bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of a novel aquaretic agent, OPC‐31260, as an orally effective, nonpeptide vasopressin V2 receptor antagonist
Authors: Yamamura Yoshitaka , Ogawa Hidenori , Yamashita Hiroshi , Chihara Tomihiko , Miyamoto Hisashi , Nakamura Shigeki , Onogawa Toshiyuki , Yamashita Tatsuya , Hosokawa Tetsumi , Mori Toyoki , Tominaga Michiaki , Yabuuchi Youichi 
Published: July 2012

OPC‐31260, a benzazepine derivative, has been studied for its ability to antagonize the binding of arginine vasopressin (AVP) to receptors in rat liver (V1) and kidney (V2) plasma membranes, for antagonism of the antidiuretic action of AVP in alcohol‐anaesthetized rats and for diuretic action in conscious normal rats.
OPC‐31260 caused a competitive displacement of [3H]‐AVP binding to both V1 and V2 receptors with IC50 values of 1.2 ± 0.2 × 10−6 m and 1.4 ± 0.2 × 10−8 m, respectively.
OPC‐31260 at doses of 10 to 100 μg kg−1, i.v., inhibited the antidiuretic action of exogenously administered AVP in water‐loaded, alcohol‐anaesthetized rats in a dose‐dependent manner. OPC‐31260 did not exert an antidiuretic activity suggesting that it is not a partial V2 receptor agonist.
After oral administration at doses of 1 to 30 mg kg−1 in normal conscious rats, OPC‐31260 dose‐dependently increased urine flow and decreased urine osmolality. The diuretic action of OPC‐31260 was characterized as aquaresis, the mode of diuretic action being different from previously known diuretic agents such as furosemide, hydrochlorothiazide and spironolactone.
The results indicate that OPC‐31260 is a selective V2 receptor antagonist and behaves as an aquaretic agent. OPC‐31260 will be a useful tool in studying the physiological role of AVP and in the treatment of various conditions characterized by water retention.
Sodium‐dependence and ouabain‐sensitivity of the synthesis of dopamine in renal tissues of the rat
Authors: Soares‐da‐Silva P. , Fernandes M. Helena 
Published: July 2012

The present study has examined the influence of sodium chloride (0–160 mm) and ouabain (100 and 500 μm), an inhibitor of the enzyme Na+–K+ ATPase, on the synthesis of dopamine in slices of rat renal cortex loaded with exogenous l‐dihydroxyphenylalanine (l‐DOPA). The deamination of newly‐formed dopamine into 3,4‐dihydroxyphenylacetic acid (DOPAC) was also examined. The assay of l‐DOPA, dopamine and DOPAC in kidney slices was performed by high performance liquid chromatography (h.p.l.c.). with electrochemical detection.
The accumulation of newly‐formed dopamine and DOPAC in kidney slices loaded with l‐DOPA (50 and 100 μm) was found to be dependent on the concentration of NaCl in the medium. A similar picture could be observed for DOPAC. The fractional rate of accumulation (k; mm NaCl−1) was at 50 and 100 μm l‐DOPA, respectively, 0.00305 ± 0.00036 and 0.00328 ± 0.00029 for dopamine and 0.00672 ± 0.00072 and 0.00641 ±0.00069 for DOPAC. The sodium‐dependent formation of dopamine was completely abolished when the experiments were performed in the absence of oxygen.
In experiments performed in the presence of 120 mm NaCl, but not in conditions of low sodium (20 mm NaCl in the medium), ouabain (100 and 500 μm) was found to inhibit the accumulation of newly‐formed dopamine and DOPAC (14–57% reduction; P < 0.05); this effect was more marked at 50 and 100 μm l‐DOPA. When the experiments were performed in the absence of oxygen the renal production of dopamine and DOPAC became markedly decreased (respectively, 40% and 77% reduction; P < 0.05) and ouabain (100 and 500 μm) was no longer able to reduce the accumulation of both newly‐formed dopamine and DOPAC.
The formation of dopamine and its deamination to DOPAC in kidney homogenates closely depended on the concentration of l‐DOPA added to the medium; ouabain (100, 500 and 1000 μm) was found to affect neither the formation of dopamine nor its deamination to DOPAC when homogenates were used instead of kidney slices.
In conclusion, the results presented here show that the formation of dopamine in kidney slices loaded with l‐DOPA is sodium‐dependent and ouabain‐sensitive suggesting the involvement of a co‐transport system of sodium and DOPA into the tubular epithelial cell.
The effects of acute and repeated nicotine treatment on nucleus accumbens dopamine and locomotor activity
Authors: Benwell Maureen E.M. , Balfour David J.K. 
Published: July 2012

