bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prejunctional β‐adrenoceptors in rabbit pulmonary artery and mouse atria: effect of α‐adrenoceptor blockade and phosphodiesterase inhibition
Authors: Johnston H. , Majewski H. 
Published: July 2012

In rabbit isolated pulmonary artery previously incubated with [3H]‐noradrenaline, isoprenaline (0.3 μM) had no effect on the stimulation‐induced outflow of radioactivity. However, if the phosphodiesterase inhibitor ICI 63,197 (30 μM) or the α‐adrenoceptor blocker phentolamine (1 μM) was present, then isoprenaline significantly enhanced the stimulation‐induced outflow, an effect blocked by propranolol (0.1 μM). ICI 63,197 (30 μM) but not phentolamine significantly enhanced the stimulation‐induced outflow of radioactivity.
In mouse isolated atria previously incubated with [3H]‐noradrenaline and stimulated at a frequency of 10 Hz, isoprenaline had no effect on the stimulation‐induced outflow of radioactivity; this is in contrast to its release‐enhancing effects at stimulation frequencies of 4 Hz and 2 Hz. The facilitation of stimulation‐induced outflow by isoprenaline at 4 Hz was blocked by propranolol (0.08 μM) which, by itself, had no effect on the stimulation‐induced outflow.
At a stimulation frequency of 2 Hz in mouse atria the facilitatory effect of isoprenaline (0.01 μM) was significantly greater in the presence of ICI 63,197 (30 μM) which, by itself, had no effect on the stimulation‐induced outflow. Similarly, the facilitatory effect of isoprenaline was significantly greater in the presence of phentolamine (1 μM) but, in this case, phentolamine significantly enhanced the stimulation‐induced outflow.
These results suggest that facilitatory prejunctional β‐adrenoceptors are present in both rabbit pulmonary artery and mouse atria. The effects of the phosphodiesterase inhibitor ICI 63,197 suggest that they are linked to adenylate cyclase in both tissues and we propose that the ability of phentolamine to facilitate the release and enhance the effect of isoprenaline may be due to the blockade of α‐adrenoceptor inhibition of adenylate cyclase. This latter proposition needs further investigation.
Endothelium‐dependent inhibition of platelet aggregation
Authors: Azuma Hiroshi , Ishikawa Masayuki , Sekizaki Satomi 
Published: July 2012

In cascade perfusion and superfusion experiments on rabbit tissues, when acetylcholine (ACh) was introduced into the circuit so as to perfuse the aorta under perfusion with noradrenaline (NA), the effluent relaxed the transverse aortic strip which had been denuded of endothelium.
The effluent from the perfused aorta which was capable of relaxing the transverse aortic strip also significantly inhibited platelet aggregation induced by arachidonic acid (AA) in a volume‐related manner. The inhibitory activity was decreased by the prolongation of transit time before addition of the effluent to platelet‐rich plasma.
Neither the inhibition of AA‐induced aggregation nor the relaxation of the transverse strip by the effluent could be observed after the removal of endothelium from the aorta, or after pretreatment of aorta with mepacrine or nordihydroguaiaretic acid (NDGA).
The AA‐induced platelet aggregation was unaffected by pretreatment of platelets with mepacrine or NDGA at the concentration tested.
Pretreatment of aorta with indomethacin failed to modify the relaxation of the transverse strip induced by the effluent.
These results strongly suggest that endothelium‐derived vascular relaxant factor (EDRF) possesses inhibitory activity on AA‐induced aggregation in addition to its vasodilator activity.
Sites and mechanisms of action of catechol (1,2‐dihydroxybenzene) in the rat olfactory cortex slice
Authors: Collins Godfrey G.S. , Dewhurst David G. 
Published: July 2012

