bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postjunctional α2‐adrenoceptors mediate vasoconstriction in human subcutaneous resistance vessels
Authors: Nielsen H. , Thom S.McG. , Hughes A.D. , Martin G.N. , Mulvany M.J. , Sever P.S. 
Published: July 2012

In vitro studies have been performed on human medium‐sized muscular arteries (internal diameter 1–4 mm) in a classical organ bath and with human subcutaneous resistance arteries (internal diameter 103–626 μm) in a microvascular myograph.
Although the medium‐sized muscular arteries showed no response to either of the α2‐agonists B‐HT 933 or UK 14304 in concentrations up to 10 μm, the subcutaneous resistance arteries from all regions examined showed well‐pronounced and concentration‐dependent responses to B‐HT 933, the pD2 (‐log EC50) being 5.11 ± 0.09.
In the resistance arteries the α2‐antagonist yohimbine caused a parallel shift to the right of the B‐HT 933 concentration‐response curve; the yohimbine pA2 for the B‐HT 933 receptor was 7.86 ± 0.12.
There was an inverse relationship between the maximum response to B‐HT 933 and the calibre of the resistance vessels.
These results indicate the presence of a postjunctional α2‐adrenoceptor in human subcutaneous resistance arteries and not in medium sized muscular arteries.
PC12 phaeochromocytoma cells contain an atypical muscarinic receptor binding site
Authors: Michel Anton D. , Stefanich Eric , Whiting Roger L. 
Published: July 2012

Kinetic, saturation and competition binding studies were conducted on the muscarinic receptor binding site labelled by [3H]‐N‐methylscopolamine ([3H]‐NMS) in intact PC12 cells and cell membranes. Similar studies were conducted on M1 receptors of rat cortex labelled with [3H]‐pirenzepine and M2 and M3 receptors present in rat heart and submaxillary gland respectively, and labelled with [3H]‐NMS.
The dissociation of [3H]‐NMS from muscarinic receptors in PC12 cells was slower than dissociation from both M2 and M3 muscarinic receptors.
The Kd of [3H]‐NMS in the PC12 cells was significantly lower than that obtained at the M2 and M3 receptor.
In competition studies the affinity data for pirenzepine, hexahydroadiphenine and 4‐diphenylacetoxy‐N‐methylpiperidine methiodide were consistent with the presence of an M3 receptor in the PC12 cells. However, for AF‐DX 116, cyclohexylphenyl(2‐piperidinoethyl)silanol and methoctramine affinity estimates in PC12 cells were 3–6 fold lower than at the M3 receptor.
On the basis of these data we conclude that the muscarinic receptor present in the PC12 cells differs from the M1, M2 and M3 subtypes already described.
Use of geographutoxin II (u‐conotoxin) for the study of neuromuscular transmission in mouse
Authors: Hong S.J. , Chang C.C. 
Published: July 2012

Endplate potentials (e.p.ps) were investigated in the presence of geographutoxin II (GTXII) in the mouse phrenic nerve diaphragm preparation. This toxin preferentially blocks muscle Na+ channels which allows the study of e.p.ps in the absence of nicotinic receptor antagonists or substances to depress acetylcholine release.
GTXII abolished muscle action potentials and antagonized the depolarization of the muscle membrane produced by the crotamine‐induced opening of Na+ channels.
E.p.ps as large as 19–25 mV were observed after 2–4 μg ml−1 GTXII. These concentrations of GTXII did not cause discernible changes of resting membrane potential and frequency and amplitude of miniature e.p.ps.
Lower concentrations (1–2 μg ml−1) of GTXII caused incomplete blockade of the muscle Na+ channel resulting in exaggerated ‘e.p.ps’, while higher concentrations of GTXII (8 μg ml−1) abolished e.p.ps by a prejunctional effect.
Trains of e.p.ps on repetitive stimulation after GTXII neither ran down, as in tubocurarine‐treated preparations, nor facilitated, as in low Ca2+ and/or high Mg2+‐treated preparations, and were indistinguishable from those of untreated cut muscle preparation.
In cut muscle preparations, GTXII did not affect the rise and decay times, amplitude or rundown of e.p.ps.
It is concluded that GTXII is a useful agent for studying neuromuscular transmission. This method provides e.p.ps which are neither attenuated nor modified because manipulations that alter transmitter release and postjunctional receptor responses are avoided.
Comparison of the sodium currents in normal Purkinje fibres and Purkinje fibres surviving infarction—a pharmacological study
Authors: Bril Antoine , Kinnaird Anne A.A. , Man Ricky Y.K. 
Published: July 2012

