.
On portal vein, BRL 34915 (0.01–50 × 10−6 M) and nicorandil (0.1–500 × 10−6 M) abolished spontaneous mechanical activity and reduced mechanical responses to noradrenaline (0.1–100 × 10−6 M) and K+ (5–20 × 10−3 M) but had little inhibitory effect on responses to K+ (40–80 × 10−3 M). The onset of the reduced responses to noradrenaline was delayed by both agents.
On portal vein, BRL 34915 (0.1–50 × 10−6 M) and nicorandil (0.5–500 × 10−6 M) abolished spontaneous electrical and mechanical activity, hyperpolarized the smooth muscle cells to a value close to their calculated potassium equilibrium potential and increased the 86Rb efflux rate coefficient.
On aorta, BRL34915 (0.2‐0.8 × 10−6 M) and nicorandil (8–32 × 10−6 M) reduced mechanical responses to noradrenaline (0.001‐1 × 10−6 M) and K+ (5–20 × 10−3 M) but had little inhibitory effect on responses to K+ (40–80 × 10−3 M).
On aorta, BRL 34915 (0.2‐0.8 × 10−6 M) increased the 86Rb efflux rate coefficient whereas nicorandil (8–32 × 10−6 M) was without effect.
It is concluded that the inhibitory actions of BRL 34915 on both aorta and portal vein result from the opening of membrane potassium channels. The resulting membrane shunt inhibits the effects of excitatory agents. The inhibitory effects of nicorandil result from a combination of the opening of potassium channels together with an additional, undefined action.
Adenosine‐modulation of cholinergic and non‐adrenergic non‐cholinergic neurotransmission in the rabbit iris sphincter
Authors: Gustafsson Lars E. , Wiklund N. Peter 
Published: July 2012

The characteristics of smooth muscle responses to transmural nerve stimulation in the rabbit iris sphincter were examined.
Transmural stimulation elicited a composite contractile response that could be divided in two phases. Atropine abolished the phase I contraction and inhibited the phase II contraction. The atropine‐resistant component of the phase II contraction which was unaltered by sympathetic denervation, was mimicked by substance P and abolished by capsaicin.
Adenosine inhibited the phase I contraction. The adenosine analogue L‐N6‐phenylisopropyladenosine (L‐PIA) was more potent than 5′‐N‐ethylcarboxamideadenosine (NECA) in mimicking this adenosine effect.
By contrast, adenosine enhanced the phase II contraction in non‐pretreated preparations, as well as the atropine‐resistant capsaicin‐sensitive part of this contraction. Here, NECA was more potent than L‐PIA.
Adenosine, NECA, L‐PIA and D‐PIA also enhanced the atropine‐sensitive component of the phase II contraction, as well as the contractile response to exogenous acetylcholine or carbachol, but not to exogenous substance P. In this respect, L‐PIA was the most powerful adenosine analogue with at least 10 fold higher potency than D‐PIA.
The adenosine antagonist 8‐p‐sulphophenyltheophylline enhanced the phase I contraction and decreased the capsaicin‐sensitive non‐adrenergic non‐cholinergic component of the phase II contraction.
We conclude that adenosine inhibited the nerve‐induced cholinergic twitch (phase I) responses by action at prejunctional A1‐receptors. Furthermore, adenosine enhanced the phase II contractile responses via postjunctional enhancement of the cholinergic transmission by action at A1‐receptors, and via enhancement of the non‐adrenergic non‐cholinergic transmission by action at presumably prejunctional A2 receptors.
Effects of calcium antagonistic drugs on the electrical activity of rabbit sino‐atrial node
Authors: Molyvdas Paschalis‐Adam , Sperelakis Nick 
Published: July 2012

