bluuebunny/crossref_metadata_2025_split huggingface dataset:
Desensitization of histamine H1 receptor‐mediated inositol phosphate accumulation in guinea pig cerebral cortex slices
Authors: Bristow D.R. , Banford P.C. , Bajusz I. , Vedat A. , Young J.M. 
Published: July 2012

Histamine stimulated the production of [3H]‐inositol phosphates in untreated (control) guinea‐pig cerebral cortex slices with a best‐fit EC50 of 17 ± 4 μm, and a best‐fit maximum response of 385 ± 23% over basal accumulation.
Histamine pretreatment desensitized guinea‐pig cortex slices to a subsequent challenge with histamine, which was observed as a reduction in the best‐fit maximum response to 182 ± 32% over basal accumulation.
The time‐course for the histamine‐induced production of [3H]‐inositol phosphates was approximately linear over 90 min of stimulation in both control and histamine pretreated slices. The rate of production in pretreated slices was significantly slowed compared to control, such that by 90 min of histamine stimulation the desensitized slices produced 2.8 times the basal [3H]‐inositol phosphate accumulation compared to 5.3 fold the basal [3H]‐inositol phosphate accumulation in the control slices.
Displacement of [3H]‐mepyramine binding to homogenates of guinea‐pig cerebral cortex by mepyramine and histamine revealed that histamine pretreatment did not alter the apparent affinity of the H1 receptor for histamine (control Kd = 6.3 ± 0.7 μm, desensitized Kd = 7.9 ± 1.6 μm) or mepyramine (control Kd = 3.4 ± 0.8 nm, desensitized Kd = 3.4 ± 1.3 nm), nor was there any reduction in the calculated maximum number of [3H]‐mepyramine binding sites (control Bmax = 192 ± 31 fmol mg−1 protein, desensitized Bmax = 220 ± 50 fmol mg−1 protein).
The histamine‐mediated desensitization of response in guinea‐pig slices was mediated by the H1 receptor subtype, since the attentuated maximum histamine‐stimulated [3H]‐inositol phosphate accumulation could not be prevented by inclusion of an H2‐ (ranitidine) and an H3‐ (thioperamide) receptor antagonist during the pretreatment period.
The desensitized histamine‐stimulated [3H]‐inositol phosphate accumulation recovered to 90% of control levels over a period of 150 min after the removal of the conditioning dose of histamine, with a half‐time of recovery of about 95 min.
Involvement of pertussis toxin‐sensitive and ‐insensitive mechanisms in α‐adrenoceptor modulation of noradrenaline release from rat sympathetic neurones in tissue culture
Authors: Hill C.E. , Powis D.A. , Hendry I.A. 
Published: July 2012

