bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of 5‐HT3 receptor antagonists on 5‐HT and nicotinic depolarizations in guinea‐pig submucosal neurones
Authors: Vanner S. , Surprenant A. 
Published: July 2012

Intracellular recordings were made from neurones of the guinea‐pig submucosal plexus. The effects of several 5‐hydroxytryptamine3 (5‐HT3) receptor antagonists on depolarizations produced by ionophoretic application of 5‐HT and acetylcholine, as well as on fast excitatory postsynaptic potentials (fast e.p.s.ps) produced by nerve stimulation were examined.
ICS 205–930, GR 38032F, MDL 72222, cocaine and curare all inhibited the fast e.p.s.p. as well as the depolarizations in response to 5‐HT and acetylcholine (ACh) ionophoresis in a dose‐dependent fashion.
IC50 values for ICS 205–930, GR 38032F, MDL 72222, cocaine and curare in inhibiting the 5‐HT mediated depolarizations were 12 nm, 100 nm, 3 μm, 3 μm and 20 μm, respectively.
IC50 values for ICS 205–930, GR 38032F, MDL 72222, cocaine and curare in inhibiting the nicotinic depolarizations were 4 μm, 12 μm, 11 μm, 6 μm and 17 μm, respectively. Similar IC50 values were obtained for inhibition of the fast e.p.s.ps by these antagonists.
The nicotinic receptor blocker, hexamethonium, inhibited the nicotinic depolarization and the fast e.p.s.p. with IC50 values of 10 μm. Hexamethonium (10 μm‐5 mm) did not alter the depolarization induced by 5‐HT.
These results demonstrate that the pharmacological profile of 5‐HT3 receptors present on submucosal neurones is identical to that of 5‐HT3 receptors on myenteric neurones and, thus, provide evidence that the enteric neuronal 5‐HT3 receptor forms a receptor subtype distinct from that characterized in other parts of the autonomic nervous system.
Activation of μ‐ and δ‐opioid receptors present on the same nerve terminals depresses transmitter release in the mouse hypogastric ganglion
Authors: Rogers Helen , Henderson Graeme 
Published: July 2012

The inhibitory actions of μ‐ and δ‐opioid receptor agonists on the strong, single fibre synaptic input to neurones contained in the mouse hypogastric ganglion have been examined.
The opioid agonists [d‐Ala2,NMePhe4,Gly‐ol5]enkephalin (DAMGO, 10 nm‐10 μm), morphine (10–30 μm), [d‐Ser2,Leu5,Thr6]enkephalin (DSLET, 3 nm‐1 μm), [d‐Pen2,d‐Pen5]enkephalin (DPDPE, 10 nm‐10 μm), all depressed the single fibre, all‐or‐nothing, nicotinic, excitatory synaptic potential (e.p.s.p.) recorded in mouse hypogastric ganglion neurones. U50488H (0.3–1 μm) was without effect.
The effect of DSLET, but not that of DAMGO, was reversed by the δ‐opioid receptor‐selective antagonist, ICI 174864 (0.3 μm). Naloxone (0.3 μm) antagonized the effect of both DSLET and DAMGO.
The site of action of the μ‐ and δ‐receptor agonists was on the presynaptic terminals, since at the concentrations which depressed the e.p.s.p. these drugs did not affect the resting membrane potential or input resistance of the postganglionic neurone body, nor did they depress the postganglionic, nicotinic response to exogenously applied acetylcholine.
Quantal analysis further confirmed the presynaptic site of action; μ‐ and δ‐opioid receptor agonists decreased the mean number of quanta released per stimulus but did not reduce the mean amplitude of the quantal unit.
It was concluded that μ‐ and δ‐opioid receptors were located on the same presynaptic nerve terminals since, in the same neurones, μ‐ and δ‐opioid receptor agonists depressed the same single fibre inputs.
The potassium channel blockers barium and quinine, at concentrations known to block opioid‐activated somatic potassium conductances, reduced slightly but did not abolish the μ‐ and δ‐opioid receptor‐mediated inhibition of the e.p.s.p.
Sodium nitroprusside modulates the fibrinolytic system in the rabbit
Authors: Lidbury Paul S. , Korbut Richard , Vane John R. 
Published: July 2012

