bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facilitation by 3,4‐diaminopyridine of regenerative acetylcholine release from mouse motor nerve
Authors: Hong S.J. , Chang C.C. 
Published: July 2012

Effects of 3,4‐diaminopyridine (DAP) on endplate potentials (e.p.ps) were studied in mouse phrenic nerve‐hemidiaphragms.
In cut muscle preparations, low concentrations of DAP (2–20 μm) increased the amplitude of e.p.ps and shifted the curve relating Ca2+ concentration to e.p.p. amplitude leftward.
High concentrations of DAP (40–4000 μm) prolonged the duration of e.p.ps dose‐dependently up to one hundred fold (ca. 200 ms), yielding, in addition to the normal phasic e.p.p., a prolonged plateau depolarization component which was often preceded by an upstroke depolarization. During the plateau depolarization, nerve stimulations did not evoke any e.p.p.
The plateau component of prolonged e.p.ps was suppressed by tubocurarine, verapamil, nifedipine, Mn2+ and Cd2+ (but not by atropine) at low concentrations that had negligible effect on the amplitude of miniature e.p.ps or the phasic component of e.p.ps. Abolition of the plateau component by these agents restored the capability of the nerve terminal to evoke e.p.ps on nerve stimulation.
Low concentrations of neostigmine (0.01–0.02 μm) markedly lengthened DAP‐prolonged e.p.ps. However, the regenerative endplate depolarization evoked in the presence of high concentrations of neostigmine (0.3–0.5 μm) was not prolonged by DAP.
Tetraethylammonium (1 mm) did not provoke prolonged e.p.ps but acted cooperatively with DAP to prolong the duration of plateau depolarization. At a high concentration (3 mm), tetraethylammonium depressed the amplitude of miniature e.p.ps and abolished DAP‐prolonged e.p.ps.
In uncut muscle preparations, DAP apparently did not modify the time course and amplitude of miniature e.p.ps. Upon direct stimulation by current injection at endplate, DAP increased the muscle action potentials by only about 30%, but induced no prolonged depolarization.
These results suggest that the prolonged e.p.ps induced in the presence of DAP are due to a regenerative release of acetylcholine from motor nerve and the induction probably involves a presynaptic Ca2+ channel different from that for normal e.p.ps. It may be inferred that the regenerative acetylcholine release is recruited by Ca2+ channels modulated by nicotinic receptors and K+ channels.
Receptors involved in mechanical responses to catecholamines in the circular muscle of guinea‐pig stomach treated with meclofenamate
Authors: Syed Mohsin Md. , Parekh Anant B. , Tomita Tadao 
Published: July 2012

In circular muscle strips of the fundus and corpus of guinea‐pig stomach, mechanical responses to catecholamines were studied mainly in the presence of a prostaglandin biosynthesis inhibitor, meclofenamate.
Normal preparations developed considerable muscle tone, and adrenaline (10–100 μm) in the presence of 3–5 μm propranolol produced a multiphasic response, generally consisting of transient relaxation and contraction, followed by slow relaxation and then contraction. Responses to phenylephrine were similar to those of adrenaline.
Meclofenamate (0.3 μm) nearly abolished the muscle tone and under this condition, both adrenaline and phenylephrine produced a simple contraction. This response was strongly inhibited by prazosin, but only weakly by yohimbine.
When muscle tone was maintained by prostaglandin E2 (10 nm) in the presence of meclofenamate, phenylephrine (30 μm) produced transient relaxation followed by slow contraction in most preparations. These were strongly inhibited by prazosin. Adrenaline produced a similar response, but the relaxation was only partially reduced by prazosin. The remaining relaxation was more dominant in the middle fundic region and this was considered to be mediated through β‐adrenoceptors.
It is concluded that in the circular muscle of the fundic region of guinea‐pig stomach, endogenous prostaglandins are involved in maintaining muscle tone and in modifying the response to catecholamines and that both contraction and relaxation are mediated by α1‐adrenoceptors.
Electrophysiological characterization of potent agonists and antagonists at pre‐ and postsynaptic GABAB receptors on neurones in rat brain slices
Authors: Seabrook G.R. , Howson W. , Lacey M.G. 
Published: July 2012