Sympathetic neurones derived from superior cervical ganglia of neonatal rats and maintained in tissue culture were used to investigate the modulation of neurotransmitter release by presynaptic receptors. Three week old cultures of neurones were loaded with [3H]‐noradrenaline to label endogenous neurotransmitter stores. Release of noradrenaline was evoked by depolarization with raised extracellular K+ in the presence of desipramine and corticosterone to prevent uptake of released catecholamine.
Potassium (55 mmol 1−1) depolarization for 30 s caused more than a four fold increase in 3H overflow from basal levels but this increase was reduced by up to 40% in the presence of exogenous noradrenaline (1 μmol 1−1). The inhibition by noradrenaline of depolarization‐evoked overflow was blocked by the α1/α2‐adrenoceptor antagonist, phentolamine. Phentolamine alone did not increase K+‐evoked 3H overflow.
The α2‐adrenoceptor antagonist, yohimbine, produced a concentration‐dependent block of the inhibition by noradrenaline of K+‐evoked overflow, while the a1‐adrenoceptor antagonist, prazosin, was without effect at concentrations up to 0.1 μmol 1−1.
The β‐adrenoceptor antagonist, propranolol, neither reduced K+‐evoked overflow nor increased the degree of inhibition caused by the addition of 1 μmol 1−1 noradrenaline.
The α2‐adrenoceptor agonist, clonidine (1 μmol 1−1) was less effective than noradrenaline at inhibiting K+‐evoked overflow, while the α1‐adrenoceptor agonist, phenylephrine (1 μmol 1−1) had no significant effect.
The L‐channel calcium blocker, nicardipine (1 μmol 1−1) significantly inhibited 3H overflow evoked by K+. In the presence of L‐channel block, however, noradrenaline still inhibited residual evoked overflow.
In the presence or absence of nicardipine, pertussis toxin pretreatment (1 nmol 1−1) reduced, but did not prevent, the effect of noradrenaline (1 μmol 1−1). Pertussis toxin alone caused a significant enhancement of K+‐evoked 3H overflow.
The data indicate that on postganglionic neurones of cultured rat sympathetic ganglia there are α2‐adrenoceptors that modulate neurotransmitter release, but no functional β‐adrenoceptors that mediate an enhancement of transmitter release. The data suggest further that in this preparation the mechanism of α2‐adrenoceptor modulation may involve pertussis toxin sensitive and insensitive G‐proteins and effects on calcium channels other than L‐type.
Calcium antagonist and antiperoxidant properties of some hindered phenols
Authors: Sgaragli G.P. , Valoti M. , Gorelli B. , Fusi F. , Palmi M. , Mantovani P. 
Published: July 2012

The calcium antagonist and antioxidant activities of certain synthetic and natural phenols, related to BHA (2‐t‐butyl‐4‐methoxyphenol), were evaluated in rat ileal longitudinal muscle and in lipid peroxidation models respectively.
Compounds with a phenol or a phenol derivative moiety, with the exception of 2,2′‐dihydroxy‐3,‐3′‐di‐t‐butyl‐5,5′‐dimethoxydiphenyl (di‐BHA), inhibited in a concentration‐dependent manner the BaCl2‐induced contraction of muscle incubated in a Ca2+‐free medium. Calculated pIC50 (m) values ranged between 3.32 (probucol) and 4.96 [3,5‐di‐t‐butyl‐4‐hydroxyanisole (di‐t‐BHA)], with intermediate activity shown by khellin < gossypol < quercetin < 3‐t‐butylanisole < BHA < nordihydroguaiaretic acid (NDGA) < 2,6‐di‐t‐butyl‐4‐methylphenol (BHT) and papaverine.
The Ca2+ channel activator Bay K 8644 overcame the inhibition sustained by nifedipine, BHA and BHT, while only partially reversing that of papaverine.
BHA, BHT, nifedipine and papaverine also inhibited in a concentration‐dependent fashion CaCl2 contractions of muscle depolarized by a K+‐rich medium. This inhibition appeared to be inversely affected by the Ca2+‐concentration used.
The inhibitory effects of nifedipine, papaverine, BHA and BHT were no longer present when muscle contraction was elicited in skinned fibres by 5 μm Ca2+ or 500 μm Ba2+, suggesting a plasmalemmal involvement of target sites in spasmolysis.
Comparative antioxidant capability was assessed in two peroxyl radical scavenging assay systems. These were based either on the oxidation of linoleic acid initiated by a heat labile azo compound or on lipid peroxidation of rat liver microsomes promoted by Fe2+ ions. Across both model systems, di‐t‐BHA, NDGA, BHT, di‐BHA, BHA and quercetin ranked as the most potent inhibitors of lipid oxidation, with calculated pIC50 (m) values ranging between 7.4 and 5.7.
Of the 32 compounds studied only 15 phenolic derivatives exhibited both antispasmogenic and antioxidant activity. Within this subgroup a linear and significant correlation was found between antispasmogenic activity and antioxidation. These bifunctional compounds were characterized by the presence of at least one hydroxyl group on the aromatic ring and a highly lipophilic area in the molecule.
Di‐t‐BHA is proposed as a lead reference compound for future synthesis of new antioxidants combining two potentially useful properties in the prevention of tissue damage after ischaemia‐reperfusion injury.
Involvement of cholecystokinin receptor types in pathways controlling oxytocin secretion
Authors: Luckman Simon M. , Hamamura Mitsuko , Antonijevic Irina , Dye Sandra , Leng Gareth 
Published: July 2012

