bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological analysis of postjunctional α‐adrenoceptors mediating contractions to (−)‐noradrenaline in the rabbit isolated lateral saphenous vein can be explained by interacting responses to simultaneous activation of α1‐and α2‐adrenoceptors
Authors: Daly C.J. , McGrath J.C. , Wilson V.G. 
Published: July 2012

The pharmacological characteristics of the α‐adrenoceptor population in the rabbit isolated saphenous vein has been examined with (–)‐noradrenaline (NA), as principal agonist, and a number of antagonists with selectivity for either α1‐ or α2‐adrenoceptors.
The rank order of potency of various agonists is consistent with a population of α2‐adrenoceptors; UK‐14304 > (—)‐noradrenaline = (—)‐adrenaline > B‐HT 920 = cirazoline > phenylephrine > amidephrine, but the rank order of pA2 values for the antagonists against (—)− noradrenaline: BDF‐6143 > rauwolscine = prazosin > CH‐38083 = YM‐12617 > Wy‐26703 = phentolamine > corynanthine, is indicative of a mixed population of α1‐ and α2‐adrenoceptors or, alternatively, a new subtype with characteristics of both the α1‐ and α2‐subtypes.
Further evidence for two discrete populations of α‐adrenoceptors is provided by, (a) the potent but non‐competitive effect of prazosin against (—)‐noradrenaline, (b) the presence of a component of the contractions elicited by NA and phenylephrine which is resistant to the selective α2‐adrenoceptor antagonists rauwolscine and CH‐38083: these responses were inhibited by the selective α1‐adrenoceptor antagonists prazosin and YM‐12617, but not by the selective α2‐adrenoceptor antagonist BDF‐6143 and, (c) the relative potency of the yohimbine diastereoisomers rauwolscine and corynanthine against NA, phenylephrine and UK‐14304.
In spite of the overwhelming evidence for a population of postjunctional α2‐adrenoceptors, prazosin was similarly effective against all agonists and failed to discriminate between those with putative selectivity for α1‐ and α2‐adrenoceptors. This suggests an interaction of the effects of agonists at the two α‐adrenoceptor subtypes.
An attempt has been made to reconcile a number of paradoxical observations with regard to the identification of postjunctional α2‐adrenoceptors in vitro, and it is suggested that in many of the isolated blood vessels presently available for examination both subtypes reside on the same smooth muscle cell. The pharmacological consequences of multiple subtypes of receptors mediating the same response is considered.
Purine receptors and guinea‐pig trachea: evidence for a direct action of ATP
Authors: Welford Laurence A. , Anderson Wayne H. 
Published: July 2012

Adenosine (3–300 μm) and ATP (1–300 μm) each induced concentration‐dependent relaxation of guinea‐pig isolated tracheal preparations that had been precontracted with methacholine.
Ectonucleotidase enzymes on the trachea dephosphorylated ATP to form adenosine which was then further metabolised to inosine and hypoxanthine.
Dipyridamole (2 μm) inhibited the metabolism of adenosine but did not inhibit the dephosphorylation of ATP. Nevertheless dipyridamole potentiated the effects of both adenosine and ATP in relaxing tracheal smooth muscle.
Although adenosine 5′‐[β,γ‐imido] triphosphate (AMP‐PNP), an analogue of ATP, was resistant to catabolism by ectonucleotidases, it was more potent at inducing relaxation than either ATP or adenosine, and was also potentiated by dipyridamole (2 μm).
Relaxations induced by ATP and by AMP‐PNP were more rapid than those induced by adenosine.
We therefore conclude that the intact ATP molecule can itself induce relaxation of the guinea‐pig trachea, without first having to be metabolised to adenosine, and furthermore that dipyridamole does not act simply by inhibiting the degradation (or uptake) of adenosine.
Acetylcholine induces vasodilatation in the rabbit isolated heart through the release of nitric oxide, the endogenous nitrovasodilator
Authors: Amezcua J.L. , Dusting G.J. , Palmer R.M.J. , Moncada S. 
Published: July 2012

