bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and metabolism of thioridazine during co‐administration of tricyclic antidepressants
Authors: Daniel Wladyslawa A , Syrek Maciej , Haduch Anna , Wójcikowski Jacek 
Published: January 2005

Because of serious side‐effects of thioridazine and tricyclic antidepressants (cardiotoxicity), a possible influence of imipramine and amitriptyline on the pharmacokinetics and metabolism of thioridazine was investigated in a steady state (2‐week treatment) in rats.
Imipramine and amitriptyline (5 and 10 mg kg−1 i.p., respectively) elevated 30 and 20 fold, respectively, the concentration of thioridazine (10 mg kg−1 i.p.) and its metabolites (N‐desmethylthioridazine, 2‐sulphoxide, 2‐sulphone, 5‐sulphoxide) in blood plasma. Similar, yet weaker increases in the thioridazine concentration were found in the brain. Moreover, an elevation of thioridazine/metabolite ratios was observed.
Imipramine and amitriptyline added to control liver microsomes in vitro inhibited the metabolism of thioridazine via N‐demethylation (an increase in Km), mono‐2‐sulphoxidation (an increase in Km and a decrease in Vmax) and 5‐sulphoxidation (mainly a decrease in Vmax). Amitriptyline was a more potent inhibitor than imipramine of the thioridazine metabolism.
The varying concentration ratios of antidepressant/thioridazine in vivo appear to be more important to the final result of the pharmacokinetic interactions than are relative direct inhibitory effects of the antidepressants on thioridazine metabolism observed in vitro.
Besides direct inhibition of the thioridazine metabolism, the decreased activity of cytochrome P‐450 towards 5‐sulphoxidation, produced by chronic joint administration of thioridazine and the antidepressants, seems to be relevant to the observed in vivo interaction.
The obtained results may also point to inhibition of another, not yet investigated, metabolic pathway of thioridazine, which may be inferred from the simultaneous elevation of concentrations of both thioridazine and the measured metabolites.

British Journal of Pharmacology (2000) 131, 287–295; doi:10.1038/sj.bjp.0703540
Expression and function of MIP‐2 are reduced by dexamethasone treatment in vivo
Authors: Schramm Rene , Liu Qing , Thorlacius Henrik 
Published: January 2005

The objective of this study was to examine the effect of dexamethasone on tumour necrosis factor‐α (TNF‐α)‐induced expression and function of macrophage inflammatory protein‐2 (MIP‐2) and neutrophil recruitment. For this purpose, we used air pouches raised on the dorsal skin of C57/B16 mice.
Initially, we examined the dose‐response (0.01–0.5 μg ml−1) and kinetics (0–24 h) of TNF‐α‐induced leukocyte accumulation. The cellular response was maximal at 0.1 μg ml−1 of TNF‐α and 4 h after challenge and comprised more than 90% neutrophils.
Intraperitoneal (i.p.) pretreatment with 10 mg kg−1 of dexamethasone for 2 h, but not 1 mg kg−1, reduced TNF‐α‐induced recruitment of neutrophils by 87%. Administration of dexamethasone had no effect on the expression of CD18 on neutrophils.
TNF‐α (0.1 μg ml−1) markedly increased the levels of MIP‐2 in the air pouches 1 h after challenge and after 4 h the MIP‐2 values returned to baseline. Notably, 2 h pretreatment with dexamethasone (10 mg kg−1, i.p.) reduced MIP‐2 expression by 65% in response to TNF‐α (0.1 μg ml−1). On the other hand, dexamethasone treatment did not change the levels of interleukin‐10 (IL‐10) in the pouch exudate.
Administration of recombinant MIP‐2 increased neutrophil accumulation at 0.5 and 1.0 μg ml−1 after 4 h of challenge. Dexamethasone pretreatment for 2 h (10 mg kg−1, i.p.) abolished the MIP‐2‐induced recruitment of neutrophils.
Taken together, our data demonstrate that dexamethasone may downregulate TNF‐α‐induced neutrophil recruitment by inhibiting both the expression and function of MIP‐2 in vivo.

British Journal of Pharmacology (2000) 131, 328–334; doi:10.1038/sj.bjp.0703543
Oxidation of nitroxyl anion to nitric oxide by copper ions
Authors: Nelli Silvia , Hillen Mark , Buyukafsar Kansu , Martin William 
Published: January 2005

