bluuebunny/crossref_metadata_2025_split huggingface dataset:
The potential role of peroxynitrite in the vascular contractile and cellular energetic failure in endotoxic shock
Authors: Zingarelli Basilia , Day Brian J , Crapo James D , Salzman Andrew L , Szabó Csaba 
Published: August 2006

Peroxynitrite is a toxic oxidant species produced from nitric oxide (NO) and superoxide. We have recently observed that the cell‐permeable superoxide dismutase mimetic Mn(III)tetrakis(4‐benzoic acid) porphyrin (MnTBAP) inhibits the suppression of mitochondrial respiration elicited by authentic peroxynitrite in vitro. Here we have investigated the relative potency of MnTBAP and a range of related compounds in terms of inhibition of peroxynitrite‐induced oxidation and cytotoxicity. In addition, we tested the effects of MnTBAP on the vascular and the cellular energetic failure in rodent models of endotoxic shock.
We observed a dose‐related inhibition of the peroxynitrite‐induced oxidation of dihydrorhodamine 123 to rhodamine by MnTBAP, ZnTBAP and FeTBAP, but not by MnTMPyP [(5,10,15,20‐tetrakis(N‐methyl‐4′‐pirydyl)porphinato)‐manganese (III)]. In addition, MnTBAP, ZnTBAP and FeTBAP, but not MnTMPyP prevented the suppression of mitochondrial respiration by authentic peroxynitrite in cultured J774 macrophages.
In rat cultured aortic smooth muscle cells, MnTBAP protected against the suppression of mitochondrial respiration in response to authentic peroxynitrite, immunostimulation and nitric oxide (NO) donor compounds. MnTBAP slightly reduced the amount of nitrite/nitrate produced in response to immunostimulation in these cells.
Administration of MnTBAP, 15 mg kg−1 i.v., before the administration of endotoxin (15 mg kg−1, i.v.) to rats ameliorated the development of vascular hyporeactivity and the development of endothelial dysfunction in the thoracic aorta ex vivo.
MnTBAP also prevented the endotoxin‐induced decrease in mitochondrial respiration, the development of DNA single strand breaks, and the depletion of intracellular NAD+ in peritoneal macrophages ex vivo.
MnTBAP did not inhibit the expression by endotoxin of the inducible NO synthase in lung samples.
MnTBAP did not alter survival rate in mice challenged with high dose endotoxin.
Our findings, taken together with previous data demonstrating protective effects of NO synthase inhibitors against the endotoxin‐induced contractile and energetic failure in the models of shock used in the current study, and with the known ability of peroxynitrite to cause cellular energy depletion, suggest a role for peroxynitrite in the pathogenesis of cellular energetic failure and contractile dysfunction in endotoxin shock.

British Journal of Pharmacology (1997) 120, 259–267; doi:10.1038/sj.bjp.0700872
Different effects of reducing agents on ω‐conotoxin GVIA inhibition of [3H]‐acetylcholine release from rat cortical slices and guinea‐pig myenteric plexus
Authors: Casali T A A , Gomez R S , Moraes‐Santos T , Romano‐Silva M A , Prado M A M , Gomez M V 
Published: August 2006

The effect of reducing reagents on ω‐conotoxin GVIA (ω‐CgTX) inhibition of the release of [3H]‐acetylcholine ([3H]‐ACh) induced by tityustoxin, K+ 50 mm and electrical stimulation was investigated in rat brain cortical slices.
In cortical slices the inhibition of tityustoxin or electrically‐stimulated [3H]‐ACh release by ω‐CgTX was dramatically increased by reducing reagents ascorbate or β‐mercaptoethanol. Dehydroascorbic acid did not substitute for ascorbate
Depolarization induced by K+ 50 mm caused [3H]‐ACh release from cortical slices which was not inhibited by ω‐CgTX, even in the presence of ascorbate.
In the guinea‐pig myenteric plexus, ω‐CgTX inhibition of the tityustoxin induced release of [3H]‐ACh was independent of ascorbate.
It is suggested that N‐type‐like calcium channels in guinea‐pig myenteric plexus may have pharmacological/biochemical diversity from similar channels of rat cerebral cortex.

