bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbachol‐induced contraction in the circular muscle of guinea‐pig stomach in calcium‐free solution
Authors: Ashoori F. , Hidaka H. , Tomita T.
Published: July 2012

In the circular muscle of the fundic part of the guinea‐pig stomach, a small tonic contraction could be repeatedly produced by carbachol in Ca‐free solution containing 2 mM EGTA.

The carbachol‐induced response was gradually increased during prolonged exposure to Ca‐free solution for 50 h, whereas a short treatment with 0.1‐0.2 mM Ca suppressed the subsequent carbachol response in Ca‐free solution. The response was not essentially modified by increasing the external K+ concentration to 40 mM.

Calmodulin antagonists, N‐(6‐aminohexyl)‐5‐chloro‐l‐naphthalene sulphonamide (W‐7) and trifluoperazine selectively suppressed the carbachol response in the presence of Ca (0.05 mM) and the contraction induced by Ca (0.1 mM), but they had little effect on the response to carbachol in Ca‐free solution at a concentration of less than 10 μM.

A vasodilator agent, N‐(2‐guanidinoethyl)‐5‐isoquinoline sulphonamide (HA‐1004), inhibited the carbachol response both in the presence and absence of Ca, as well as the Ca‐induced contraction, to a similar extent, provided that the external Ca concentration was less than 0.1 mM.

These results led us to propose that the contraction evoked by carbachol in the absence of external Ca is mediated by a process independent of the Ca‐calmodulin system.
Effects of Bay K 8644 on 45Ca uptake and efflux and on contraction in the rabbit aorta
Authors: Dong Y.J. , Wadsworth R.M.
Published: July 2012

Contractions induced by K+, noradrenaline and 11,9‐epoxymethano prostaglandin H2 (11,9‐epoxymethano PGH2) were accompanied by a large, moderate and negligible stimulation of 45Ca uptake in rabbit aortic rings, respectively. Bay K 8644, 14 and 56 nM, enhanced both the contraction and the 45Ca uptake stimulated by all 3 agonists.

In the absence of agonists, Bay K 8644 (14 and 56 nM) caused a small contraction and increase in 45Ca uptake.

45Ca efflux was increased by noradrenaline, and Bay K 8644 augmented this.

In Ca‐free solution, contractions induced by noradrenaline or 11,9‐epoxymethano PGH2 were not augmented by Bay K 8644.

Nifedipine (0.1 μM) antagonized 45Ca uptake stimulated by K+ or noradrenaline. Nifedipine also reduced the stimulant effect of Bay K 8644 on 45Ca uptake in the presence of all three agonists.

It is concluded that, in the rabbit aorta, Bay K 8644 enhances the opening of Ca channels both during depolarization and in the presence of receptor‐specific agonists and is also able to open Ca channels under basal conditions. Bay K 8644 appears not to reduce Ca efflux or enhance Ca release from intracellular stores.
Effects of calcium entry blockers on tension development and calcium influx in rat uterus
Authors: Granger Susan E. , Hollingsworth M. , Weston A.H.
Published: July 2012

Spontaneous and potassium chloride (KCl)‐induced tension development of strips of whole uterus from the day‐22 pregnant rat was reduced when the tissues were incubated in a calcium ion (Ca2+)‐free medium.

Strips of whole uterus, in an initially Ca2+‐free medium, responded to the cumulative addition of Ca2+ with graded phasic tension development and associated rapid electrical discharges. The spasms were inhibited by gallopamil (100 nM) and diltiazem (1 μM).

Strips of whole uterus in a depolarizing (40 mM K+) medium, which was initially Ca2+‐free, responded to the cumulative addition of Ca2+ with graded tonic tension development without associated electrical discharges. These spasms were inhibited by calcium entry blockers with a rank order of potency of nifedipine = gallopamil > diltiazem > cinnarizine.

KCl‐induced tension development in endometrium‐free uterine strips was antagonized by calcium entry blockers with a rank order of potency of nifedipine > gallopamil > diltiazem > cinnarizine.

Ca2+ influx into endometrium‐free uterine strips was assessed by means of the lanthanum method'. KCl induced a concentration‐dependent increase in 45Ca2+ influx which was suppressed or abolished by nifedipine (2.5 nM), gallopamil (100 nM), diltiazem (500 nM) or cinnarizine (5 μM).