Purkinje fibres surviving infarction showed a lower maximum upstroke velocity (Vmax) and a longer action potential duration when compared to normal Purkinje fibres. A reduction in the fast sodium current and an increase in the sodium ‘window’ current may be responsible for the observed alterations in (Vmax and action potential duration respectively.
Since voltage clamp studies were not feasible, a pharmacological approach was used. The responses to tetrodotoxin (TTX) and lignocaine in normal Purkinje fibres and Purkinje fibres surviving infarction were used to examine the sodium currents in these fibres.
Vmax, an indirect measure of the fast sodium current, was more sensitive to lignocaine in Purkinje fibres surviving infarction than in normal Purkinje fibres. The reduction in Vmax by lignocaine was more prominent at the shorter stimulation cycle length. Significant reduction of Vmax was observed with the higher concentration of TTX and no differential effect on Vmax between normal Purkinje fibres and Purkinje fibres surviving infarction was detected.
Reduction of action potential duration in the presence of TTX or lignocaine was used as a measure of the sodium ‘window’ current. A greater reduction of action potential duration by TTX and lignocaine was observed in normal Purkinje fibres than in Purkinje fibres surviving infarction.
The results suggested that the fast sodium current in Purkinje fibres surviving infarction is more sensitive to pharmacological agents with local anaesthetic properties and the prolonged action potential duration in these Purkinje fibres cannot be due to an increase in the sodium ‘window’ current. The results are compatible with an enhanced effect of antiarrhythmic drugs on Vmax and conduction in the ischaemic heart.
The cardiovascular actions of clonidine and neuropeptide‐Y in the ventrolateral medulla of the rat
Authors: McAuley M.A. , Macrae I.M. , Reid J.L. 
Published: July 2012

The cardiovascular responses to neuropeptide‐Y (NPY) (25 and 50 pmol) and clonidine (10 and 20 nmol) were examined following microinjection into the rostral ventrolateral medulla (RVLM) and the caudal ventrolateral medulla (CVLM). Mean arterial pressure (MAP) and heart rate (HR) were measured in anaesthetized rats, pre‐ and post‐injection.
The α2‐adrenoceptor agonist clonidine (10 and 20 nmol) reduced MAP and HR significantly when microinjected into the CVLM and RVLM.
NPY (25 and 50 pmol) microinjected into the CVLM decreased MAP and HR. However, in the RVLM neither dose had a significant cardiovascular effect.
The possibility of a functional interaction between the adrenergic system and NPY was examined by co‐administration of clonidine and NPY in doses that gave submaximal blood pressure responses. In the CVLM this produced hypotension and bradycardia which was similar in magnitude to the sum of their individual responses, indicating that in this area their actions appear to be independent.
In the RVLM, where NPY has no significant cardiovascular effects, co‐administration with clonidine, did not alter the response to clonidine.
It appears that in the areas investigated, there is no functional interaction between NPY and clonidine.
The effect of EU4093 (azumolene sodium) on the contraction of intrafusal muscle in the soleus muscle of the anaesthetized rat
Authors: Leslie G.C. , Part N.J. 
Published: July 2012