Synaptic transmission in the isolated olfactory cortex slice from the rat was monitored by recording the surface field potentials evoked on lateral olfactory tract (LOT) stimulation. Catechol (approximately 0.05 to 2 mM) caused a concentration‐dependent, partially reversible increase in the amplitudes of all field potentials.
In a series of conditioning experiments, catechol (1 mM) potentiated postsynaptic inhibition by a mechanism which was at least partially picrotoxin‐insensitive.
When the relationship between the stimulus input and evoked output was investigated in picrotoxin‐treated slices, for a given tract action potential amplitude, catechol (0.25 and 0.5 mM) increased the amplitude of the field potential known as the N‐wave; in contrast, for a given N‐wave amplitude, the latency of the population spike was increased.
Catechol (1 mM) increased the K+‐evoked release of endogenous aspartate by a tetrodotoxin‐insensitive mechanism whereas the release of glutamate and γ‐aminobutyric acid (GABA) was unaffected.
Catechol (1 mM) had no effect on submaximal depolarizations evoked by L‐aspartate, L‐glutamate or GABA.
It is concluded that catechol potentiates excitatory transmission at the LOT‐superficial pyramidal cell synapse, possibly by increasing evoked transmitter release. Other synaptic actions of catechol may be consequent upon this increased excitatory input but the results do not exclude the possibility of separate and distinct actions on polysynaptic transmission.
Nimodipine‐induced changes in the distribution of carotid blood flow and cardiac output in pentobarbitone‐anaesthetized pigs
Authors: Duncker D.J. , Heiligers J. , Mylecharane E.J. , Saxena P.R. , Verdouw P.D. 
Published: July 2012

In view of the claimed effectiveness of nimodipine in migraine and its possible selectivity for cerebral vessels, we investigated the effects of nimodipine in anaesthetized pigs on the fractionation of carotid arterial blood flow into non‐nutrient (arteriovenous anastomoses; AVAs) and nutrient (capillary) parts, and on regional tissue blood flows and vascular conductances.
Intracarotid infusions of nimodipine (0.05‐1.25 μg kg−1 min−1) redistributed carotid blood flow in favour of its nutrient compartment, particularly to the skeletal muscles and tongue. Vascular conductance in the non‐nutrient (AVAs) compartment decreased (40%), most likely, as a result of ‘steal’ following profound (5.5 fold) arteriolar dilatation.
Intravenous infusions of nimodipine (0.05–6.25 μg kg−1 min−1) caused hypotension, bradycardia, a decrease in conduction in the non‐nutrient fraction, and an increase in conduction in the nutrient fraction (mostly in the skeletal muscles, but also in the gastrointestinal tract, cerebral hemispheres, heart and adrenals).
Probably due to the hypotensive effect, only skeletal muscle blood flow increased. The nimodipine‐induced increase in vascular conductance in the skeletal muscles showed regional variation; the effect was most pronounced in the cheek muscles, followed by the muscles of the chest, abdominal, trunk and gluteal regions.
We conclude that: (i) AVA flow seems to represent a ‘reserve’ perfusion which can be readily diverted to tissues in the case of increased metabolism and/or vasodilatation, (ii) though the overall response to nimodipine of carotid blood flow distribution qualitatively resembles that to some anti‐ migraine drugs, the relevance of such acute effects in the prophylactic usefulness of nimodipine in migraine remains to be ascertained, and (iii) nimodipine lacks a selective cerebral vasodilator action in the anaesthetized pig.
Opioid inhibition of adenylate cyclase in the striatum and vas deferens of the rat
Authors: Bhoola K.D. , Pay S. 
Published: July 2012

The activity of adenylate cyclase in striatal membrane‐enriched fractions (25,000 g) was inhibited by morphine, β‐endorphin, [D‐Ala2‐D‐Leu5] enkephalin (DADLenk), fentanyl and bremazocine. Whereas guanosine triphosphate (GTP) appeared essential for the expression of this effect, sodium chloride seemed to enhance the degree of inhibition. Dopamine stimulation and sodium fluoride activation of the enzyme was also suppressed by morphine, β‐endorphin and DADLenk.
β‐Endorphin and DADLenk inhibited adenylate cyclase activity in vasa deferentia membrane‐enriched fractions (25,000 g); both opioids required GTP and NaCl and were inhibited by a δ‐opioid receptor antagonist and by naloxone. Morphine, bremazocine and tifluadom did not significantly alter the activity of the vas deferens enzyme.
Basal cyclic AMP values of striatal slices were not significantly altered by morphine, β‐endorphin or DADLenk. However, dopamine‐induced elevation of cyclic AMP was reduced by morphine and this effect of the opiate was suppressed by naloxone.
Only β‐endorphin lowered the basal cyclic AMP values in the vas deferens.
The physiological relevance of adenylate cyclase coupling to opioid receptor subtypes is considered.
The mechanism of action of the optical enantiomers of verapamil against ischaemia‐induced arrhythmias in the conscious rat
Authors: Curtis M.J. , Walker M.J.A. 
Published: July 2012

