bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for prejunctional M2 muscarinic receptors in pulmonary cholinergic nerves in the rat
Authors: Aas Pål , Maclagan Jennifer 
Published: July 2012

The effects of muscarinic antagonists considered to be selective for M1 receptors (pirenzepine) and for M2 receptors (gallamine and methoctramine) were used to investigate the existence of prejunctional muscarinic receptors on cholinergic nerves in the rat lung. The tracheal tube preparation was used in vitro, and contraction of the trachealis muscle was induced by electrical field stimulation (EFS) and by application of an exogenous muscarinic agonist (pilocarpine), and measured as an increase in intraluminal pressure in the tube.
The muscarinic antagonists, gallamine and methoctramine, enhanced the contractions induced by nerve stimulation, while contractions elicited by exogenous application of pilocarpine were inhibited by the antagonists.
In contrast, pirenzepine blocked contractions induced by both EFS and pilocarpine in a dose‐dependent manner (EC50 0.1 μm) due to blockade of the postjunctional muscarinic receptors on airway smooth muscle. Potentiation of the response to EFS was never seen with this antagonist.
The muscarinic agonist, pilocarpine, caused a slow maintained increase in tone of the tracheal tube and at the same time reduced the contractions induced by EFS. This inhibitory effect was blocked by gallamine and methoctramine.
The results suggest that prejunctional inhibitory muscarinic receptors may be localised on the parasympathetic cholinergic nerve terminals innervating tracheal smooth muscle in the rat. This confirms previous findings obtained by measuring transmitter release in this species. The present results suggest that these receptors are of the M2 subtype. Blockade of these autoreceptors with gallamine or methoctramine would increase the output of acetylcholine (ACh) and thereby enhance the nerve‐induced contraction of tracheal smooth muscle.
Characterization of the dopamine receptor mediating the hyperpolarization of cockroach salivary gland acinar cells in vitro
Authors: Evans A.M. , Green K.L. 
Published: July 2012

Intracellular recordings have been made of the hyperpolarization of cockroach salivary gland cells induced by nerve stimulation and dopamine.
The relative potency of a number of dopamine antagonists in inhibiting the dopamine‐ and nerve‐mediated hyperpolarization was studied. SCH23390 (10–50 μm), chlorpromazine (0.1–5 μm), haloperidol (10–100 μm) and metoclopramide (1 mm) inhibited the hyperpolarization.
In contrast, domperidone and (±)‐sulpiride potentiated the hyperpolarization induced by both nerve stimulation and dopamine.
Apparent dissociation constants (KDApp) were obtained for the blockade of the dopamine‐induced hyperpolarization. The rank order of potency (KDapp in parentheses) was as follows: chlorpromazine (0.2 μm); haloperidol (3.3 μm); SCH23390 (4.1 μm); metoclopramide (265μm), domperidone and (±)‐sulpiride (inactive).
It is concluded that the receptor subserving the dopamine‐induced hyperpolarization of the salivary gland acinar cells is the same as that mediating the secretory response to dopamine. In addition these data support our findings, which suggested that this receptor is similar to the D1 dopamine receptor, but distinct from the D2 receptor found in mammalian systems.
The effects of neuropeptide Y and its fragments upon basal and electrically stimulated ion secretion in rat jejunum mucosa
Authors: Cox H.M. , Cuthbert A.W. 
Published: July 2012

The effects of neuropeptide Y (NPY) and a range of C terminal fragments were investigated both on basal short circuit current (s.c.c.) and electrical field stimulated responses in voltage clamped preparations in rat jejunal mucosa.
Most of the NPY fragments tested had direct effects upon the mucosa, reducing baseline s.c.c. with EC50 values of 1 μm or more. NPY was 30 times more effective than any of the fragments tested and the order of potency was: NPY ≫ NPY (11–36) ≥ (12–36) ≥ (13–36) ≥ (14–36). NPY (15–36), (16–36), (20–36) and (22–36) were still less effective and complete concentration‐response curves could not be constructed. NPY (26–36), des amido NPY and the C‐terminal flanking peptide of NPY (CPON) were all inactive and did not significantly alter responses to NPY.
Electrical field stimulation (EFS) of mucosal preparations elicited rapid transient secretory responses in the presence of hexamethonium and atropine. NPY and fragments attenuated these secretory responses and where concentration‐response relationships could be compared at a given time point the following order of potency was obtained: NPY ≫ NPY (11–36) > NPY (13–36). Again NPY (26–36), des amido NPY and CPON were ineffective, while at single concentrations (300 nm) a graded attenuation of EFS responses was obtained with NPY (14–36) ≥ NPY (15–36) > NPY (16–36) ≥ NPY (20–36) > NPY (22–36).
The attenuation of EFS responses by these peptides was not dependent upon the basal secretory state. Pretreatment of tissues with piroxicam reduced s.c.c. and attenuated further reductions in s.c.c. by NPY, but had no effect upon NPY‐mediated inhibition of electrically‐stimulated secretory responses.
NPY fragments attenuated both basal and EFS generated secretion. Since fragments are effective these receptors must, by definition be Y2‐like. NPY (11–36) and NPY (13–36) at 300 nm and 1 μm did not significantly attenuate secretory responses to either carbachol (CCh) or substance P (SP). A 1 μm concentration of either fragment was equivalent in effect to 30 nm NPY upon basal current, but NPY at this concentration significantly reduced both CCh‐ and SP‐induced secretion. The reduced spectrum of fragment activity together with the different order and potency ratios obtained with these three peptides indicates a presynaptic action for NPY and the fragments.
Functional evidence for heterogeneity of peripheral prejunctional α2‐adrenoceptors
Authors: Connaughton Sonia , Docherty James R. 
Published: July 2012