It is concluded that spontaneous and KCl‐induced tension development of rat uterus involves Ca2+ influx from the extracellular medium into the myometrial cell. These results support the hypothesis that nifedipine, gallopamil, diltiazem and cinnarizine inhibit Ca2+‐ and KCl‐induced tension development of rat uterus by reduction of Ca2+ influx.
Oestrogenic and antioestrogenic actions in a series of triphenylbut‐1‐enes: modulation of prolactin synthesis in vitro
Authors: Jordan V.C. , Koch R. , Mittal S. , Schneider M.R.
Published: July 2012

The oestrogenic and antioestrognic activities of a series of substituted derivatives of 1,1,2 triphenylbut‐1‐ene have been determined using primary cultures of rat pituitary gland cells to monitor prolactin synthesis in vitro.

The relative binding affinity of the agonists for the oestrogen receptor was consistent with their oestrogenic potency.

Bis para substitution at C1 of 1,1,2 triphenylbut‐1‐ene with either phenolic or acetoxy groups produced partial agonists. The antioestrogenic properties were reversible by the incubation of cells with increasing concentrations of oestradiol.

The results lend support to a hypothetical single binding site model of oestrogen action, based upon an adaptation of Belleau's macromolecular perturbation theory.
The role of catecholamines in the production of ischaemia‐induced ventricular arrhythmias in the rat in vivo and in vitro
Authors: Daugherty Alan , Frayn Keith N. , Redfern William S. , Woodward Brian
Published: July 2012

The role of catecholamines in the production of ischaemia‐induced ventricular arrhythmias in vivo and in vitro was studied using coronary artery ligation in the rat.

Increases in plasma catecholamine concentrations during coronary artery ligation in pentobarbitone‐anaesthetized animals were prevented by either acute adrenalectomy or chronic adrenal demedullation, but these procedures did not protect against the occurrence of ventricular arrhythmias. Thus plasma catecholamines were not obligatory mediators of arrhythmogenesis.

Three protocols were used in vitro to evaluate the possible influence of intramyocardial release of noradrenaline, produced by the local conditions of ischaemia, on the production of ventricular arrhythmias. During coronary artery ligation in isolated perfused hearts, no enhanced output of 3H could be detected from [3H]‐noradrenaline loaded hearts, even in the presence of inhibitors of catecholamine uptake processes, although washout of lactate from ischaemic regions was readily demonstrable.

Both optical isomers of propranolol were equally effective in reducing the incidence of arrhythmias, implying a non‐specific effect, since the (+)‐isomer possesses considerably less β‐adrenoceptor blocking activity. The equipotency of optical isomers of propranolol combined with a lack of effect of atenolol suggested that arrhythmia production was not a consequence of β‐adrenoceptor stimulation.

The α‐adrenoceptor blockers phentolamine and prazosin, both exerted antiarrhythmic actions of similar potency, but phenoxybenzamine and trimazosin had no significant effects. An evaluation of the pharmacological properties of the α‐adrenoceptor blockers showed that those drugs which had demonstrable local anaesthetic properties also exerted significant antiarrhythmic effects. No relationship was found between potency of α‐adrenoceptor blockade and antiarrhythmic efficacy.

The overall conclusion from these multifaceted approaches was that catecholamines were not necessary mediators of the early phase of ventricular arrhythmias in the rat.
Effect of low intravenous doses of TRH, acid‐TRH and cyclo(His‐Pro) on cerebral and peripheral blood flows
Authors: Koskinen Lars‐Owe D.
Published: July 2012

Local cerebral and peripheral blood flow in conscious and anaesthetized rabbits were investigated with the microsphere method, before and after the i.v. administration of 25 or 50 μg kg−1 thyrotropin‐releasing hormone (TRH). Before the experiment, the cervical sympathetic chain was sectioned on one side in order to evaluate the possible effect of the sympathetic nerves on cranial and extracranial blood flows.

Blood flow was also determined in anaesthetized rabbits before and after the administration of the TRH metabolites cyclo(His‐Pro) and acid‐TRH and after subsequent administration of 50 μg kg−1 TRH.

