bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonism between (–)‐N6‐phenylisopropyl‐adenosine and the calcium channel facilitator Bay K 8644, on guinea‐pig isolated atria
Authors: Caparrotta L. , Fassina G. , Froldi G. , Poja R. 
Published: July 2012

Antagonism between (–)‐N6‐phenylisopropyladenosine (PIA) and the dihydropyridine calcium channel facilitator Bay K 8644 was investigated in guinea‐pig spontaneously beating or electrically driven isolated atria, taken from normal and from reserpine‐treated animals.
PIA (3–100 nm) produced a dose‐dependent decrease in contractile tension and frequency in spontaneously beating atria being more effective in reserpinized preparations.
Bay K 8644 (5–200 nm) produced an increase in contractile tension in both normal and reserpinized atria. In electrically driven left atria the positive inotropic effect of Bay K 8644 was similar to that in spontaneously beating preparations. The positive chronotropic effect of Bay K 8644 was slight and variable.
PIA produced a rightward parallel shift of the concentration‐response curves for the positive inotropic effects of Bay K 8644 in all experimental conditions. In spontaneously beating atria from normal guinea‐pigs, the Schild regression plot was linear and its slope near to unity; pA2 of PIA 8.63 ± 0.05 (IC50 2.35 ± 0.25 nm). In electrically driven atria the antagonism by PIA of the effects of Bay K 8644 was apparently competitive, and the IC50 of PIA was 18.6 ± 0.4 nM. PIA antagonized the positive chronotropic effect of Bay K 8644 in spontaneously beating preparations, both from normal and from reserpine‐treated animals.
Carbachol did not modify the positive inotropic effects of Bay K 8644.
These data indicate that PIA may interact with Bay K 8644 at the level of the slow calcium channels, and may decrease the transmembrane calcium flux into the cell.
Lack of involvement of α‐adrenoceptors in sympathetic neural vasoconstriction in the hindquarters of the rabbit
Authors: Hirst G.D.S. , Lew M.J. 
Published: July 2012

The hypothesis that sympathetic nerves in arterial blood vessels activate excitatory receptors distinct from α‐adrenoceptors was investigated in vivo in the rabbit.
In anaesthetized, ganglion‐blocked rabbits, graded stimulation of the lumbar sympathetic nerve chains caused graded hind limb vasoconstriction. The responses to single pulses and short trains of stimuli were unaffected by benextramine (10 mg kg‐1) and the longer trains were enhanced. Phenoxybenzamine (5 mg kg−1) slightly reduced the responses to short trains of stimuli and did not affect the responses to long trains. The dose‐response curve to intra‐arterial noradrenaline (after β‐adrenoceptor blockade) was shifted rightwards about ten fold by benextramine (10 mg kg−1) and by phenoxybenzamine (5 mg kg−1).
In conscious rabbits the vasoconstriction caused by the nasopharyngeal reflex initiated by smoke inhalation was unaffected by benextramine (10 mg kg−1).
Small mesenteric arteries (<250 μm) taken from untreated rabbits responded to noradrenaline with a threshold concentration of about 1 μm. Similar tissues from benextramine (10 mg kg−1)‐treated rabbits were unresponsive to noradrenaline at concentrations up to 300 μm. However, these tissues were able to respond to potassium and angiotensin II. Aortic ring segments taken from the same rabbits were only about ten fold less sensitive to noradrenaline than segments from control rabbits.
These results are in accord with the hypothesis that sympathetic nerves activate non‐α‐receptors in the vasculature of the rabbit.
A pharmacological study of the rabbit saphenous artery in vitro: a vessel with a large purinergic contractile response to sympathetic nerve stimulation
Authors: Burnstock Geoffrey , Warland Jennifer J.I. 
Published: July 2012

