bluuebunny/crossref_metadata_2025_split huggingface dataset:
Actions of adenine dinucleotides in the guinea‐pig taenia coli: NAD acts indirectly on P1purinoceptors; NADP acts like a P2‐purinoceptor agonist
Authors: Burnstock Geoffrey , Hoyle Charles H.V. 
Published: July 2012

The actions of the adenine dinucleotides β‐nicotinamide adenine dinucleotide (NAD) and β‐nicotinamide adenine dinucleotide phosphate (NADP) were examined on the carbachol‐contracted taenia coli of the guinea‐pig.
Both were capable of inducing full relaxations in a concentration‐dependent manner; NADP was 21.4 times more effective than NAD at EC50; the threshold for NADP was approximately 0.1 μm and for NAD approximately 1.0 μm.
The P1‐purinoceptor antagonist, 8‐phenyltheophylline (10 μm), produced a large parallel rightward shift in the NAD concentration‐response curve; in contrast it produced a small parallel leftward shift in the NADP concentration‐response curve.
Dipyridamole (0.2 μm), a purine nucleoside uptake inhibitor, markedly potentiated responses to NAD and slightly potentiated NADP. 8‐Phenyltheophylline antagonized the dipyridamole potentiation of both NAD and NADP.
By use of high performance liquid chromatography it was shown that the action of NAD involves a breakdown to adenosine.
Apamin, a K+ channel blocker, which antagonizes P2‐purinoceptor activation in the intestine, abolished responses to NADP but not to NAD.
The α‐ and β‐adrenoceptor antagonists, phentolamine (1 μm) and propranolol (1 μm), did not affect responses to NAD or NADP.
Tetrodotoxin, a neurotoxin, did not abolish responses to either NAD or NADP.
It is concluded that NAD acts largely indirectly as a P1‐purinoceptor agonist following its breakdown to adenosine by ectoenzymes, while NADP acts in a similar manner to a P2‐purinoceptor agonist.
Baclofen activates voltage‐dependent and 4‐aminopyridine sensitive K+ conductance in guinea‐pig hippocampal pyramidal cells maintained in vitro
Authors: Inoue Masumi , Matsuo Tadashi , Ogata Nobukuni 
Published: July 2012

The ionic mechanism underlying the effect of (—)‐baclofen in the hippocampus was investigated using guinea‐pig brain slices.
(—)‐Baclofen either perfused or applied directly by microiontophoresis hyperpolarized the membrane and decreased the membrane input resistance of pyramidal cells in a dose‐dependent manner.
The value of the reversal potential for the baclofen‐induced hyperpolarization, as estimated from the current‐voltage relationships, was about −95 mV.
The reversal potential of the baclofen‐induced hyperpolarization measured directly coincided with that for the post‐burst hyperpolarization which is known to result from an activation of Ca2+‐activated K+ conductance.
The amplitude of the baclofen‐induced hyperpolarization was increased in low K+ (1.24 mm) medium whereas the hyperpolarization was decreased or abolished in high K+ (12.4 and 25 mm). Low Cl− (10.2 mm) medium had no noticeable effect on the baclofen‐induced hyperpolarization.
The effect of baclofen was antagonized by a low dose of 4‐aminopyridine (5 × 10−6 m) whereas it was unaffected by Picrotoxin (2 × 105m).
These results strongly suggest that the effect of baclofen is mediated by an increase in K+ conductance.
Dopamine autoreceptors and the effects of drugs on locomotion and dopamine synthesis
Authors: Brown Frank , Campbell William , Mitchell Paul J. , Randall Karl 
Published: July 2012