Intravenous administration of cholecystokinin (CCK) results in a transient activation of oxytocin neurones in the rat, and hence to oxytocin secretion: this activation is followed by expression of c‐fosmRNA and of Fos‐like immunoreactivity (Fos‐LI) in magnocellular oxytocin neurones. Fos‐like immunoreactivity is also induced in the regions of the brainstem that are thought to relay information from the periphery to the hypothalamus.Administration of the selective CCKAreceptor antagonist MK‐329, but not the CCKBreceptor antagonist L‐365,260, prior to CCK injection, prevented oxytocin release as measured by radioimmunoassay and oxytocin neuronal activation as measured by electrophysiology and by the lack of induction ofc‐fosmRNA.MK‐329 abolished the release of adrenocorticotrophic hormone (ACTH) following injection of CCK.MK‐329 prevented the expression of Fos‐LI in the hypothalamic magnocellular nuclei and in the area postrema and dorsal vagal complex of the brainstem.L‐365,260 had no effect on the expression of Fos‐LI in the brainstem, but attenuated that seen in the hypothalamic magnocellular nuclei.We conclude that CCK acts on CCKAreceptors, either in the area postrema or on peripheral endings of the vagus nerve, to cause the release of hypothalamic oxytocin and ACTH. Information may be carried to the hypothalamus in part by CCK acting at CCKBreceptors.
Endothelin‐induced contraction and mediator release in human bronchus
Authors: Hay Douglas W.P. , Hubbard Walter C. , Undem Bradley J. 
Published: July 2012

To elucidate the role of acetylcholine and various autacoids in endothelin‐1 (ET‐1)‐induced contraction in human bronchus, the effects of various receptor antagonists were examined. In addition, the ability of ET‐1 to stimulate the release of histamine, peptidoleukotrienes and prostanoids was determined.
ET‐1 was a potent and effective contractile agonist in human bronchus, possessing similar potency and efficacy to leukotriene D4 (LTD4); EC50 (−log m): ET‐1 = 7.76 ± 0.09, n = 7; LTD4 = 8.46 ± 0.53, n = 7; P > 0.2; maximum response (% 10 μm pre‐carbachol): ET‐1 = 103.8 ± 17.4, n = 7; LTD4 = 95.5 ± 9.3, n = 7; P > 0.6.
The cyclo‐oxygenase inhibitor, sodium meclofenamate (1 μm) or the potent and selective thromboxane receptor antagonist, SQ 29,548 (1 μm) were without significant effect on ET‐1 concentration‐response curves.
In the presence of sodium meclofenamate (1 μm), the muscarinic receptor antagonist, atropine (1 μm), the platelet activating factor (PAF) receptor antagonist, WEB 2086 (1 μm) or the combination of the H1‐histamine receptor antagonist, mepyramine (10 μm) and the leukotriene receptor antagonist, SK&F 104353 (10 μm), were without marked effect on ET‐1 concentration‐response curves. In addition, the combination of all four receptor antagonists did not antagonize ET‐1‐induced contraction.
ET‐1 (0.3 μm) did not stimulate the release of histamine or immunoreactive leukotrienes from human bronchus.
ET‐1 (0.3 μm) significantly stimulated the release of prostaglandin D2 (PGD2), 9α, 11β PGF2 (PGD2 metabolite), PGE2, 6‐keto PGF1α (PGI2 metabolite), PGF2α and thromboxane B2 (TxB2) a lower concentration, 10 nm, was without effect on prostanoid release. The production of PGD2 was increased 7.5 fold, whereas the release of the other prostanoids was stimulated only about 1.6 to 2.7 fold.
These data provide evidence that ET‐1 elicits contraction of human isolated bronchus predominantly via a direct mechanism with no significant involvement of the release of acetylcholine, leukotrienes, histamine or PAF. Although ET‐1 increased the release of several prostanoids they did not have a significant modulatory effect on the smooth muscle contraction.
The β‐adrenoceptors mediating relaxation of rat oesophageal muscularis mucosae are predominantly of the β3‐, but also of the β2‐subtype
Authors: de Boer Robert E.P. , Brouwer Frans , Zaagsma Johan 
Published: July 2012

