bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular selectivity of adenosine receptor agonists in anaesthetized dogs
Authors: Gerencer R.Z. , Finegan B.A. , Clanachan A.S. 
Published: July 2012

In order to determine the relevance of adenosine (Ado) receptor classification obtained from in vitro methods to the cardiovascular actions of Ado agonists in vivo, the cardiovascular effects of adenosine 5′‐monophosphate (AMP), N6‐cyclohexyladenosine (CHA, 400 fold A1‐selective), 5′‐N‐ethylcarboxamidoadenosine (NECA, A1 ≅ A2) and 2‐phenylaminoadenosine (PAA, 5 fold A2‐selective) were compared in open‐chest, fentanyl‐pentobarbitone anaesthetized dogs.
Graded doses of CHA (10 to 1000 μg kg−1), NECA (0.5 to 100 μg kg−1) or PAA (0.1 to 20 μg kg−1) were administered intravenously and changes in haemodynamics and myocardial contractility were assessed 10 min following each dose. The effects of graded infusions of AMP (200 to 1000 μg kg−1 min−1) were also evaluated.
AMP and each of the Ado analogues (NECA > PAA > CHA) increased the systemic vascular conductance index (SVCI) in a dose‐dependent manner and reduced mean arterial pressure (MAP). At doses causing similar increases in SVCI, these agonists caused (i) similar reflex increases in heart rate (HR) and cardiac index (CI) and decreases in AV conduction interval (AVi) and (ii) similar increases in coronary vascular conductance (CVC).
After cardiac autonomic blockade with atropine (0.2 mg kg−1) and propranolol (1 mg kg−1), AMP, CHA and PAA still increased SVCI and CVC and decreased MAP. CHA and PAA had no marked effects on HR, CI or AVi. As in the absence of cardiac autonomic blockade, equieffective vasodilator doses of CHA and PAA had identical effects on CVC, CI and AVi.
Myocardial contractility, as assessed by Emax measurements, was stimulated by AMP in control animals. Following cardiac autonomic blockade, PAA increased contractility while AMP and CHA had no significant effects.
Despite marked differences in receptor selectivity in vitro, no marked differences between the actions of these A1‐ and A2‐selective Ado receptor agonists on the cardiovascular system in vivo were apparent. Difficulties therefore exist in the application of in vitro Ado receptor selectivity data to the prediction of the cardiovascular effects of Ado agonists in vivo.
Pterins inhibit nitric oxide synthase activity in rat alveolar macrophages
Authors: Jorens Philippe G. , van Overveld Frans J. , Bult Hidde , Vermeire Paul A. , Herman Arnold G. 
Published: July 2012

The synthesis of nitrite and citrulline from l‐arginine by immune‐stimulated rat alveolar macrophages and the modulation of this synthesis were studied. 2,4‐Diamino‐6‐hydroxypyrimidine (DAHP), 6R‐5,6,7,8‐tetrahydro‐l‐biopterin (BH4) and l‐sepiapterin were potent inhibitors of the recombinant interferon‐γ induced production of nitrogen oxides in intact cultured cells with I50 values for BH4 and l‐sepiapterin of approximately 10 μm. They were equally effective in inhibiting the induced production of citrulline. This inhibitory effect was concentration‐dependent for all three modulators investigated.
The inhibitory effects were not dependent on incubation times of either 24 or 48 h, on the immune‐stimulus used (lipopolysaccharide, interferon‐γ), or whether these stimuli were added during or after the induction period.
Pterin‐6‐carboxylic acid (PCA), which cannot be converted into BH4, and methotrexate (MTX), which inhibits dihydrofolatereductase but not de novo biosynthesis of BH4, did not change the production of nitrite.
The data indicate that DAHP, an inhibitor of the de novo biosynthesis of the co‐factor BH4, blocks the nitric oxide synthase activity in intact cells. Since the pterins BH4 and l‐sepiapterin blocked the l‐arginine dependent production of nitrite and citrulline, the activity of nitric oxide synthase in phagocytic cells may be regulated by metabolic endproducts of the de novo biosynthesis of BH4.
Inflammatory mechanisms in the passive cutaneous anaphylactic reaction in the rabbit: evidence that novel mediators are involved
Authors: Hellewell Paul G. , Jose Peter J. , Williams Timothy J. 
Published: July 2012