British Journal of Pharmacology (1997) 120, 88–92; doi:10.1038/sj.bjp.0700873
Calcium‐antagonist effects of norbormide on isolated perfused heart and cardiac myocytes of guinea‐pig: a comparison with verapamil
Authors: Bova Sergio , Cargnelli Gabriella , D'Amato Elvira , Forti Stefano , Yang Quan , Trevisi Lucia , Debetto Patrizi , Cima Lorenzo , Luciani Sisto , Padrini Roberto 
Published: August 2006

Cardiac effects of norbormide and verapamil were compared in single ventricular myocytes, right atria, and Langendorff perfused hearts isolated from guinea‐pigs.
In ventricular myocytes, norbormide 50 μm inhibited the peak calcium current (ICa) by 49.6±3.9% without altering the shape of the current‐voltage relationship; verapamil 1 μm inhibited ICa by 83.2±3.3%. Neither norbormide nor verapamil affected ICa at the first beat after a 3 min quiescence period; during repeated depolarizations, both drugs cumulatively blocked ICa (use‐dependence), with time constants of 23.0±7.0 s for norbormide and 91.3±8.4 s for verapamil.
In constant‐flow perfused hearts electrically driven at 2.5 Hz or 3.3 Hz, both norbormide and verapamil concentration‐dependently decreased ventricular contractility (dP/dtmax), atrio‐ventricular (AV) conduction velocity and coronary pressure. Intraventricular conduction velocity was slightly decreased by norbormide but not by verapamil. At an equivalent change in AV conduction, norbormide depressed heart contractility less than verapamil. The effects of norbormide on AV conduction, intraventricular conduction, and contractility were frequency‐dependent. Furthermore, the curves correlating the mechanical and electrical effects of norbormide at the two frequencies used were apparently coincident, while those of verapamil were clearly separated.
In spontaneously beating right atria, norbormide and verapamil decreased the frequency of sinus node (SA) in a concentration‐dependent way. At an equivalent effect on the AV conduction, norbormide exerted a greater effect on sinus frequency than verapamil.
These results indicate that in guinea‐pig heart norbormide has the pharmacological profile of a Ca‐antagonist with strong electrophysiological properties. In comparison with verapamil, norbormide is more selective on SA and AV node tissues and exerts a weaker negative inotropic effect on ventricles. In principle, this pattern of effects may be an advantage in treating supraventricular tachyarrhythmias in patients with heart failure. The effect of norbormide on intraventricular conduction may represent an additional antiarrhythmic mechanism.

British Journal of Pharmacology (1997) 120, 19–24; doi:10.1038/sj.bjp.0700876
The effect of CP‐99994 on the responses to provocative motion in the cat
Authors: Lucot J B , Obach R S , McLean S , Watson J W 
Published: August 2006

The NK1 receptor antagonist CP‐99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat.
CP‐99994 displaced [3H]‐substance P from cat cortex with IC50 of 0.52±0.08 nm. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h.
Subcutaneous administration of CP‐99994 inhibited motion‐induced vomiting in the cat with an ED50 of 144 μg kg−1 but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 μg kg−1. The antiemetic effect of CP‐99994 can be attributed to antagonism of the NK1 receptor because its enantiomer, CP‐100,263, which is 900 fold weaker as an NK1 antagonist, had no effects on any response to provocative motion.
The inhibitory effect of CP‐99994 on motion‐induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours.
An investigation into whether the failure of CP‐99994 to alter the epiphenomena will also predict a lack of anti‐nausea effects in man will provide critical information on the neural organization of the emetic reflex.

British Journal of Pharmacology (1997) 120, 116–120; doi:10.1038/sj.bjp.0700888
Mechanism of contraction induced by bradykinin in the rabbit saphenous vein
Authors: Eguchi Daihiko , Nishimura Junji , Kobayashi Sei , Komori Kimihiro , Sugimachi Keizo , Kanaide Hideo 
Published: August 2006