The actions of (‐)‐verapamil (0.2–6 mg kg−1) and (+)‐verapamil (0.4–12 mg kg−1) against arrhythmias induced by coronary artery occlusion were studied in conscious rats.
Intravenously administered (‐)‐ and (+)‐verapamil dose‐dependently reduced ventricular arrhythmias. (‐)‐Verapamil was consistently 4 times more potent than (+)‐verapamil.
In the same animals, (‐)‐verapamil was approximately 4 times more potent than (+)‐verapamil for effects on heart rate and blood pressure. Both enantiomers prolonged P‐R interval, but had no effect on QRS interval.
In separate groups of conscious rats, neither enantiomer influenced the threshold voltage and pulse width required to elicit fibrillo‐flutter, or altered the maximum following frequency, during electrical stimulation of the left ventricle.
In isolated, paced, Langendorff‐perfused ventricles of the rat, both enantiomers dose‐dependently reduced contractility, (‐)‐verapamil being 8–21 times more potent than (+)‐verapamil; both absolute and relative potencies were dependent on potassium concentration.
These results are compatible with the hypothesis that calcium antagonism in the ischaemic ventricular myocardium is antiarrhythmic during acute myocardial ischaemia.
Mode of action of (‐)‐pindolol on feline and human myocardium
Authors: Kaumann Alberto J. , Lobnig Brigitte M. 
Published: July 2012

(‐)‐Pindolol antagonized competitively and to a similar extent the positive inotropic effects of both (‐)‐noradrenaline and (‐)‐adrenaline in human ventricular preparations. An equilibrium dissociation constant KD (‐log mol 1−1 = pKD) of 9.2–9.3 was estimated regardless of disease present or agonist used.
(‐)‐Pindolol antagonized competitively the positive inotropic effects of (‐)‐adrenaline more than those of (‐)‐noradrenaline in human atrial preparations. pKD values of (‐)‐pindolol were 9.6 against (‐)‐adrenaline and 9.1 against (‐)‐noradrenaline. The results are consistent with a moderate selectivity of (‐)‐pindolol for β2‐ compared to β1‐adrenoceptors in human atrium.
(‐)‐Pindolol competed with [3H]‐(‐)‐bupranolol with a pKD of 9.4 for β‐adrenoceptors of human ventricle.
Positive inotropic effects of (‐)‐pindolol were not detected on human atrium or ventricle in a concentration range of 1–1000 nmol 1−1.
The affinity of (‐)‐pindolol estimated for human myocardial β‐adrenoceptors, its moderate β2‐selectivity and its lack of intrinsic activity for contractile force agreed with similar characteristics in other species.
(‐)‐Pindolol caused marked positive chronotropic effects in kitten right atria with an intrinsic activity of 0.5 with respect to catecholamines. On kitten left atria it caused only weak positive inotropic effects with an intrinsic activity of 0.1. (‐)‐Pindolol (0.6–6000 nmol−1) did not cause positive inotropic effects in kitten papillary muscle.
The concentration‐effect curve for (‐)‐pindolol on kitten right and left atria was biphasic. Its positive chronotropic and inotropic effects were not blocked by methysergide, suggesting that 5‐hydroxytryptamine (5‐HT)‐receptors were not involved. Low concentrations of antagonists selective for β1‐ and β2‐adrenoceptors blocked the high sensitivity component but not the low sensitivity component of the positive chronotropic and inotropic effects.
The biphasic nature of the positive chronotropic effects of (‐)‐pindolol in kitten agreed with previous observations made on guinea‐pig right atria and support the concept that 3 receptors in the sinoatrial pacemaker contribute to these chronotropic effects: β1 β2 and a low‐affinity receptor for (‐)‐pindolol which is neither β1 nor β2. The partial agonistic activity of (‐)‐pindolol in the heart appears to be mainly (kitten) or completely (man) restricted to the sinoatrial pacemaker.
Potentiation of the depression by adenosine of rat cerebral cortical neurones by progestational agents
Authors: Phillis John W. 
Published: July 2012