We have investigated the effect of sodium nitroprusside (NP) and glyceryl trinitrate (GTN) on fibrinolysis in anaesthetized rabbits ex vivo and in vitro by measurement of euglobulin clot lysis time (ECLT), plasma levels of tissue plasminogen activator (t‐PA) activity, plasma t‐PA antigen levels and plasminogen activator inhibitor (PAI‐1) activity.
In vivo, NP (30 μg kg−1), GTN (30 μg kg−1) and prostacyclin (3 μg kg−1) caused similar transient decreases in left ventricular systolic pressure. However, while prostacyclin induced near‐maximal inhibition of ex vivo platelet aggregation, NP or GTN had no effect.
Ex vivo, NP caused a significant decrease in ECLT and an increase in plasma t‐PA activity.
Intravenous co‐administration of t‐PA (30 μg kg−1) with NP caused substantial prolongation of plasma t‐PA activity, without affecting t‐PA antigen levels.
In whole blood in vitro, NP (30 μg kg−1) prevented the time‐dependent increase in PAI‐1 activity and inhibited inactivation of added t‐PA (10 ng ml−1).
We propose that NP exhibited fibrinolytic activity through increased t‐PA activity as a result of inhibition of PAI‐1 release from platelets. These results could have important therapeutic consequences when t‐PA and nitrate treatments are combined.
An examination of the 5‐HT3 receptor mediating contraction and evoked [3H]‐acetylcholine release in the guinea‐pig ileum
Authors: Fox Alyson J. , Morton Ian K.M. 
Published: July 2012

The relative contributions of two classes of 5‐hydroxytryptamine (5‐HT) receptor (5‐HT2 and 5‐HT3) to the contractile action of 5‐HT, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT) and α‐methyl‐5‐hydroxytryptamine (α‐methyl‐5‐HT) were studied in the guinea‐pig ileum longitudinal muscle‐myenteric plexus strip (LMMP) preparation. Contractility studies were combined with an analysis of the effects of the three agonists on [3H]‐acetylcholine ([3H]‐ACh) release from preparations preincubated with [3H]‐choline.
In contracting the LMMP, 5‐HT was approximately one order of magnitude more active than 2‐methyl‐5‐HT and α‐methyl‐5‐HT, with relative activities for 5‐HT: 2‐methyl‐5‐HT: α‐methyl‐5‐HT of 1.00:0.13:0.10.
Ketanserin (1 μm) was without effect on the concentration‐response curves for contraction to 5‐HT, 2‐methyl‐5‐HT or α‐methyl‐5‐HT, whilst ondansetron (GR38032F; 1 μm) produced a parallel rightward displacement of the upper part of the concentration‐response curves to 5‐HT and α‐methyl‐5‐HT and of the entire curve to 2‐methyl‐5‐HT.
In increasing the spontaneous release of [3H]‐ACh from the LMMP, 5‐HT was again approximately one order of magnitude more active than 2‐methyl‐5‐HT and α‐methyl‐5‐HT with relative activities for 5‐HT: 2‐methyl‐5‐HT: α‐methyl‐5‐HT of 1.00: 0.19: 0.11.
Ondansetron (1 μm) greatly attenuated the increase in spontaneous [3H]‐ACh release evoked by all three agonists. pKB estimates of 7.62 ±0.12 and 7.64 ± 0.09 were obtained for ondansetron antagonism of 5‐HT and 2‐methyl‐5‐HT‐evoked increases respectively.
These data suggest that the contractile action of 5‐HT, 2‐methyl‐5‐HT and α‐methyl‐5‐HT in the guinea‐pig ileum can, under these conditions, be accounted for largely in terms of 5‐HT3 receptor activation. Estimates for pKB obtained with ondansetron are in accordance with those previously obtained from contractility studies in this preparation and these findings are discussed in terms of the postulated existence of subtypes of 5‐HT3 receptors.
A novel series of non‐quaternary oxadiazoles acting as full agonists at muscarinic receptors
Authors: Freedman S.B. , Harley E.A. , Patel S. , Newberry N.R. , Gilbert M.J. , McKnight A.T. , Tang J.K. , Maguire J.J. , Mudunkotuwa N.T. , Baker R. , Street L.J. , MacLeod A.M. , Saunders J. , Iversen L.L. 
Published: July 2012