Mechanical responses to transmural electrical stimulation were recorded in isolated transverse ring preparations of rabbit saphenous artery. Electrical stimulation for a period of 1 s produced a rapid monophasic contraction and, for a period of 1 min, a biphasic contraction consisting of a rapid constriction followed by a slower sustained constriction. All contractions were abolished in the presence of tetrodotoxin (1 μg ml−1) or guanethidine (4 μm).
After desensitization of the P2‐purinoceptor with α,β‐methylene ATP, contractions to electrical stimulation for 1 s were reduced significantly at all frequencies tested: responses evoked by stimulation at 4 Hz were usually almost completely inhibited, whereas those evoked by stimulation at 64 Hz were only partially inhibited. On the other hand, in the presence of the α‐adrenoceptor antagonist, prazosin, neurogenic contractions were only partially reduced: at 4 Hz there was no significant reduction in the neurogenic contractions while at 32 and 64 Hz, contractions were reduced by an average of 20 and 28% respectively. Usually all contractions were abolished by a combination of the two drugs.
Prazosin antagonized contractions of the vessel to exogenously applied noradrenaline but not to ATP, whereas desensitization of the P2‐purinoceptor with α,β‐methylene ATP blocked responses to ATP but not those to noradrenaline. The concentration‐response curve to histamine was not affected by treatment of the vessel with prazosin, or after desensitization of the P2‐purinoceptor with α,β‐methylene ATP.
These results suggest that noradrenaline and ATP are co‐released from sympathetic nerves supplying the rabbit saphenous artery, both substances being involved in the mechanical contractions of this tissue. Further, the ratio of ATP to noradrenaline involved in these mechanical contractions is dependent upon the frequency of stimulation, but at all frequencies tested the purinergic component is greater than the adrenergic component.
Electrical changes produced by injury to the rat myocardium in vitro and the protective effects of certain antiarrhythmic drugs
Authors: Northover B.J. 
Published: July 2012

Glass microelectrodes were used to record intracellular electrical activity from rat isolated and superfused atrial myocardium during external electrical stimulation.
After 2 h in normal oxygenated physiological salt solution the muscle was exposed for 30 min to a superfusate simulating the composition of extracellular fluid during myocardial ischaemia (SI). This fluid contained lactate (20 mm), a raised potassium concentration (7 mm), no glucose and a pH lowered to 6.4, and was gassed with N2 in place of O2 (hypoxia).
During SI the diastolic threshold voltage for stimulation increased, the speed of action potential conduction between the right and left atria slowed, and both the effective and functional refractory periods of the right atrium shortened, as did the duration of the right atrial action potential.
The only component of SI which separately caused electrical changes similar to those of the full simulation was hypoxia.
Addition to the superfusate of verapamil (0.5 μg ml−1), sulphinpyrazone (1–20 μg ml−1) or indomethacin (10–20 μg ml−1) attenuated many of the Sl‐induced electrical changes, although indomethacin was much less effective than the other two drugs.
Lowering the calcium concentration of the superfusate from 2 mm to 0.5 mm protected against the Si‐induced electrical changes that were inhibitable with sulphinpyrazone and verapamil.
Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver
Authors: Endo Yasuo 
Published: July 2012

Experiments were done to examine whether the accumulation of 5‐hydroxytryptamine (5‐HT) in the liver is responsible for the hypoglycaemia induced in mice by 5‐hydroxytryptophan (5‐HTP) and lipopolysaccharides (LPS).
(±)‐α‐Monofluoromethyldopa (FMD), a potent irreversible inhibitor of aromatic amino acid decarboxylase, suppressed the 5‐HTP‐induced accumulation of 5‐HT in the liver at a dose of 2 mg kg−1 or more, but potentiated the accumulation at a lower dose of 0.4 mg kg−1. Corresponding to these effects, the hypoglycaemic response was prevented by the higher doses of FMD and potentiated by the lower dose. These contrasting effects of FMD were explicable by the amounts of 5‐HTP entering the liver.
In contrast, FMD did not prevent either the hypoglycaemia or the accumulation of 5‐HT in the liver induced by LPS.
These results further support the hypothesis that the accumulation of 5‐HT in the liver is causally related to the hypoglycaemia induced by 5‐HTP and indicate that the LPS‐induced 5‐HT accumulation in the liver is not derived from stimulation of 5‐HT synthesis. It is still not clear whether the accumulation of 5‐HT in the liver is involved in the hypoglycaemic response to LPS.
Paf‐acether‐induced death in mice: involvement of arachidonate metabolites and β‐adrenoceptors
Authors: Criscuoli Marco , Subissi Alessandro 
Published: July 2012