TRH caused an increase in mean arterial blood pressure (MAP) of about 1 to 2 kPa whereas cyclo(His‐Pro) and acid‐TRH had no effect on MAP.

In the anaesthetized animal an increase in total cerebral blood flow (CBFtot), from 71 ± 7 to 107 ± 12 g min−1 100g−1 (P < 0.05) was observed on the sympathetic intact side after 25 μg kg−1 TRH and a further increase to 130 ± 9 g min−1 100g−1 (P < 0.01) after 50 μg kg−1 TRH. A similar effect was observed on the sympathotomized side.

An effect on CBF in the conscious animal was not detected. The control CBFtot (104 ± 8 g min−1 100g−1) was higher in these animals than in the anaesthetized animals (P < 0.02).

Neither cyclo(His‐Pro) nor acid‐TRH mimicked the effect of TRH on CBF.

In several peripheral tissues, e.g. skin, pancreas and gastric mucosa, a reduction in blood flow was noted after the administration of TRH in both anaesthetized and conscious rabbits.

It was concluded that TRH can induce cerebral vasodilatation in animals with a depressed CBF, whereas the vasoconstrictor effect of TRH in peripheral organs is not markedly affected by the state of consciousness.

I wish to thank Professor Anders Bill for advice, Ms Ann‐Sofi Hoist for technical assistance, Ms Lena Henriksson for secretarial work and Ms Monica Thorén for drawing the figures. This study was supported by grant No. B84‐14X‐00147 from the Swedish Medical Research Council and grant No. 5 ROI Ey 00475 from the National Eye Institute, U.S. Public Health Service.
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.
An in vitro analysis of purine‐mediated renal vasoconstriction in rat isolated kidney
Authors: Kenakin Terry P. , Pike Nicholas B.
Published: July 2012

In the rat isolated perfused kidney, 2‐chloroadenosine and l‐N6‐phenyl‐isopropyl adenosine (l‐PIA) produced a modest vasodilatation.

After kidneys had been pretreated with methoxamine (to elevate vascular tone) and forskolin (to activate adenyl cyclase and reduce vascular tone), both purine agonists produced vasoconstriction at low doses and vasodilatation at higher doses. This was consistent with the working hypothesis that vasoconstriction resulted from activation of A1‐purinoceptors mediating adenyl cyclase inhibition and vasodilatation from activation of A2‐purinoceptors stimulating adenyl cyclase.

These kidney preparations also demonstrated a marked potentiation of purine‐mediated vasoconstriction in the presence of various concentrations of 8‐p‐sulpho‐phenyltheophylline (8‐SPT), a drug reported in the literature to be a competitive antagonist of A1‐and A2‐purinoceptors.

Maximal renal vasoconstriction to 2‐chloroadenosine and l‐PIA was observed in the presence of 10 mm 8‐SPT; the fact that this vasoconstriction was sensitive to the selective A1‐receptor antagonist 8‐(2‐amino‐4‐chlorophenyl)‐1,3‐dipropylxanthine (PACPX) and that the order of potency of agonists for this effect was l‐PIA > 2‐chloroadenosine > d‐PIA > N6‐ethylcarboxamide adenosine (NECA) was consistent with activation of vascular A1‐purinoceptors.

While these data are consistent with the hypothesis that purines activate vascular A1‐and A2‐receptors in the rat isolated kidney, the nature of the results did not allow definitive classification of the receptors mediating the purine effects.
Differential effects of pertussis toxin and lithium on muscarinic responses in the atria and ileum: evidence for receptor heterogeneity
Authors: Eglen R.M. , Huff M.M. , Montgomery W.W. , Whiting R.L.
Published: July 2012

Pretreatment with pertussin toxin was shown to inhibit selectively muscarinic responses in the atria, but have no effect on responses in the ileum. The converse was true when the animals were pretreated with lithium. These data are consistent with the hypothesis that muscarinic receptors in the atria are coupled to an inhibition of adenylate cyclase, whilst those in the ileum are coupled to inositol phospholipid hydrolysis and indicate differences in the muscarinic receptors in these two tissues.
Increased gut cholinergic activity and antagonism of 5‐hydroxytryptamine M‐receptors by BRL 24924: potential clinical importance of BRL 24924
Authors: Sanger G.J.
Published: July 2012

The mechanisms by which BRL 24924 ([(±)‐(endo)]‐4‐amino‐5‐chloro‐2‐methoxy‐N‐(1‐azabicyclo‐[3.3.1]‐non‐4‐yl) benzamide hydrochloride stimulates gut motility and the relationships between BRL 24924 and 5‐hydroxytryptamine (5‐HT) receptors have been studied.