A novel series of non‐quaternary oxadiazole‐based muscarinic agonists demonstrated high affinity for muscarinic receptors.
These agonists possessed high efficacy in the nanomolar range at muscarinic receptors in the superior cervical ganglion, atrium and ileum but did not show selectivity across the tissue preparations.
Two amino oxadiazoles, one from a quinuclidine series (L‐660,863) and one from a 1‐azanorbornane series (L‐670,207) possessed a high ratio of potency for displacing the binding of [3H]‐N‐methylscopolamine ([3H]‐NMS) to potency for displacing the agonist [3H]‐oxotremorine‐M ([3H]‐oxo‐M) (NMS/oxo‐M ratio) predictive of high efficacy in the cortex.
The two azanorbornane derivatives L‐670,548 and L‐670,207 stimulated the turnover of phosphatidylinositol in the cortex with a potency higher than that obtained with any other known muscarinic agonist (ED50 0.26 and 0.18 μm respectively).
The maximum response obtained with L‐670,207 was greater than that observed for carbachol but was comparable to that of the natural ligand acetylcholine.
These oxadiazole muscarinic agonists are among the most potent and efficacious non‐quaternary muscarinic agonists ever described.
Alterations in histamine receptors of guinea‐pig ileal smooth muscle produced during agonist‐induced desensitization
Authors: Horio Shuhei , Nakamura Shigeki , Ishida Yukio 
Published: July 2012

The effects of prolonged treatment with histamine (10−4 m, 30 min) on desensitization at histamine H1‐receptors of guinea‐pig ileal longitudinal muscle were investigated.
This treatment did not change either the maximum amount or dissociation constant (Kd) of [3H]‐mepyramine binding to membranes of guinea‐pig ileal muscle.
In contrast, this treatment shifted the histamine inhibition curves of [3H]‐mepyramine binding to the right both in the presence and absence of 0.5 mm guanosine‐5′‐triphosphate (GTP). This rightward shift of the curves occurred rapidly in the first 10 min of exposure to histamine.
The histamine inhibition curves were analyzed with a two binding sites model. It was shown that the histamine‐induced affinity change of the receptor for the agonist occurred with the high affinity binding component (which comprise about 80% of the total), whereas no significant change occurred with the low affinity component. The GTP‐dependent decrease in the affinity of the receptor for the agonist also occurred with the high affinity component both in control and histamine‐treated preparations.
These studies suggest that histamine‐induced desensitization was caused by alteration in the affinity of the receptor for the agonist rather than reduction in the number of the receptors and that the interaction of the receptor with a guanine nucleotide regulatory protein was retained in the desensitized state.
Regional and cardiac haemodynamic effects of NG‐nitro‐l‐arginine methyl ester in conscious, Long Evans rats
Authors: Gardiner S.M. , Compton A.M. , Kemp P.A. , Bennett T. 
Published: July 2012