Acetylcholine (ACh, 0.03–3.0 μm) induced a dose‐dependent vasodilatation in the isolated Langendorff‐perfused heart of the rabbit. The vasodilatation was mimicked by exogenous nitric oxide (NO, 0.045–4.5 nmol).
There was no detectable vascular relaxing activity in the cardiac effluent when these concentrations of ACh or NO were injected through the heart, even in the presence of an infusion of superoxide dismutase (SOD).
Acetylcholine (0.03–3.0 μm), however, induced the release into the cardiac effluent of a material which produced a chemiluminescent signal when reacted with ozone, a response which could be mimicked with exogenous NO (0.045–4.5 nmol) injected through the heart.
The effects of ACh, but not those of NO, were antagonized by atropine (2 μm). Prostacyclin (1 μm) injected through the heart induced vasodilatation without the release of a biologically active or chemiluminescent material.
During passage through the heart, >99% of the biological activity of exogenous NO disappeared, whereas there was approximately 50% reduction of its chemiluminescent response. This indicates complete transformation into a mixture containing approximately 50% NO2− and 50% of other non‐chemiluminescent material(s), presumably NO3−.
This study suggests that ACh induces endothelium‐dependent vasodilatation in the coronary circulation through the release of the endogenous nitrovasodilator, NO, which is rapidly converted to NO2− and NO3−.
A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists
Authors: Lodge D. , Davies S.N. , Jones M.G. , Millar J. , Manallack D.T. , Ornstein P.L. , Verberne A.J.M. , Young N. , Beart P.M. 
Published: July 2012

Phosphonate analogues of glutamate have been tested and compared as N‐methyl‐d‐aspartate (NMDA) antagonists in electrophysiological and binding experiments. The compounds tested were three established NMDA antagonists: d‐2‐amino‐5‐phosphonopentanoate (d‐AP5), dl‐2‐amino‐7‐phosphonoheptanoate (dl‐AP7), 3‐(2‐carboxypiperazin‐4‐yl)propyl‐l‐phospnonate (CPP), and two novel putative NMDA antagonists: 3‐(2‐carboxypiperidin‐4‐yl)propyl‐l‐phosphonate (CPPP) and 3‐(2‐carboxy‐piperidin‐4‐yl)methyl‐1‐phosphonate (CPMP).
When administered electrophoretically to rat spinal neurones in vivo, these compounds were found to be selective NMDA antagonists with little effect on excitations evoked by quisqualate and kainate. CPMP and CPPP were approximately equipotent with CPP and about 5 times more potent than d‐AP5.
Following systemic administration, 2–5 mg kg−1 i.v. of CPP, CPMP and CPPP reduced NMDA‐evoked excitations by 70–100% whereas 50–100 mg kg−1 of d‐AP5 and dl‐AP7 produced a similar effect. The onset of the effects required 20–30 min and lasted more than six hours.
On bath application to cortical wedges, the IC50 values (μm) for antagonism of 40 μm NMDA were: CPP, 0.64 ± 0.06 (mean ± s.e.mean; n > 4); CPMP, 1.65 ± 0.13; CPPP 0.89 ± 0.09; d‐AP5, 3.7 ± 0.32; dl‐AP7, 11.1 ± 2.1; and dl‐AP4 and dl‐AP6 were inactive at 100 μm.
In binding studies with [3H]‐CPP, the Ki values (nm) were: CPP, 446 ± 150 (mean ± s.e.mean; n ≥ 3); CPMP, 183 ± 74 and CPPP, 179 ± 13 whereas against NMDA (10 μm)‐stimulated [3H]‐TCP (thienylcyclohexylpiperidine) binding the IC50 values (μm) for CPMP and CPPP respectively were 5.6 ± 2.7 and 4.5 ± 2.2.
Systemic administration of CPPP and CPMP, at doses sufficient to antagonize NMDA, also reduced cardiovascular responses to 5‐hydroxytryptamine (Bezold‐Jarisch reflex). This illustrates a role for NMDA receptors in central cardiovascular control.
The results indicate the systemic doses of piperidine and piperazine analogues of d‐AP5 which may be used for assessing the role of NMDA receptors in central synaptic function.
Control of anion and fluid secretion by apical P2‐purinoceptors in the rat epididymis
Authors: Wong P.Y.D. 
Published: July 2012