EU4093 (azumolene sodium) is a direct acting, skeletal muscle relaxant with structural similarities to dantrolene sodium in that the para‐nitro phenyl group of dantrolene sodium is replaced by a para‐bromo phenyl group.
The effect of EU4093 on the twitch of the intact rat soleus preparation is nearly maximal at a dose of 20 mg kg−1. This dose of EU4093 reduces the amplitude of the twitch to 31.9% of the control value. By comparison, dantrolene sodium reduced the twitch amplitude to 31.3% of the control value at a dose of 5 mg kg−1.
The contraction of intrafusal muscle as measured by the response of spindle afferent discharge was also reduced by EU4093.
The most significant difference between the effect of EU4093 and dantrolene sodium on the contraction of intrafusal muscle was that EU4093 had an appreciable depressant action at high stimulation frequencies at which dantrolene sodium had only a minimal relaxant effect on the intrafusal muscle contraction.
The significance of this difference in the actions of EU4093 and dantrolene sodium is discussed in terms of the possible effect of the drug in the intact animal and human patient. It is concluded that, because the discharge frequency is not likely to move into the high frequency range at which dantrolene sodium and EU4093 have significantly different effects, the overall effect of these two drugs is likely to be similar.
Modulation of non‐adrenergic, non‐cholinergic neural bronchoconstriction in guinea‐pig airways via GABAB‐receptors
Authors: Belvisi M.G. , Ichinose M. , Barnes P.J. 
Published: July 2012

Evidence suggests that γ‐aminobutyric acid (GABA) and its receptors are present in the peripheral nervous system. We have now investigated the effect of GABA and related substances on non‐adrenergic, non‐cholinergic (NANC) neurally‐evoked bronchoconstriction in the anaesthetised guinea‐pig.
Bilateral vagal stimulation (5 V, 5 ms, 3 or 5 Hz) for 30 s, after propranolol (1 mg kg−1 i.v.) and atropine (1 mg kg−1 i.v.) evoked a NANC bronchoconstrictor response manifest as a mean tracheal pressure rise of 21.9 ± 1.04 cmH2O (n = 70). The bronchoconstrictor response was reproducible for any given animal.
GABA (10 μg‐10 mg kg−1 i.v.) did not alter basal tracheal pressure but reduced the NANC bronchoconstrictor response to vagal stimulation in a dose‐dependent manner (ED50 = 186 μg kg−1 with a maximal inhibition of 74 ± 3.4% at 10 mg kg−1). Neither the opioid antagonist naloxone (1 mg kg−1 i.v.) nor the α‐adrenoceptor antagonist phentolamine (2.5 mg kg−1 i.v.) had any significant effect on the inhibitory response produced by GABA (500 μg kg−1).
GABA‐induced inhibition was not antagonised by the GABAA‐antagonist bicuculline (2 mg kg−1 i.v.).
The GABAB‐agonist baclofen (10 μg‐3 mg kg−1 i.v.) caused a dose‐dependent inhibition of the NANC response (ED50 = 100 μg kg−1 with a maximal inhibition of 35.5 ± 2.8% at 3 mg kg−1). The GABAA‐agonist, 4,5,6,7‐tetrahydroisoxazolo[5,4‐C] pyridin‐3‐ol (THIP), also inhibited the NANC bronchoconstrictor response. However, the dose of THIP required for this effect was high (3 mg kg−1) and the effect (< 10% inhibition) was small.
Substance P (SP; 5 μg kg−1 or 25 μg kg−1), produced a bronchoconstrictor response equivalent to that produced by NANC vagal stimulation. This response was significantly increased by injection of GABA. Baclofen had no significant effect on responses evoked by exogenous SP.
We conclude that GABA inhibits the release of transmitter from NANC nerves via an action at GABAB receptors and that GABA might play a role in the regulation of neurogenic responses in the airways.
Comparison of the prejunctional β‐adrenoceptor stimulating actions of adrenaline and isoprenaline in the dog mesenteric vein
Authors: Seki Narihito , Suzuki Hikaru 
Published: July 2012