In guinea‐pig isolated ileum, BRL 24924 (10−4‐10−6 m) increased electrically‐evoked, cholinergically‐mediated contractions, probably by increasing acetylcholine (ACh) release. This action of BRL 24924 was prevented by the presence of high concentrations of 5‐HT, but not by hexamethonium, phentolamine and propranolol, methysergide or ICS 205–930.

The mechanism by which BRL 24924 can increase gut ACh release is not certain, but most likely involves activation of an enteric 5‐HT receptor which differs from those 5‐HT M‐receptors antagonized by ICS 205–930 or by higher concentrations of BRL 24924 in other test systems.

BRL 24924 antagonized 5‐HT‐evoked, cholinergically‐mediated contractions of guinea‐pig isolated ileum (pA2 = 7.56 ± 0.12). Similar and higher concentrations of BRL 24924 did not antagonize contractions evoked by nicotinic receptor stimulation. In rabbit isolated heart, BRL 24924 1–10 nm reduced the tachycardia evoked by 5‐HT.

In anaesthetized rats, BRL 24924 0.3–83 nmol kg−1 i.v. antagonized the Bezold‐Jarisch reflex evoked by 5‐HT; the ID50 for BRL 24924 was 10.2 ± 3.0 nmol kg−1 (3.7 ± 1.1 μg kg−1). A direct action of BRL 24924 on nerve function was excluded.

In rat cortex, BRL 24924 10−6 m did not displace [3H]‐5‐HT or [3H]‐ketanserin binding to 5‐HT1 and 5‐HT2 receptors.

The actions of BRL 24924 are discussed in terms of its potential clinical use as a stimulant of gastric motility and as a 5‐HT M‐receptor antagonist.
The action of noradrenaline on single smooth muscle cells freshly dispersed from the guinea‐pig pulmonary artery
Authors: Byrne N.G. , Large W.A.
Published: July 2012

Responses to ionophoretically‐applied noradrenaline were investigated with micro‐electrodes in whole tissue preparations and with patch pipettes in isolated cells dispersed from the guinea‐pig pulmonary artery.

In whole tissue and dispersed cells noradrenaline evoked monophasic depolarizations which had a similar time course.

In dispersed cells the amplitude of electronic potentials was reduced during the noradrenaline‐evoked depolarization. Under voltage clamp noradrenaline elicited an inward current, which persisted in 18 mm external potassium with the membrane potential set at the potassium equilibrium potential.

In voltage clamp experiments the amplitude of current steps to hyperpolarizing voltage jumps was increased during the noradrenaline‐induced inward current. These data suggest that the depolarization to noradrenaline in the guinea‐pig pulmonary artery is mediated by an increase in membrane conductance.
Developmental responses to opioids reveals a lack of effect on stress‐induced corticosterone levels in neonatal rats
Authors: Bailey Clare C. , Kitchen Ian
Published: July 2012

The neonate has an unusual capacity for survival and the possibility exists that mechanisms for controlling stress responses may differ in the developing animal. In adults both endogenous and exogenous opioids can modulate the corticosterone responses to stress. We have studied this effect in neonatal rats and found that opioid modulation is absent in early postnatal development.

Neonatal rats of either sex were injected with morphine (5–50 mg kg−1), fentanyl (10–100 μg kg−1), buprenorphine (0.1 − 30 mg kg−1) or naloxone (0.1 − 10 mg kg−1) and plasma corticosterone measured fluorimetrically 15 or 20 min later. In addition naloxone reversibility studies (1 mg kg−1, co‐administered) were carried out for the opioid agonists.