The effects of several calcium antagonistic drugs (slow channel blockers), mesudipine, FR‐34235 (nilvadipine), nifedipine, and verapamil, were compared on the naturally‐occurring slow action potentials (APs) of the isolated spontaneously‐contracting sinoatrial (SA)‐node of the rabbit.
Mesudipine, at 1 × 10−8 M, had little or no effect on the AP parameters and beating frequency. At 1 × 10−7 M, mesudipine depressed the amplitude, + V̇max and frequency of the APs. A higher concentration of mesudipine (3 × 10−7 M) completely blocked the slow APs.
The concentration of FR‐34235 required for 50% depression of V̇max was 3 × 10−8 M, and complete block required 1 × 10−7 M.
The verapamil and nifedipine concentrations required for complete block were 1 × 10−6 M and 1 × 10−7 M, respectively.
The cells blocked by these drugs were depolarized to about − 40 mV.
Cells blocked and depolarized by the drugs responded to intensive field stimulation with a transient after‐hyperpolarization, followed by damped oscillations.
When [Ca]o was elevated from 1.8 mM to 5.4 mM, full block required a higher concentration of mesudipine (1 × 10−6 M) and FR‐34235 (1 × 10−6 M).
The order of potency of the drugs tested was: nifedipine = FR‐34235 > mesudipine > verapamil.
The effects of mesudipine, FR‐34235, and nifedipine were easily reversible upon washout for 10 min, whereas those of verapamil required longer periods.
The results indicate that the slow channel blockers, mesudipine, FR‐34235, nifedipine, and verapamil depress the APs and automaticity of the SA‐node.
Positive inotropic action of saponins on isolated atrial and papillary muscles from the guinea‐pig
Authors: Enomoto Yoshikazu , Ito Katsuaki , Kawagoe Yasushi , Mono Yasunori , Yamasaki Yasundo 
Published: July 2012

The effects of several saponins of animal and plant origin on the contractile activity of atrial and papillary muscles of the guinea‐pig were tested. In a concentration of 1 × 10−5 M, holothurin‐A (HL‐A), holothurin‐B, echinoside‐A, echinoside‐B and sakuraso‐saponin (Saku) exhibited positive inotropic and chronotropic actions whereas desacyl‐jego‐saponin and ginsenoside‐Rd did not.
Saponins having a positive inotropic action caused haemolysis of rabbit erythrocytes whereas those without inotropic action did not cause haemolysis.
The positive inotropic action of saponins was not affected by practolol, chlorpheniramine, cimetidine and indomethacin.
Verapamil (10−6 M) inhibited the inotropic actions due to HL‐A and isoprenaline (10−8 M) to the same extent but had a small efect on those due to ouabain (10−7 M).
In high K+ (30 mM K+) medium where the action potential and the contraction were depressed, HL‐A, Saku and isoprenaline restored the action potential and the contraction of the ‘slow response’ type whereas ouabain failed to do so.
In normal medium HL‐A and Saku reduced the resting membrane potential by 15–20 mV.
These results suggest that modification of the Ca channel is involved in the positive inotropic action of saponins.
Stereoselective accumulation of hydroxylated metabolites of amphetamine in rat striatum and hypothalamus
Authors: Dougan D.F.H. , Duffield A.M. , Duffield P.H. , Wade D.N. 
Published: July 2012