β‐Adrenoceptor‐mediated relaxation of rat oesophageal smooth muscle was investigated by studying the effects of β1‐ and β2‐selective antagonists on the relaxation induced by (−)‐isoprenaline, the β2‐selective agonists fenoterol and clenbuterol and the β3‐agonist, BRL 37344.
The highly β1‐selective antagonist CGP 20712A did not antagonize (−)‐isoprenaline‐ or BRL 37344‐induced relaxations in concentrations up to 10 μm. Only at 100 μm of CGP 20712A were clear rightward shifts of the agonist concentration‐response curves (CRCs) observed, with pA2 values of 4.70 and 4.97 against (−)‐isoprenaline and BRL 37344, respectively.
ICI 118,551, a potent and selective β2‐antagonist, at 100 nm caused moderate rightward shifts of the CRCs of (−)‐isoprenaline, fenoterol and clenbuterol; with fenoterol and clenbuterol, this was accompanied by a clear steepening of the curve. Only at the highest concentration (100 μm ICI 118,551) did the shifts to the right further increase substantially. Resulting Schild‐plots were clearly biphasic. BRL 37344‐induced relaxations were only antagonized at 100 μm ICI 118,551, yielding a pA2 value of 5.48.
These results clearly demonstrate that the BRL 37344‐induced relaxation of rat oesophageal muscularis mucosae is mediated solely through β3‐adrenoceptors, whereas (−)‐isoprenaline‐, fenoterol‐ and clenbuterol‐induced relaxations were shown to involve both β2‐ and, predominantly, β3‐adrenoceptors.
Mediation of the neuroprotective action of R‐phenylisopropyladenosine through a centrally located adenosine A1 receptor
Authors: MacGregor D.G. , Miller W.J. , Stone T.W. 
Published: July 2012

Systemic injections of kainic acid, 10 mg kg−1, into adult rats resulted in lesions in the hippocampus, as assessed by peripheral benzodiazepine ligand binding. Co‐administration of clonazepam at 1 mg kg−1 or 0.2 mg kg−1 prevented major seizures associated with kainate injections, but did not alter significantly the production of hippocampal damage.
The co‐administration of the adenosine A1 agonist R‐phenylisopropyladenosine (R‐PIA, 25 μg kg−1, i.p.) abolished the lesions induced by kainic acid.
The presence of the selective A1 antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (250 or 50 μg kg−1, i.p.) abolished the R‐PIA neuroprotective action.
The A1/A2 antagonist, 8‐(p‐sulphophenyl)theophylline (20 mg kg−1, i.p.) which cannot cross the blood brain barrier, did not alter significantly the neuroprotective action of R‐PIA, indicating that the neuroprotective action of the purine may be predominantly central.
The time course of the neuroprotection was also examined. R‐PIA was effective when administered 2 h before or after kainate administration.
The results emphasise the potential utility of systemically active adenosine A1 receptor ligands in reducing CNS gliosis induced by the activation of excitatory amino acid receptors.
Differential effects of B2 receptor antagonists upon bradykinin‐stimulated phospholipase C and D in guinea‐pig cultured tracheal smooth muscle
Authors: Pyne Susan , Pyne Nigel J. 
Published: July 2012