In adult rats, elevations in plasma corticosterone caused by injection stress were potentiated by morphine, fentanyl and buprenorphine. In neonates, though injection stress‐induced rises in plasma corticosterone were absent at 10 days, elevations were observed at 21 days and later. However, significant potentiation of this corticosterone response by fentanyl was absent at 21 days and at later ages (30 and 40 days) for morphine and buprenorphine. The potentiating effect of all three agonists did not become fully effective until day 45. In addition, in animals acclimatized to injection stress by 7 day injection pretreatment, fentanyl did not significantly alter corticosterone levels in 30 day old neonates.

High doses of naloxone (10 mg kg−1) significantly increased the corticosterone response to injection stress in adult rats but this effect was absent in 30 day old animals. A dose of naloxone (1 mg kg−1) which had no significant effect on the corticosterone response inhibited the effects of morphine, fentanyl and buprenorphine in 45 day old and adult rats.

This late development of opioid action is unusual in comparison with the maturation of endogenous peptides, receptors and antinociceptive responses and suggests that alternative mechanisms may be involved in stress‐control in the neonate.
The effect of vasoactive intestinal peptide on smooth muscle tone and mucus secretion from the ferret trachea
Authors: Webber S.E. , Widdicombe J.G.
Published: July 2012

The effect of vasoactive intestinal peptide (VIP) was examined on the smooth muscle contraction and mucus secretion produced by methacholine and phenylephrine in the ferret whole trachea in vitro.

VIP (0.5 to 800 nm) produced a concentration‐dependent relaxation of the ferret trachea contracted by methacholine (1 μm) and phenylephrine (10 μm). The concentration‐response curves for methacholine‐and phenylephrine‐induced contractions were both shifted to the right by VIP (0.1 μm).

Methacholine‐induced secretion was inhibited in a concentration‐dependent manner by VIP, whereas that due to phenylephrine was enhanced. The concentration‐response curve for methacholine‐induced secretion was shifted to the right by VIP, whereas the curve for phenylephrine was shifted to the left.

Methacholine produced a concentration‐dependent increase in the rate of output of lysozyme from the ferret trachea with no corresponding increase in the concentration of lysozyme in the mucus. Phenylephrine produced a concentration‐dependent increase in the rate of output and in the concentration of lysozyme.

VIP (0.1 μm) significantly increased the concentration of lysozyme in the mucus produced by methacholine with no increase in the rate of lysozyme output. However, the rate of lysozyme output due to phenylephrine was significantly increased by VIP (0.1 μm) with no increase in concentration.

We suggest that VIP inhibits secretion from mucous cells stimulated by methacholine, and enhances the secretion produced by phenylephrine from serous cells.
Influence of α‐chymotrypsin and trypsin on the non‐adrenergic non‐cholinergic relaxation in the rat gastric fundus
Authors: De Beurme Freya A. , Lefebvre Romain A.
Published: July 2012

Relaxations of the rat gastric fundus were induced by electrical stimulation of the non‐adrenergic non‐cholinergic (NANC) neurones, by vasoactive intestinal polypeptide (VIP), by noradrenaline and by isopropylnoradrenaline. The influence of α‐chymotrypsin and trypsin thereupon was studied.

α‐Chymotrypsin 2 u ml−1, present for 30 min, antagonized completely the VIP‐induced relaxation, but not the stimulation‐induced relaxation; α‐chymotrypsin 10 u ml−1 also partially antagonized the stimulation‐induced relaxation. When α‐chymotrypsin 2 u ml−1 was added after the relaxation had occurred, it antagonized completely the VIP‐induced relaxation, but it also partially antagonized the stimulation‐induced relaxation. The partial antagonism of the stimulation‐induced relaxation was more pronounced with α‐chymotrypsin 10 u ml−1.

Trypsin, 10−6 m and 3 × 10−6 m, had effects on VIP‐and stimulation‐induced relaxations similar to those of α‐chymotrypsin.

The relaxations induced by noradrenaline and isopropylnoradrenaline were not influenced by α‐chymotrypsin or trypsin, respectively.

The results suggest that a peptide, possibly VIP, is involved in the NANC relaxation of the rat gastric fundus.
Effects of l‐serine borate on antagonism of leukotriene C4‐induced contractions of guinea‐pig trachea
Authors: Charette L. , Jones T.R.
Published: July 2012

The antagonist activity of three leukotriene D4 (LTD4) receptor antagonists and a number of bronchodilators was determined against LTC4‐induced contractions of guinea‐pig isolated tracheal chains in the absence and presence of the γ‐glutamyltranspeptidase inhibitor, l‐serine borate (SB).