Regional haemodynamic responses to i.v. bolus doses (0.1–10.0 mg kg−1) of NG‐nitro‐l‐arginine methyl ester (l‐NAME) were measured in conscious, Long Evans rats (n = 8) chronically instrumented with renal, mesenteric and hindquarters pulsed Doppler flow probes and intravascular catheters.
l‐NAME caused dose‐dependent pressor effects associated with renal, mesenteric and hindquarters vasoconstrictions. The mesenteric vascular bed showed earlier onset with more rapid, and greater, maximum vasoconstrictions than the renal or hindquarters vascular beds; however, the hindquarters vasoconstriction was more persistent. d‐NAME was without significant effects (n = 2).
Primed infusion of l‐arginine (100 mg kg−1 bolus followed by 100 mg kg−1 h−1 infusion), starting 10 min after an i.v. bolus injection of l‐NAME (10 mg kg−1), caused significant reversal of the pressor responses, and renal and mesenteric vasoconstrictions, but not of the hindquarters vasoconstriction. Primed infusions of l‐arginine (100 mg kg−1, 100 mg kg−1 h−1) starting 5 min after l‐NAME (1 mg kg−1) additionally caused some reversal of the hindquarters vasoconstriction, but this effect was transient.
Primed infusion of l‐arginine (100 mg kg−1, 100 mg kg−1 h−1) starting 30 min before i.v. bolus injection of l‐NAME (10 mg kg−1) caused significant attenuation of the pressor effects and the renal and mesenteric vasoconstrictions but not of the hindquarters vasoconstriction.
In a separate group of rats (n = 8) chronically instrumented with thoracic aortic electromagnetic flow probes for the measurement of cardiac haemodynamics, i.v. bolus injection of l‐NAME (10 mg kg−1) produced significant reductions in total peripheral conductance, cardiac output, stroke volume, peak thoracic aortic flow and the maximum rate of rise of aortic flow; these were coincident with the maximum pressor and vasoconstrictor effects.
These results, collectively, are consistent with l‐NAME interfering with l‐arginine‐nitric oxide pathways that have important influences on regional vascular conductances in vivo. The pressor effect resulting from l‐NAME‐induced vasoconstrictions is offset by a substantial reduction in cardiac function that may depend on direct and/or indirect effects of l‐NAME on the heart.
Reduced high‐affinity α1‐adrenoceptors in liver of senescent rats: implications of assessment at various temperatures
Authors: Borst Stephen E. , Scarpace Philip J. 
Published: July 2012

We investigated the changes occurring as a result of aging in α1‐adrenoceptors in the livers of Fisher 344 female rats. For comparison, we also measured β‐adrenoceptors in this tissue. Three age groups were studied, including young adults (aged 6 months), mature adults (aged 16 months) and senescent animals (aged 25 months).
The density of α1‐receptors was measured by use of [3H]‐prazosin and was found to be reduced 39% (P > 0.01) at 25 months compared with 6 months. The percentage of α1‐receptors displaying high affinity for adrenaline was also reduced from 85.6% at 6 months to 51.6% at 25 months (P > 0.02).
In contrast, the density of β‐receptors, which was measured with [125I]‐iodocyanopindolol, was increased 104% between 6 months and 25 months. The affinity of both α1‐ and β‐adrenoceptors for antagonists was unchanged with age.
We found that receptor affinity for agonists may be measured accurately in binding studies conducted at 4°C or 25°C, but that the apparent affinity for agonist was artifactually reduced in studies conducted at 37°C. This effect is poorly reversible, in that reduced agonist‐affinity is also observed in tissue which has been incubated at 37°C and then cooled to 4°C before performing the binding studies.
It is concluded that liver α1‐adrenoceptor function is reduced and β‐adrenoceptor function increased in senescence.
Two distinct α1‐adrenoceptor subtypes involved in noradrenaline contraction of the rabbit thoracic aorta
Authors: Muramatsu Ikunobu , Kigoshi Shigeru , Oshita Masafumi 
Published: July 2012

Recently, α1‐adrenoceptors in blood vessels have been classified into three subtypes (α1H, α1L and α1N). We examined which subtype (or subtypes) is involved in the noradrenaline‐induced contraction of rabbit thoracic aorta.
Noradrenaline produced a concentration‐dependent contraction in the rabbit isolated thoracic aorta. Prazosin antagonized the contractions to noradrenaline, resulting in a rightward displacement of the concentration‐response curve. However, the shift was not proportional to the concentration of prazosin; Schild plots showed that the inhibition by prazosin was biphasic, implying that noradrenaline acted through two receptor populations. Two affinity constants (pKB values of 10.02 and 8.83) were determined for prazosin at these sites.
However, under continuous treatment with 1 nm prazosin, or in strips pretreated with chlorethylclonidine (CEC; an α1H inactivating agent) to remove the contribution of one receptor population, prazosin showed a single pKB or pA2 value of approximately 8.3.
Yohimbine also produced biphasic antagonism of noradrenaline‐induced contractions, resulting in two affinity constants (pKB = 6.52 and 6.17). However, a monophasic Schild plot was obtained for yohimbine either in the presence of 1 nm prazosin (pA2 = 6.08) or in strips pretreated with CEC (pA2 = 6.03).
The Schild plot for HV723 (a selective α1N‐antagonist) yielded a monophasic slope (pKB = 8.47) and the inhibition was not affected by 1 nm prazosin or CEC‐pretreatment.
[3H]‐prazosin bound to α1‐adrenoceptors of the aortic membrane preparations with two different affinities (pKD = 9.94 and 8.37). The high but not the low affinity site was completely masked by 1 nm prazosin and inactivated by pretreatment with CEC.
These results strongly suggest that noradrenaline‐induced contraction of the rabbit thoracic aorta is mediated through two distinct α1‐adrenoceptor subtypes, designated α1H and α1L.
Relative potencies for barbiturate binding to the Torpedo acetylcholine receptor
Authors: Dodson Barbara A. , Urh Rhonda R. , Miller Keith W. 
Published: July 2012