The effects of acute and subchronic nicotine and (+)‐amphetamine on the extracellular levels of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens (NAc) have been studied in conscious, freely‐moving rats by use of in vivo microdialysis.
In rats which had been habituated to the test apparatus for approximately 80 min, the acute subcutaneous (s.c.) administration of nicotine (0.1 or 0.4 mg kg−1) caused a dose‐dependent increase (P < 0.01) in spontaneous activity and evoked significant increases (P < 0.05) in the extracellular levels of DOPAC and HVA.
Measurements made 24 h after the last injection of nicotine showed that pretreatment with the higher doses tested (0.4 mg kg−1) resulted in increased basal levels of dopamine (P < 0.01) and decreased basal levels of DOPAC (P < 0.05) in the NAc dialysates.
Pretreatment with nicotine (0.1 or 0.4 mg kg−1 daily for 5 days) enhanced the effects of the drug on spontaneous locomotor activity and enhanced the effects of the drug on extracellular levels of dopamine to the extent that the response became significant (P < 0.05).
If a dopamine uptake inhibitor, nomifensine, was added to the Ringer solution used to dialyse the probe, the s.c. administration of both acute and subchronic nicotine (0.4 mg kg−1) resulted in significant increases (P < 0.05) in the dopamine concentration in the dialysate. Under these conditions, pretreatment with nicotine prior to the test day prolonged (P < 0.05) the dopamine response to a challenge dose of nicotine.
Subcutaneous injections of (+)‐amphetamine (0.2 or 0.5 mg kg−1) evoked dose‐dependent increases in both spontaneous activity and the concentration of dopamine in NAc dialysates. These responses were unaffected by 5 days pretreatment with the drug.
The results of this study support the conclusion that the enhanced locomotor response to nicotine observed in animals pretreated with the drug prior to the test day is associated with potentiation of its effects on dopamine secretion in the NAc.
Changes in adenosine sensitivity in the hippocampus of rats with streptozotocin‐induced diabetes
Authors: Morrison P.D , Mackinnon M.W.B. , Bartrup J.T. , Skett P.G. , Stone T.W. 
Published: July 2012

Hippocampal slices have been used to assess the sensitivity of the CNS to adenosine and γ‐aminobutyric acid (GABA) in diabetes. The effects of adenosine, 2‐chloroadenosine, GABA, muscimol and baclofen were studied on orthodromic synaptic potentials recorded in the CA1 region of slices taken from normal rats or animals made diabetic by the injection of streptozotocin.
In diabetic animals the sensitivity to adenosine was increased 4 fold compared with normal rats. The potency of 2‐chloroadenosine was unchanged.
The nucleoside transport inhibitor, hydroxynitrobenzylthioinosine (HNBTI), increased the potency of adenosine in slices from normal rats but not in slices from diabetic rats.
No change was observed in the potency of GABA or muscimol, although a small but significant decrease was detected in the EC50 value for baclofen.
Treatment of diabetic animals with insulin restored the potency of adenosine to control levels.
It is concluded that the diabetic state is accompanied by substantial changes of adenosine sensitivity due to the loss of nucleoside uptake processes. Secondary neurochemical changes following from this in human diabetic patients may contribute to the reported behavioural changes.
Effect of metformin on glucose metabolism in the splanchnic bed
Authors: Bailey C.J. , Wilcock Carol , Day Caroline 
Published: July 2012