By using fura‐PE3 fluorometry and receptor‐coupled permeabilization by α‐toxin, the mechanism of the bradykinin (BK)‐induced contraction was determined in the rabbit saphenous vein (RSV). The receptor subtype responsible for the BK‐induced contraction of RSV was determined by means of a pharmacological blocker study and reverse transcription polymerase chain reaction (RT‐PCR).
In the presence of extracellular Ca2+ (1.25 mM), BK (10−11‐3 × 10−7 m) induced increases in both the cytosolic Ca2+ concentration ([Ca2+]i) and force, in a concentration‐dependent manner. Both the release of Ca2+ from the store site and the influx of extracellular Ca2+ contribute to an increase in [Ca2+]i induced by BK.
In the absence of extracellular Ca2+, the application of 10−7 M BK induced transient elevations of [Ca2+]i and force, both of which thereafter declined to the levels observed before the application of BK. When extracellular Ca2+ was replenished (1.25 mM), [Ca2+]i and force increased to form a peak, followed by a sustained elevation in the presence of BK. When an RSV strip was pretreated with 10−5 M thapsigargin for 20 min, the BK‐induced transient increases in both [Ca2+]i and force were markedly inhibited.
These responses induced by BK were inhibited by Hoe 140 (D‐Arg‐[Hyp3, Thi5, D‐Tic7, Oic8] bradykinin), a highly specific bradykinin B2 receptor antagonist, in a concentration‐dependent manner. In RT‐PCR, B2‐receptor mRNA was expressed in the smooth muscle of RSV.
The [Ca2+]i‐force relationships, which were determined by cumulative applications of extracellular Ca2+ (0–5 mM) during 118 mM K+‐depolarization, shifted to the upper left in the presence of BK, thus indicating that BK induced a greater force than 118 mM K+‐depolarization for a given level of [Ca2+]i.
In α‐toxin‐permeabilized preparations of RSV, application of 10−7 M BK after a steady state contraction had been induced by a mixture of 5 × 10−7 M Ca2+, 10−6 M GTP and 10−6 M captopril caused an additional force development at a constant [Ca2+]i. However, treatment with 1 mM guanosine‐5′‐O‐(β‐thiodiphosphate) (GDPβS) for 5 min before and during the application of BK (10−7 m), abolished this BK‐induced additional contraction.
These results indicated that in RSV: (1) BK elicits vasoconstriction by increasing the Ca2+ influx from the extracellular space, Ca2+ release from intracellular thapsigargin‐sensitive storage sites and increasing the Ca2+ sensitivity of the contractile apparatus, (2) the BK‐induced increase in Ca2+ sensitivity is mediated by G‐protein, (3) the BK‐induced contractions are mediated via B2‐receptors and (4) the smooth muscle cells express B2‐receptor mRNA.
Effects of riluzole on rat cortical neurones: an in vitro electrophysiological study
Authors: Siniscalchi Antonio , Bonci Antonello , Mercuri Nicola B , Bernardi Giorgio 
Published: August 2006

The electrophysiological effects of riluzole on rat prefrontal and frontal cortical neurones were investigated by using both extracellular (field) and intracellular recording techniques in brain slices.
Bath applied riluzole (3–200 μm) depressed the cortico‐cortical stimulus‐evoked field potential in a concentration‐related manner (EC50=29.5 μm).
Riluzole (3–100 μm) reduced the tonic firing of the neocortical neurones which was caused by intracellular current injection, while it did not have any effect on the resting membrane potential and apparent input resistance of these cells.
In the presence of tetrodotoxin (1 μm) and tetraethylammonium (30 mm), the injection of a depolarizing current step generated a calcium spike in the neocortical neurones. Riluzole (30 μm) abolished this calcium‐dependent action potential. However, when the amount of the depolarizing current was increased the calcium‐dependent regenerative potential was evoked again.
The depolarization of the membrane (10–20 mV) caused by brief (8–15 s) bath applications of glutamate (300 μm–1 mm) were not changed in the presence of riluzole (30 μm).
It is concluded that riluzole has direct actions on rat neocortical neurones: (a) it blocks the repetitive discharge of sodium action potentials and (b) it increases the threshold for the generation of the calcium spike. These two cellular mechanisms might at least in part account for the depression of the cortico‐cortical field potential caused by this drug.