Exogenous adenosine triphosphate (ATP) stimulated the short circuit current (SCC) in primary monolayer cultures of rat epididymal cells when added to the apical but not to the basolateral side of the monolayers. Half‐maximal stimulation was achieved at 5 × 10−8m ATP.
The increase in SCC induced by ATP was dependent on the presence of extracellular Cl in the bathing solutions.
The effects of other adenosine derivatives, and purine and pyrimidine nucleotides were studied. Their orders of potency in stimulating SCC were: ATP > adenosine diphosphate > adenosine monophosphate, adenosine, and ATP > inosine triphosphate > guanosine triphosphate > cytidine triphosphate. These results indicate that ATP interacts with a P2‐purinoceptor at the apical membrane of the epididymal cells.
The SCC response to ATP was not blocked by 8‐phenyltheophylline, a P1 ‐purinoceptor antagonist or by propranolol. Although pretreatment of the cultures with piroxicam abolished the SCC response to bradykinin, it did not affect the response to ATP. This indicates that the SCC response to ATP was not mediated by an increase in the synthesis of prostaglandins.
Serosal to mucosal Cl flux (Js‐m Cl) and net water flux were measured in the luminally perfused rat epididymis in vivo. ATP (1 μm) added to the luminal perfusion solution caused an increase in Js‐m CI and net water secretion by the epididymal duct.
Since spermatozoa contain a high concentration of ATP, it is proposed that ATP released from spermatozoa may affect anion and fluid secretion by the epididymis. The control of secretion via the apical purinoceptors offers a means by which spermatozoa regulate the fluidity of their own environment.
Sodium‐dependent inhibition by PN200‐110 enantiomers of nicotinic adrenal catecholamine release
Authors: Cárdenas A.M. , Montiel C. , Artalejo A.R. , Sánchez‐García P. , García A.G. 
Published: July 2012

Dimethylphenylpiperazinium (DMPP) or high K concentrations evoke catecholamine release from perfused cat adrenal glands; in both cases the secretory response was significantly enhanced in the absence of Na. Tetrodotoxin did not modify the nicotinic secretory response.
The (+)‐ and (−)‐enantiomers of the dihydropyridine Ca channel blocker PN200‐110 show a high degree of stereoselectivity in the inhibition of catecholamine secretion evoked by high K or by DMPP in the presence of Na, the (+)‐enantiomer being 57 and 80 times more potent, respectively, than the (−)‐enantiomer. Both, noradrenaline and adrenaline release were equally depressed by PN200‐110.
The IC50 values for (+)‐ and (−)‐PN200‐110 for blockade of the secretory response induced by K or DMPP in the presence of Na are in the same range. In the absence of Na, (−)‐PN200‐110 did not affect DMPP‐evoked secretion; however, the (+)‐enantiomer partially inhibited it.
The results suggest that the physiological catecholamine release from chromaffin cells is preceded by Na entry through the nicotinic receptor‐associated ionophore; this causes cell depolarization, opening of voltage‐dependent, dihydropyridine‐sensitive Ca channels and Ca entry into the cell. In the absence of Na, additional Ca influx through an alternative pathway (the nicotinic cholinoceptor ionophore?) might also activate secretion.
Antinociception and physical dependence produced by [D‐Arg2] dermorphin tetrapeptide analogues and morphine in rats
Authors: Chaki Kyoji , Kawamura Shunsuke , Kisara Kensuke , Sakurada Shinobu , Sakurada Tsukasa , Sasaki Yusuke , Sato Takumi , Susuki Kenji 
Published: July 2012