Use of the antihyperglycaemic agent, metformin, is often associated with a small rise in circulating lactate. This study investigates the source of the lactate and examines the effect of metformin on glucose metabolism by the intestine and liver of rats.
Changes in plasma glucose and lactate were measured in the inferior vena cava (IVC), hepatic portal vein (HPV), hepatic vein (HV) and aorta (A) after intrajejunal administration of metformin (50 and 250 mg kg−1) without and with glucose (2 g kg−1).
Metformin 250 mg kg−1 reduced the hyperglycaemic response to a glucose challenge, associated with a greater reduction of glucose concentrations in the HPV (average decrease of 33% at 60 and 120 min) than at other sites.
Both doses of metformin increased lactate concentrations in the glucose‐loaded state: the highest concentration (2.5 fold increase) was recorded in the HPV 60 min after administration of 250 mg kg−1 metformin, with a high lactate concentration persisting in the HV at 120 min. Metformin 250 mg kg−1 also increased lactate concentrations in the basal state, with highest concentrations (2 fold increase) in the HPV.
Two hours after intrajejunal administration of metformin, 50 mg kg−1, rings of tissue from the small intestine showed an average 22% decrease in glucose oxidation ([14C]‐glucose conversion to 14CO2) and a 10% increase in lactate production. Since glucose metabolism in the gut is predominantly anaerobic, metformin caused an overall 9.5% increase of intestinal glucose utilization.
Metformin, 10−6 and 10−4 mol l−1, did not significantly alter glucose oxidation or lactate production by isolated hepatocytes, but a very high concentration of metformin (10−2 mol l−1) increased lactate production by 60%.
The results support the view that metformin increased intestinal glucose utilization and lactate production by the intestine. Under basal conditions there was net extraction of lactate by the liver but not after an enteral glucose load.
Discrimination between ETA‐ and ETB‐receptor‐mediated effects of endothelin‐1 and [Ala1,3,11,15]endothelin‐1 by BQ‐123 in the anaesthetized rat
Authors: Bigaud Marc , Pelton John T. 
Published: July 2012

The influence of BQ‐123 (a selective ETA‐receptor antagonist) on the haemodynamic response elicited by endothelin‐1 (ET‐1) and [Ala1,3,11,15]ET‐1 (a selective ETB‐receptor agonist) was studied in anaesthetized rats instrumented with ultrasonic Doppler flow probes on the carotid, coeliac, mesenteric, renal and iliac arteries.
BQ‐123 alone (1.6 μmol kg−1, i.v.) induced a decrease in femoral mean arterial pressure (AP), accompanied by a systemic vasodilatation. The response was maximal after 3 min and then returned slowly to baseline. None of these effects was observed after a 0.016 μmol kg−1 dose of BQ‐123.
ET‐1 (1 nmol kg−1, i.v.) induced a biphasic response characterized by a transient initial decrease in AP accompanied by regional vasodilatation (mainly in the carotid and iliac beds) and by immediate mesenteric and renal vasoconstrictions. This was followed, within 1 min, by a marked and prolonged increase in AP accompanied by systemic vasoconstriction. Pretreatment with BQ‐123 (1.6 μmol kg−1, i.v., 8 min before ET‐1) increased and prolonged the vasodilator effect of ET‐1 (mainly in the carotid, coeliac, mesenteric and iliac beds) and reduced its systemic vasoconstrictor effects with marked regional differences (the coeliac, mesenteric and renal beds being poorly affected).
[Ala1,3,11,15]ET‐1 (3 nmol kg−1, i.v.) induced an initial and marked decrease in AP accompanied by regional vasodilatation (mainly in the carotid, coeliac and iliac beds) and by mesenteric and renal vasoconstrictions. This was followed, within 5 min, by a small increase in AP and systemic vasoconstriction. All these effects were dose‐dependent. Pretreatment with BQ‐123 (1.6 μmol kg−1; 8 min before ET‐1) did not modify the early effect of [Ala1,3,11,15]ET‐1, but abolished its secondary vasoconstrictor effect except in the mesenteric bed.
This study demonstrates that pretreatment with BQ‐123 not only reduced a large part of the sustained vasoconstrictor activity of ET‐1, suggesting the involvement of ETA‐receptors, but also enhanced the early vasodilator activity of ET‐1 revealing a functional antagonism between the two effects. The vasodilator effect of [Ala1,3,11,15]ET‐1 was not affected by BQ‐123 and ET‐1 induced a similar vasodilatation, that was potentiated by BQ‐123, suggesting the involvement of ETB‐receptors in this vasodilator response. Marked regional differences were however observed which might be partly related to different levels of functional antagonism between ETB‐ and ETA‐mediated effects, but differences in receptor types, or subtypes, cannot be excluded, mainly in the mesenteric and renals beds.
Modulation of barrier function of bovine aortic and pulmonary artery endothelial cells: dissociation from cytosolic calcium content
Authors: Buchan Kevin W. , Martin William 
Published: July 2012