The structural requirements of an allosteric barbiturate binding site on acetylcholine receptor‐rich membranes isolated from Torpedo electroplaques have been characterized by the ability of fourteen barbiturates to displace [14C]‐amobarbitone binding.
The barbiturates could be grouped into two classes with ten barbiturates producing a strong inhibition of [14C]‐amobarbitone binding (class one) and with four exerting minimal effects (class two).
Eight of the ten class one barbiturates displaced essentially all of the [14C]‐amobarbitone from its binding site, while, at their respective aqueous solubility limits, two of these barbiturates (thiopentone and dimethylbutylbarbitone (DMBB)) inhibited [14C]‐amobarbitone binding by nearly 80%. The apparent inhibition constants (KI) for the class one barbiturates ranged from 13 μm for amobarbitone to 2.8 mm for barbitone with the other eight agents lying in the range 100–600 μm, and having the rank order pentobarbitone ≅ secobarbitone > thiopentone > DMBB > butabarbitone ≅ phenobarbitone > aprobarbitone > allylbarbitone.
By contrast, the class two barbiturates had minimal effects even at close to saturating concentrations. [14C]‐amobarbitone binding was reduced slightly (< 30%) by hexobarbitone, mephobarbitone and methohexitone and was enhanced slightly (< 20%) by metharbitone.
All of the class two, but none of the class one barbiturates, were N‐methylated.
The pharmacological properties of the imidazobenzodiazepine, FG 8205, a novel partial agonist at the benzodiazepine receptor
Authors: Tricklebank M.D. , Honoré T. , Iversen S.D. , Kemp J.A. , Knight A.R. , Marshall G.R. , Rupniak N.M.J. , Singh L. , Tye S. , Watjen F. , Wong E.H.F. 
Published: July 2012