Criteria for distinguishing dopamine autoreceptor agonism from other mechanisms of inhibiting locomotion were examined, together with the relationship between inhibition of locomotion and dopamine synthesis.
ED50 potencies to inhibit locomotion of mice were established for drugs from a number of categories. Spiperone 0.02 mg kg−1 significantly (P<0.05) reversed inhibition of locomotion by known dopamine agonists but not that by the other types of drug. Idazoxan antagonized inhibition of locomotion due to α2‐agonists but not dopamine agonists. RU 24926 (N‐propyl‐N,N‐di[2‐(3‐hydroxyphenyl)ethyl]amine) was antagonized by both spiperone and idazoxan.
Only for dopamine agonists was there good correlation (r = 0.97) between potencies to inhibit locomotion in mice and 1‐dihydroxyphenylalanine (1‐DOPA) accumulation in the nucleus accumbens of rats treated with γ‐butyrolactone and 3‐hydroxybenzylhydrazine. The specific dopamine D1‐agonist, SK&F 38393 (2,3,4,5‐tetrahydro‐7,8‐dihydroxy‐1‐phenyl‐1H‐3‐benzazepine), was inactive in both tests at doses up to 10 mg kg−1. The mixed dopamine agonist/antagonist, (—)‐3‐(3‐hydroxyphenyl)‐N‐propylpiperidine, commonly known as (—)‐3‐PPP, acted as a dopamine agonist in both tests but inhibited locomotion more potently than 1‐DOPA accumulation.
The inhibitory effects of dopamine agonists on locomotion were not prevented by α‐methyl‐p‐tyrosine pretreatment.
The data suggest that spiperone‐reversible inhibition of locomotion in mice is a good criterion for dopamine autoreceptor agonists. The receptors involved are affected by low doses of both dopamine agonists and antagonists and seem similar to those involved in the autoreceptor mediated inhibition of dopamine synthesis. However, inhibition of locomotion is not due simply to suppression of dopamine release brought about as a secondary consequence of effects on synthesis; a separate mechanism for inhibiting dopamine release is probably involved.
Some effects of nifedipine in guinea‐pig isolated trachealis
Authors: Ahmed F. , Foster R.W. , Small R.C. 
Published: July 2012

In trachealis depolarized by a K+‐rich medium, nifedipine (0.001–1 μmol 1−1) caused concentration‐dependent antagonism of CaCl2‐induced increase in tension, moving the CaCl2 log concentration‐effect curve to the right and depressing the maximal response.
In trachealis in normal Krebs solution, similar concentrations of nifedipine had marked antispasmogenic activity against the responses to potassium chloride (KCl) and tetraethylammonium (TEA). However, nifedipine had little, if any, antispasmogenic activity against the responses to acetylcholine or histamine.
Nifedipine 1 μmol 1−1 was tested for spasmolytic activity in tissues generating tension in response to the EC50 of acetylcholine, KCl or CaCl2. In producing spasmolysis nifedipine was most effective against CaCl2 and least effective against acetylcholine.
Nifedipine (0.01–1 μmol−1) had little or no effect on the tone of trachealis in normal Krebs solution.
Intracellular electrophysiological recording showed that nifedipine 1 μmol 1−1 could abolish spontaneous slow wave activity. This was associated with very minor depolarization and little or no loss of mechanical tone. In tissues treated with TEA (8 mmol 1−1) nifedipine abolished spike and slow wave discharge and reduced mechanical activity to the pre‐TEA level.
It is concluded that nifedipine prevents KCl‐ or TEA‐induced spasm by inhibition of Ca2+ influx. Spasm evoked by acetylcholine or histamine and the maintenance of spontaneous tone depend largely on mechanisms for increasing the cytoplasmic concentration of free Ca2+ which are resistant to nifedipine.
Tryptamine‐induced vasoconstrictor responses in rat caudal arteries are mediated predominantly via 5‐hydroxytryptamine receptors
Authors: Bradley P.B. , Humphrey P.P.A. , Williams R.H. 
Published: July 2012

It has been suggested that tryptamine can stimulate specific receptors distinct from those for 5‐hydroxytryptamine (5‐HT). We have examined this possibility in the rat isolated caudal artery, paying particular attention to the involvement of monoamine oxidase metabolism and α‐adrenoceptors, two factors that can complicate the quantification of antagonist potencies at 5‐HT receptors.
5‐HT and tryptamine were agonists over the concentration‐ranges 3.0 × 10−8 − 3.0 × 10−5 moll−1 and 1.0 × 10−6−3.0 × 10−4 moll−1 respectively. The sensitivity of the caudal artery to tryptamine was increased by about 44 fold in the presence of iproniazid (5.0 × 10−5 moll−1) and about 17 fold in the presence of pargyline (1.0 × 10−5 moll−1), while responses to 5‐HT and methoxamine were unaffected.
In the absence of iproniazid, ketanserin and methysergide were potent antagonists of responses to 5‐HT with pA2 values of 9.08 and 9.11 and slopes of the Schild regressions of 1.15 and 1.00 respectively. However, against tryptamine the antagonists were weaker such that pA2 values were similar to those against 5‐HT but the slopes of the Schild regressions were 0.47 and 0.47.
In the presence of iproniazid (or pargyline), the 5‐HT antagonists were more potent against tryptamine such that the pA2 values and the slopes of the Schild regressions were not significantly different from those against 5‐HT. Phentolamine was a weak antagonist of responses to both 5‐HT and tryptamine in the presence of iproniazid.
The findings in this study suggest that the contractile action of tryptamine in rat caudal artery is mediated predominantly by the same receptor as 5‐HT and that the differential inactivation of tryptamine by monoamine oxidase enzymes largely accounts for the different susceptibilities of 5‐HT and tryptamine to the antagonists examined.
The use of [3H]‐[d‐Pen2,d‐Pen5]enkephalin as a highly selective ligand for the δ‐binding site
Authors: Cotton R. , Kosterlitz H.W. , Paterson S.J. , Rance M.J. , Traynor J.R. 
Published: July 2012