Barrier function and cytosolic free calcium content [Ca2+]i was measured in monolayers of bovine pulmonary artery endothelial cells (BPAEC) and bovine aortic endothelial cells (BAEC).
Thrombin (1 u ml−1) increased albumin transfer across monolayers of BPAEC but not BAEC, yet induced biphasic increases in [Ca2+]i in both endothelial cell types, consisting of a rapid, initial phasic component which decayed to a lower, more sustained plateau phase.
4β‐Phorbol 12‐myristate 13‐acetate (PMA; 0.3–3000 nm) increased albumin transfer across monolayers of BPAEC and BAEC, but had no effect on basal levels of [Ca2+]i in either endothelial cell type.
Treatment of BPAEC and BAEC with forskolin (30 μm), an activator of adenylate cyclase, had no effect on resting transfer of albumin, but inhibited that stimulated by PMA (600 nm). It also inhibited the thrombin (1 u ml−1)‐induced increase in albumin transfer across monolayers of BPAEC, but enhanced the plateau phase of the associated increase in [Ca2+]i.
Treatment of BPAEC and BAEC with either atriopeptin II (100 nm), an activator of particulate guanylate cyclase, or 8 bromo cyclic GMP (30 μm) had no effect on resting or PMA (600 nm)‐stimulated transfer of albumin. Both agents did, however, inhibit the thrombin (1 u ml−1)‐induced increase in albumin transfer across monolayers of BPAEC, but had no effect on the associated increase in [Ca2+]i.
These data suggest a dissociation between the ability of agents that increase or decrease albumin transfer and their effects on [Ca2+]i. Consequently, activation of protein kinase C may be the major stimulus for trans‐endothelial transfer of macromolecular solutes. Endothelial barrier function is enhanced by elevation of either cyclic AMP or cyclic GMP content. Cyclic AMP appears to act by inhibiting the actions of protein kinase C, while cyclic GMP may act to inhibit a key step proximal to activation of this enzyme.
Enhanced responsiveness of ovalbumin‐sensitized guinea‐pig alveolar macrophages to tachykinins
Authors: Brunelleschi Sandra , Parenti Astrid , Ceni Elisabetta , Giotti Alberto , Fantozzi Roberto 
Published: July 2012