Intravenous Paf‐acether (Paf, 15–80 μg kg−1) killed conscious Swiss mice in a dose‐dependent manner, without causing platelet aggregation in the lung micro vasculature, or pulmonary oedema.
Propranolol (0.01–10 mg kg−1, i.p.) potentiated the effects of an LD20 of Paf dose‐dependently, while the β1‐adrenoceptor selective antagonist, metoprolol, was three orders of magnitude less potent in this respect. Salbutamol (1 mg kg−1, i.p.) provided complete protection against an LD80 of Paf.
High doses of indomethacin, aspirin, benoxaprofen and FPL 55712 given i.p. failed to inhibit the effects of an LD80 of Paf, while BW 755C (50–100 mg kg−1) exerted a dose‐dependent protection and benzydamine (50 mg kg−1) and nordihydroguaiaretic acid (200 mg kg−1) were partially active. Dexamethasone (1–5 mg kg−1, s.c.) exerted a dose‐dependent protection, when administered at least 4h before Paf.
In mice anaesthetized with urethane, Paf (1–30 μg kg−1) produced hypotension which was not clearly dose‐related. The effects of the highest dose were also tested on the resistance of the lungs to inflation and found to produce bronchoconstriction.
It may be concluded that pharmacological manipulation of β2‐adrenoceptors modulates Paf‐induced death in mice, while arachidonate metabolites of the cyclo‐oxygenase pathway and peptidoleukotrienes do not appear to be involved. However, lipoxygenase products, distinct from peptidoleukotrienes, may play a role in this phenomenon. It is suggested that bronchoconstriction, probably associated with cardiovascular effects, is a major determinant of the acute toxicity of Paf in mice.
Functional and direct binding studies using subtype selective muscarinic receptor antagonists
Authors: Kunysz E.L. , Michel Anton D. , Whiting Roger L. 
Published: July 2012

Muscarinic receptor antagonists were examined in direct binding studies on guinea‐pig cardiac and cortical muscarinic receptors. Pirenzepine, dicyclomine and hexahydroadiphenine were shown to be selective ligands for the putative M1‐muscarinic receptor.
Functional affinity estimates of the muscarinic ligands studied was determined from their ability to inhibit carbachol‐stimulated inositol phosphate (IP) accumulation in guinea‐pig cortical slices.
The affinity estimates for the inhibition of muscarinic agonist‐stimulated IP accumulation were better correlated with affinity estimates obtained from binding studies on the M1 than the M2 muscarinic receptor.
These data provide additional evidence, both from direct binding and functional studies, for the presence of M1 and M2 muscarinic receptor subtypes.
Endothelium‐dependent hyperpolarization of canine coronary smooth muscle
Authors: Feletou Michel , Vanhoutte Paul M. 
Published: July 2012

Experiments were designed to determine whether endothelium‐dependent relaxing factor(s) released by acetylcholine from the canine femoral artery influences the membrane potential of coronary arterial smooth muscle.
The membrane potential was recorded in small canine coronary arteries (internal diameter ≤ 500 μm; without endothelium) by means of intracellular microelectrodes. The organ bath also contained a strip of left descending coronary artery without endothelium in which isometric force was measured to bioassay relaxing factors(s) as well as segments of femoral artery with endothelium, which served as the source of endothelium‐derived relaxing factor(s).
Acetylcholine induced endothelium‐dependent, transient hyperpolarizations and relaxations that were not affected by indomethacin.
Inhibition of the sodium‐potassium pump by ouabain or potassium‐free solution did not inhibit the relaxation to acetylcholine but prevented the corresponding hyperpolarization.
Activation of the sodium‐potassium pump of the smooth muscle cells by readmission of potassium ions after incubation in potassium‐free solution caused relaxation and marked hyperpolarization.
These results suggest that endothelium‐derived relaxing factor(s) induces hyperpolarization of vascular smooth muscle of the canine coronary artery, possibly by activation of sodium‐potassium pumping, but that this effect on the cell membrane may only partially explain endothelium‐dependent relaxations evoked by acetylcholine.
Mechanisms of action of lipoxygenase and cytochrome P‐450‐mono‐oxygenase inhibitors in blocking endothelium‐dependent vasodilatation
Authors: Förstermann Ulrich , Alheid Ute , Frölich Jürgen C. , Mülsch Alexander 
Published: July 2012