We have examined the mechanisms of local oedema formation in the passive cutaneous anaphylactic (PCA) reaction in the rabbit.
IgE‐containing antiserum was injected i.d. and allowed to sensitize skin sites for periods up to 240 h. Antigen (bovine gamma globulin) was injected i.d. or i.v. and local oedema formation assessed by the accumulation of i.v. injected 125I‐labelled rabbit serum albumin. Potential inhibitors were mixed with antigen prior to i.d. injection or were administered i.v.
Maximum oedema formation was observed when a sensitization period of 48–72 h was used. Oedema formation in the PCA reaction was of short duration with a t1/2 of approximately 15 min. No evidence of late oedema formation (up to 6 h) was found.
Local oedema formation in the PCA was reduced by indomethacin suggesting that vasodilator, oedema‐potentiating prostaglandins were released. However, it was likely that other vasodilators were also generated.
Antihistamines were poor inhibitors of oedema formation as were PAF antagonists, a 5‐lipoxygenase inhibitor, a kallikrein inhibitor, a bradykinin antagonist and anti‐C5a antibody.
Local oedema formation in the PCA was partially reduced by neutrophil depletion and colchicine suggesting that neutrophil‐dependent mediators were involved.
Exudate fluid from anaphylactic reactions in the rabbit peritoneal cavity contained permeability‐increasing activity when injected into rabbit skin. This activity is now being characterized.
A vasodilator prostaglandin appears to be released in the rabbit PCA reaction but none of the established permeability‐increasing mediators appears to be involved. Thus, there may be novel inflammatory mediators generated in this reaction which may have relevance for human allergic skin diseases.
Effect of murine recombinant interleukin‐5 on the cell population in guinea‐pig airways
Authors: Iwama T. , Nagai H. , Suda H. , Tsuruoka N. , Koda A. 
Published: July 2012

An intratracheal injection of murine recombinant interleukin 5 (mrIL‐5, 2–15 μg/0.25 ml/animal) induced a dose‐dependent increase in the number of macrophages, eosinophils, neutrophils and epithelial cells in the bronchoalveolar lavage fluid (BALF) of guinea‐pigs 24 h after administration. Bovine serum albumin (15 μg/0.25 ml/animal), used as a reference material, did not cause any change of this type.
The intratracheal administration of mrIL‐5 at a dose of 15 μg showed a tendency to increase the number of these pulmonary inflammatory cells and epithelial cells in the BALF at 12 h with a significant increase observed at 24 h.
Prednisolone (20 mg kg−1, i.p.) inhibited the mrIL‐5‐induced increase in macrophages, eosinophils, neutrophils and epithelial cells. Ketotifen (2 mg kg−1, i.p.) reduced the mrIL‐5‐induced increase in the eosinophil, neutrophil and epithelial cell populations. The simultaneous injection of 2% disodium cromoglycate (DSCG) into the trachea prevented the mrIL‐5‐induced increase in the number of airway epithelial cells, without affecting changes in the other inflammatory leukocytes.
These results suggest that mrIL‐5 is a potent inducer of lung inflammation, in terms of increased inflammatory leukocytes and epithelial cells in guinea‐pig BALF. Prednisolone, DSCG and ketotifen are effective against mrIL‐5‐induced pulmonary inflammation, especially the desquamation of bronchial epithelial cells.
Blockade by local anaesthetics of the single Ca2+‐activated K+ channel in rat hippocampal neurones
Authors: Oda Masao , Yoshida Atsuya , Ikemoto Yoshimi 
Published: July 2012

