bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereoselective effects of the enantiomers of bupivacaine on the electrophysiological properties of the guinea‐pig papillary muscle
Authors: Vanhoutte Filip , Vereecke Johan , Verbeke Norbert , Carmeliet Edward 
Published: July 2012

Direct myocardial effects of the S(−)‐ and R(+)‐enantiomers of bupivacaine were compared in the guinea‐pig isolated papillary muscle by recording transmembrane action potentials with the standard microelectrode technique.
In 5.4 mm K+, at a stimulation rate of 1 Hz, the maximal rate of depolarization () was reduced to 59.9 ± 1.4% (n = 10) of control (mean ± s.e.mean) in the presence of 10 μm R(+)‐bupivacaine, and to 76.7 ± 1.2% (n = 14) in the presence of the same concentration of S(−)‐bupivacaine. This was mainly due to a difference in time constant at which block dissipated during the diastolic period. Recovery was slower in the presence of R(+)‐bupivacaine. The slower recovery in the presence of R(+)‐bupivacaine resulted also in a more pronounced frequency‐dependent block of .
Time constants for recovery from use‐dependent block became significantly faster for both enantiomers on hyperpolarization, while no significant change was observed at depolarization. At all membrane potentials recovery was slower in the presence of R(+)‐bupivacaine.
The action potential duration (APD) was shortened to a greater extent in the presence of R(+)‐bupivacaine over a large range of stimulation frequencies.
We conclude that S(−)‐bupivacaine affects and APD in the guinea‐pig papillary muscle less than the R(+)‐enantiomer at different rates of stimulation and resting membrane potentials.
Determination of the role of noradrenergic and 5‐hydroxytryptaminergic neurones in postsynaptic α2‐adrenoceptor desensitization by desipramine and ECS
Authors: Heal D.J. , Prow M.R. , Buckett W.R. 
Published: July 2012

Experiments were conducted to determine the respective roles which noradrenergic and 5‐hydroxytryptaminergic neurones play in the down‐regulation of postsynaptic α2‐adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine‐induced mydriasis in conscious mice.
Mydriasis to clonidine (0.1 mg kg−1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg−1, i.p.) for 14 days or ECS (200 V, 2 s) given five times over ten days confirming our previous observations.
The neurotoxin, DSP‐4 (100 mg kg−1, i.p. × 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS.
Lesioning of central 5‐hydroxytryptaminergic neurones with 5,7‐dihydroxytryptamine (75 μg, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS.
Since noradrenergic neurones are essential for the desensitization of postsynaptic α2‐adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5‐HT‐containing neurones do not play a permissive role in the down‐regulation of postsynaptic α2‐adrenoceptors by either antidepressant treatment.
Analgesic doses of morphine do not reduce noxious stimulus‐evoked release of immunoreactive neurokinins in the dorsal horn of the spinal cat
Authors: Lang C.W. , Duggan A.W. , Hope P.J. 
Published: July 2012

Antibody microprobes were used to detect immunoreactive neurokinin A release in the dorsal spinal cord of barbiturate‐anaesthetized spinal cats.
Noxious mechanical stimulation of the ipsilateral hind paw and electrical stimulation (suprathreshold for unmyelinated primary afferent fibres) of the ipsilateral tibial nerve evoked immunoreactive neurokinin A release.
Systemic morphine, 5 mg kg−1, i.v., did not block immunoreactive neurokinin A release in response to these stimuli.
Subsequent naloxone administration, 0.5 mg kg−1, i.v., did not alter this stimulus‐evoked release.
Basal levels of immunoreactive neurokinin A were unaltered by morphine or naloxone.
These results suggest that the analgesic effects of morphine at the spinal cord level are not brought about by activation of presynaptic opiate receptors on neurokinin A containing afferent terminals.
Role of the σ receptor in the inhibition of [3H]‐noradrenaline uptake in brain synaptosomes and adrenal chromaffin cells
Authors: Rogers Cheryl , Lemaire Simon 
Published: July 2012