Intracellular recordings were made from neurones in striatum (caudate‐putamen) and substantia nigra pars compacta in rat brain slices. Three GABAB agonists, baclofen, 3‐aminopropylphosphinic acid (3‐APPA) and 3‐aminopropyl(methyl)phosphinic acid (SK&F 97541), depressed excitatory postsynaptic potentials (e.p.s.ps) mediated by glutamate in the striatum, and hyperpolarized neurones in the substantia nigra. The ability of 3‐aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), 3‐aminopropyl (hexyl)phosphinic acid (3‐APHPA) and phaclofen to antagonize these responses was assessed.
Striatal e.p.s.ps, studied in the presence of bicuculline (30 μm), were reduced in amplitude by 92% with 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX; 30 μm). These e.p.s.ps were depressed by up to 95% by SK&F 97541 and baclofen with EC50s of 0.092 μm and 1.25 μm respectively. The maximal effect of 3‐APPA was 67% with an EC50 of 0.83 μm. Agonist concentration‐effect data fitted a single‐site logistic model. GABAB agonists were without effect on striatal neurone membrane potential, input resistance or depolarizations induced by applied glutamate.
The depression of striatal e.p.s.ps by SK&F 97541 was reversibly antagonized by CGP 35348, 3‐APHPA and phaclofen with estimated equilibrium dissociation constants (KB) of 11.2 ± 1.7 μm (n = 4), 13.3 ± 0.4 μm (n = 3), and 405 ± 43 μm (n = 3) respectively. CGP 35348 and 3‐APHPA appeared to act competitively (Schild plot slopes of 0.99 and 1.01 respectively).
Nigral neurones were hyperpolarized by up to 25 mV by SK&F 97541 and baclofen with EC50s of 0.15 μm and 3.6 μm respectively. The maximum hyperpolarization by 3‐APPA was only 84% that of the other agonists, with an EC50 of 9.0 μm. Agonist concentration‐effect data fitted a single‐site logistic model.
The SK&F 97541‐induced hyperpolarization was reversibly antagonized by CGP 35348, 3‐APHPA and phaclofen with estimated KBs of 17.6 ± 4.4 (n = 3), 14.0 ± 1.5 (n = 4), and >400 μm (n = 1) respectively. CGP 35348 appeared competitive (Schild plot slope of 0.99). Antagonists were also tested with baclofen as agonist, yielding similar KB estimates as for SK&F 97541.
It is concluded that at both the presynaptic and postsynaptic sites examined, SK&F 97541 was about 10 fold more potent than baclofen or 3‐APPA. The antagonists CGP 35348 and 3‐APHPA (KB 10–20 μm) were about 20 fold more potent than phaclofen. The similarities in relative agonist potency and estimated antagonist affinity between these two functionally distinct GABAB receptors renders them pharmacologically indistinguishable at present.
Effect of clonidine, nimodipine and diltiazem on the in vitro opioid withdrawal response in the guinea‐pig ileum
Authors: Alfaro M.J. , Colado M.I. , López F. , Martín M.I. 
Published: July 2012