Effects of local anaesthetics on single Ca2+‐activated K+ channels were investigated using the inside‐out configuration of the patch‐clamp technique in single pyramidal neurones, which were freshly dissociated from rat hippocampus by use of proteolytic enzymes.
No significant effect was observed when 2 mm benzocaine was applied on either side of the membrane patch, or when 3 mm lignocaine or QX‐314 was applied to the external surface of the membrane.
Lignocaine 1 mm, applied to the internal surface, slightly reduced the amplitude of the single K+ channel current. When applied to the internal surface, QX‐314 reduced the amplitude of the K+ channel current, accompanied by an increase in noise in the open channel current, suggesting a fast flickering block. The blocking effect of QX‐314 on the outward current increased with depolarization, suggesting a binding site for the drug at an electrical distance of about 0.5 across the membrane field.
The open time histogram showed one exponential component and the closed time histogram showed at least two components. The mean open time of the outward current was increased when the amplitude was reduced by the drugs.
The ionized form of the local anaesthetics had a similar action on the Ca2+‐activated K+ channels to that on Na+ channels, that is, they enter into the channel from the cytoplasmic side to induce open channel block. The blocking kinetics, however, might be so fast that they were beyond the frequency response of our recording apparatus, thus the recorded current amplitude was decreased. In contrast the K+ channel was not accessible via hydrophobic pathways for the neutral form, which is also known to block the sodium channel.
Role of muscarinic receptor subtypes in central antinociception
Authors: Bartolini A. , Ghelardini C. , Fantetti L. , Malcangio M. , Malmberg‐Aiello P. , Giotti A. 
Published: July 2012

The ability to modify the pain threshold by the two M1‐muscarinic agonists: McN‐A‐343 and AF‐102B and by the specific M2‐agonist arecaidine was examined in mice and rats by using three different noxious stimuli: chemical (writhing test), thermic (hot‐plate test) and mechanical (paw pressure test).
In the mouse hot‐plate test McN‐A‐343 (20–50 μg per mouse i.c.v.) and AF‐102B (1–10 mg kg−1 i.p.) produced significant antinociception which was prevented by atropine (1 μg per mouse i.c.v.) and by the two selective M1 antagonists: pirenzepine (0.01 μg per mouse i.c.v.) and dicyclomine (0.08 μg per mouse i.c.v. or 10 mg kg−1 i.p.) but not by the specific M2‐antagonist AFDX‐116 (0.1 μg per mouse i.c.v.), naloxone (1 mg kg−1 i.p.) or by the acetylcholine (ACh) depletor hemicholinium‐3 (HC‐3) (1 μg per mouse i.c.v.). McN‐A‐343 and AF‐102B were able to increase the pain threshold also in the mouse acetic acid writhing test and in rat paw pressure test. These antinociceptive effects were completely prevented by dicyclomine (0.08 μg per mouse i.c.v. or 10 mg kg−1 i.p.) but not by AFDX‐116 (0.1 μg per mouse or rat i.c.v.).
In contrast with the M1‐agonists, the M2‐agonist arecaidine (0.1–2 μg per mouse or rat i.c.v.) did not induce antinociception in all three analgesic tests. However, arecaidine, at the same i.c.v. doses, was able to reduce the pain threshold in the hot‐plate and paw pressure tests.
The site of muscarinic control of the pain threshold is localized in the CNS since drugs which do not cross the blood‐brain barrier such as McN‐A‐343, pirenzepine and arecaidine exerted their effects only if injected i.c.v.
On the basis of the above findings and existing literature we suggest that the postsynaptic muscarinic receptors involved in antinociception belong to the M1 subtype. Nevertheless, presynaptic autoreceptors (M2 subtype) may play a role in pain regulation since they are involved in modulation of endogenous ACh release.
Role of the adrenal medulla in the metabolic and pressor actions of 8‐OH‐DPAT
Authors: Bouhelal Rochdi , Mir Anis K. 
Published: July 2012

