bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subtypes of muscarinic receptor on cholinergic nerves and atrial cells of chicken and guinea‐pig hearts
Authors: Jeck D. , Lindmar R. , Löffelholz K. , Wanke M. 
Published: July 2012

Electrically driven chicken and guinea‐pig atria were used to investigate the negative inotropic effects of the muscarinic agonists methacholine and acetylcholine (ACh). The release of ACh from isolated hearts into the perfusate in response to (preganglionic) vagal or (pre‐and postganglionic) field stimulation was bioassayed on the guinea‐pig ileum or determined by labelling with [3H]‐choline.
Concentration‐response curves for the negative inotropic effect of methacholine were shifted to the right by pirenzepine in various concentrations (0.03 to 10 μmol l−1). The pA2 values were 7.76 in chicken atria and 6.53 in guinea‐pig atria. Pirenzepine and atropine antagonized the negative inotropic response to 0.3 μmol l−1 ACh. The half‐maximally effective concentrations (IC50) of pirenzepine (Pz) and atropine were 40 and 5.4 nmol l−1 in chicken atria and 330 and 3.5 nmol l−1, respectively, in guinea‐pig atria. Thus, the respective potency ratios (IC50Pz/IC50atropine) were 7.4 and 94.3 in the two species.
Pirenzepine in low concentrations increased the release of unlabelled and 3H‐labelled ACh from isolated hearts evoked by vagal and field stimulation only in chicken, but not in guinea‐pigs. The half‐maximally‐effective concentration of pirenzepine was about 30 nmol l−1 in the chicken heart, whereas, in the guinea‐pig heart, an increased release was observed at 300 nmol l−1.
(+)‐Tubocurarine [(+)‐Tc; 100 μmol l−1] reduced the release of ACh evoked by (preganglionic) vagal stimulation to a (+)‐Tc‐resistant release of about 30%. The time‐course of the neuronal release of [3H]‐ACh was markedly altered: the onset was delayed and the termination was extended beyond the period of stimulation (1 min or 5 s) by several seconds. The (+)‐Tc‐resistant release was nearly abolished by 30 nmol l−1 pirenzepine.
In conclusion, the pre‐and post‐synaptic muscarinic receptors of the parasympathetic neuroeffector junction of the heart both belong to the M1‐subtype in the chicken and to an M2‐subtype in the guinea‐pig. Block of the nicotinic ganglionic transmission in the chicken heart by (+)‐Tc unmasked a muscarinic transmission, which presumably was mediated through M1‐receptors stimulating a low and prolonged postganglionic release of ACh.
Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo‐M ratio as an index of efficacy at cortical muscarinic receptors
Authors: Freedman S.B. , Harley E.A. , Iversen L.L. 
Published: July 2012

Radioligand binding assays using [3H]‐N‐methylscopolamine (NMS) and [3H]‐oxotremorine M (Oxo‐M) have been devised to predict the efficacy of test compounds at muscarinic receptors in rat cerebral cortex.
Muscarinic antagonists, including non‐selective and both M1‐ and M2‐selective compounds, displayed similar affinity for both binding assays.
Full agonists such as carbachol and muscarine possessed a ratio of potencies against the antagonist versus the agonist ligand (NMS/Oxo‐M ratio) of > 4000.
Compounds which have been shown previously to display partial agonist activity in functional assays e.g. pilocarpine and RS86 had intermediate NMS/Oxo‐M ratios of 100–150. A second group of compounds which included oxotremorine had somewhat higher ratios (500–1400).
The ratio of affinity constants for the two assays predicted the ability of agonists to stimulate cortical phosphatidyl‐inositol turnover.
These results suggest that the NMS/Oxo‐M ratio may be a useful prediction of efficacy for novel compounds acting at cortical muscarinic receptors.
Clonidine effects on disposition of xenobiotics in rats: inhibited elimination of flow‐limited but not extraction‐limited agents
Authors: Ben‐Zvi Zvi , Hurwitz Aryeh 
Published: July 2012