British Journal of Pharmacology (1997) 120, 225–230; doi:10.1038/sj.bjp.0700905
The effects of tamsulosin, a high affinity antagonist at functional α1A‐ and α1D‐adrenoceptor subtypes
Authors: Noble A J , Chess‐Williams R , Couldwell C , Furukawa K , Uchyiuma T , Korstanje C , Chapple C R 
Published: August 2006

The actions of the α1‐adrenoceptor antagonist tamsulosin have been examined at functional α1‐adrenoceptor subtypes and compared with those at the human prostate receptor.
At the α1D‐adrenoceptors of the rat aorta, tamsulosin acted as a competitive antagonist with a high affinity (pKB=10.1).
At the α1B‐adrenoceptor of the rat spleen and rabbit corpus cavernosum penis, tamsulosin again acted as a competitive antagonist but with a significantly lower affinity (pKB=8.9–9.2).
Tamsulosin acted as an unsurmountable antagonist of the α1A‐adrenoceptor‐mediated responses of the rat and human vas deferens, reducing maximal responses to phenylephrine by 20% and 50%, respectively, at an antagonist concentration of 1 nm. Responses of depolarized (100 mm KCl) rat vas deferens preparations were unaffected by 10 nm tamsulosin but this concentration reduced maximal responses to 5‐hydroxytryptamine (5‐HT) in this tissue.
When longer antagonist incubation periods (60 min) were used, tamsulosin behaved as a competitive antagonist on the human prostate with a significantly higher affinity (pKB=10.0) than obtained at the α1B‐adrenoceptor.
The data demonstrate that tamsulosin is a high affinity antagonist at functional α1‐adrenoceptors with a selectivity α1Dα1A>α1B. In some tissues the compound exhibits an additional unsurmountable antagonist action, the clinical significance of which is unknown.

British Journal of Pharmacology (1997) 120, 231–238; doi:10.1038/sj.bjp.0700907
Mechanisms involved in the effect of nitric oxide synthase inhibition on L‐arginine‐induced insulin secretion
Authors: Gross R. , Roye M. , Manteghetti M. , Broca C. , Hillaire‐Buys D. , Masiello P. , Ribes G. 
Published: August 2006

A constitutive nitric oxide synthase (NOSc) pathway negatively controls L‐arginine‐stimulated insulin release by pancreatic β cells. We investigated the effect of glucose on this mechanism and whether it could be accounted for by nitric oxide production.
NOSc was inhibited by N∞‐nitro‐L‐arginine methyl ester (l‐NAME), and sodium nitroprusside (SNP) was used as a palliative NO donor to test whether the effects of L‐NAME resulted from decreased NO production.
In the rat isolated perfused pancreas, L‐NAME (5 mM) strongly potentiated L‐arginine (5 mM)‐induced insulin secretion at 5 mM glucose, but L‐arginine and L‐NAME exerted only additive effects at 8.3 mM glucose. At 11 mM glucose, L‐NAME significantly inhibited L‐arginine‐induced insulin secretion. Similar data were obtained in rat isolated islets.
At high concentrations (3 and 300 μm), SNP increased the potentiation of arginine‐induced insulin output by L‐NAME, but not at lower concentrations (3 or 30 nM).
L‐Arginine (5 mM) and L‐ornithine (5 mM) in the presence of 5 mM glucose induced monophasic β cell responses which were both significantly reduced by SNP at 3 nM but not at 30 nM; in contrast, the L‐ornithine effect was significantly increased by SNP at 3 μm.
Simultaneous treatment with L‐ornithine and L‐arginine provoked a biphasic insulin response.
At 5 mM glucose, L‐NAME (5 mM) did not affect the L‐ornithine secretory effect, but the amino acid strongly potentiated the alteration by L‐NAME of L‐arginine‐induced insulin secretion.
L‐Citrulline (5 mM) significantly reduced the second phase of the insulin response to L‐NAME (5 mM) + L‐arginine (5 mM) and to L‐NAME + L‐arginine + SNP 3 μm.
The intermediate in NO biosynthesis, NG‐hydroxy‐L‐arginine (150–300 μm) strongly counteracted the potentiation by L‐NAME of the secretory effect of L‐arginine at 5 mM glucose.
We conclude that the potentiation of L‐arginine‐induced insulin secretion resulting from the blockade of NOSc activity in the presence of a basal glucose concentration (1) is strongly modulated by higher glucose concentrations, (2) is not due to decreased NO production but (3) is probably accounted for by decreased levels of NG‐hydroxy‐L‐arginine or L‐citrulline, resulting in the attenuation of an inhibitory effect on arginase activity.
Pharmacological classification of α1‐adrenoceptors mediating contractions of rabbit isolated ear artery: comparison with rat isolated thoracic aorta
Authors: Fagura M S , Lydford S J , Dougall I G 
Published: August 2006