Rat brain synaptosomes and cultured bovine adrenal chromaffin cells were used to monitor the inhibitory effects of phencyclidine (PCP) and sigma (σ)‐receptor ligands on the uptake of [3H]‐noradrenaline ([3H]‐NA).
A Na+‐dependent high affinity uptake was observed in synaptosomes (30°C) and chromaffin cells (37°C) with Km of 0.22 and 0.56 μm and Vmax of 2.5 pmol min−1 mg−1 protein and 0.7 pmol min−1 per 106 cells, respectively.
PCP and haloperidol inhibited the high affinity uptake with IC50 of 0.17 and 0.42 μm, respectively in synaptosomes and 0.24 and 0.47 μm, respectively in adrenal chromaffin cells.
A close correlation (r = 0.96) was established between the ability of various PCP and σ‐receptor ligands to inhibit [3H]‐NA uptake in both systems: PCP > TCP > haloperidol > 3‐(+)‐PPP > MK‐801 ≥ (−)‐butaclamol > (+)‐SKF‐10047 > DTG. Spiperone and opioid receptor ligands were ineffective at 20 μm.
These results indicate that the central and peripheral inhibitory effects of PCP and σ‐receptor ligands on [3H]‐NA uptake involves a receptor (σ1‐like) which is distinct from that (PCP2) recognized for the inhibition of [3H]‐dopamine uptake by PCP.
Identification of a D1 dopamine receptor, not linked to adenylate cyclase, on lactotroph cells
Authors: Schoors Danny F. , Vauquelin Georges P. , De Vos Hilde , Smets Gerda , Velkeniers Brigitte , Vanhaelst Luc , Dupont Alain G. 
Published: July 2012

We studied the lactotroph cells of the rat by both in vivo and in vitro pharmacological techniques for the presence of D1‐receptors. Both approaches revealed the presence of a D2‐receptor, stimulated by quinpirole (resulting in an inhibition of prolactin secretion) and blocked by domperidone.
Administration of fenoldopam, the most selective D1‐receptor agonist currently available, resulted in a dose‐dependent decrease of prolactin secretion in vivo (after pretreatment with α‐methyl‐p‐tyrosine) and in vitro (cultured pituitary cells). This increase was dose‐dependently blocked by the selective D1‐receptor antagonist, SCH 23390, and although the effect of fenoldopam was less than that obtained by D2‐receptor stimulation, these data suggest that a D1‐receptor also controls prolactin secretion.
In order to detect the location of these dopamine receptors, autoradiographic studies were performed by use of [3H]‐SCH 23390 and [3H]‐spiperone as markers for D1 and D2‐receptors, respectively. Specific binding sites for [3H]‐SCH 23390 were demonstrated. Fenoldopam dose‐dependently reduced [3H]‐SCH 23390 binding, but had no effect on [3H]‐spiperone binding. Immunocytochemical labelling of prolactin cells after incubation with [3H]‐SCH 23390 revealed that the granulae and hence, D1 binding sites were present on the lactotroph cells.
Radioligand binding studies performed on membranes from anterior pituitary cells revealed the presence of the D2‐receptor (54 fmol mg−1 protein) with a Kd of 0.58 nm for [3H]‐spiperone, but failed to detect D1 ‐receptors.
Finally, we studied the effect of dopamine and of fenoldopam on the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) content of anterior pituitary cells. Although cyclic AMP increased upon prostacyclin administration, indicating an intact adenylate cyclase system, fenoldopam failed to increase the cyclic AMP production.
It is tempting to speculate that fenoldopam reduces prolactin secretion through interaction with a non‐cyclase‐linked D1‐receptor on the lactotroph cells.
Measurements of tacrine and monoamines in brain by in vivo microdialysis argue against release of monoamines by tacrine at therapeutic doses
Authors: Baldwin H.A. , De Souza R.J. , Sarna G.S. , Murray T.K. , Green A.R. , Cross A.J. 
Published: July 2012

The concentration of tacrine (tetrahydroaminoacridine or THA) in plasma, regions of brain and cerebral extracellular fluid has been studied in the rat at various times following injection of a dose of 5 mg kg−1, i.p.
The peak plasma THA concentration was 2.46 nmol ml−1, and occurred 30 min post injection and clearance was first order (t1/2 = 90min). The concentration in the brain peaked between 30–60 min, and was around 30 times plasma concentration (striatum peak concentration = 65 ± 3 nmol g−1). Extracellular cerebral concentration measured by in vivo microdialysis was similar to plasma concentration with the peak occurring 100 min post‐injection.
No evidence was obtained by in vivo dialysis for THA inducing dopamine release from striatum or 5‐hydroxytryptamine (5‐HT) release from the frontal cortex. Enhanced release of dopamine did occur after (+)‐amphetamine (5 mg kg−1, i.p.) injection, while KCl (100 mm) in the probe released both dopamine and 5‐HT.
Since the minimum plasma THA concentration achieved in this study was at least twice that found in the plasma of patients given THA for the treatment of dementia, these results suggest that monoamine release in the brain does not occur during therapy.
Effect of NG‐monomethyl l‐arginine (l‐NMMA) and NG‐nitro l‐arginine (l‐NOARG) on non‐adrenergic non‐cholinergic relaxation in the circular muscle of the human ileum
Authors: Maggi Carlo Alberto , Barbanti Gabriele , Turini Damiano , Giuliani Sandro 
Published: July 2012