The α2‐adrenoceptor agonist, clonidine, reduces the hepatobiliary clearance of the anionic dye, sulphobromophthalein (BSP) in rodents. We now compare the effects of clonidine on BSP elimination with its effects on disposition of compounds which are metabolized by hepatic microsomal mixed function oxidases.
BSP, 100 mg kg−1 was administered i.v. to rats at 4h after s.c. saline or clonidine, 0.2 mg kg−1. Thirty min later, plasma BSP levels were 121.4 ± 2.25 μg ml−1 in saline‐treated rats, while in clonidine‐treated rats they were 631.5 ± 141.0 μg ml−1. Clonidine raised hepatic BSP levels from 256.0 ± 28.9 μg g−1 tissue to 568.5 ± 86.5 μg g−1.
Acute administration of clonidine (0.2 mg kg−1 s.c.) or repeated clonidine dosing (0.2 mg kg−1, s.c. twice daily for 10 days) did not affect the disposition of intravenously administered [14C]‐antipyrine (15 mg kg−1).
Activities of the P450 mixed function oxidase enzymes, aniline hydroxylase and aminopyrine N‐demethylase, were identical in liver microsomes from saline‐treated rats and in microsomes from rats given single or multiple s.c. doses of clonidine (0.2 mg kg−1).
Addition of clonidine or other 2‐substituted imidazoles at concentrations up to 2 μm did not affect the activities of aniline hydroxylase or of aminopyrine N‐demethylase in suspensions of rat liver microsomes. Other substituted imidazoles, including cimetidine, clotrimazole and metronidazole, at concentrations of 0.2 μm or higher, inhibited the activities of these microsomal enzymes.
Clonidine slowed BSP elimination, which is probably hepatic blood flow‐limited, but not the extraction‐limited elimination of antipyrine, which is metabolized by hepatic microsomal enzymes.
Evidence that mCPP may have behavioural effects mediated by central 5‐HT1C receptors
Authors: Kennett G.A. , Curzon G. 
Published: July 2012

The effects of 1‐(3‐chlorophenyl)piperazine (mCPP) and 1‐[3‐(trifluoromethyl)phenyl] piperazine (TFMPP) on activity of rats in a novel cage, and on the rotorod and elevated bar co‐ordination tests was examined.
Peripherally administered mCPP and TFMPP dose‐dependently reduced locomotion, rearing, and feeding scores but not grooming of freely fed rats placed in a novel observation cage. Yawning behaviour was increased. Similar effects were also observed after injection of mCPP into the 3rd ventricle.
Co‐ordination on a rotating drum of both untrained and trained rats was impaired following mCPP but co‐ordination on an elevated bar was not.
The hypoactivity induced by mCPP was opposed by three antagonists with high affinity for the 5‐hydroxytryptamine (5‐HT1C) site; metergoline, mianserin, cyproheptadine and possibly also by a fourth antagonist mesulergine. Metergoline, mianserin and cyproheptadine also opposed the reduction in feeding scores. However, neither effect of mCPP was antagonized by the 5‐HT2‐receptor antagonists ketanserin or ritanserin, the 5‐HT3‐receptor antagonist ICS 205–930, the 5‐HT1A and 5‐HT1B‐receptor antagonists (—)‐pindolol, (—)‐propranolol and (±)‐cyanopindolol or the 5‐HT1A‐, 5‐HT2‐ and dopamine receptor antagonist spiperone. The specific α2‐adrenoceptor antagonist idazoxan was also without effect.
Hypoactivity induced by TFMPP was similarly antagonized by mianserin but unaffected by (±)‐cyanopindolol.
These results suggest that the hypoactivity is mediated by central 5‐HT1C‐receptors and that mCPP and possibly TFMPP may be 5‐HT1C‐receptor agonists.
As mianserin, cyproheptadine and mesulergine in the absence of mCPP did not increase locomotion but increased the number of feeding scores, the activation of 5‐HT1C‐receptors may be of physiological importance in the control of appetite. The possible relevance of these results to the therapeutic and side‐effects of clinically used antidepressants (particularly trazodone and mianserin) and anorexigenic drugs is discussed.
The origin of the anticholinesterase‐induced repetitive activity of the phrenic nerve‐diaphragm preparation of the rat in vitro
Authors: Ferry C.B. 
Published: July 2012