The pharmacological properties of the benzodiazepine receptor ligand, FG 8205 (7‐chloro‐5,6‐dihydro‐5‐methyl‐6‐oxo‐3‐(5‐isopropyl‐1,2,4‐oxadiazol‐3‐yl)‐4H‐imidazol[1,5a][1,4]benzodiazepine) have been examined.
FG 8205 potently displaced [3H]‐flumazenil binding in rat cortical membranes with a Ki of 3.3 nm, but was inactive at 13 neurotransmitter recognition sites.
Consistent with a partial agonist profile, the affinity of FG 8205 for the benzodiazepine recognition site was increased in the presence of γ‐aminobutyric acid (GABA, 300 μm) by a degree (−log [IC50 in the presence of GABA/IC50 alone] = 0.34) significantly less than found for diazepam (0.46). FG 8205 also potentiated the inhibitory potency of the GABAA‐receptor agonist, isoguvacine, on the hippocampal CA1 population spike and, again, the maximum shift (−log dose‐ratio = 0.2) was significantly less than that seen with diazepam (0.4).
In anticonvulsant studies, the ED50 doses of FG 8205 and diazepam needed to antagonize seizures induced by pentylenetetrazol (PTZ) or by sound in audiogenic seizure prone mice were similar with values of 0.2–0.3 mg kg−1, i.p. However, even high doses of FG 8205 (50 mg kg−1) did not protect against seizures induced by electroshock.
FG 8205 released responding suppressed by footshock in a rat operant conditioned emotional response task over the dose range 0.5–50 mg kg−1 (i.p.). Similar doses of FG 8205 had a marked taming effect in cynomolgus monkeys. However, measures of sedation and ataxia (as measured by rotarod in the mouse, climbing behaviour in the rat, and by scoring arousal and co‐ordination in primates) were slight and only transiently affected by FG 8205, and FG 8205 significantly antagonized the rotarod performance deficit induced by diazepam in the mouse.
While the potentiation by FG 8205 of the response to isoguvacine in the rat hippocampal slice and the anxiolytic‐like effects of the compound in both rats and primates were reversed by the benzodiazepine receptor antagonist, flumazenil, high doses of the antagonist were able only marginally to block the protective effects of FG 8205 against seizures induced by PTZ in the mouse.
Thus, FG 8205 does not show the marked motor impairment characteristic of full agonists at the benzodiazepine receptor, consistent with its partial agonist profile in in vitro assay systems. Nevertheless, the compound has sufficient intrinsic activity to maintain high efficacy in anticonvulsant and anxiolytic tests.
SK&F S‐106203 inhibits leukotriene C4, leukotriene D4 and leukotriene E4 vasopressor responses in the conscious rat
Authors: Smith Edward F. , Slivjak Mark J. , Egan John W. , Eckardt R.D. , Newton J.F. 
Published: July 2012

The purpose of these experiments was to investigate the effects of the selective peptidoleukotriene receptor antagonist, SK&F S‐106203, on leukotriene C4 (LTC4), LTD4 and LTE4 vasopressor responses in the conscious, normotensive rat. SK&F S‐106203 was administered as a bolus followed by a continuous infusion in order to provide information on the relationship between antagonism of leukotriene responses and steady‐state plasma concentrations.
Infusion of SK&F S‐106203 at doses of 0.2 mg kg−1 + 1 mg kg−1 h−1, 1 mg kg−1 + 3 mg kg−1 h−1 or 2 mg kg−1 + 10 mg kg−1 h−1 produced dose‐dependent steady‐state plasma drug concentrations of 1.0, 3.2 and 23.8 μg ml−1, respectively. Plasma SK&F S‐106203 concentrations appeared to increase in a linear fashion at doses of 1 and 3 mg kg−1 h−1; at the highest dose the increment in plasma drug concentrations (i.e., 7–8 fold) was greater than the increment in dose (i.e., 3 fold), suggesting saturation of the primary clearance mechanism(s) at this dose.
SK&F S‐106203 (2 mg kg−1 + 10 mg kg−1 h−1) had no effect on noradrenaline‐, vasopressin‐, isoprenaline‐, or U 46619‐induced responses.
SK&F S‐106203 produced dose‐dependent rightward shifts in the LTC4 and LTE4 dose‐response curves. Administration of SK&F S‐106203 at doses of 0.2 mg kg−1 + 1 mg kg−1 h−1, 1 mg kg−1 + 3 mg kg−1 h−1, or 2 mg kg−1 + 10 mg kg−1 h−1 produced dose‐ratios of 1.0, 3.1 and 19.9, respectively, against LTC4 responses, and dose‐ratios of 1.6, 3.8 and 9.1, respectively, against LTE4 responses.
Against LTD4 responses, SK&F S‐106203 at doses of 0.2 mg kg−1 + 1 mg kg−1 h−1, 1 mg kg−1 + 3 mg kg−1 h−1, or 2 mg kg−1 + 10 mg kg−1 h−1 produced dose‐ratios of 2.5, 2.8, and 11.4, respectively. Administration of d‐penicillamine, a non‐competitive LTD4 dipeptidase inhibitor, had no effect on LTD4 responses.
The similarity in the LTD4 dose‐ratios at the two lower infusion rates, despite increases in the plasma drug concentrations, suggests the existence of pharmacologically heterogeneous LTD4 receptors. These results indicate that SK&F S‐106203 is a potent, selective and apparently competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the intact rat.