The prejunctional β‐adrenoceptor stimulating actions of adrenaline and isoprenaline were compared by recording junction potentials from smooth muscle cells of the dog mesenteric vein.
The potency of adrenaline and isoprenaline on β‐adrenoceptors in the postjunctional membrane was estimated from hyperpolarization of the membrane in smooth muscle cells of the guinea‐pig facial vein. In the presence of yohimbine, both agents hyperpolarized the membrane to a similar extent.
In the dog mesenteric vein, amplitude of the excitatory junction potential (e.j.p.) and slow depolarization was inhibited by adrenaline and potentiated by isoprenaline; the former but not the latter was accompanied by depolarization of the smooth muscle membrane.
In the presence of yohimbine, adrenaline inhibited the e.j.p. without depolarization of the smooth muscle membrane; the action was weaker than in the absence of yohimbine. The isoprenaline‐induced potentiation of the e.j.p. was further enhanced by yohimbine.
It is concluded that adrenaline and isoprenaline have similar stimulating actions on postjunctional β‐adrenoceptors in the guinea‐pig facial vein, but have different actions on prejunctional β‐adrenoceptors in the dog mesenteric vein; isoprenaline but not adrenaline stimulates this β‐adrenoceptor to facilitate the release of transmitter substances from perivascular noradrenergic nerves.
Perinatal lead exposure impairs opioid but not non‐opioid stress‐induced antinociception in developing rats
Authors: Jackson Helen C. , Kitchen Ian 
Published: July 2012

The development of opioid systems has been shown to be sensitive to perinatal exposure to lead. We have studied the effects of such exposure on opioid and non‐opioid mediated stress‐induced antinociception in developing rats.
Lead was administered in the maternal drinking water from conception to postnatal day 14 at 300 and 1000 p.p.m. Twenty and 25 day old rats were subjected to swimming stress and antinociception measured using the tail immersion test.
A 3 min swim‐stress induced an opioid‐mediated antinociceptive response in 20 day old rats which was attenuated by 300 p.p.m. lead and by 1000 p.p.m. lead treatment in a dose‐related manner. A 10 min swim‐stress induced a non‐opioid mediated antinociceptive response in 25 day old rats which was not antagonised by 300 or 1000 p.p.m. lead.
Naloxone antagonised the residual antinociception observed in 20 day old animals treated with 300 p.p.m. lead and had no effect on antinociception in control or lead‐treated 25 day old rats.
Using a lead exposure model considered to represent subclinical lead toxicity in man, it was shown that perinatal lead exposure disrupts opioid but not non‐opioid mediated stress antinociception.
Pharmacological properties of a C‐fibre response evoked by saphenous nerve stimulation in an isolated spinal cord‐nerve preparation of the newborn rat
Authors: Nussbaumer Jean‐Claude , Yanagisawa Mitsuhiko , Otsuka Masanori 
Published: July 2012

An isolated spinal cord‐peripheral nerve preparation of the newborn rat was developed. In this preparation it is possible to record spinal reflexes from a lumbar ventral root in response to stimulation of the ipsilateral saphenous or obturator nerve.
Single shock, weak intensity stimulation of the saphenous nerve induced a fast conducted compound action potential in the L3 dorsal root and a fast depolarizing response in the ipsilateral L3 ventral root. As a stronger stimulus was applied to the saphenous nerve, a slowly conducted compound action potential appeared in the dorsal root and a slow depolarizing ventral root potential (v.r.p.) in the L3 ventral root.
Single shock stimulation of the obturator nerve induced a rapidly conducted compound action potential in the L3 dorsal root and monosynaptic and polysynaptic reflexes, with a fast time course, in the ipsilateral L3 ventral root.
The slow v.r.p. evoked by saphenous nerve stimulation was depressed by the tachykinin antagonist, [D‐Arg1, D‐Trp7,9, Leu11] substance P (spantide), 4–16 μm. The response recovered its original shape and size 30–60 min after the removal of this antagonist.
The saphenous nerve‐evoked slow v.r.p. was depressed by [Met5] enkephalin (0.1–1 μm), dynorphin (1–13)(0.2 μm) and morphine (1–2 μm), and these effects were reversed by naloxone (1 μm).
Two endogenous peptides, galanin (1–2 μm) and somatostatin (1–2.5 μm), inhibited the slow v.r.p. evoked by saphenous nerve stimulation, whereas another endogenous peptide, calcitonin gene‐related peptide (0.1‐0.5 μm), potentiated the slow v.r.p. The slow v.r.p. was also inhibited by γ‐aminobutyric acid (GABA, 20 μm) and muscimol (0.2 μm), and their effects were antagonized by bicuculline (1 μm).
The present results suggest that substance P and neurokinin A are involved in the saphenous nerve‐evoked C‐fibre response in the spinal cord of the newborn rat.
The X‐ray crystal structure of 4‐diphenylcarbamyl‐N‐methylpiperidine methobromide (the carbamate analogue of 4‐DAMP methiodide)
Authors: Barlow R.B. , Johnson O. 
Published: July 2012