The effects of four progestational agents pregnenolone sulphate, cyproterone acetate, norethindrone acetate and progesterone, on adenosine‐evoked depression of the firing of rat cerebral cortical neurones have been studied.
When applied iontophoretically, pregnenolone sulphate, cyproterone, and norethindrone enhanced the actions of iontophoretically applied adenosine and failed to potentiate the depressant effects of adenosine 5′‐N‐ethylcarboxamide and γ‐aminobutyric acid.
Cyproterone acetate (50 μg kg−1) and progesterone (200 μg kg−1) administered intravenously enhanced the depressant actions of iontophoretically applied adenosine.
When applied by large currents, cyproterone, and less frequently norethindrone, depressed the firing of cerebral cortical neurones. The depressant effects of cyproterone were antagonized by caffeine.
Pregnenolone sulphate tended to excite cortical neurones but neither this action, nor its potentiation of adenosine were reproduced by application of sulphate ions.
It is hypothesized that some of the psychotropic actions of progestational agents may involve an enhancement of ‘purinergic’ tone in the central nervous system.
Vasodilator actions of TRK‐100, a new prostaglandin I2 analogue
Authors: Akiba Tetsuro , Miyazaki Mizuo , Toda Noboru 
Published: July 2012

TRK‐100, a stable analogue of prostaglandin I2 (PGI2), relaxed isolated arteries of the dog precontracted with PGF2α or K+; the relaxation was in the order of mesenteric and renal > coronary and femoral > basilar and middle cerebral arteries. The relaxation by TRK‐100 was not affected by treatment with atropine, propranolol, cimetidine, aminophylline, and indomethacin, but was suppressed by diphloretin phosphate, a prostaglandin antagonist.
Treatment with TRK‐100 attenuated the contraction induced by PGF2α and Ca2+ in mesenteric and basilar arteries previously exposed to Ca2+‐free medium, but did not significantly alter the contractile response to Ca2+ in the arteries exposed to Ca2+‐free medium and depolarized by excess K+.
TRK‐100 and nitroglycerin relaxed isolated mesenteric arteries to a similar extent; however, when continuously infused into mesenteric arteries in anaesthetized dogs, TRK‐100 produced greater vasodilatation than nitroglycerin.
It is concluded that TRK‐100 relaxes dog mesenteric and renal arteries more than cerebral arteries; the relaxation appears to derive from interference with the release of Ca2+ from intracellular stores and with the transmembrane Ca2+ influx through a receptor‐operated channel. TRK‐100 may vasodilate large and small mesenteric arteries and resistance vessels to a similar extent, whereas nitroglycerin preferentially dilates the large artery.
Alterations with age of the response to vasodilator agents in isolated mesenteric arteries of the beagle
Authors: Shimizu Ikuko , Toda Noboru 
Published: July 2012

Responses to vasodilator agents were compared in helical strips of mesenteric arteries from beagles of different ages (30 days, 3 months, 2 years and 12 years old), precontracted with prostaglandin F2α (PGF2α). Relaxations induced by isoprenaline and adenosine were related inversely to age, whereas those induced by PGI2 and K+ (5 mM) did not alter with age.
Acetylcholine‐induced relaxations were less in the arteries from the aged (12 year old) beagles than in those from the younger beagles. Histamine‐induced relaxations related directly to age between 30 days and 2 years. Acetylcholine‐induced relaxation was reversed to a contraction in infant (30 day old) beagle arteries by removal of the endothelium, and significantly attenuted in the older beagle arteries. In adult (2 year old) and aged beagle arteries, removal of the endothelium attenuated the histamine‐ induced relaxation. Treatment with indomethacin reversed the histamine‐induced relaxation to a marked contraction in aged beagle arteries.
It may be concluded that responses mediated by β‐adrenoceptors and P1‐purinoceptors are less in aged mesenteric arteries than in those from the younger beagles, whereas responses mediated by PGI2 receptors and the electrogenic Na+ pump do not alter with age. The release of endothelium‐derived relaxing factor(s) by acetylcholine appears to be inversely related to age. However, the release of PGI2 possibly caused by histamine may be less in infant beagle mesenteric arteries than in those from the older beagles.
A kinetic analysis of the endplate ion channel blocking action of disopyramide and its optical isomers
Authors: Dempster J. , Jones S.V.P. , Marshall I.G. 
Published: July 2012