Action potentials have been recorded in contracting muscle cells of the phrenic nerve‐diaphragm preparation from rats. After the organophosphorous anticholinesterase, ecothiopate, some cells fired repetitive action potentials. In 0.1 mm [Mg2+]o the repetitive activity was generated presynaptically or postsynaptically, and in 1 mm [Mg2+]o, probably only postsynaptically.
The repetitive action potentials in muscle were generated ectopically about 0.2 mm away from the usual site.
In mm [Mg2+]o, spontaneous action potentials in muscle were generated presynaptically. These were often followed by repetitive action potentials generated either presynaptically or postsynaptically.
The initiation of centripetal action potentials in the phrenic nerve was coincident with the repetitive firing in the muscle.
The results are discussed in relation to the manner of generation of repetitive activity in nerve and muscle after anticholinesterases.
Comparison of the effects of some muscarinic agonists on smooth muscle function and phosphatidylinositol turnover in the guinea‐pig taenia caeci
Authors: Gardner A.L. , Choo L.K. , Mitchelson F. 
Published: July 2012

The effects of the muscarinic agonists acetylcholine (ACh), carbachol (CCh), AHR‐602, and McN‐A‐343 on contractility and on inositol phosphate accumulation in the presence of lithium were compared in the taenia of the guinea‐pig caecum.
Compared to CCh, ACh was a full agonist for contraction but AHR‐602 and McN‐A‐343 were partial agonists producing 80–85% of the maximal response to CCh. Similar to previous findings with CCh, tonic contractions produced by AHR‐602 and McN‐A‐343 were less sensitive to inhibition by nifedipine or verapamil than tonic contractions to ACh.
CCh and ACh produced similar increases in inositol phosphate accumulation and the effect of CCh (0.1 mm) was inhibited by atropine (IC50 8.5 nm) and pirenzepine (IC50 450 nm). The accumulation of inositol phosphates in the presence of AHR‐602 or McN‐A‐343 was not significantly different (P > 0.05) from basal levels.
A concentration of 0.2 mm AHR‐602 produced a parallel shift of the concentration‐response curve to CCh on inositol phosphate accumulation. The IC50 value for inhibition of CCh (0.1 mm) was > 50 fold higher than the EC50 value for contraction produced by the partial agonist. McN‐A‐343 (20 μm) produced a flattening of the concentration‐response curve to CCh for inositol phosphate accumulation.
The results suggest that the increase in phosphatidylinositol turnover produced by muscarinic agonists, like the contractile response, involves an M2‐muscarinic receptor. AHR‐602 and McN‐A‐343 are partial agonists for the contractile response and while producing no significant increase in phosphatidylinositol turnover inhibit the response to CCh.
Psoriatic skin lesions contain a novel lipid neutrophil chemokinetic compound which is distinct from known chemoattractant eicosanoids
Authors: Camp R.D.R. , Cunningham F.M. , Fincham N.J. , Greaves M.W. , Black A. Kobza , Mallet A.I. , Woollard P.M. 
Published: July 2012

Lipid extracts of scale from the lesions of the skin disease psoriasis were purified by high performance liquid chromatography (h.p.l.c.). Assay of fractions by an agarose microdroplet method showed the presence of a novel neutrophil chemokinetic compound which possessed the chromatographic properties of a monohydroxy fatty acid, yet was distinct from the chemoattractant eicosanoid, 12‐hydroxyeicosatetraenoic acid, previously isolated in psoriasis.
The novel material, termed compound X, was also detected in fractions collected on h.p.l.c. of extracts of chamber fluid samples obtained from abraded psoriatic lesions, but was not detectable in samples from clinically normal skin.
Comparison of the straight and reversed phase h.p.l.c. retention times of compound X with those of a range of standard monohydroxy fatty acids, together with further analysis by gas chromatography — mass spectrometry and assay of selected standards for neutrophil chemokinetic activity, failed to reveal the structural identity of compound X.
The finding of a further compound in psoriatic lesions, which stimulates neutrophil movement, highlights the complexity of inflammatory mediator production in this disease.
Identification of two taurine receptor subtypes on the primary afferent terminal of frog spinal cord
Authors: Kudo Yoshihisa , Akiyoshi Eri , Akagi Hiroyuki 
Published: July 2012