We have investigated the effect of the NO synthesis inhibitors, NG‐monomethyl l‐arginine (l‐NMMA) and NG‐nitro l‐arginine (l‐NOARG) on the non‐adrenergic non‐cholinergic (NANC) relaxation produced by electrical field stimulation in the circular muscle of the human ileum.
In the presence of atropine and guanethidine (1 and 3 μm, respectively), electrical field stimulation produced tetrodotoxin‐sensitive relaxation of the strips. l‐NMMA, starting from 100 μm, produced a concentration‐dependent inhibition of the evoked relaxations (2 Hz); maximal inhibition at 1 mm averaged about 35%.
The inhibitory effect of l‐NMMA was unchanged by previous incubation with d‐arginine while it was prevented by l‐arginine (l‐Arg). l‐NMMA did not affect isoprenaline‐induced relaxation.
l‐NOARG (1–30 μm) concentration‐dependently inhibited the evoked relaxations at 2 Hz, up to a maximum of 65% inhibition, although in some strips complete inhibition of the response was observed. The effect of l‐NOARG was reversed by l‐Arg. l‐NOARG did not affect isoprenaline‐induced relaxation.
These results suggest that NO may be involved in inhibitory NANC transmission in the circular muscle of the human ileum.
Capsaicin‐sensitive vagal stimulation‐induced gastric acid secretion in the rat: evidence for cholinergic vagal afferents
Authors: Sharkey Keith A. , Oland Lorraine D. , Kirk David R. , Davison Joseph S. 
Published: July 2012

The effects of electrical vagal stimulation on frequency‐dependent gastric acid secretion were investigated in urethane‐anaesthetized rats in vivo.
Stimulation at 4, 16 or 32 Hz was performed in rats treated with atropine (1mg kg−1, i.v.), hexamethonium (10 mg kg−1, i.v. bolus and 1 mg kg−1 min−1, i.v. infusion) or atropine and hexamethonium (doses as above); in some experiments pentagastrin (1.2 μg kg−1 h−1, i.v. infusion) was infused prior to stimulation.
Maximal acid secretion occurred at 16 Hz. This was significantly reduced but not abolished by atropine or hexamethonium and completely abolished after atropine and hexamethonium. In the presence of pentagastrin, the acid secretory response to 16 Hz stimulation was augmented, atropine or hexamethonium reduced stimulated secretion by about 70%, whereas atropine and hexamethonium completely abolished stimulated secretion.
In rats in which the vagus nerve was pretreated with capsaicin 10–14 days before experimentation there was a significant reduction (by about 40%) in stimulated acid secretion at 16 Hz, which was virtually abolished by atropine treatment. After acute treatment of the vagus nerve with capsaicin (at the time of experimentation) maximally stimulated acid secretion was significantly reduced by about 50%.
Taken together, these results indicate that capsaicin‐sensitive afferent fibres contribute to the acid secretory response induced by electrical vagal stimulation in the rat. Based on pharmacological evidence, the capsaicin‐sensitive afferent fibres may be cholinergic, since atropine and hexamethonium totally abolish vagal stimulation‐induced acid secretion.
R‐(+)‐HA‐966, a glycine/NMDA receptor antagonist, selectively blocks the activation of the mesolimbic dopamine system by amphetamine
Authors: Hutson P.H. , Bristow L.J. , Thorn L. , Tricklebank M.D. 
Published: July 2012

The effects of the glycine/NMDA receptor antagonist, (+)‐HA‐966 on the neurochemical and behavioural responses to amphetamine have been determined in the mouse and rat.
In vehicle‐treated control mice, (+)‐HA‐966 (30–100 mg kg−1) did not affect dopamine synthesis in either the nucleus accumbens or striatum and was without marked effect on spontaneous locomotor activity.
In the mouse, (+)‐HA‐966 (30 and 100 mg kg−1) dose‐dependently blocked the enhancement of dopamine synthesis induced in the nucleus accumbens by amphetamine, but was without effect on the increase in dopamine synthesis in the striatum.
Intracerebroventricular administration of the glycine/NMDA receptor antagonist, 5,7‐dichlorokynurenic acid, in the mouse (10 μg) also significantly attenuated amphetamine‐enhanced DOPA accumulation in the nucleus accumbens, but not in the striatum.
The decrease of dopamine synthesis in striatum and nucleus accumbens induced by the dopamine receptor agonist, apomorphine, was unaffected by (+)‐HA‐966 (100 mg kg−1).
(+)‐HA‐966 (30 mg kg−1) failed to attenuate the hyperactivity induced by the systemic administration of amphetamine in the mouse, but totally prevented the hyperlocomotion following infusion of amphetamine into the rat nucleus accumbens. In contrast, stereotyped behaviour induced by infusion of amphetamine into the rat striatum was not altered following pretreatment with (+)‐HA‐966 (30 mg kg−1).
The results are consistent with a selective facilitatory role of glycine/NMDA receptors on mesolimbic dopaminergic neurones.
Electrophysiological studies of the GABAA receptor ligand, 4‐PIOL, on cultured hippocampal neurones
Authors: Kristiansen U. , Lambert J.D.C. , Falch E. , Krogsgaard‐Larsen P. 
Published: July 2012