Intravenous administration of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT, 150 μg kg−1) into conscious sham‐operated rats caused significant increases in basal glycaemia with minor changes in basal insulinaemia. Glucose‐stimulated (intravenous glucose tolerance test) plasma insulin levels were significantly inhibited in 8‐OH‐DPAT‐treated sham‐operated animals. These metabolic changes were associated with significant and sustained falls in blood pressure (BP) and heart rate (HR) preceded by transient (< 5 min) increases only in BP.
In adrenodemedullated animals, 8‐OH‐DPAT failed to cause an initial vasoconstriction, hyperglycaemia, or inhibition of glucose‐stimulated plasma insulin despite eliciting falls in BP and HR that were comparable to those observed in sham‐operated animals.
Noradrenaline, adrenaline and dopamine levels in the adrenal tissue were reduced by about 95% in adrenodemedullated rats as compared to sham‐operated rats. A functionally intact adrenal cortex was indicated by the presence of corticosterone in the plasma of both adrenodemedullated and sham‐operated rats.
The present data demonstrate that 8‐OH‐DPAT mediates an initial increase in BP and changes in metabolic parameters via intact adrenal medulla and may thus be consequential to the release of adrenaline, whereas the sustained cardiovascular effects of 8‐OH‐DPAT are not.
Oxidative modification of low‐density lipoproteins and the inhibition of relaxations mediated by endothelium‐derived nitric oxide in rabbit aorta
Authors: Plane Frances , Bruckdorfer K. Richard , Kerr Paul , Steuer Alan , Jacobs Michael 
Published: July 2012

The mechanism by which Cu2+‐oxidized low‐density lipoproteins (oxLDL) inhibit acetylcholine (ACh)‐evoked relaxations mediated by endothelium‐derived nitric oxide (EDRF) in rabbit aortic rings was investigated. The proposed role of lysophosphatidylcholine (LPC) in the inhibition was also studied.
The kinetics of lipid peroxidation of native low‐density lipoproteins (LDL) from individual donors, as measured by changes in conjugated diene concentration, were related to the inhibitory effects of the resultant oxLDL. It was found that the more susceptible LDL was to oxidation, the greater the inhibition.
No correlation was found between the inhibitory effects of oxLDL and LPC content.
Synthetic 1‐palmitoyl LPC produced an inhibition of ACh‐induced relaxations and when added to precontracted rings evoked nitric oxide‐mediated endothelium‐dependent relaxation. This latter effect was not elicited by oxLDL.
Synthetic 1‐palmitoyl (10 μm) had no effect on relaxations evoked by glyceryl trinitrate in endothelium‐denuded aortic rings in contrast to the inhibition found previously for oxLDL.
Concentrations of oxLDL and phospholipase A2‐treated LDL which inhibited relaxation contained very different LPC concentrations. Unlike oxLDL, the inhibitory effects of phospholipase A2‐treated LDL preparations were independent of the donors and showed no lag period.
We sugggest that there are differences in the mechanisms by which oxLDL and 1‐palmitoyl LPC exert their inhibitory effects on relaxation.
The inhibition of relaxation by oxLDL (1–2 mg protein ml−1) was prevented by the presence of high‐density lipoproteins (HDL; 1–2 mg protein ml−1).
It is proposed that prevention of the inhibition of relaxation by HDL is consistent with the inhibitory factor(s) being lipophilic constituents of oxLDL. However, variations in the inhibitory effects of oxLDL preparations are not due to differences in their LPC content and factors other than LPC must contribute to the inhibition.
Response to atrial natriuretic peptide, endopeptidase 24.11 inhibitor and C‐ANP receptor ligand in the rat
Authors: Wilkins M.R. , Settle S.L. , Kirk J.E. , Taylor S.A. , Moore K.P. , Unwin R.J. 
Published: July 2012