The characteristics of the binding of [3H]‐[d‐Pen2,d‐Pen5]enkephalin were determined in homogenates of guinea‐pig and rat brain.
In the guinea‐pig, the maximum binding capacity for [3H]‐[d‐Pen2,d‐Pen5]enkephalin was 4.19 pmol g−1 and the KD 1.61 nm. In the rat, the corresponding values were 2.47 pmol g−1 and 5.42 nm. In both species, the maximum binding capacity and the affinity were not altered when μ‐binding was suppressed with [d‐Ala2, MePhe4, Gly‐ol5]enkephalin.
The μ‐agonists, [d‐Ala2, MePhe4, Gly‐ol5]enkephalin and morphine, displaced a small portion of the binding of [3H]‐[d‐Pen2,d‐Pen5]enkephalin with high affinities.
Postganglionic muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea‐pig
Authors: Faulkner D. , Fryer Allison D. , Maclagan Jennifer 
Published: July 2012

The location of neuronal inhibitory muscarinic receptors in pulmonary parasympathetic nerves was investigated in vivo and in vitro. The effects of an agonist for neuronal muscarinic receptors (pilocarpine) and an antagonist (gallamine) were tested on contractions of airway smooth muscle induced by pre‐ and postganglionic cholinergic nerve stimulation.
In anaesthetized guinea‐pigs, gallamine potentiated constriction of the tracheal tube and smaller airways induced by preganglionic stimulation. Gallamine also potentiated postganglionic stimulation induced by transmural stimulation of the tracheal tube and by 1‐1‐dimethyl‐4‐phenylpiperazinium iodide in the rest of the lung.
Bronchoconstriction and contraction of the tracheal tube induced by intravenous acetylcholine were not potentiated by gallamine, indicating that postjunctional muscarinic receptors in airway smooth muscle were not involved in the potentiation.
The muscarinic agonist, pilocarpine, had the opposite effect to gallamine and inhibited contractions of the tracheal tube induced by both types of nerve stimulation.
In vitro, the inhibitory effect of pilocarpine was demonstrated in the tracheal tube preparation stimulated both pre‐ and postganglionically. The effect of pilocarpine was antagonized by gallamine.
Because gallamine and pilocarpine affected the responses to postganglionic stimulation, the inhibitory muscarinic receptors must be located on the postganglionic neurones of the parasympathetic nerves innervating the trachea and the smaller airways. However, these experiments cannot exclude the possibility that muscarinic receptors may also be located on the soma of the ganglion cells.
Effect of long term amineptine treatment on pre‐ and postsynaptic mechanisms in rat brain
Authors: Ceci A. , Garattini S. , Gobbi M. , Mennini T. 
Published: July 2012

The effect of amineptine and its two metabolites on monoamine uptake, release and receptor binding was studied in vitro.
Amineptine and its two metabolities did not displace labelled ligands for known neurotransmitters and drug receptor sites.
Amineptine and its two metabolities did not influence [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) uptake or release by rat brain synaptosomes. Amineptine inhibited [3H]‐dopamine and [3H]‐noradrenaline ([3H]‐NA) accumulation, with IC50 values of 1.4 and 10 μM, respectively. The effect was retained, though with lower efficacy, by the two metabolites.
Amineptine released [3H]‐dopamine from preloaded synaptosomes. Metabolite 1 had no effect on catecholamine release, and metabolite 2 was about half as active as the parent compound on [3H]‐dopamine release.
The releasing effect of amineptine on [3H]‐dopamine was potentiated by reserpine pretreatment, suggesting that the drug acts on the cytoplasmic neurotransmitter pool.
Chronic treatment with amineptine (20 mg kg−1, twice daily for 15 days followed by a 3 days drug withdrawal period) resulted in a decrease of [3H]‐spiperone binding sites in striatum, and of [3H]‐dihyroalprenolol and [3H]‐clonidine in cortex.
Chronic treatment with amineptine reduced basal [3H]‐dopamine accumulation in striatal synaptosomes, without affecting [3H]‐NA or [3H]‐5‐HT accumulation.
The adaptive changes in the pre‐ and postsynaptic dopamine mechanisms observed after long term treatment with amineptine are consistent with the drug acting as an indirect dopamine agonist.
The down regulation of β‐ and α2‐noradrenoceptors observed after long term amineptine treatment may play a role in the antidepressant activity of the drug.
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.