The present study attempted to classify pharmacologically the α1‐adrenoceptor subtype(s) present in two isolated, vascular ring preparations, the rabbit ear artery and rat thoracic aorta.
In the ear artery, the agonist effects of phenylephrine were antagonized by 5‐methyl urapidil (pA2=7.90; Schild slope=0.85) and BMY 7378 (pA2=6.11; Schild slope=0.80) but not in a simple competitive manner. The shallow Schild slopes are consistent with the activation of a heterogeneous receptor population. Indeed the 5‐methyl urapidil data set could be fitted to a two‐receptor model yielding a high antagonist affinity (pKBH) estimate of 7.85 and a low affinity (pKBL) estimate of 6.03.
The effects of clonidine in the ear artery were competitively antagonised by 5‐methyl urapidil (pKB=7.91) and BMY 7378 (pKB=5.53). These data are consistent with contractions to clonidine being mediated by a single receptor subtype.
In the aorta, the effects of phenylephrine were antagonized by 5‐methyl urapidil (pA2=7.95; Schild slope=1.11) and BMY 7378 (pA2=9.08; Schild slope=0.73). Neither data set was consistent with a simple competitive interaction. The BMY 7378 data suggested again, that phenylephrine was acting at a heterogeneous receptor population. Subsequent analysis by the two‐receptor model yielded a high affinity (pKBH) estimate of 8.95 and a low affinity (pKBL) estimate of 7.00.
The alkylating agent, chloroethylclonidine (CEC) elicited concentration‐dependent contractions in the ear artery with a potency (p[A]50) of 5.57. Pretreatment of this tissue with CEC (5 μm, 30 min incubation) had no effect on subsequent responses to phenylephrine. In contrast, in the aorta, CEC demonstrated no agonism but pretreatment with this agent (5 μm, 15 min incubation) caused a rightward shift and depression of subsequent phenylephrine concentration‐effect curves.
The affinity of clonidine in the rabbit ear artery (pKA=6.17) was found to be significantly different to its affinity in the rat thoracic aorta (pKA=7.12) suggesting that this agonist activates different α1‐adrenoceptor subtypes in the two tissues.
These results suggest that heterogeneous populations of α1‐adrenoceptors are present in both tissues. In the ear artery, the profile of antagonist and agonist activity is most consistent with α1A‐adrenoceptors being the predominant receptor subtype. The second receptor population does not appear to correspond to any of the recognized α1‐adrenoceptor subtypes. In the aorta α1D‐adrenoceptors appear to predominate, with α1A‐adrenoceptors being the most likely candidate for the second receptor population.

British Journal of Pharmacology (1997) 120, 247–258; doi:10.1038/sj.bjp.0700917
Pharmacological characterization of the sulphonylurea receptor in rat isolated aorta
Authors: Löffler Cornelia , Quast Ulrich 
Published: August 2006

The binding of the sulphonylurea [3H]‐glibenclamide, a blocker of adenosine 5′‐triphosphate (ATP)‐sensitive K+ channels (KATP channels), was studied in endothelium‐denuded rings from rat aorta.
[3H]‐glibenclamide labelled two classes of binding sites with KD values of 20 ± 5 nM and 32± 1 μM. The high affinity component, which comprised 17% of total binding at 1 nM [3H]‐glibenclamide, had an estimated binding capacity of 150 fmol mg3 wet weight.
Other sulphonylureas such as glipizide and glibornuride and the sulphonylurea‐related carboxylate, AZ‐DF 265, inhibited high affinity [3H]‐glibenclamide binding with the potencies expected from their K+ channel activity. At very high concentrations, AZ‐DF 265 and glipizide started to interact also with the low affinity component of [3H]‐glibenclamide binding.
Openers of the ATP‐sensitive K+ channel belonging to different structural groups inhibited only the high affinity [3H]‐glibenclamide binding; the potencies in this assay were similar to those obtained in functional (i.e. vasorelaxation) studies.
High affinity [3H]‐glibenclamide binding was abolished by prolonged hypoxia combined with metabolic inhibition.
The data indicate that the high affinity component of [3H]‐glibenclamide binding mediates the block of the KATP channel by the sulphonylureas in rat aorta; hence, it represents the sulphonylurea receptor in this vessel. The pharmacological properties of this binding site resemble those of the binding site for the openers of the KATP channel; present evidence suggests that these two classes of sites are negatively allosterically coupled.