We have examined the potencies of a series of α2‐adrenoceptor antagonists in functional studies of prejunctional α2‐adrenoceptors in rat atrium and vas deferens, and compared potencies with affinities for the α2A‐ligand binding site of human platelet and the α2B‐ site of rat kidney.
Antagonist potency in rat atrium was expressed as an EC30 (concentration producing 30% increase in the stimulation‐evoked overflow of tritium in tissues pre‐incubated with [3H]‐noradrenaline). Antagonist potency in rat vas deferens was expressed as a pA2 or KB at antagonizing the inhibition by the α2‐adrenoceptor agonist xylazine of the isometric twitch to a single stimulus, or as an EC30.
In ligand binding studies, Ki values were obtained for the displacement by α‐adrenoceptor antagonists of [3H]‐yohimbine binding to human platelet or rat kidney membranes.
In functional studies, three antagonists (ARC 239, prazosin and chlorpromazine) distinguished between prejunctional α2‐adrenoceptors of rat atrium (EC30) and rat vas deferens (pA2) and showed 49, 12 and 7 times higher potency in rat atrium, respectively. ARC 239 was also 17 times more potent in rat atrium than rat vas deferens when EC30 values were compared.
The correlation of affinity for the α2A‐ site of human platelet was better with prejunctional potency in rat vas deferens than rat atrium.
The correlation of affinity for the α2B‐site of rat kidney was better with prejunctional potency in rat atrium than rat vas deferens.
It is concluded that prejunctional α2‐adrenoceptors of rat vas deferens and rat atrium differ, and these receptors may resemble the α2A‐ and α2B‐ligand binding sites, respectively.
The effects of substance P analogues on the scratching, biting and licking response induced by intrathecal injection of N‐methyl‐d‐aspartate in mice
Authors: Sakurada Tsukasa , Manome Yoichi , Tan‐No Koichi , Sakurada Shinobu , Kisara Kensuke 
Published: July 2012

Intrathecal (i.t.) administration of N‐methyl‐d‐aspartate (NMDA) elicited a dose‐dependent behavioural response consisting of licking, biting and scratching in mice.
Repeated i.t. injections of 0.4 nmol NMDA, at 5 min intervals, resulted in the rapid development of desensitization to this NMDA‐induced behavioural phenomenon.
The NMDA‐induced response was dose‐dependently inhibited by the simultaneous injection of a selective NMDA‐receptor antagonist, d‐2‐amino‐5‐phosphonovaleric acid.
The substance P (SP) analogues [d‐Pro2, d‐Trp7,9] SP and [d‐Arg1, d‐Trp7,9, Leu11] SP (spantide) inhibited NMDA‐induced behavioural responses in a dose‐dependent manner. However, [d‐Phe7, d‐His9] SP (6–11), a SP analogue selective for neurokinin1 (NK1) receptors, failed to inhibit NMDA‐induced responses even at a dose of 4.0 nmol.
These results indicate that NMDA‐induced behavioural responses are mainly mediated through NMDA receptors without affecting NK1 receptors in the spinal cord.
Evidence for BK1 bradykinin‐receptor‐mediated prostaglandin formation in osteoblasts and subsequent enhancement of bone resorption
Authors: Ljunggren Östen , Lerner Ulf H. 
Published: July 2012