Effects of taurine on primary afferent terminals in the frog spinal cord were examined by a sucrose‐gap method applied to a dorsal root (9th or 10th segment).
In a normal Ringer solution, taurine (1 mM, applied for 5 s at a rate of 0.04 ml s−1, 0.2 μmol) caused a hyperpolarization, but a higher concentration (10 mM, applied at the same rate, 2.0 μmol) caused a biphasic response consisting of a hyperpolarization followed by a slow onset depolarization. A similar biphasic response could also be observed in tetrodotoxin‐treated preparations.
When the concentration of extracellular Mg2+ was increased up to 9.0 mM, the depolarizing response to taurine was augmented. The rate of the augmentation was dependent upon the extracellular Mg2+ concentration.
The depolarizing effect was selectively antagonized by bicuculline in concentrations (10–30 μm) that had no significant antagonizing action on γ‐aminobutyric acid (GABA)‐induced depolarization. On the other hand the hyperpolarizing effect of taurine was selectively reduced by strychnine (0.1 μm) which had no antagonizing effect on responses to glycine.
These results suggest that in the frog spinal cord there are at least two subtypes of taurine receptor whose pharmacological profiles resemble GABA and glycine receptors in the mammalian central nervous system, and whose sensitivity may be modulated by extracellular Mg2+.
GR43175, a selective agonist for the 5‐HT1‐like receptor in dog isolated saphenous vein
Authors: Humphrey P.P.A. , Feniuk W. , Perren M.J. , Connor H.E. , Oxford A.W. , Coates I.H. , Butina D. 
Published: July 2012

We describe the actions of a novel and selective 5‐HT1‐like receptor agonist, GR43175, in a range of isolated tissue preparations containing different 5‐hydroxytryptamine (5‐HT) receptor types.
GR43175 was a potent agonist at 5‐HT1‐like receptors mediating contraction of the dog isolated saphenous vein and also at those inhibiting neuronally mediated contractions in the same preparations. For both actions, GR43175 was approximately four times weaker than 5‐HT.
GR43175 was devoid of agonist properties at 5‐HT1‐like receptors mediating relaxation of the cat isolated saphenous vein.
GR43175 was devoid of agonist properties at 5‐HT2 receptors mediating contraction of the rabbit isolated aorta, pig coronary artery, greyhound coronary artery and beagle femoral artery.
GR43175 was devoid of agonist properties at 5‐HT3 receptors mediating depolarization of the rat isolated vagus nerve.
The contractile response to GR43175 in the dog isolated saphenous vein was selectively antagonized by methiothepin but was resistant to antagonism by the 5‐HT2 receptor blocking drug ketanserin and the 5‐HT3 receptor blocking drug MDL 72222. Methiothepin antagonized the contractile action of 5‐HT and GR43175 to an equal extent suggesting that both agonists act at the same receptor.
The results demonstrate that GR43175 is a highly selective agonist for the 5‐HT1‐like receptors found in the dog saphenous vein. The absence of an action of GR43175 at 5‐HT1‐like receptors mediating relaxation of the cat isolated saphenous vein provides further evidence that 5‐HT1‐like receptors are heterogeneous.
Evidence that neutrophil accumulation induced by interleukin‐1 requires both local protein biosynthesis and neutrophil CD18 antigen expression in vivo
Authors: Rampart M. , Williams T.J. 
Published: July 2012