The antinociceptive effects of [D‐Arg2] dermorphin tetrapeptide analogues, H‐Tyr‐D‐Arg‐Phe‐Gly‐NH2 and H‐Tyr‐D‐Arg‐Phe‐β‐Ala‐OH when administered subcutaneously (s.c.) in rats were measured by the tail‐flick test. In addition, the appearance of typical withdrawal signs upon cessation of administration or on subsequent treatment with naloxone were measured after chronic administration of either peptide or morphine.
The dose of peptides and of morphine in the physical dependence test was determined from the AD50 to inhibit the tail‐flick test in rats. Doses from 4 to 64 times the AD50 doses were employed in the s.c. administration schedules.
The intensity of the antinociception induced by either peptide was greater than that produced by morphine. Moreover, the antinociception induced by the peptides was of much longer duration than that produced by morphine.
Abrupt withdrawal after chronic administration of either peptide produced only slight loss of body weight. In contrast, morphine withdrawal produced sharp loss of body weight.
Naloxone precipitated withdrawal signs after chronic administration of either peptide were less intense than those after chronic morphine.
These results suggest that the antinociception produced by these peptides is more intense and of longer duration than that produced by morphine. It is also interesting to note that the physical dependence produced by these peptides is less marked than that produced by morphine.
Effects of sulphonylureas and diazoxide on insulin secretion and nucleotide‐sensitive channels in an insulin‐secreting cell line
Authors: Sturgess N.C. , Kozlowski R.Z. , Carrington C.A. , Hales C.N. , Ashford M.L.J. 
Published: July 2012

The effects of various sulphonylureas and diazoxide on insulin secretion and the activity of various channels have been studied using tissue culture and patch‐clamp methods in an insulinsecreting cell line derived from a rat islet cell tumour.
Tolbutamide, glibenclamide and HB699 increased the rate of insulin release by 2–5 fold. The concentrations of tolbutamide and glibenclamide giving half‐maximum effects on insulin secretion were approximately 40 μM and 0.2 μM, respectively.
Diazoxide (0.6‐1.0 mM) per se, had either no effect or produced a small increase in insulin secretion, whereas when secretion was maximally stimulated by the combination of glucose (3 mM) and leucine (20 mM), it produced inhibition. Tolbutamide‐induced release was also inhibited by diazoxide.
Tolbutamide, glibenclamide, HB699 and HB985 reduced the open‐state probability of the ATP‐K+ channel in a dose‐dependent manner. Tolbutamide and glibenclamide were shown to be effective regardless of which side of the membrane they were applied.
In whole cell recording, in which the total ATP‐sensitive K+ conductance of the cell could be measured, dose‐inhibition curves for tolbutamide and glibenclamide were constructed, resulting in Ki values of 17 μM and 27 nM, respectively. The value of Ki for tolbutamide was unchanged when ATP (0.1 mM) was present in the electrode.
Diazoxide (0.6 mM) activated the ATP‐K+ channels only when they had first been inhibited by intracellular ATP (0.1 mM) or bath applied tolbutamide (3–30 μM). The inhibition produced by glibenclamide could not be reversed by diazoxide.
Neither tolbutamide (1.0 mM) nor glibenclamide (10 μM) altered the open‐state probability of the Ca2+‐activated K+ channel or the Ca2+‐activated non‐selective cation channel which are present in this cell line.
It is concluded that the sulphonylureas and related hypoglycaemic drugs and diazoxide regulate insulin secretion by direct effects on the ATP‐K+ channel or a protein closely associated with this channel.
Leucocyte infiltration and cartilage proteoglycan loss in immune arthritis in the rabbit
Authors: Pettipher E.R. , Henderson B. , Moncada S. , Higgs G.A. 
Published: July 2012