The effects of the BK1 bradykinin (BK)‐receptor agonist des‐Arg9‐BK on bone resorption and prostaglandin formation in osteoblasts have been studied.
Des‐Arg9‐BK (1 μm) stimulated the release of 45Ca from prelabelled neonatal mouse calvarial bones and the formation of prostaglandin E2 (PGE2) in calvarial bones. The stimulatory effect on bone resorption and PGE2 formation could be totally inhibited by indomethacin, flurbiprofen and hydrocortisone.
The BK1 receptor antagonist des‐Arg9‐Leu8‐BK (10 μm) inhibited des‐Arg9‐BK (0.01–0.1 μm)‐induced release of 45Ca from prelabelled neonatal mouse calvarial bones, while leaving BK (0.1–1 μm)‐induced 45Ca release unaffected.
In isolated osteoblast‐like cells from neonatal mouse calvarial bones, des‐Arg9‐BK (1 μm) induced a slowly developing increase in PGE2 formation that was significantly different from untreated controls after 24 h. Treatment with BK caused a rapid burst (within minutes) of PGE2 formation.
Des‐Arg9‐Leu8‐BK (10 μm) selectively inhibited des‐Arg9‐BK (1 μm)‐induced PGE2 and prostacyclin formation in isolated osteoblast‐like cells incubated for 72 h. Des‐Arg9‐Leu8‐BK did not affect BK and Lys‐BK (1 μm)‐induced PGE2 and prostacyclin formation in isolated osteoblast‐like cells incubated for 72 h.
These data indicate that osteoblasts are equipped with BK1‐receptors mediating enhanced prostaglandin formation and subsequent bone resorption.
The crucial role of physiological Ca2+ concentrations in the production of endothelial nitric oxide and the control of vascular tone
Authors: Lopez‐Jaramillo P. , Gonzalez M.C. , Palmer R.M.J. , Moncada S. 
Published: July 2012

The effect of varying the extracellular Ca2+ concentration on the basal and acetylcholine (ACh)‐induced release of nitric oxide (NO) from the rabbit aorta was investigated by use of a superfusion bioassay system.
Changes between 0.5 and 2.0 mm in the concentration of Ca2+ superfusing the detector bioassay tissues or perfusing endothelium‐denuded donor aortae had no effect on the tone of these tissues.
Increasing the concentration of Ca2+ perfusing endothelium‐containing donor aortae from zero to 1.25 mm caused a transient (24 ± 9 min), concentration‐dependent basal release of NO, which was attenuated at higher concentrations of Ca2+ (1.5–2.0 mm).
The duration of the effect of Ca2+ on the basal release of NO was increased by a concomitant infusion of l‐arginine (100 μm) through the donor aorta.
Changes in the concentration of Ca2 + between 0.5 and 2.0 mm had a similar biphasic effect on the release of NO induced by ACh, which was also maximal at 1.25 mm Ca2+.
When Ca2+ was removed from the Krebs buffer perfusing the donor aorta, the basal release of NO declined within 2 min. In contrast, the release of NO induced by ACh declined progressively over 60 min.
Thus changes in the concentration of Ca2+ around the physiological range modulate the synthesis of NO by the vascular endothelium and consequently, vascular tone. This may account for the effects of dietary Ca2+ supplements on the control of some hypertensive states.
Vasodilatation and inhibition of mediator release represent two distinct mechanisms for prostaglandin modulation of acute mast cell‐dependent inflammation
Authors: Raud J. 
Published: July 2012

Intravital microscopy of the hamster cheek pouch was used to examine the influence of vasodilator prostanoids (prostaglandin E2 (PGE2), PGI2), forskolin, and nitroprusside on the microvascular changes during acute inflammation induced by antigen or histamine. The results extend our previous finding that PGE2 modulates allergic inflammation and histamine release in the cheek pouch model.
The microvascular actions of arachidonic acid and different cyclo‐oxygenase products (PGE2, PGD2, PGI2, PGF2α, and the thromboxane A2 (TXA2)‐analogue U‐44069) were first compared with respect to their effects on arteriolar tone. Of the prostaglandins, only PGE2 and PGI2 were potent vasodilators and markedly increased local blood flow. Nitroprusside and forskolin also caused vasodilatation and increased blood flow, but were somewhat less potent than PGE2 and PGI2.
Topically applied PGE2 and PGI2 in vasodilator concentrations suppressed the antigen‐induced plasma leakage. On the other hand, although the antigen response was predominantly mediated by histamine, both prostaglandins enhanced the plasma leakage evoked by exogeneous histamine.
In contrast, the vasodilator nitroprusside, in a dose causing an increase in blood flow equal to that of PGE2 and PGI2, potentiated both the histamine‐induced plasma leakage, as well as the plasma and leukocyte extravasation after antigen challenge, indicating that the anti‐inflammatory actions of the prostaglandins were unrelated to their vasodilator properties per se.
Because forskolin, a specific activator of adenylate cyclase, mimicked the actions of PGE2 and PGI2, i.e. inhibition of the antigen‐induced plasma extravasation and enhancement of the histamine response, it is possible that the observed antiallergic effects of the prostaglandins were related to accumulation of intracellular adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP).
Taken together, there appears to be a competition between pro‐ and anti‐inflammatory effects of PGE2 and PGI2 in reactions involving release of endogeneous inflammatory mediators in vivo, i.e. enhancement of inflammatory mediator target action on one hand (‘two mediator synergism’), and suppression of mediator release on the other. Moreover, the observations indicate that vasodilatation and inhibition of mediator release are two distinct actions of PGE2 and PGI2.
Contractile responses of smooth muscle strips from rat and guinea‐pig urinary bladder to transmural stimulation: effects of atropine and α,β‐methylene ATP
Authors: Brading A.F. , Williams J.H. 
Published: July 2012