The stereoselective accumulation of α‐methyl‐p‐tyramine (AMPT) and α‐methyl‐p‐octopamine (AMPO) in rat striatum and hypothalamus after acute and chronic administration of the (+)‐and (−)‐isomers of amphetamine (Amphet) and the acute administration of (+)‐ and (−)‐AMPT has been investigated by chemical ionization gas chromatography mass spectrometry (c.i.g.c.m.s.).
Two h after the administration of (+)‐ or (−)‐AMPT (5 mg kg−1 i.p.), the concentrations of the isomers in striatal tissue were approximately equal; 18 h later, the concentration of the (+)‐isomer was 10 times that of the (−)‐isomer.
The concentrations of AMPO in the striatum and hypothalamus 20 h after administration of (+)‐AMPT were 68 ng g−1 and 484 ng g−1 respectively. After the administration of the (−)‐isomer of AMPT, small quantities of AMPO were detected in both brain areas.
Twenty h after the last of 7 daily injections of (+)‐Amphet (5 mg kg−1, i.p.), the concentration of AMPO in the hypothalamus was 5.4 times the concentration at 20 h after one injection. In the striatum, the corresponding ratio for AMPO was 3.5 and for AMPT was 2.5.
These data indicate that, although both isomers of AMPT formed from Amphet administered systemically, cross the blood brain barrier, the (+)‐isomers AMPT and AMPO are preferentially stored in striatal and hypothalamic aminergic nerve terminals.
The accumulations of AMPT and AMPO in rat striatum and hypothalamus after chronic administration of Amphet demonstrates that these metabolites persist in neuronal storage in these brain areas for days after administration. The half‐lives of (+)‐AMPT and (+)‐AMPO in striatal neuronal storage, calculated from this data, were 1.5 days and 2.5 days, respectively. The corresponding half‐life for hypothalamic (+)‐AMPO was 7 days.
These findings suggest the involvement of accumulated AMPT and AMPO in the development of behavioural augmentation to repeated injections of Amphet (Randrup & Munkvad, 1970).
Pharmacological analysis of the inhibition by pirenzepine and atropine of vagal‐stimulated acid secretion in the isolated stomach of the mouse
Authors: Black J.W. , Shankley N.P. 
Published: July 2012

The muscarinic receptors involved in the vagal stimulation of gastric acid secretion in the mouse isolated stomach assay have been examined by analysing the effects of pirenzepine and atropine on fully‐defined frequency‐effect curves.
Both atropine and pirenzepine produced concentration‐dependent inhibition of vagal‐stimulated acid secretion in a manner consistent with a model describing competitive antagonism of endogenous acetylcholine, which was assumed to be released by vagal stimulation.
The results obtained are quite compatible with the hypothesis that vagal stimulation involves muscarinic receptors which are homogeneous with those previously found on histamine and oxyntic cells in the mouse stomach assay.
These results find no evidence for muscarinic receptor heterogeneity and reinforce the hypothesis that the selectivity of pirenzepine in vivo relative to atropine is due to the loss of atropine into the gastric secretion.
Characterization of prostanoid relaxant/inhibitory receptors (ψ) using a highly selective agonist, TR4979
Authors: Gardiner P.J. 
Published: July 2012

TR4979, an analogue of prostaglandin E1 (PGE1) was evaluated on respiratory and non‐respiratory isolated tissues known to contain heterogeneous or homogeneous populations of the two classes of prostanoid (prostaglandins and thromboxanes) receptors. These receptors are classified as ‘χ’ the contractant/stimulant receptor with ‘χ1,2,3’ being three subdivisions and ‘ψ’ the relaxant/inhibitory receptor(s).
On a respiratory tissue (cat trachea) containing predominantly ‘ψ’‐receptors, TR4979 was 26 times less potent than PGE1 or PGE2.
On other respiratory tissues known to contain mixtures of the ‘χ1,2.3’‐ and ‘ψ’‐receptors (guinea‐pig trachea and lung strip, cat lung strip and human bronchial muscle), TR4979 consistently acted as a potent relaxant whereas PGE2 and to a lesser extent PGE1 had significant contractant activities.
Human pregnant uterus, guinea‐pig and rat pseudo‐pregnant uteri, rat colon and fundic strips and chick ileum are known to contain one or more of the three subclasses of the ‘χ’‐receptor. TR4979 (10−9 − 10−5 M) was inactive on all these tissues whereas all of the reference prostanoids were contractants of varying potencies.
PGE, and histamine‐induced contractions of the guinea‐pig isolated ileum were both noncompetitively antagonized by increasing concentrations of TR4979 suggesting that ‘ψ’‐receptors also exist on this tissue.
TR4979 is a highly selective agonist of prostanoid ‘ψ’ (relaxant/inhibitory)‐receptors which at present have been demonstrated to exist mainly in the lung. This prostaglandin analogue is a useful new selective pharmacological tool for revealing as yet unidentified prostanoid ‘ψ’‐receptors and actions in a wide range of non‐respiratory tissues/organs such as the guinea‐pig ileum.