The relationship between phagocytic leucocyte infiltration and cartilage degradation in immune arthritis has been investigated in groups of normal and neutropenic rabbits.
Injection of antigen into the knee joints of sensitized control animals induced joint swelling, prostaglandin E2 (PGE2) synthesis, leucocyte accumulation and proteoglycan loss from articular cartilage.
Intravenous injection of nitrogen mustard caused a selective depletion of circulating neutrophils and monocytes with little or no effect on platelets or lymphocytes. In neutropenic animals challenged with antigen, there was virtually no joint swelling, PGE2 synthesis or leucocyte infiltration but cartilage proteoglycan loss was unchanged after 1 day and increased by day 4 compared to control animals.
The numbers of circulating leucocytes returned to normal 3–4 days after nitrogen mustard treatment and leucocyte infiltration occurred in antigen‐challenged joints but this was not accompanied by joint swelling. Subsequent intra‐articular injection of PGE2 did, however, cause swelling.
Lysosomal enzyme levels in arthritic joint fluids were measured. The levels of β‐glucuronidase, which is released by activated phagocytes, were decreased in neutropenic animals but the levels of N‐acetyl‐β‐glucosaminidase, which is a marker of tissue damage, were not changed by neutrophil depletion.
Intra‐articular injections of the cytokine interleukin‐1 (IL‐1) induced a pattern of leucocyte infiltration and cartilage proteoglycan loss similar to that seen in immune arthritis. In neutropenic animals, IL‐1 did not cause significant accumulation of leucocytes in the joint but the loss of proteoglycan from cartilage was unimpaired.
These results indicate that both leucocyte infiltration and prostaglandin synthesis are required for joint swelling but that tissue degradation is mediated by resident cells. It is likely that release of IL‐1 by synovial cells stimulates the synthesis and activation of metalloproteinases which initiate the process of tissue degradation.
Estimation of opioid receptor agonist dissociation constants with β‐chlornaltrexamine, an irreversible ligand which also displays agonism
Authors: Leff P. , Dougall I.G. 
Published: July 2012

The irreversible opioid receptor antagonist β‐chlornaltrexamine (β‐CNA) has been shown previously to have agonist activity in the guinea‐pig ileum preparation. However, the receptor type or types mediating this effect have not been established.
In this study, the agonism of β‐CNA was investigated by use of the competitive antagonist 16‐methylcyprenorphine (RX8008M). Non‐cumulative concentration‐effect curves for β‐CNA were displaced in a non‐parallel fashion indicating that the agonism was mediated by both μ‐ and κ‐receptors.
In principle, expression of agonism by an irreversible receptor antagonist could compromise its use in estimating agonist dissociation constants (pKAs) due to desensitization operating in addition to receptor inactivation. For κ‐receptors, this possibility was checked by use of ethylketocyclazocine (EKC) to mimic the agonist effects of β‐CNA and test whether subsequent EKC concentration‐effect curves were displaced. For μ‐receptors it was necessary to perform more involved experiments in which [D‐Ala2, MePhe4, Gly‐ol5]enkephalin (DAGOL) was used as a standard agonist and its pKA was estimated under different conditions of β‐CNA incubation.
These analyses indicated that neither the μ‐ nor the κ‐receptor‐mediated agonism of β‐CNA was associated with appreciable receptor desensitization. In turn it was concluded that the usefulness of β‐CNA as a pharmacological tool for the estimation of μ‐ and κ‐opioid receptor agonist dissociation constants is not compromised by the agonist effects that the compound demonstrates at these receptors.
Substance P, neurokinin A and neurokinin B in the ocular response to injury in the rabbit
Authors: Beding‐Barnekow Britt , Brodin Ernst , Håkanson Rolf 
Published: July 2012