The effects of clonidine, nimodipine and diltiazem, on the in vitro withdrawal contracture induced by naloxone in the guinea‐pig ileum obtained from morphine‐dependent animals, were evaluated.
The in vitro incubation with clonidine (0.01, 0.1 and 1 μm), diltiazem (0.25, 0.5 and 1 μm) or nimodipine (0.05, 0.1 and 1 μm) reduced significantly the force of the contracture induced by naloxone in the morphine‐dependent guinea‐pig ileum.
The intraperitoneal administration of clonidine (0.3 mg kg−1), nimodipine (5 mg kg−1) or diltiazem (20 mg kg−1) reduced the contractile response induced by naloxone in the morphine‐dependent guinea‐pig ileum.
It is concluded that at least part of the effect of clonidine, nimodipine and diltiazem on withdrawal contractures is mediated via a peripheral, rather than a central site of action. Even though, the mechanism responsible for the effect of the calcium channel blockers differs from that of α2‐adrenoceptor agonists, all of the drugs tested prevented the contracture induced by naloxone in morphine‐dependent guinea‐pig ileum.
Receptors mediating the effects of 5‐hydroxytryptamine on the tracheal vasculature and smooth muscle of sheep
Authors: Webber S.E. , Salonen R.O. , Widdicombe J.G. 
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) and the selective 5‐HT3 receptor agonist 2‐methyl‐5‐HT were examined on the tracheal vasculature in anaesthetised, paralysed and artificially ventilated sheep. The cranial tracheal arteries were perfused with blood at constant flow and perfusion pressure was measured. 5‐HT and 2‐methyl‐5‐HT were injected into the arterial perfusate. Changes in tracheal smooth muscle tone were also measured.
5‐HT contracted the tracheal smooth muscle. This contraction was not affected by the 5‐HT2 receptor antagonist ketanserin, but was blocked by the combined ‘5‐HT1‐like’ and 5‐HT2 receptor antagonist methysergide. 2‐methyl‐5‐HT had no effect on the tracheal smooth muscle.
5‐HT had a complex action on the tracheal vasculature producing either a biphasic change (vasoconstriction followed by dilatation) or just a constriction. 2‐methyl‐5‐HT had a weak vasoconstrictor effect.
The vasoconstrictions produced by 5‐HT and 2‐methyl‐5‐HT were blocked by ketanserin. The vasodilatation produced by 5‐HT was resistant to ketanserin but was antagonised by methysergide.
Thus 5‐HT contracts the tracheal smooth muscle of sheep by stimulating ‘5‐HT1‐like’ receptors. 5‐HT constricts the tracheal vascular bed by stimulating 5‐HT2 receptors or dilates the vascular bed by stimulating ‘5‐HT1‐like’ receptors. 5‐HT3 receptors appear not to be involved in the responses of the tracheal vasculature or smooth muscle to 5‐HT.
The antimigraine drug, sumatriptan (GR43175), selectively blocks neurogenic plasma extravasation from blood vessels in dura mater
Authors: Buzzi M. Gabriella , Moskowitz Midiael A. 
Published: July 2012

We describe the actions of GR43175, a 5‐hydroxytryptamine1 (5‐HT1)‐like receptor agonist, on neurogenically‐mediated plasma protein extravasation within an important pain‐sensitive intracranial tissue, the dura mater.
GR43175 markedly attenuated extravasation of 125I‐albumin from blood vessels within ipsilateral dura mater when administered to rats (100 μg kg−1) fifteen minutes before unilateral electrical trigeminal stimulation (1.2 mA, 5 Hz, 5 ms, 5 min.); the ratio (stimulated/unstimulated sides) decreased from 1.81 to 1.23, P < 0.005).
GR43175 (100 μg kg−1, i.v., rats; 30 μg kg−1, i.v., guinea‐pigs) decreased the leakage of radiolabeled albumin from 163% to 119% (P < 0.005, guinea‐pig) or from 174 to 118% (P < 0.05, rat) above vehicle‐treated controls when injected ten minutes before systemic capsaicin treatment (0.5 or 1 μmol kg−1, i.v.).
GR43175 (30–300 μg kg−1) did not block plasma protein extravasation within extracranial tissues of rats and guinea‐pigs innervated by the trigeminal nerve (conjunctiva, eyelid and lip).
The protein leakage which followed the i.v. administration of 5‐HT (1 μmol kg−1) or neuropeptides which mediate neurogenic plasma extravasation, substance P (0.3 nmol kg−1 or 1 nmol kg−1) and neurokinin A (1 nmol kg−1), was not blocked by GR43175 (100, 300 μg kg−1) despite the presence of leakage in amounts equivalent to that following neurogenic stimulation.
GR43175 (100 μg kg−1) decreased bradykinin (10 μmol kg−1)‐induced extravasation from 142 to 115% above vehicle‐treated animals (P < 0.05).
These results demonstrate an important action of GR43175 on neurogenic mechanisms in dural blood vessels. Since the ergot alkaloids possess a similar profile of drug activity, it is suggested that drugs useful in the treatment of acute vascular headaches may share a similar mechanism of action.
Locomotor activity in rats after administration of nicotinic agonists intracerebrally
Authors: Reavill C. , Stolerman I.P. 
Published: July 2012