Mechanisms involved in neutrophil accumulation induced by intradermal injection of interleukin‐1 (IL‐1) in the rabbit were investigated using intravenously‐injected 111In‐labelled neutrophils. C5a des Arg, N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) and leukotriene B4 (LTB4) were included for comparison.
Local inhibition of protein biosynthesis in the skin using actinomycin‐D or cycloheximide blocked 111In‐neutrophil accumulation induced by IL‐1, but not that induced by the other mediators.
Actinomycin‐D and cycloheximide had no effect on local plasma protein leakage induced by intradermally‐injected C5a des Arg, or that induced by zymosan. 111In‐neutrophil accumulation induced by zymosan was, however, partially suppressed.
A monoclonal antibody, MoAb 60.3, recognising neutrophil surface CD18 antigen, was preincubated with 111In‐neutrophils before intravenous injection. This pretreatment did not affect circulating numbers of radiolabelled cells, but it inhibited their accumulation in response to IL‐1, C5a des Arg and the other mediators.
The results suggest that neutrophil accumulation induced by IL‐1, but not the other mediators, requires local protein biosynthesis, probably in the microvascular endothelium. Neutrophil accumulation to IL‐1 and the other mediators appears to require neutrophil surface antigen, CD18. The inflammatory response to zymosan may be mediated by both endogenous C5a des Arg and IL‐1.
Alteration of fate of vasoactive autacoids in pulmonary circulation following monocrotaline‐induced lung vascular injury in rats
Authors: Ito Katsuaki , Hayashi Katsuya , Nakashima Teruyuki , Murakami Takayuki 
Published: July 2012

To learn how pulmonary vascular injury alters the ability of the lung to metabolize vasoactive autacoids, lung vascular lesions were produced in rats by a single subcutaneous injection of monocrotaline (90 mg kg−1), and the blood pressure responses to angiotensin I (AI), angiotensin II (AII), bradykinin, prostaglandin E2 (PGE2) and substance P were examined. Vasoactive agents were given intravenously or intra‐arterially.
On histological examination of the lung at 3 weeks after monocrotaline treatment, degeneration or necrotization of endothelial cells was evident.
The conversion of AI to AII was only slightly depressed by monocrotaline treatment. On the other hand, the depressor response to intravenously injected bradykinin was enhanced in monocrotaline‐treated rats. When the rats were pretreated with indomethacin the depressor response to intravenous bradykinin was the same for both control and monocrotaline‐treated groups which suggests that endogenous prostaglandins are involved in the enhancement of the response to bradykinin.
In monocrotaline‐treated rats the depressor response to intravenous PGE2 was significantly enhanced depending on the period following the treatment, while that to the intra‐arterial injection did not differ from control.
The data suggest that monocrotaline‐induced lung injury impairs the metabolism of PGE2 during pulmonary circulation but has little effect on the conversion of AI to AII and the degradation of bradykinin in rats.
Comparison of the cardiovascular effects of trans‐diclofurime with different types of calcium antagonists in conscious spontaneously hypertensive rats
Authors: Petty Margaret A. , Mir Anis K. 
Published: July 2012