Crystals of 4‐diphenylcarbamyl‐N‐methylpiperidine methobromide contain 2 conformers, one with the ester group equatorial and the other with the ester group axial to the piperidine ring.
In both conformers and diphenylcarbamyl nitrogen is trigonally substituted and flat compared with the tetrahedral substitution of the corresponding carbon atom in 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP) methiodide.
The low activity and selectivity of the carbamate at muscarinic receptors is comparable with that of compounds containing only one phenyl ring, e.g. phenylacetyl‐N‐methyl piperidine methiodide or phenylacetylcholine. It is suggested that the high affinity of 4‐DAMP metho‐salts and their selectivity depend upon interactions with groups arranged in three dimensions and that the trigonal arrangement about the nitrogen atom in the carbamate makes it impossible for both benzene rings to interact at once.
An examination of the putative σ‐receptor in the mouse isolated vas deferens
Authors: Kennedy Charles , Henderson Graeme 
Published: July 2012

The effects of several ligands which interact with the σ‐binding site were studied on the electrically‐evoked (0.1 Hz) neurogenic twitch contractions of the mouse isolated vas deferens.
(+)‐3‐(3‐Hydroxyphenyl)‐N‐(1‐propyl)piperidine ((+)‐3‐PPP) (10−8–10−5m), inhibited the neurogenic twitch contractions. This inhibitory action was unaffected by naloxone (10−6m), idazoxan (10−6m), cocaine (10−6m) or tyramine (10−4–3 × 10−4m), but was abolished by the dopamine D2‐antagonist, sulpiride (10−6m). Therefore, in order to study the potentiating actions of σ ligands, sulpiride (10−6m) was used to prevent any inhibitory actions mediated via dopamine D2‐receptors.
In the presence of sulpiride (10−6m), haloperidol (10−6–10−5m), (+)‐3‐PPP (10−6−3 × 10−4m) and (+)‐N‐allyl‐N‐normetazocine ((+)‐SKF 10,047) (10−5–10−4m) each reversibly potentiated the neurogenic twitch contractions in a concentration‐dependent manner. The rank order of potency was haloperidol > (+)‐3‐PPP > (+)‐SKF 10,047.
The stereoisomers of 3‐PPP displayed stereoselectivity with (+)‐3‐PPP being more potent than (−)‐3‐PPP.
At a concentration that did not potentiate the twitch contractions, (3 × 10−7m), haloperidol did not antagonize the potentiating action of (+)‐3‐PPP (3 × 10−5m).
1,3‐Di‐O‐tolyguanidine (DTG) (10−8–10−5m) had no effect on the amplitude of twitch contractions and did not affect the potentiating action of (+)‐3‐PPP (10−5−3 × 10−5m).
It is concluded that σ‐ligands potentiate neurogenic twitch contractions of the mouse isolated vas deferens via a site that is different from the central σ‐binding site.
Demonstration in Tupaia papillary muscle preparations of α‐adrenoceptors mediating positive inotropic effects: comparison with guinea‐pigs
Authors: Koga T. , Shiraki Y. , Sakai K. 
Published: July 2012