Whole‐cell, patch‐clamp recordings from cultured hippocampal neurones have been used to characterize the action of the GABAA ligand, 5‐(4‐piperidyl)isoxazol‐3‐ol (4‐PIOL). The action of 4‐PIOL was compared with that of the established GABAA agonist, isoguvacine.
With a symmetrical Cl−gradient across the membrane and a holding potential of −60 mV, both isoguvacine and 4‐PIOL evoked an inward current. The reversal potentials of the responses to both agents were identical (+8.8 mV, n = 4) and the current/voltage relationships showed outward‐going rectification.
The response to 300 μm 4‐PIOL was completely blocked by the GABAA antagonist, bicuculline methobromide (BMB, 10 μm). The pA2 of BMB was >6.46. With 2 mm 4‐PIOL about 15% of the response remained in the presence of 100 μm BMB. This may represent a non‐specific component of the response to large concentrations of 4‐PIOL.
4‐PIOL was about 200 times less potent as an agonist than isoguvacine. Because of the rapid fade (desensitization) of isoguvacine‐induced currents, the maximum response to this agonist was not determined. However, the response to 2 mm 4‐PIOL was only a small fraction of that evoked by submaximal concentrations of isoguvacine.
Setting the response to 1 mm 4‐PIOL as maximum, the EC50 for 4‐PIOL was 91 μm (95% confidence limits: 73–114 μm).
4‐PIOL antagonized the response to isoguvacine with a parallel shift to the right of the dose‐response curve. The antagonist action of 4‐PIOL was about 30 times weaker than that of BMB. When allowance was made for the intrinsic agonist action of 4‐PIOL, the Ki was 116 μm (95% confidence limits: 102–130 μm). This was not significantly different from EC50 (P = 0.86; non‐parametric Mann‐Whitney test).
It is concluded that 4‐PIOL is a partial agonist at the GABAA receptor on cultured hippocampal neurones.
Pharmacological analysis of agonist‐antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay
Authors: Durant P.A.C. , Shankley N.P. , Welsh N.J. , Black J.W. 
Published: July 2012

Agonist‐antagonist interactions at acetylcholine (ACh) muscarinic receptors have been analysed by use of an improved urinary bladder assay, isolated and intact, from the mouse. With 5‐methylfurmethide as agonist, validated cumulative concentration‐effect curves were obtained in less than 7 min by re‐dosing before the response plateaux began to fade.
The pKB value estimated for pirenzepine was 6.76. The pKB values estimated for atropine and N‐methylatropine from data obtained at concentrations which produced dose‐ratios greater than 20 and 60 were 8.90 and 9.58, respectively.
The deviation from simple competitive behaviour at low dose‐ratios with atropine and N‐methylatropine was consistent with the operation of saturable antagonist removal processes. The deviation observed with atropine was corrected by pre‐incubation with methylbutyrate, an alternative substrate for ‘atropine esterase’.
The simple competitive behaviour of N‐methylatropine was restored following pre‐incubation with the neuronal choline uptake blocker hemicholinium‐3 (HC‐3). However, the pKB estimated for N‐methylatropine under these conditions was low. This latter result could be accounted for by the observed behaviour of HC‐3 as a competitive antagonist of ACh muscarinic receptors (pKB = 4.01).
We conclude that the modified mouse urinary bladder assay is suitable for the quantitative analysis of muscarinic receptor interactions. In addition, we postulate the existence of a previously undescribed uptake mechanism for quaternary muscarinic receptor antagonists.
Factors affecting the regional haemodynamic responses to glyceryl trinitrate and molsidomine in conscious rats
Authors: Phillips K. , Gardiner S.M. , Kemp P.A. , Bennett T. 
Published: July 2012