Nicotine (0.13 and 0.4 mg kg−1, s.c.) increased the ambulatory component of locomotor activity in rats previously exposed to the drug. Nicotine did not increase repeated movements reliably.
An infusion of either nicotine (8 μg) or the potent nicotinic agonist cytisine (4 μg) into the ventral tegmental area of the forebrain increased ambulation but not repeated movements.
An infusion of nicotine or cytisine into the nucleus accumbens, striatum, dorsal hippocampal formation or motor thalamus did not increase ambulatory or repeated movements.
Mecamylamine (0.1–1.0 mg kg−1, s.c.) blocked increases in locomotor activity produced by an infusion of nicotine or cytisine into the ventral tegmental area.
The locomotor activity produced by systemically administered nicotine may be mediated, in part, through nicotinic receptors located in the ventral tegmental area of the mesolimbic dopamine system.
Characterization of the muscarinic receptor subtype involved in phosphoinositide metabolism in bovine tracheal smooth muscle
Authors: Roffel A.F. , Meurs H. , Elzinga C.R.S. , Zaagsma J. 
Published: July 2012

The muscarinic receptor subtype involved in the methacholine‐induced enhancement of phosphoinositide metabolism in bovine tracheal smooth muscle was identified by using the M2‐selective antagonist AF‐DX 116 and the M3‐selective antagonist 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP) methobromide, in addition to the M1‐selective antagonist pirenzepine, in a classical Schild analysis.
All the antagonists shifted the methacholine dose‐response curve to the right in a parallel and concentration‐dependent fashion, yielding Schild plots with slopes not significantly different from unity. The pA2 values (6.94, 6.32 and 8.54 for pirenzepine, AF‐DX 116 and 4‐DAMP methobromide respectively) indicate that it is the M3 (smooth muscle/glandular), but not the M2 (cardiac) muscarinic receptor subtype, present in this tissue, that mediates phosphoinositide turnover, in accordance with our previous contractile studies.
The results provide additional evidence for the involvement of phosphoinositide turnover in the pharmacomechanical coupling between muscarinic receptor stimulation and contraction in (bovine tracheal) smooth muscle.
Characterization of MDL 73005EF as a 5‐HT1A selective ligand and its effects in animal models of anxiety: comparison with buspirone, 8‐OH‐DPAT and diazepam
Authors: Moser P.C. , Tricklebank M.D. , Middlemiss D.N. , Mir A.K. , Hibert M.F. , Fozard J.R. 
Published: July 2012

With radioligand binding techniques, MDL 73005 EF (8‐[2‐(2,3‐dihydro‐1,4‐benzodioxin‐2‐yl‐methylamino)ethyl]‐8‐azaspiro[4,5]decane‐7,9‐dione methyl sulphonate) shows high affinity (pIC50 8.6) and selectivity (>100 fold compared to other monoamine and benzodiazepine receptor sites) for the 5‐hydroxytryptamine (5‐HT)1A recognition site; it was both more potent and more selective than buspirone in this respect.
In rats pretreated with reserpine, 8‐hydroxy‐2‐(di‐n‐propyl‐amino) tetralin (8‐OH‐DPAT) induced forepaw treading and flat body posture; in the same model, MDL 73005EF and buspirone showed minimal agonist activity and at high doses MDL 73005EF inhibited responses to 8‐OH‐DPAT.
In rats trained to discriminate 8‐OH‐DPAT from saline in a drug discrimination paradigm, both MDL 73005EF and buspirone generalized dose‐dependently and completely to the 8‐OH‐DPAT cue.
To define the anxiolytic potential of MDL 73005EF, it was examined in the elevated plus‐maze test and in the water‐lick conflict test in comparison with diazepam and buspirone. In both tests MDL 73005EF induced effects similar to those seen following diazepam. Buspirone had similar effects to both MDL 73005EF and diazepam in the water‐lick conflict test but opposite effects in the elevated plus‐maze. 8‐OH‐DPAT also had opposite effects in the elevated plus‐maze test to MDL 73005EF and diazepam.
The anti‐conflict effects of MDL 73005EF were reversed by low doses of the 5‐HT1A receptor agonist, 8‐OH‐DPAT; those of buspirone were neither antagonised nor mimicked by 8‐OH‐DPAT.
These results suggest that an interaction with 5‐HT1A receptors is the basis of the anxiolytic‐like activity of MDL 73005EF. However, its mechanism of action is clearly different from that of buspirone, possibly reflecting a greater selectivity for the 5‐HT1A receptors located presynaptically on central 5‐hydroxytryptaminergic neurones.
Nimodipine has no effect on the cerebral circulation in conscious pigs, despite an increase in cardiac output
Authors: van der Giessen W.J. , Duncker D.J. , Saxena P.R. , Verdouw P.D. 
Published: July 2012