Substance P (SP) and neurokinin A‐ (NKA)/neurokinin B (NKB)‐like immunoreactivity (LI) were measured by radioimmunoassay in extracts of the rabbit uvea. The iris‐ciliary body complex contained 3–4 times more NKA/NKB‐LI than SP‐LI. Tachykinins are thought to mediate many of the responses to ocular injury in the rabbit. Their possible role in the miosis and breakdown of the blood‐aqueous barrier (BAB) was studied in vitro and in vivo.
In vitro, NKA had a more short‐lasting contractile effect on the sphincter pupillae muscle than either SP or NKB, but SP was more potent than the other two. The tachykinin antagonist, spantide, dose‐dependently suppressed the response to electrical stimulation (by 90% at 10−4 M) and to the three tachykinins. An antiserum against SP (no cross‐reaction with NKA or NKB) greatly suppressed the response to SP (by 90%) as well as to electrical field stimulation (by 40%). The responses to NKA and NKB were unaffected.
In vivo studies revealed that SP was more potent than NKA and NKB as a miotic. SP evoked a moderate breakdown of the BAB at high doses while NKA and NKB were virtually inactive.
We conclude that besides SP other tachykinins might play a role in the mediation of miosis in the rabbit eye but, of the three peptides investigated, only SP can be of importance for the break‐down of the BAB.
Properties of intracellular calcium stores in pregnant rat myometrium
Authors: Kanmura Y. , Missiaen L. , Casteels R. 
Published: July 2012

The properties of the Ca2+ stores in myometrium of 21‐day pregnant rats were studied by recording the contractile responses of saponin‐treated skinned muscles.
After accumulation of Ca2+ into the stores in the presence of 5mM NaN3, inositol 1,4,5‐trisphosphate (InsP3) at concentrations exceeding 3 μM produced a contraction. The amplitude of this contraction was maximal at about 20 μM. A second application of 20 μM InsP3 produced a smaller contraction than the first one. However after reloading the stores with Ca2+, 20 μM InsP3 produced a contraction of the same amplitude as the initial one.
After application of 20 μM InsP3, 1 μM A23187 still evoked a large contraction. If A23187 was applied first, the subsequent application of InsP3 or A23187 no longer induced a contraction, even after Ca2+ loading.
Guanosine triphosphate (GTP) or arachidonic acid, both 100 μM neither evoked a contraction nor enhanced the subsequent contraction elicited by 20 μM InsP3.
Caffeine 25 mM did not induce a contraction nor did it affect the contraction elicited by 20 μM InsP3.
The results indicate that in pregnant rat myometrium InsP3 releases Ca2+ from intracellular stores as has been proposed in vascular smooth muscles.
Na+‐K + pump activity in rat peritoneal mast cells: inhibition by extracellular calcium
Authors: Knudsen Torben , Johansen Torben 
Published: July 2012

Pure populations of rat peritoneal mast cells were used to study cellular potassium uptake. The radioactive potassium analogue, 86rubidium, was used as a tracer for potassium for measurements of the activity of the cellular potassium uptake process.
The ouabain‐sensitive and the ouabain‐resistant potassium (86rubidium) uptake of mast cells incubated in the presence of calcium, 1 mmol l−1, were very low, 52 and 147 pmol per 106 cells min−1.
Calcium‐deprivation of the cells uncovered a large capacity ouabain‐sensitive potassium (86rubidium) uptake mechanism. The activity of the uptake mechanism was decreased by reintroduction of calcium into the cell suspension, and it was dependent on cellular energy metabolism, temperature and pH.
The potassium (86rubidium) uptake of mast cells incubated in a calcium‐free medium occurs through an active and ouabain‐sensitive mechanism that has the nature of an enzyme, and it is mediated by the Na+‐K+ pump located in the plasma membrane. It is demonstrated that the activity of the Na+‐K+ pump mechanism is inhibited by low concentrations of extracellular calcium (0.1–1.2 mmoll−1). The possibility is discussed that calcium‐deprivation may increase the pump activity by increasing the permeability of the plasma membrane for Na+.