Acetylcholine, ionophore A23187 and melittin induced endothelium‐dependent relaxations of preconstricted strips of rabbit aorta. These relaxations are likely to be mediated by endothelium‐derived relaxing factor (EDRF).
Relaxations in response to acetylcholine (1 μm) were inhibited by the following lipoxygenase inhibitors, with the approximate IC50 values indicated in parentheses: gossypol (1.5 μm), nordi‐hydroguairetic acid (NDGA, 5 μm), AA 861 (20 μm), phenidone (30 μm), quercetin (40 μm), BW 755C (300 μm), and piriprost (500 μm); with cirsiliol 50% inhibition was not achieved. Acetylcholine‐induced relaxations were also blocked by the cytochrome P‐450‐mono‐oxygenase inhibitors proadifen (SKF 525A, 4 μm), metyrapone (300 μm), and cimetidine (300 μm); 7,8 benzoflavone had no effect up to 100 μm.
The more potent inhibitors were also tested against relaxations induced by A23187 (0.1 μm) and melittin (1 μm) and produced partial inhibition of these relaxations.
The mechanism of action of the more potent inhibitors was investigated in a bioassay system. EDRF was produced in columns filled with cultured human endothelial cells. The factor was bioassayed with endothelium denuded segments of rabbit femoral artery. When added to effluent of the column, NDGA, AA861, proadifen and metyrapone inhibited the EDRF‐induced vasodilatation, whereas gossypol had no effect. Gossypol, however, blocked EDRF production when infused through the column.
The more potent inhibitors were also tested to determine their effect on purified soluble guanylate cyclase. While gossypol, NDGA and proadifen had no appreciable effects, basal and nitroprusside (50 μm)‐stimulated guanylate cyclase activity was inhibited by AA861 and metyrapone.
These data suggest that many of the above compounds inhibit EDRF by mechanisms other than lipoxygenase‐ or cytochrome P‐450‐mono‐oxygenase inhibition.
Pentoxifylline does not reduce infarct size in a canine model of acute myocardial infarction
Authors: Campbell Colin A. , Clavenna Carl F. , Wynne Joshua , Kloner Robert A. 
Published: July 2012

The effect of the haemorrheological agent pentoxifylline was investigated in a canine model of acute myocardial infarction, induced by occlusion of the left anterior descending coronary for 6 h. Thirty minutes post‐occlusion the dogs were randomized to receive either distilled water or pentoxifylline (0.3 mg kg−1 min−1 for 1 h followed by 0.15 mg kg−1 min−1 for 4.5 h) intravenously.
At 6 h post‐occlusion the in vivo area at risk was determined with monastral blue dye and the area of necrosis was determined with triphenyltetrazolium chloride. The area at risk was 16.5 ± 1.3% in the control group (n = 10) and 17.2 ± 1.8% in the pentoxifylline treated group (n = 10; NS). The area of necrosis was 12.3 ± 1.9% in the control group and 11.9 ± 2.2% in the pentoxifylline treated group (NS). The area of necrosis expressed as a percentage of the area at risk was 69.3 ± 7.7% in the control group and 63.6 ± 7.4% in the pentoxifylline treated group (NS).
Pentoxifylline had no significant effects on heart rate, systolic or diastolic blood pressure. Regional myocardial blood flow, measured by the radioactive microsphere technique, was not significantly different between the groups.
Thus, pentoxifylline does not reduce infarct size in this model of acute myocardial infarction and does not enhance coronary collateral blood flow.
A modified mouse air pouch model for evaluating the effects of compounds on granuloma induced cartilage degradation
Authors: Bottomley K.M.K. , Griffiths R.J. , Rising T.J. , Steward A. 
Published: July 2012

Employing rat femoral head cartilage implanted in a 6 day old mouse air pouch, the effects of inflammatory stimuli (i.e. cotton pellets, carrageenan, zymosan) on the loss of proteoglycan and collagen and granuloma formation have been studied.
Wrapping of the cartilage in cotton resulted in granuloma formation with accelerated loss of proteoglycan and collagen over the 14 day implantation period. The amount of loss increased with increasing weight of cotton.
The effects of different classes of anti‐rheumatic drugs on granuloma formation and proteoglycan and collagen loss from cotton wrapped femoral head cartilage in the mouse air pouch have been studied.
Non‐steroidal anti‐inflammatory drugs (NSAIDs) had no influence on granuloma formation, but in general accelerated the rates of proteoglycan and collagen loss.
Dexamethasone and prednisolone significantly reduced granuloma formation and had a marked protective effect on cartilage breakdown.
Of the slow acting anti‐rheumatic drugs examined, only gold sodium thiomalate (GSTM) and dapsone significantly decreased cartilage loss, with an accompanying modest decrease in granuloma formation.
The immunosuppressants cyclophosphamide and methotrexate, but not azathioprine, reduced cartilage degradation, but had no effect on granuloma formation.
The results for the different classes of anti‐inflammatory and anti‐rheumatic drugs are discussed in relation to their effects in other animal models and their reported therapeutic activities in man. It is concluded that the mouse air pouch method as described offers advantages as an animal model over existing procedures to predict therapeutic efficacy in man.
Lipophilicity and pharmacodynamics of cardiotonic steroids in guinea‐pig isolated heart muscle preparations
Authors: Dzimiri Nduna , Fricke Uwe 
Published: July 2012