Trans‐diclofurime has been shown to be a potent group II calcium antagonist in in vitro and in vivo test systems. In contrast to the dihydropyridines, group II calcium antagonists have a reduced propensity to cause reflex tachycardia due to well‐balanced inhibitory effects in smooth muscle and heart. Since effects on autonomic reflexes are more reliably assessed in conscious animals, the cardiovascular effects of trans‐diclofurime have been examined and compared to those of nifedipine, verapamil and diltiazem in the conscious spontaneously hypertensive rat (SHR).
Each SHR had an indwelling catheter in the femoral artery to record mean arterial pressure (MAP) and heart rate (HR) and a cannula in the femoral vein for drug infusion over 1 min.
Nifedipine (0.1–3.0 μmol kg−1 i.v.) caused dose‐related falls in MAP accompanied by dose‐related increases in HR. Trans‐diclofurime and verapamil (0.3–3.0 μmol kg−1 i.v.) also caused dose‐related decreases in MAP, but significant tachycardia was only seen at 1.0 and 3.0 μmol kg−1, Trans‐diclofurime (0.3 μmol kg−1) induced a significant fall in HR. Diltiazem (1.0–10.0 μmol kg−1 i.v.) induced dose‐related falls in MAP, significant bradycardia was evident with 1.0 μmol kg−1 and tachycardia with 10 μmol kg−1. Trans‐diclofurime and diltiazem induced less tachycardia than nifedipine and verapamil for equivalent falls in MAP.
These results suggest that trans‐diclofurime is a potent antihypertensive agent in conscious SHR and, like diltiazem, the hypotensive effects are associated with less tachycardia than is usually apparent with calcium antagonists such as nifedipine or verapamil.
The cardiovascular effects of trans‐diclofurime in conscious SHR are those expected of a class II calcium antagonist and are consistent with its proposed mode of interaction with the diltiazem site in the calcium channel.
Modulation of the GABAA receptor by depressant barbiturates and pregnane steroids
Authors: Peters John A. , Kirkness Ewen F. , Callachan Helen , Lambert Jeremy J. , Turner Anthony J. 
Published: July 2012

The modulation of the γ‐aminobutyric acidA (GABAA) receptor by reduced metabolites of progesterone and deoxycorticosterone has been compared with that produced by depressant barbiturates in: (a) voltage‐clamp recordings from bovine enzymatically isolated chromaffin cells in cell culture, and (b) an assay of the specific binding of [3H]‐muscimol to a preparation of porcine brain membranes.
The progesterone metabolites 5α‐ and 5β‐pregnan‐3α‐ol‐20‐one (≥30 nm) reversibly and dosedependently enhanced the amplitude of membrane currents elicited by locally applied GABA (100 μm), and over the concentration range 30 nM‐100 μm stimulated the binding of [3H]‐muscimol. In contrast, 5α‐ and 5β‐pregnan‐3β‐ol‐20‐one (30 nM‐100 μm) had little effect in either assay, indicating a marked stereoselectivity of steroid action.
Scatchard analysis of the ligand binding data suggested an apparent increase in the number, rather than the affinity, of detectable [3H]‐muscimol binding sites as the principle action of the active steroid isomers.
GABA‐evoked currents were also potentiated by androsterone (1 μm) and the deoxycorticosterone metabolite 5α‐pregnane‐3α,21‐diol‐20‐one (100 nm).
Secobarbitone (10–100 μm), pentobarbitone (10–300 μm) and phenobarbitone (100–500 μm) reversibly and dose‐dependently potentiated the amplitude of GABA‐evoked currents in the absence of any change in their reversal potential.
At relatively high concentrations (≥ 30 μm) secobarbitone and pentobarbitone directly elicited a membrane current. It is concluded that such currents result from GABAA receptor‐channel activation since they share a common reversal potential with GABA‐evoked responses (≥0mV), are reversibly antagonized by bicuculline (3 μm), and potentiated by either diazepam (1 μm) or 5β‐pregnan‐3α‐ol‐20‐one (500 nm).
Secobarbitone (1 μm‐1 mm) dose‐dependently enhanced the binding of [3H]‐muscimol. In common with the active steroids, an increase in the apparent number of binding sites was responsible for this effect.
A saturating concentration (1 mm) of secobarbitone in the ligand binding assay did not suppress the degree of enhancement of control binding produced by 5β‐pregnan‐3α‐ol‐20‐one (30 nM‐100 μm). Similarly the steroid, at a concentration of 100 μm, did not influence the enhancement of [3H]‐muscimol binding by secobarbitone (1 μm‐1 mm). In all combinations of concentrations tested, the effects of secobarbitone and 5β‐pregnan‐3α‐ol‐20‐one on [3H]‐muscimol binding were additive.
In conjunction with previously published observations, the present data indicate close similarities in the GABA‐mimetic and potentiating actions of barbiturates and steroids. However, the results obtained with combinations of steroids and barbiturates in the ligand binding assay appear inconsistent with the two classes of compound interacting with a common site to modulate the GABAA receptor activity.