Strength‐duration curves for threshold mechanical responses to single transmural stimuli were identical for rat and guinea‐pig detrusor. In both species atropine had no effect on the curves, but the curves were shifted to the right by nerve blockade with tetrodotoxin (TTX), and by blockade of P2‐purinoceptors with α,β‐methylene ATP (α,β‐MeATP).
With short duration pulses of 50 V and less, the responses were nerve‐mediated. Increase in either the strength or duration of the stimulus caused direct muscle stimulation, resistant to blockade with atropine, TTX and α‐β‐MeATP.
The shape of the contractile response to a single nerve stimulus varied from tissue to tissue. The responses could be mono‐, bi‐, or multiphasic. Bi‐ or multiphasic responses were normally seen in tissues which were spontaneously active. The multiphasic nature of the response was enhanced by factors which increased the excitability of the cells and was reduced by factors which decreased the excitability.
The frequency‐response curves in the rat are similar to those previously obtained in the guinea‐pig. Atropine suppresses the high frequency response by 25%, with little effect at low frequencies, whereas desensitization of P2‐purinoceptors with α,β‐MeATP suppresses the responses maximally at low frequencies but still by 75% at high frequencies. A combination of both drugs eliminates the nerve‐mediated responses.
It is concluded that the response to a single nerve stimulus is mediated by a non‐cholinergic transmitter, through activation of P2‐purinoceptors. The possibility that simultaneous release of acetylcholine can modify the excitability of cells and thus the configuration of the response to a single stimulus is discussed.
Release of endothelium‐derived relaxing factor from pig cultured aortic endothelial cells, as assessed by changes in endothelial cell cyclic GMP content, is inhibited by a phorbol ester
Authors: Smith J.A. , Lang D. 
Published: July 2012

Cultured aortic endothelial cells of the pig respond to the endothelium‐derived relaxing factor (EDRF) they release with an increase in cyclic GMP content. This response is inhibited by haemoglobin or by l‐NG‐monomethyl‐arginine (l‐NMMA), and has been used to investigate the effects of phorbol esters on EDRF release.
Pretreatment with phorbol‐12,13‐dibutyrate (PDB) but not the inactive 4α‐phorbol‐12,13,‐didecanoate (PDD), inhibited increases in cyclic GMP induced by substance P (10−8 m) in a time and concentration‐dependent manner. PDB did not affect basal cyclic GMP levels.
PDB (3 × 10−7 m), but not PDD (3 × 10−7 m), also inhibited ATP (10−5 m)‐induced increases in cyclic GMP, but did not affect those induced by bradykinin (10−7 m).
Increases in cyclic GMP induced by low (10−7 m) but not high (10−6 m) concentrations of the calcium ionophore A23187 were inhibited by PDB (3 × 10−7 m). This inhibitory effect was due to enhanced destruction of EDRF by superoxide anions rather than inhibition of EDRF release, as the inhibition was abolished in the presence of superoxide dismutase (SOD, 30 u ml−1) and catalase (CAT, 100 u ml−1).
SOD and CAT did not affect the inhibitory action of PDB on substance P or ATP‐induced increases in cyclic GMP.
Increases in endothelial cell cyclic GMP content induced by sodium nitroprusside (10−5 m) were unaffected by PDB pretreatment.
The inhibitory effects of PDB are probably a result of an action of protein kinase C on the steps between receptor occupation and phospholipase C activation.
Mechanism of the potentiation of neurally‐induced bronchoconstriction by gallamine in the guinea‐pig
Authors: Del Monte Marco , Omini Claudio , Subissi Alessandro 
Published: July 2012