We studied the effects of four doses of nimodipine (0.5, 1, 2 and 4 μg kg−1 min−1) on systemic haemodynamics and on regional vascular beds, in particular the cerebral circulation, in conscious pigs.
Nimodipine caused dose‐dependent, probably reflex‐mediated, increases in heart rate (42% with the highest dose) and cardiac output (54%), while arterial blood pressure was only minimally affected. Left ventricular end‐diastolic pressure and systemic vascular resistance decreased dose‐dependently (35–40% at the highest dose) while stroke volume remained unchanged.
Total brain blood flow was not affected by the drug. Furthermore, we could not demonstrate any regional cerebral differences, as blood flows to both cerebral hemispheres as well as the diencephalon, cerebellum and brain stem remained unchanged.
Blood flow to the kidneys, liver, small intestine and skin also did not change. Nimodipine caused dose‐dependent increases in blood flow to the stomach (95%), myocardium (97%) and adrenal glands (102%), while blood flow to skeletal muscles (267%) increased most.
It is concluded that in the conscious pig, nimodipine is an arterial vasodilator which shows some selectivity for the skeletal muscle vasculature but does not increase total or regional cerebral blood flow.
Effects of calmodulin antagonists on calcium‐activated potassium channels in pregnant rat myometrium
Authors: Kihira M. , Matsuzawa K. , Tokuno H. , Tomita T. 
Published: July 2012

The effects of W‐7, trifluoperazine, and W‐5 on Ca2+‐activated K+‐channels were investigated with the inside‐out patch‐clamp method in smooth muscle cells freshly dispersed from pregnant rat myometrium. These drugs are known to have different potencies as calmodulin antagonists.
In the presence of 1 μm Ca2+ on the cytoplasmic side ([Ca2+]i), the fraction of time the channel was open (open probability, Po) was about 0.9 and the calmodulin antagonists (1–30 μm) applied to the cytoplasmic face reduced Po to 0.65‐0.55 dose‐dependently. In the presence of 0.1‐0.16 μm Ca2+, when Po was very low (0.02), calmodulin antagonists increased Po. All antagonists used produced almost identical effects at the same concentration.
The probability density function of the open time distribution could be described by the sum of two exponentials. W‐7 decreased the time constant of the slow component of distribution and at 30 μm the slow component disappeared both at 1 and 0.25 μm [Ca2+]i, reflecting the appearance of flickering channel activity. The probability density function of the closed time distribution could be fitted with three exponentials. The time constants of these components were not significantly altered by W‐7.
Internally applied calmodulin (1–5 μm) did not produce any significant effect on channel activity.
The effects of calmodulin antagonists are considered to be due to a direct action of these compounds on the channel, and suggest that channel activation by Ca2+ is not mediated by calmodulin.
Effects of μ‐opioid receptor agonists on circulatory responses to simulated haemorrhage in conscious rabbits
Authors: Evans Roger G. , Ludbrook John 
Published: July 2012