The present studies compared the renal and hypotensive response to (a) exogenous atrial natriuretic peptide (ANP) (99–126), (b) an endopeptidase‐24.11 inhibitor (candoxatrilat) and (c) an antagonist of ANP clearance receptors (SC 46542) in conscious rats.
Infusion of low‐dose‐ANP (100 ng kg−1 min−1) produced a gradual increase in urinary sodium and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) excretion without significant change in glomerular filtration rate (GFR) or fractional lithium clearance (FeLi). There was a significant fall in blood pressure.
Infusion of high‐dose ANP (300 ng kg−1 min−1) produced a brisk, 3 fold increase in urinary sodium and cyclic GMP excretion along with a rise in GFR, but had no significant effect on FeLi compared to the control group. The renal response was accompanied by a pronounced fall in blood pressure.
Candoxatrilat or SC 46542, alone, had no significant effect on sodium excretion compared to control animals. Both compounds enhanced the natriuretic and cyclic GMP responses to a low‐dose ANP infusion (100 ng kg−1 min−1) to levels similar to, or greater than, those observed with the high‐dose ANP (300 ng kg−1 min−1). However, unlike high‐dose ANP, these renal effects were not accompanied by a significant change in GFR and neither compound potentiated the hypotensive effect of the low‐dose ANP infusion. Only candoxatrilat when given with ANP produced a marked rise in FeLi.
Similarly, combined administration of candoxatrilat and SC 46542 (without exogenous ANP) induced an increase in sodium and cyclic GMP excretion comparable to high‐dose ANP but did so without a significant increase in GFR and with a significantly smaller fall in blood pressure. Interestingly, there was no increase in FeLi with the combination of the two compounds, suggesting that the major contribution to sodium excretion came from SC 46542.6 Both candoxatrilat and SC 46542 increased sodium and cyclic GMP excretion in the rat A‐V fistula model of heart failure, a model hyporesponsive to infusions of ANP, without significant change in blood pressure.7 These data show that candoxatrilat and SC 46542 do not simply reproduce the effects of an ANP infusion but preferentially enhance the natriuretic response to ANP. Inhibition of E‐24.11 may potentiate a tubule action of ANP while the renal mechanism of action of the C‐ANP receptor ligand needs further study. Both manipulations are of potential value in the management of heart failure.
MDL 26,479: a potential cognition enhancer with benzodiazepine inverse agonist‐like properties
Authors: Miller Jerry A. , Dudley Mark W. , Kehne John H. , Sorensen Stephen M. , Kane John M. 
Published: July 2012

The present study investigated biochemical, electrophysiological and behavioural properties of the novel cognition enhancer, MDL 26,479 (5‐(3‐fluorophenyl)‐2,4,‐dimethyl‐3H‐1,2,4‐triazole‐3‐thione).
The 5‐aryl‐1,2,4‐triazole, MDL 26,479, potently (0.22 ± 0.05 mg kg−1) inhibited [3H]‐flumazenil (Ro15–1788) binding in mouse cortex but was ineffective in vitro at displacing radioligand binding to the GABAA receptor complex.
Parenteral administration of MDL 26,479 (1 mg kg−1) or the benzodiazepine (BZD) inverse agonist methyl 6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM) (0.3 mg kg−1) increased cortical ex vivo binding of [3H]‐hemicholinium‐3 ([3H]‐HC‐3), a marker for cholinergic activation. This effect of MDL 26,479 was blocked by pretreatment with the antagonist flumazenil (1 mg kg−1).
MDL 26,479 (20 μm) and DMCM (1 μm) increased excitation in the hippocampal long‐term potentiation (LTP) slice preparation; however, unlike DMCM, the effect of MDL 26,479 was not blocked by flumazenil.
In behavioural studies, MDL 26,479 did not exhibit adverse properties characteristic of drugs associated with the GABAA receptor complex. It lacked convulsant, anxiogenic, anxiolytic, or depressant effects. Since MDL 26,479 lacks activity with the BZD receptor in vitro we suggest that it acts via the GABAA receptor complex at another site on this receptor or in an as yet undefined manner or an active metabolite is formed in vivo.6 Previous work showed that MDL 26,479 enhances learning acquisition in animal models. The present study suggests that at least some of the cognition enhancing properties are due to the enhancement of cortical and hippocampal cholinergic function and LTP.
Suramin inhibits excitatory junction potentials in guinea‐pig isolated vas deferens
Authors: Sneddon Peter 
Published: July 2012