Electrical stimulation of the cervical vagi (15 Hz, 0.2 ms, 3 s, 7–15 V) produced a slight bronchoconstriction in the anaesthetized guinea‐pig. This effect was fully abolished by atropine, while gallamine (0.1–10 μmol kg−1) produced a dose‐dependent increase up to ten fold.
Gallamine‐induced potentiation of neurally‐mediated bronchoconstriction was not inhibited by depletion of sensory neuropeptides with capsaicin or by pretreatment with pyrilamine. In propranolol‐pretreated guinea‐pigs the potentiation induced by gallamine 3 and 10 μmol kg−1 was inhibited by 40 and 46%, respectively.
Physostigmine (0.5 mg kg−1) produced a very slight and slowly developing bronchoconstriction in the anaesthetized guinea‐pig, which was also potentiated dose‐dependently by gallamine (0.1–10 μmol kg−1).
Gallamine (10 μmol kg−1) potentiated the bronchial anaphylactic response induced by aerosol challenge with ovalbumin in actively sensitized guinea‐pigs.
These results suggest that neither sensory neuropeptides nor histamine are involved in the gallamine‐induced potentiation of neurally‐mediated bronchoconstriction, while inhibition of the sympathetic nervous system may play a minor role. They are in general agreement with the hypothesis that gallamine antagonizes acetylcholine selectively at prejunctional muscarinic receptors in the guinea‐pig airways, thus increasing its release from parasympathetic nerve terminals. These autoreceptors appear to be operant during anaphylactic bronchoconstriction.
The influence of 5‐hydroxytryptamine agonists and antagonists on identified sympathetic preganglionic neurones in the rat, in vivo
Authors: Lewis D.I. , Coote J.H. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) was applied by microiontophoresis in the vicinity of identified sympathetic preganglionic neurones in the upper thoracic spinal cord of the rat, in vivo.
Sympathetic preganglionic neurones responded in one of three ways to 5‐HT: by (a) excitation (76%), (b) inhibition (4%) or (c) in a biphasic manner (5%).
The excitatory responses evoked by 5‐HT were mimicked by 5‐carboxamidotryptamine (5‐CT) and α‐methyl‐5‐hydroxytryptamine (α‐Me‐5‐HT). The inhibitory and biphasic responses evoked by 5‐HT were mimicked by 2‐methyl‐5‐hydroxytryptamine (2‐Me‐5‐HT). The observed responses evoked by 5‐HT and selective agonists may be different on the same cell. In several instances a single neurone excited by one agonist was inhibited by another agonist.
The 5‐HT2‐receptor antagonists, ketanserin and LY 53857, failed to abolish selectively the excitatory responses evoked by 5‐HT and α‐Me‐5‐HT, when applied by microiontophoresis. The antagonists non‐selectively reduced the excitatory responses evoked by 5‐HT, 5‐CT, α‐Me‐5‐HT, d,l‐homocysteic acid (DLH) and noradrenaline (NA). A reduction in synaptically evoked activity was also observed.
The 5‐HT3‐receptor antagonist, ICS 205–930, failed to abolish the inhibitory responses evoked by 5‐HT.
It was concluded that the excitatory responses evoked by 5‐HT are mediated by a receptor that is neither 5‐HT2 or 5‐HT3, but shows similarities to the 5‐HT1‐like receptor profile. The inhibitory actions of 5‐HT are mimicked by 2‐Me‐5‐HT, but the receptor is not 5‐HT3, or 5‐HT1‐like or 5‐HT2.
Actions of cocaine on rat dopaminergic neurones in vitro
Authors: Lacey M.G. , Mercuri N.B. , North R.A. 
Published: July 2012

Intracellular recordings were made from neurones in vitro in the rat substantia nigra zona compacta and ventral tegmental area; the neurones had the characteristic properties of dopamine‐containing cells, and fired action potentials spontaneously.
Cocaine (1–10μm) inhibited spontaneous firing, hyperpolarized the membrane and (in neurones voltage‐clamped at −60 mV) caused an outward membrane current; the minimally effective concentration was 1 μm. These effects were blocked by sulpiride (30 nm–1 μm).
Dopamine (3–100 μm) also inhibited firing, hyperpolarized and caused an outward current. These effects of dopamine were potentiated about five fold by cocaine (10 μm).
It is concluded that cocaine (1–10 μm) inhibits the firing and hyperpolarizes substantia nigra zona compacta neurones in vitro by blocking the uptake of dopamine which the cells continuously release.