Cardiac output, arterial pressure, heart rate, systemic vascular conductance, respiratory rate and arterial blood Po2 and Pco2 were measured in unanaesthetized rabbits. Haemorrhage was simulated by inflating a cuff placed around the inferior vena cava so that cardiac output fell at a constant rate of about 8% of its resting value per min.
The effects of drug treatments on resting haemodynamic and respiratory variables, and on the haemodynamic response to simulated haemorrhage, were tested. The treatments were; 4th ventricular (−)−naloxone HCl (10–100 nmol), 4th ventricular H‐Tyr‐d‐Ala‐Gly‐MePhe‐NH(CH2)2OH (DAMGO; 30–300 pmol), and i.v. morphine sulphate (0.5‐5.0 μmol kg−1). The interactions of graded 4th ventricular doses of naloxone (3–100 nmol) with the actions of DAMGO (100–300 pmol) on these responses were also assessed.
After sham treatments, the circulatory response to simulated haemorrhage had two phases. During the first compensatory phase, systemic vascular conductance fell, heart rate rose, and mean arterial pressure fell by only about 7 mmHg. A second decompensatory phase supervened when cardiac output had fallen by about 50%. At this point systemic vascular conductance rose abruptly and arterial pressure fell to ≥ 40 mmHg.
Low 4th ventricular doses of naloxone (10–30 nmol) and DAMGO (30–100 pmol) had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of naloxone (30–100 nmol) and DAMGO (100–300 pmol) prevented the decompensatory phase. These high doses of naloxone and DAMGO lowered resting heart rate without affecting the other haemodynamic or respiratory variables.
Low doses of i.v. morphine (0.5‐1.5 μmol kg−1) also had no discernible effect on the circulatory response to simulated haemorrhage. Higher doses of morphine (1.5‐5.0 μmol kg−1) abolished the decompensatory phase. These high doses caused respiratory depression without affecting the resting haemodynamic variables.
The prevention of circulatory decompensation by high doses of DAMGO was reversed by 3–10 nmol of naloxone in 3 out of 4 rabbits and by 10–30 nmol of naloxone in all 4 rabbits. The decompensatory phase was, however, prevented by the combined high doses of DAMGO (100–300 pmol) and naloxone (30–100 nmol).
These findings provide strong evidence that activation of μ‐opioid receptors in the central nervous system abolishes circulatory decompensation during acute reduction of central blood volume in conscious rabbits. This effect does not appear to be due to activation of arterial chemoreceptors or to a non‐specific increase in sympathetic vasoconstrictor drive, since respiratory depression and hypertension were not observed after 4th ventricular doses of DAMGO which abolished circulatory decompensation. Our results also provide indirect confirmation of our previous finding that naloxone acts to prevent circulatory decompensation by an antagonist action at central δ‐receptors.
Systemic and regional haemodynamic interactions between K+ channel openers and the sympathetic nervous system in the pithed SHR
Authors: Richer Christine , Mulder Paul , Doussau Marie‐Pascale , Gautier Patrick , Giudicelli Jean‐François 
Published: July 2012

The interactions between two K+ channel openers, cromakalim and SR 44866 (infused i.v. at equihypotensive doses), and the sympathetic nervous system at the systemic and regional (mesentery, kidney, hindlimb) vascular levels were investigated in the pithed spontaneously hypertensive rat (SHR) by use of the pulsed Doppler technique.
The two K+ channel openers did not affect postsynaptic α1‐ but slightly reduced postsynaptic α2‐adrenoceptor mediated systemic pressor and regional vasoconstrictor responses.
Both drugs significantly decreased the systemic pressor and regional vasoconstrictor responses elicited by spinal cord stimulation. These sympathoinhibitory effects were not homogeneously distributed among the different vascular beds, the decreasing rank order being: mesentery > kidney > hindlimb. Simultaneously, the spinal cord stimulation‐induced tachycardia remained unaffected.
After treatment with K+ channel openers, restoration of initial blood pressure and vascular tone values by infusion of prostaglandin F2α (PGF2α) and vasopressin respectively did not affect and abolished the sympathoinhibitory effects of cromakalim and SR 44866.
We conclude that in SHRs the two K+ channel openers that we investigated exert similar sympathohibitory effects which affect some vascular beds more than others. These effects are not dependent upon the arterial blood pressure level and are most likely prejunctionally located.