The inhibitory potency of cardiotonic steroids on myocardial Na+‐K+‐ATPase increases with increasing lipophilicity. Employing the inotropic action on guinea‐pig isolated left atria, the relationship between lipophilicity, chemical structure and the pharmacodynamic properties of cardiac glycosides was further examined. Nineteen digitoxigenin‐and digoxigenin‐derivatives, whose lipophilic nature and inhibitory effects on the myocardial Na+‐K+‐ATPase have been previously investigated, were tested.
All steroids exhibited positive inotropic effects which varied with the lipophilicity of these drugs. The dependence of the relationship between these two parameters on structural transformations of the steroids showed qualitatively very close parallelism to that between lipophilicity and their inhibitory effects on myocardial Na+‐K+‐ATPase.
The positive inotropic effects and the inhibitory effects on myocardial Na+‐K+‐ATPase also correlated very well, exhibiting similar patterns in their respective correlations with the individual lipophilicity parameters.
It is inferred that (a) the positive inotropic effects of the cardiac glycosides vary with their lipophilicity, exhibiting trends similar to those shown for their inhibitory effects on myocardial Na+‐K+‐ATPase, (b) this interdependence is secondary to the influence of structural changes, particularly on the steroid nucleus, and (c) both the lipophilic nature and pharmacodynamic behaviour of the cardiac glycosides almost exclusively depend on the steroid nucleus itself.
Quinidine blocks cardiac sodium channels during opening and slow inactivation in guinea‐pig papillary muscle
Authors: Hondeghem Luc M. , Matsubara Tetsu 
Published: July 2012

In order to quantify the time‐and voltage‐dependent block of sodium channels by quinidine, we voltage clamped guinea‐pig papillary muscles and measured the maximum upstroke velocity () of the cardiac action potential.
Quinidine reduces presumably by blocking cardiac sodium channels. In therapeutic concentrations, quinidine causes a small amount of tonic block. Upon depolarization of the cardiac cell membrane, a use‐dependent block develops.
A slow component of use‐dependent block has time‐and voltage‐dependence similar to that of slow inactivation, develops for the duration of the depolarization or until a steady state is reached.
In addition, closely associated with the action potential upstroke, a fraction of the channels blocks very quickly. This represents block of activated or open channels.
Near the normal resting potential, channels recover from block with a time constant of 3 to 8 s. At more negative membrane potentials recovery from block occurs slightly faster, while at more positive potentials recovery from block proceeds somewhat more slowly.
In terms of the modulated receptor hypothesis, quinidine has a low affinity for the rested state, avidly blocks open sodium channels, but does not bind significantly to inactivated channels. In addition, quinidine blocks channels as they exhibit slow inactivation.
Studies on the mechanism by which tryptophan efflux from isolated synaptosomes is stimulated by depolarization
Authors: Collard K.J. , Wilkinson L.S. , Lewis D.J. 
Published: July 2012

The efflux and influx of tryptophan across the synaptosomal plasma membrane has been studied under a variety of experimental conditions, in order to examine the mechanism by which depolarization enhances the efflux of tryptophan from superfused synaptosomes.
Efflux of [3H]‐tryptophan from preloaded superfused synaptosomes was found to be enhanced by K+ depolarization in a Ca2+ and dose‐dependent manner. In contrast, [3H]‐phenylalanine efflux was only poorly stimulated by depolarization and only by very high concentrations of K+.
Tryptophan efflux was also enhanced by decreasing the extracellular Na+ concentration, but this effect was not dependent on extracellular Ca2+.
Influx of [3H]‐tryptophan into synaptosomes was stimulated by extracellular Na+ removal, but the uptake of [3H]‐phenylalanine was unaffected by this procedure.
Both the induced influx and efflux of tryptophan observed under these experimental conditions was inhibited by immobilizing the plasma membrane carrier with parachlorophenylalanine. This implied that both the enhanced influx and efflux arose as a consequence of the activation of the membrane tryptophan carrier, the direction of the observed effect being dependent upon the manner in which the experiments were conducted.
The relationship between depolarization, the activation of the membrane tryptophan carrier and the significance of this to the in vivo situation is discussed.