The effects of the antiarrhythmic agent disopyramide was studied on responses from voltage‐clamped endplates at the neuromuscular junction of the garter snake.
Disopyramide reduced endplate current amplitude and decay time constant in a concentration‐and voltage‐dependent manner. Endplate current decays remained monophasic in the presence of the drug. These results were interpreted in terms of the drug blocking the open form of the acetylcholine receptor‐ion channel complex.
Disopyramide produced a greater reduction of the amplitude of endplate currents than of miniature endplate currents. The reduction in miniature endplate current amplitude was not voltage‐dependent. Analysis of endplate current driving functions showed that this was due to the rapid occurrence of channel block during the rising phase of the endplate current. The residual reduction, apart from that produced by channel block, is most probably due to receptor block.
Disopyramide had a voltage‐dependent blocking rate constant of about 107 m−1 s−1 at −90 mV. The unblocking rate constant was estimated from the results of experiments using paired ionophoretically applied pulses of acetylcholine. This value was again voltage‐dependent and approximately 1 s−1.
The actions of the (+)‐and (‐)‐stereoisomers of disopyramide on endplate current decay were identical, indicating that the channel binding site at the neuromuscular junction is not stereoselective.
Effects of diacylglycerol and phorbol ester on acetylcholine release and action at the neuromuscular junction in mice
Authors: Murphy Richard L.W. , Smith Margaret E. 
Published: July 2012

Miniature endplate potentials and nerve‐evoked endplate potentials were studied in a phrenic nerve‐diaphragm preparation of the mouse.
A phorbol ester, phorbol‐12β,13α‐dibutyrate, and a diacylglycerol, 1‐oleyl‐2‐acetyl‐sn‐glycerol, both increased the frequency of miniature endplate potentials. The effect of the phorbol ester on the frequency was still significant when the preparation was incubated in a calcium‐deficient solution.
The phorbol ester, but not the diacylglycerol, caused a significant increase in the amplitude of the miniature potentials.
The phorbol ester also increased the amplitude of the endplate potentials in the presence of (+)‐tubocurarine.
The mechanisms of action of phorbol ester and diacylglycerol are discussed in relation to the control of acetylcholine release and action at the neuromuscular junction.
N‐propargylbenzylamine, a major metabolite of pargyline, is a potent inhibitor of monoamine oxidase type B in rats in vivo: a comparison with deprenyl
Authors: Karoum Farouk 
Published: July 2012

In an effort to explore the contribution of the metabolites of pargyline towards the in vivo inhibition of monoamine oxidase (MAO), the effects of pargyline and its major metabolites on the production and metabolism of a number of biogenic amines were studied in rats. The administration of pargyline gave rise to three major ethyl acetate extractable metabolites: benzylamine, N‐methylbenzylamine and N‐propargylbenzylamine (NPB). Only NPB demonstrated in vivo monoamine oxidase inhibitory properties at an acute dose of 30 mg kg−1.
The acute effects of pargyline, NPB, and deprenyl on urine and brain concentrations of a number of biogenic amines (phenylethylamine (PEA), m‐ and p‐tyramine, noradrenaline (NA), dopamine, and 5‐hydroxytryptamine (5‐HT) and their metabolites were evaluated. Increased urine and brain concentrations of PEA were considered to represent in vivo inhibition of type B MAO while decreased concentrations of NA and 5‐HT metabolites were regarded as indicators of an in vivo inhibition of MAO type A. NPB, like deprenyl and pargyline, significantly increased urine and brain PEA while only pargyline reduced 5‐HT metabolism, suggesting that the metabolism of pargyline to NPB may contribute towards the MAO type B inhibitory effects of pargyline in vivo.
Since the therapeutic benefits of MAO inhibitors in clinical practice usually require some period of chronic treatment, the chronic effects of repeated 14 daily doses of the above MAO inhibitors on central and peripheral biogenic amines were evaluated at the following times: during treatment, one day and five days after termination of treatment. The biochemical changes observed during the course of chronic NPB, pargyline and deprenyl treatments generally follow the expected in vitro characteristics of these drugs, but the detailed changes observed suggest clear differences. For example, the in vivo effect of pargyline on urine 5‐hydroxyindoleacetic acid excretion was considerably weaker than its effect on the excretion of NA and dopamine metabolites. These changes are opposite to the in vitro effects of pargyline on 5‐HT, dopamine and NA oxidative deamination.
Inhibitions of the metabolism of all the amines studied were clearly observed during chronic MAOI treatments, but these effects were less evident five days after the end of treatment, suggesting an almost normal metabolism of biogenic amines.
It is concluded that while MAO inhibitors may be the primary compound responsible for MAO inhibition, the effects of their metabolites in some cases may also play equally important roles in the regulation of monoamines both in the periphery and the brain. Thus, as demonstrated here, NPB was found to be as potent as pargyline and deprenyl with regard to its in vivo MAO type B inhibitory properties.