Guinea‐pig tracheal smooth muscle cells were isolated and maintained in culture for 14–21 days prior to the study of the effect of a selective bradykinin B1 agonist and B2 antagonists upon bradykinin‐stimulated phospholipase C and D activities.
Bradykinin‐stimulated phospholipase C activity was determined by mass measurement of inositol (1,4,5)trisphosphate (Ins(1,4,5)P3) in unlabelled cells, whereas phospholipase D activity was assayed by the accumulation of [3H]‐phosphatidylbutanol ([3H]‐PtdBut) in [3H]‐palmitate‐labelled cells, which were stimulated in the presence of butan‐1‐ol (0.3%, v/v).
Bradykinin elicited the rapid and transient formation of Ins(1,4,5)P3, in a concentration‐dependent manner (log EC50 = −7.55 ± 0.1 m, n = 3). Bradykinin also rapidly activated the concentration‐dependent (log EC50 = −8.3 ± 0.4 m, n = 3) phospholipase D‐catalysed accumulation of [3H]‐PtdBut; the accumulation of [3H]‐PtdBut was sustained. These effects were not inhibited by pretreatment of the cells with indomethacin (1 μm).
The bradykinin B1 agonist, desArg9‐bradykinin (1 μm) was without effect upon phospholipase C or phospholipase D activity. Bradykinin‐stimulated (10 nm, EC40) Ins(1,4,5)P3 formation was inhibited by B2 receptor antagonists, d‐Arg‐[Hyp3,d‐Phe7]‐bradykinin (NPC 567) and d‐Arg‐[Hyp3,Thi5,8,d‐Phe7]‐bradykinin (NPC 349), with log IC50 values of −6.3 ± 0.5 m and −6.3 ± 0.4 m, respectively. However, bradykinin‐stimulated (10 nm, EC100) [3H]‐PtdBut accumulation was poorly inhibited and with low potency by each B2 receptor antagonist and bradykinin‐stimulated phospholipase D activity persisted at concentrations of antagonist that completely blocked bradykinin‐stimulated Ins(1,4,5)P3 formation (30 μm).
These observations suggest that the activation of phospholipase C by bradykinin may be mediated through a bradykinin B2 receptor population, whereas bradykinin‐stimulated phospholipase D may be activated via a distinct population of bradykinin receptors that do not appear to be either B1 or B2 receptor types, based upon pharmacological specificity. The mechanism of the activation of phospholipase D by bradykinin and the role of the putative B3 bradykinin receptor are discussed.
Antitussive effects of GABAB agonists in the cat and guinea‐pig
Authors: Bolser Donald C. , Aziz Sultan M. , DeGennaro Frances C. , Kreutner William , Egan Robert W. , Siegel Marvin I. , Chapman Richard W. 
Published: July 2012

GABAB agonists inhibit neuronal processes which are important in the pathogenesis of airway disease, such as bronchospasm. Cough is a prominent symptom of pulmonary disease, but the effects of GABAB agonists on this airway reflex are unknown. Experiments were conducted to determine the antitussive effect of GABAB receptor agonists in comparison to the known antitussive agents, codeine and dextromethorphan.
Unanaesthetized guinea‐pigs were exposed to aerosols of 0.3 mm capsaicin to elicit coughing, which was detected with a microphone and counted. Cough also was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity.
In guinea‐pigs, the GABAB agonists baclofen and 3‐aminopropyl‐phosphinic acid (3‐APPi) produced dose‐dependent inhibition of capsaicin‐induced cough when administered by subcutaneous or inhaled routes. The potencies of baclofen and 3‐APPi compared favourably with codeine and dextromethorphan.
The GABAB antagonist, CGP 35348 (0.3– 30 mg kg−1, s.c.) inhibited the antitussive effect of baclofen (3.0 mg kg−1, s.c). However, CGP 35348 (10 mg kg−1, s.c.) had no effect on the antitussive activity of codeine (30 mg kg−1, s.c). The antitussive effect of baclofen was not influenced by the GABAA antagonist, bicuculline (3 mg kg−1, s.c.) or naloxone (0.3 mg kg−1, s.c).
In the cat, baclofen (0.3–3.0 mg kg−1, i.v.) decreased mechanically‐induced cough in a dose‐dependent manner. In this model, baclofen (ED50 = 0.63 mg kg−1) was less potent than either codeine or dextromethorphan. The antitussive effect of baclofen in the cat was antagonized by the GABAB antagonists, CGP 35348 (10 mg kg−1, i.v.) and 3‐aminopropylphosphonic acid (3 mg kg−1, i.v.).
We show that baclofen and 3‐APPi have antitussive effects in the guinea‐pig and cat and these effects are mediated by GABAB receptors.
Increases in intracellular calcium via activation of an endogenous P2‐purinoceptor in cultured CHO‐K1 cells
Authors: Iredale Philip A. , Hill Stephen J. 
Published: July 2012