We have evaluated the ability of substance P (SP), neurokinin A (NKA) and the selective NK2 receptor agonist [β‐Ala8]‐NKA(4–10) to induce superoxide anion (O2−) production and prostanoid (prostaglandin E2, thromboxane B2) release from alveolar macrophages (AMs) isolated from control or actively sensitized guinea‐pigs.
The dose‐response curves for NKA and SP were shifted to the left (three orders and one order of magnitude, respectively) in AMs isolated from sensitized animals, with no variation in maximal effects.
By evaluating the effects of [β‐Ala8]‐NKA(4–10), we observed that not only was the concentration‐response curve shifted to the left in both the functional parameters examined, but also maximal effects were significantly enhanced in AMs isolated from sensitized guinea‐pigs.
This varied responsiveness seems to be specific for tachykinins, as it was not reproduced by another AM stimulant, the bacterial peptide N‐formylmethionyl‐leucyl‐phenylalanine (fMLP).
Only small amounts of β‐glucuronidase were released following tachykinin or ovalbumin stimulation both in control and sensitized AMs.
These results indicate that AMs isolated from sensitized guinea‐pigs show an increased responsiveness to NK2 receptor stimulation and further stress the role played by AMs in allergic lung diseases.
Differential sensitivities of the prostacyclin and nitric oxide biosynthetic pathways to cytosolic calcium in bovine aortic endothelial cells
Authors: Parsaee Heydar , McEwan Jean R. , Joseph Sunil , MacDermot John 
Published: July 2012

Bovine aortic endothelial cells were cultured in vitro, and shown to release both prostacyclin (PGI2; Kact = 24.1 nm) and endothelium‐derived relaxing factor (EDRF, NO; Kact = 0.7 nm) in a concentration‐dependent manner when exposed to bradykinin.
The bradykinin‐dependent release of PGI2 (but not EDRF) was inhibited by 1 μm isoprenaline or 5 μm forskolin, and the inhibitory effect of isoprenaline could be reversed by the β2‐adrenoceptor antagonist, ICI 118551. In contrast, isoprenaline had no capacity to inhibit PGI2 release stimulated by exogenous arachidonic acid.
Exposure of cells to bradykinin increased the cytosolic concentration of Ca2+ ions ([Ca2+]i; Kact = 4.8 nm), and the effect was inhibited by both 1 μm isoprenaline and 5 μm forskolin.
In similar experiments, exposure of cells to ionomycin also increased [Ca2+]i and the values of [Ca2+]i were calibrated in terms of the ionomycin concentration. In subsequent experiments involving exposure of endothelial cells to selected concentrations of ionomycin, it was possible to show that the biosynthesis of NO was triggered at ionomycin concentrations about one tenth of that required for PGI2 biosynthesis and that these corresponded to a [Ca2+]i threshold of 350 nm for PGI2 release while that for EDRF release was less than 200 nm.
These differences in Ca2+ ion sensitivity explain the selective inhibition of bradykinin‐stimulated PGI2 biosynthesis (to the exclusion of NO biosynthesis) by isoprenaline or forskolin, both of which attenuate bradykinin‐dependent increases in [Ca2+]i.
Blockade by antiarrhythmic drugs of glibenclamide‐sensitive K+ channels in Xenopus oocytes
Authors: Sakuta Hidenari , Okamoto Koichi , Watanabe Yasuhiro 
Published: July 2012

The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes (I‐IV) of antiarrhythmic drugs on this KRN2391‐induced response.
All class I antiarrhythmic drugs (Na+ channel blockers) tested concentration‐dependently suppressed KRN2391‐induced responses with the rank order of potency (IC50 in μm), disopyramide (17.8) > aprindine (29.5) > propafenone (63.1) > ajmaline (145) > quinidine (151). Flecainide, SUN1165, lignocaine, mexiletine and procainamide were much less potent (IC50, 450– > 1000 μm) than quinidine.
The class II antiarrhythmic drugs (β‐blockers), timolol, (−)‐ and (±)‐ propranolol, and (+)‐propranolol (a non‐β‐blocker) inhibited KRN2391‐induced K+ currents in a concentration‐dependent manner with values for IC50 (μm) of 79, 131, 151 and 129, respectively, whilst butoxamine, oxprenolol, alprenolol, pindolol, nadolol, metoprolol and acebutolol were either weak (IC50, 300 μm — 600 μm) or virtually inactive (IC50, > 1000 μm).
The class III antiarrhythmic drugs, amiodarone and (+)‐sotalol scarcely affected KRN2391 responses.
All class IV drugs (Ca2+ antagonists) tested suppressed KRN2391‐induced responses in a concentration‐dependent manner with an IC50 of 6.3 μm for bepridil, 38 μm for prenylamine, 85 μm for verapamil and 135 μm for diltiazem.
In conclusion, antiarrhythmic drugs of classes I, II and IV potently blocked glibenclamide‐sensitive K+ channels in Xenopus oocytes.
Involvement of cyclic GMP in non‐adrenergic, non‐cholinergic inhibitory neurotransmission in dog proximal colon
Authors: Ward Sean M. , Dalziel Hugh H. , Bradley Michael E. , Buxton Iain L.O. , Keef Kathleen , Westfall David P. , Sanders Kenton M. 
Published: July 2012