The LTD4 receptor antagonists FPL‐55712, L‐649,923 and L‐648,051 effectively antagonized LTC4 responses in the absence of SB but were ineffective in the presence of 15 and/or 45 mm SB.

Salbutamol > isobutylmethylxanthine (IBMX) > dibutyryl cyclic AMP > aminophylline > nifedipine antagonized contractions to LTC4 in the absence of SB. In contrast, in the presence of SB the antagonist activity of all of these agents except nifedipine was significantly reduced. The antagonist activity of the Ca2+ entry blocker, nifedipine, was similar in the absence and presence of SB.

Salbutamol and IBMX were potent functional antagonists of LTE4‐induced contractions both in the absence and presence of SB.

These results are consistent with the hypothesis that there are contractile LTC4 receptor mechanisms in guinea‐pig trachea which are unmasked by SB and are not blocked by LTD4 receptor antagonists and which are less effectively down modulated by cyclic AMP‐dependent bronchodilators.
Complex effects of Gillichthys urotensin II on rat aortic strips
Authors: Gibson A.
Published: July 2012

The aim of this study was to determine whether the fish neuropeptide, Gillichthys urotensin II (GUII), possesses significant biological activity on rat aortic strips.

On intact strips, pre‐contracted by noradrenaline (100 nm), low concentrations (0.1‐0.5 nm) of GUII produced relaxations, while higher concentrations (1–10 nm) caused further contraction. On strips rubbed to remove endothelial cells, relaxations were absent but contractile responses to higher concentrations of GUII remained.

GUII (0.2–10 nm) produced dose‐related contractions of quiescent, intact aortic strips. These contractions consisted of two components, tonic and phasic, and were potentiated in rubbed strips and in the presence of the antioxidant drug hydroquinone (10 μm).

Mepacrine (40 μm) and p‐bromophenacyl bromide (50 μm) completely abolished contractions to GUII, but indomethacin (10 μm) and nordihydro‐guaiaretic acid (10 μm) were without effect.

The phasic, but not the tonic, component of the contractile response was inhibited by nitrendipine (200 nm), and was absent in bathing medium from which Ca2+ had been omitted. Addition of EGTA (2 mm) to Ca2+‐free bathing medium abolished the residual tonic component.

GUII‐induced contractions were completely abolished by the calmodulin antagonists trifluoperazine (50 μm) and W‐7 (30 μm).

It is concluded that GUII, previously considered devoid of significant activity on mammalian tissues, produces potent endothelium‐dependent relaxations and endothelium‐independent contractions of rat aorta, and possible mechanisms underlying each response are discussed.
Studies on the mechanism by which indomethacin increases the anticancer effect of methotrexate
Authors: Bennett A. , Gaffen J.D. , Melhuish P.B. , Stamford I.F.
Published: July 2012

The effect of indomethacin on the response of the NC carcinoma to methotrexate has been examined in vivo and in vitro.

Survival was prolonged in mice treated with indomethacin 1.25 mg kg−1 twice daily plus methotrexate 4 mg kg−1 daily, compared to mice given either drug alone or controls.

Indomethacin 1 μg ml−1 increased the killing of cultured NC cells by methotrexate. This was not due to displacement of methotrexate from binding sites on the serum proteins. Nor was it due (entirely) to inhibition of prostaglandin synthesis, since flurbiprofen did not mimic the effect. Inhibition of cyclic AMP phosphodiesterase seems unlikely to explain the effect of indomethacin since theophylline had little or no effect on NC cell killing by methotrexate.

Indomethacin 1 μg ml−1 increased the accumulation of tritium in NC cells incubated with [3H]‐methotrexate.

In contrast, with normal epithelial cells from human embryonic intestine, indomethacin 1 μg ml−1 did not alter the cytotoxicity of methotrexate or the accumulation of tritium during incubation with [3H]‐methotrexate.

The beneficial interaction between indomethacin and methotrexate may have therapeutic potential in man.