Increases in intracellular calcium ([Ca2+]i) were measured in Chinese hamster cultured ovary cells (clone, CHO‐K1), by use of the fluorescent, calcium‐sensitive dye, fura‐2.
Addition of both ATP and UTP elicited rapid increases in [Ca2+]i due to mobilization from intracellular stores and calcium entry across the plasma membrane.
Omission of calcium from the extracellular medium and pre‐incubation with the inorganic calcium channel blocker, nickel (Ni2+) prevented the calcium entry components of the responses.
Investigation of the concentration‐response relationships of various analogues of ATP suggests the presence of a purinoceptor which cannot be characterized as P2X or P2Y. In addition, there appears to be a sub‐population of P2Y‐purinoceptors which do not cross‐react with the ‘nucleotide’ receptor population.
Cross‐desensitization and additivity experiments suggest that both ATP and UTP activate the same receptor.
Pre‐incubation with the tumour‐promoting agent, β‐phorbol‐12,13 dibutyrate (PDBu), caused a reduction in the increases in [Ca2+]i, suggesting a role for protein kinase C in feedback inhibition of purinoceptor responses in this cell line.
In summary, we present evidence for the existence of an endogenous P2U‐purinoceptor (or ‘nucleotide receptor’) which is linked to increases in [Ca2+]i in CHO‐K1 cells.
Zeneca ZD7114 acts as an antagonist at β3‐adrenoceptors in rat isolated ileum
Authors: Growcott James W. , Holloway Brian , Green Michelle , Wilson Campbell 
Published: July 2012

The relaxant effects of Zeneca ZD7114, BRL37344 (putative β3‐adrenoceptor agonists) and various phenylethylamine‐based agonists were studied in isolated ileum of the rat where tone was increased with carbachol (0.5 μm). Agonist‐induced relaxation was measured under equilibrium conditions with α‐, β1‐ and β2‐adrenoceptors inhibited.
Relaxant responses were obtained to isoprenaline, noradrenaline, and BRL37344, although, the efficacy of this latter agent was significantly lower than that of isoprenaline. Salbutamol caused weak relaxation (<20%) at high concentrations (10 μm) and ZD7114 was without significant relaxant effect even at high concentrations (10 μm).
Relaxant responses to isoprenaline and BRL37344 were weakly antagonized by high concentrations of (±)‐propranolol (10 and 100 μm) yielding pKB values of 5.7 with isoprenaline as the agonist and 5.5 with BRL37344 as the agonist.
The non‐selective β‐adrenoceptor antagonist, (±)‐alprenolol (1–100 μm) caused competitive antagonism of the relaxant responses to isoprenaline (pA2 value = 6.5). A similar pKB value was obtained when BRL37344 was used as the agonist (6.4).
Relaxant effects of isoprenaline and BRL37344 were also antagonized by ZD7114 (1–100 μm) yielding pA2 and pKB values of 6.3 and 6.7 respectively.
The low potencies of (±)‐propranolol and (±)‐alprenolol as antagonists of the relaxant responses to isoprenaline and BRL37344 indicate that both the agonists and antagonists employed in the current study may interact with β3‐adrenoceptors in the rat isolated ileum. Contrary to the previous findings in guinea‐pig ileum, where BRL37344 and ZD7114 were full agonists, in the current study, BRL37344 was a partial agonist and ZD7114 an antagonist at the β3‐adrenoceptor in rat ileum.