Positive inotropic responses to α‐ and β‐adrenoceptor agonists of isolated papillary muscles from the tree shrew (Tupaia), were compared with those from guinea‐pigs.
In Tupaia, the concentration‐response curve for phenylephrine, unlike that for isoprenaline, was not affected by pindolol in a concentration (10−8m) sufficient to block β‐adrenoceptor‐mediated responses, but it was significantly shifted to the right by phentolamine (10−6m). In guinea‐pig papillary muscles, however, the concentration‐response curve for phenylephrine, like that for isoprenaline, was shifted to the right by pindolol (10−8m) but was unaltered by phentolamine (10−6m). Furthermore, when the mean concentrations of agonists inducing maximal positive inotropic responses were compared (relative to that of isoprenaline = 1.0), phenylephrine was found to be only slightly less potent (0.84 ± 0.04; n = 5) in Tupaia and much less potent (0.33 ± 0.06; n = 5) in the guinea‐pig.
Although in Tupaia papillary muscles the increase in developed tension induced by a combination of phenylephrine and isoprenaline did not significantly differ from that by phenylephrine alone, it was approximately 3 times larger than that produced by phenylephrine alone in guinea‐pigs.
These results indicate that in papillary muscles from Tupaia, unlike the guinea‐pig, the positive inotropic effects of phenylephrine can be mediated by α‐adrenoceptors.
Muscarinic suppression of the M‐current in the rat sympathetic ganglion is mediated by receptors of the M1‐subtype
Authors: Marrion N.V. , Smart T.G. , Marsh S.J. , Brown D.A. 
Published: July 2012

Under voltage‐clamp dissociated adult and foetal rat superior cervical ganglion (s.c.g.) cells exhibited a non‐inactivating voltage‐ and time‐dependent component of K+ current termed the M‐current (IM). IM was detected and measured from the current decay during hyperpolarizing voltage steps applied from potentials where IM was pre‐activated.
Neither the resting membrane current nor the amplitude of these current decay relaxations were reduced by omitting Ca from the bathing fluid, showing that the M‐current was not a ‘Ca‐activated’ K‐current dependent on a primary Ca‐influx. Concentrations of (+)‐tubocurarine sufficient to block the slow Ca‐activated K‐current IAHP did not inhibit IM or antagonize the effect of muscarinic agonists on IM, showing that IM was not contaminated by IAHP. Tetraethylammonium (1 mm), which blocks the fast Ca‐activated K‐current Ic, produced a small inhibition of IM. This was not due to contamination of IM by Ic since muscarinic agonists did not consistently block Ic.
The muscarinic agonists muscarine, oxotremorine, McN‐A‐343 and methacholine reversibly suppressed IM, resulting in an inward (depolarizing) current. The rank order of potency was: oxotremorine ≥ muscarine > McN‐A‐343 > methacholine.
The suppression of IM by muscarine was similar in cultured cells derived from adult and foetal tissue to that seen in the intact ganglia.
IM‐suppression by muscarine was inhibited by pirenzepine (Pz) and AF‐DX 116 with mean pKB values of 7.53 ± 0.13 (n = 3) and 6.02 ± 0.13 (n = 4) respectively.
The suppression of IM by muscarinic agonists was not affected by gallamine (10–30 μm). 4‐Diphenylacetoxy‐N‐methylpiperidine methiodide inhibited the response at 300 nM.
Pirenzepine inhibited the contractions of the guinea‐pig isolated ileum produced by muscarine with a mean pKB of 6.37 ± 0.03 (n = 8).
These results suggest that the receptors mediating suppression of the M‐current accord with those designated pharmacologically as M1 and that these receptors reach maturity at a very early stage in the development of the rat s.c.g.