A series of experiments was performed in conscious, unrestrained, male, Long Evans rats, chronically instrumented for the measurement of regional haemodynamics.
Infusion of glyceryl trinitrate (GTN, 0.1 mg kg−1 min−1, i.v.) for 10 min elicited tachycardia, but no sustained change in mean arterial blood pressure. Renal haemodynamics were unaffected, but there were reductions in hindquarters flow and vascular conductance together with substantial increases in flow and conductance in the mesenteric vascular bed.
In the presence of captopril (2 mg kg−1 bolus, and 1 mg kg−1 h−1 infusion, i.v.) GTN elicited significant hypotension and increases in renal blood flow and vascular conductance, indicating that activation of the renin‐angiotension system opposed the dilator effects of GTN in this vascular bed. However, the mesenteric and hindquarters haemodynamic effects of GTN were not affected by captopril. In contrast, in the presence of enalaprilat (2 mg kg−1 bolus, and 1 mg kg−1 h−1 infusion, i.v.) there was significant enhancement of the mesenteric, as well as renal, haemodynamic effects of GTN. Hence, these results provide no evidence for the sulphydryl groups in captopril exerting a specific effect to enhance the haemodynamic actions of GTN in our experimental protocols.
Administration of molsidomine alone (1 mg kg−1, i.v. bolus) elicited tachycardia and hypotension; there were no changes in mesenteric or hindquarters haemodynamics, but renal flow and vascular conductance fell. Thus, the hypotensive effect of molsidomine was probably due to a reduction in cardiac output, consequent upon venodilatation.
In the presence of captopril or enalaprilat, molsidomine evoked renal and mesenteric vasodilatations in association with hypotension, indicating that activation of the renin‐angiotensin system contributed to the lack of vasodilator responses to administration of molsidomine alone. However, since the effects of enalaprilat were more marked than those of captopril (in spite of the dose of both drugs being supramaximal for inhibition of angiotensin‐converting enzyme), other factors must have been involved.
In a separate experiment, pretreatment with the nitric oxide synthesis inhibitor, NG‐nitro‐l‐arginine methyl ester (1 mg kg−1 h−1, i.v.), enhanced the mesenteric vasodilator effect of molsidomine. Collectively, these results are consistent with in vitro data showing that endogenous nitric oxide can inhibit the vasodilator effects of nitric oxide derived from molsidomine, and that the sulphydryl groups of captopril can protect endogenous nitric oxide from inactivation by oxygen‐derived free radicals, thereby enhancing the inhibitory effect of endogenous nitric oxide on the vasodilator responses to exogenous nitric oxide derived from molsidomine (or GTN).
The effects of sham and full spinalization on the systemic potency of μ‐ and κ‐opioids on spinal nociceptive reflexes in rats
Authors: Herrero Juan F. , Headley P. Max 
Published: July 2012

Flexor withdrawal reflexes to noxious mechanical pinch stimuli were recorded as single motor unit activity in α‐chloralose anaesthetized rats, by means of tungsten bipolar electrodes inserted per‐cutaneously into hindlimb flexor muscles. The relative spinal and supraspinal contributions to μ‐ and κ‐opioid agonists in inhibiting these spinal reflexes, together with possible potency changes elicited by surgical trauma, were examined by comparing their relative potencies in spinally unoperated, sham spinalized and spinalized rats.
The noxious stimuli, which were of comparable intensity in the three groups, elicited similar mean firing rates of the motor units in all groups. This indicates that the excitability levels in the reflex pathway were not greatly affected by either sham or actual spinalization.
The μ‐agonists morphine and fentanyl, and the κ‐agonist U‐50,488H, inhibited the reflexes in a dose‐dependent manner, when administered intravenously in a log2 cumulative dose regime.
The surgery of sham spinalization had little effect on the potency of morphine and fentanyl, whereas it doubled the potency of U‐50,488.
Spinalization did not affect the potency of morphine. In contrast it decreased the potency of fentanyl 2–4 fold and that of U‐50,488 approximately 6 fold.
The effects of all agonists were antagonized by naloxone. Dose‐dependence studies indicating that antagonism of U‐50,488H required about 5 times the dose of naloxone that antagonized morphine.
The data suggest that surgical trauma to the spinal column and/or dura mater triggers supraspinal mechanisms that significantly enhance the potency of κ‐ but not μ‐agonists.
It is concluded that most of the effects of systemic morphine on spinal reflexes are mediated, under all three conditions tested, by direct effects in the spinal cord. In contrast, the inhibition of reflexes by U‐50,488H is mediated at both spinal and supraspinal levels, the latter being enhanced in the presence of surgical trauma. The differences between morphine and fentanyl remain unexplained.