Nitric oxide (NO) may serve as a non‐adrenergic, non‐cholinergic (NANC) neurotransmitter released from enteric inhibitory nerves in the gastrointestinal tract. We tested whether guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) may serve as a second messenger in transducing the NO signal into inhibitory junction potentials (i.j.ps) and relaxation in the canine proximal colon.
The membrane permeable analogue of cyclic GMP, 8‐bromo cyclic GMP (8‐Br‐cyclic GMP) mimicked the effects of NO by hyperpolarizing cells near the myenteric border of the circular muscle layer and shortening slow waves in cells near the submucosal surface of the circular muscle layer. 8‐Br‐cGMP also inhibited spontaneous phasic contractions.
The specific cyclic GMP phosphodiesterase inhibitor, M&B 22948, hyperpolarized cells near the myenteric border and prolonged the duration of i.j.ps. M&B 22948 also inhibited phasic contractile activity.
Methylene blue failed to reduce significantly the amplitude and duration of i.j.ps and had variable effects on contractions.
Cyclic GMP levels were assayed in unstimulated muscles and in muscles exposed to exogenous NO and electrical field stimulation. Both stimuli hyperpolarized membrane potential, inhibited contractions, and elevated cyclic GMP levels.
Treatment of muscles with l‐NG‐nitroarginine methyl ester (l‐NAME) increased spontaneous contractile activity and lowered cyclic GMP levels. The inhibitory effect of M&B 22948 on contractions was greatly reduced after muscles were treated with l‐NAME.
These data support the concept that the effects of NANC nerve stimulation and NO (which may be one of the enteric inhibitory transmitters) may be mediated by cyclic GMP.
Inositol 1,4,5‐trisphosphate generation and calcium mobilisation via activation of an atypical P2 receptor in the neuronal cell line, N1E‐115
Authors: Iredale Philip A. , Martin Keith F. , Alexander Stephen P.H. , Hill Stephen J. , Kendall David A. 
Published: July 2012

Alterations in the levels of intracellular calcium ([Ca2+]i) and d‐myo‐inositol‐1,4,5‐trisphosphate (InsP3) were measured in the murine neuroblastoma cell line clone, N1E‐115, by use of the calcium‐sensitive dye, fura‐2 and a radioreceptor assay, respectively.
Exposure of the cells to ATP (100 μm) elicited rapid and transient increases in [Ca2+]i and InsP3, with both responses reaching a maximum between 10– 20 s after agonist addition.
Investigation of concentration‐response data by use of various analogues of ATP suggests the presence of an extracellular receptor which fails to fit into the current classification of purinoceptors.
Cross‐desensitization experiments suggest that the same receptor can also be activated by the structurally different pyrimidine base, UTP.
Application of the tumour‐promoting agent, β‐phorbol‐12,13 dibutyrate (PDBu) caused a reduction in the increases in both [Ca2+]i and InsP3, suggesting a role for protein kinase C in feedback inhibition of purinoceptor responses in this cell line.
In summary, we present the first evidence for the existence of an atypical purinoceptor on a cell line of CNS origin. This receptor is linked to stimulation of phosphoinositide turnover and subsequent mobilisation of intracellular calcium.