. Intracellular microelectrode recording techniques were used to investigate the action of the putative P2‐purinoceptor antagonist, suramin, on sympathetic neurotransmission in the guinea‐pig isolated vas deferens.
. The resting membrane potential of the control cells was 67.4 ± 0.7 mV (n = 48). Field stimulation of the sympathetic nerves innervating the vas deferens produced excitatory junction potentials (e.j.ps) which reached a mean magnitude of 8.5 ± 0.8 mV (n = 23) when fully facilitated at a stimulation frequency of 0.5 Hz.
. Introduction of suramin 1–100 μm produced no change in the resting membrane potential of the smooth muscle cells, but gradually reduced e.j.p. magnitude. Suramin, 20 μm, reduced the mean magnitude of the fully facilitated e.j.ps to 1.4 ± 0.3mV (n = 18).
. After suramin‐induced inhibition of e.j.ps, nerve stimulation at 1–8 Hz resulted in summation of e.j.ps to a subthreshold level. Subsequent introduction of the α‐adrenoceptor antagonists, prazosin or phentolamine (1 μm) did not reduce the magnitude of the summated e.j.ps.
. The results support the proposal that e.j.ps in vas deferens are mediated by adenosine 5′‐triphosphate, and not by noradrenaline, and confirm that suramin can antagonize responses mediated via P2‐purinoceptors.
H3 receptor antagonist, thioperamide, inhibits adrenal steroidogenesis and histamine binding to adrenocortical microsomes and binds to cytochrome P450
Authors: LaBella F.S. , Queen G. , Glavin G. , Durant G. , Stein D. , Brandes L.J. 
Published: July 2012

Thioperamide (TP), an imidazole and a highly potent, specific antagonist of the histamine H3 receptor, inhibited the secretion of cortisol from bovine isolated adrenocortical cells (IC50 0.20 μm) and, in the rat (5 mg kg−1) prevented both basal and stress‐induced secretion of corticosterone.
In adrenocortical microsomes, low affinity binding of [3H]‐histamine (KD 27.7 μm) was potently inhibited by TP (Ki 0.33 μm).
In adrenocortical microsomal membranes, both histamine and TP yielded type II difference absorption spectra, characteristic of the interaction between imidazole and cytochrome P450 enzymes. Dissociation constants for binding to P450, calculated from spectral data, were 15.9 μm and 1.5 mm for histamine, and 0.3 μm and 3.7 μm for TP.
In view of previously reported evidence for an intracellular mediator role of histamine in platelets, the present findings suggest a physiological role for histamine in the modulation of adrenal P450 monooxygenases that generate adrenocortical steroids.
The results suggest that direct adrenocortical inhibition by thioperamide at a non‐H3 intracellular site must be taken into account in studies designed to elucidate functional roles of H3 receptors.
Cardiac α1‐adrenoceptor densities in different mammalian species
Authors: Steinfath Markus , Chen Yi‐Yue , Lavický Jan , Magnussen Olaf , Nose Monika , Rosswag Sebastian , Schmitz Wilhelm , Scholz Hasso 
Published: July 2012

α1‐Adrenoceptor densities were studied in cardiac membrane preparations from several mammalian species including human failing hearts under identical experiment conditions; the α1‐adrenoceptor antagonist, [3H]‐prazosin, was used as radioligand. End‐stage heart failure (NYHA IV) in human hearts was due to idiopathic dilated cardiomyopathy.
The ventricular α1‐adrenoceptor densities were not significantly different in guinea‐pig, mouse, pig, calf, and man (11 to 18 fmol mg−1 protein) but about 5 to 8 fold smaller than in rat (about 90 fmol mg−1 protein). Right and left ventricular receptor densities were similar in these species.
A sufficient amount of right and left atrial tissue was obtained from rabbit, pig, calf, and man only. The α1‐adrenoceptor densities in both atria of these species were found to be at the detection limit of the method used (less than 8 fmol mg−1 protein).
The equilibrium dissociation constant (KD) was similar in all species studied ranging from 0.047 ± 0.006 to 0.063 ± 0.007 nmol l−1.
It is concluded that differences in α1‐adrenoceptor density between atria and ventricles may exist in mammalian species. The exceptionally high density of these receptors in rat ventricles seem to be a particular feature in these animals.