This study made use of a nitric oxide‐sensitive electrode to examine possible means of generating nitric oxide from nitroxyl anion (NO−) released upon the decomposition of Angeli's salt.
Our results show that copper ions (from CuSO4) catalyze the rapid and efficient oxidation of nitroxyl to nitric oxide. Indeed, the concentrations of copper required to do so (0.1–100 μM) are roughly 100‐times lower than those required to generate equivalent amounts of nitric oxide from S‐nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP).
Experiments with ascorbate (1 mM), which reduces Cu2+ ions to Cu+, and with the Cu2+ chelators, EDTA and cuprizone, and the Cu+ chelator, neocuproine, each at 1 mM, suggest that the oxidation is catalyzed by copper ions in both valency states.
Some compounds containing other transition metals, i.e. methaemoglobin, ferricytochrome c and Mn(III)TMPyP, were much less efficient than CuSO4 in catalyzing the formation of nitric oxide from nitroxyl, while FeSO4, FeCl3, MnCl2, and ZnSO4 were inactive.
Of the copper containing enzymes examined, Cu‐Zn superoxide dismutase and ceruloplasmin were weak generators of nitric oxide from nitroxyl, even at concentrations (2500 and 30 u ml−1, respectively) vastly greater than are present endogenously. Two others, ascorbate oxidase (10 u ml−1) and tyrosinase (250 u ml−1) were inactive.
Our findings suggest that a copper‐containing enzyme may be responsible for the rapid oxidation of nitroxyl to nitric oxide by cells, but the identity of such an enzyme remains elusive.

British Journal of Pharmacology (2000) 131, 356–362; doi:10.1038/sj.bjp.0703550
L‐NAME‐resistant bradykinin‐induced relaxation in porcine coronary arteries is NO‐dependent: effect of ACE inhibition
Authors: Danser A H Jan , Tom Beril , De Vries René , Saxena Pramod R 
Published: January 2005

NO synthase (NOS) inhibitors partially block bradykinin (BK)‐mediated vasorelaxation. Here we investigated whether this is due to incomplete NOS inhibition and/or NO release from storage sites. We also studied the mechanism behind ACE inhibitor‐mediated BK potentiation.
Porcine coronary arteries (PCAs) were mounted in organ baths, preconstricted, and exposed to BK or the ACE‐resistant BK analogue Hyp3‐Tyr(Me)8‐BK (HT‐BK) with or without the NOS inhibitor L‐NAME (100 μM), the NO scavenger hydroxocobalamin (200 μM), the Ca2+‐dependent K+‐channel blockers charybdotoxin+apamin (both 100 nM), or the ACE inhibitor quinaprilat (10 μM).
BK and HT‐BK dose‐dependently relaxed preconstricted vessels (pEC50 8.0±0.1 and 8.5±0.2, respectively). pEC50's were &10 fold higher with quinaprilat, and &10 fold lower with L‐NAME or charybdotoxin+apamin. Complete blockade was obtained with hydroxocobalamin or L‐NAME+ charybdotoxin+apamin.
Repeated exposure to 100 nM BK or HT‐BK, to deplete NO storage sites, produced progressively smaller vasorelaxant responses. With L‐NAME, the decrease in response occurred much more rapidly. L‐Arginine (10 mM) reversed the effect of L‐NAME.
Adding quinaprilat to the bath following repeated exposure (with or without L‐NAME), at the time BK and HT‐BK no longer induced relaxation, fully restored vasorelaxation, while quinaprilat alone had no effect. Quinaprilat also relaxed vessels that, due to pretreatment with hydroxocobalamin or L‐NAME+charybdotoxin+apamin, previously had not responded to BK.
In conclusion, L‐NAME‐resistant BK‐induced relaxation in PCAs depends on NO from storage sites, and is mediated via stimulation of guanylyl cyclase and/or Ca2+‐dependent K+‐channels. ACE inhibitors potentiate BK independent of their effect on BK metabolism.

British Journal of Pharmacology (2000) 131, 195–202; doi:10.1038/sj.bjp.0703555
Abnormal activation of K+ channels in aortic smooth muscle of rats with endotoxic shock: electrophysiological and functional evidence
Authors: Chen Shiu‐Jen , Wu Chin‐Chen , Yang San‐Nan , Lin Cheng‐I , Yen Mao‐Hsiung 
Published: January 2005

This study examined the role of K+ channels in vascular hyporeactivity of rats with endotoxic shock ex vivo.
At the end of the in vivo experiments, thoracic aortas were removed from endotoxaemic and control rats. After removal of the endothelium, aortic segments were mounted in myographs for recording of isometric tension and smooth muscle membrane potential.
Membrane potentials recorded from endotoxaemic rats were hyperpolarized compared to those of the controls. This hyperpolarization was partially reversed by tetraethylammonium, charybdotoxin or glibenclamide, but not significantly affected by apamin. The hyperpolarization was also partially attenuated by Nω‐nitro‐L‐arginine methyl ester (L‐NAME) or 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐l‐one (ODQ).
In phenylephrine‐contracted aortic rings, both agonists of K+ channels, NS1619 and pinacidil, induced greater relaxations and re‐polarizations in the preparations obtained from endotoxaemic rats. The NS1619‐induced relaxation and re‐polarization in arteries from endotoxaemic rats were partially inhibited by tetraethylammonium and completely inhibited by charybdotoxin, L‐NAME or ODQ, but not significantly affected by apamin. Similarly, the greater relaxation and re‐polarization induced by pinacidil in arteries from endotoxaemic rats were also inhibited by glibenclamide, L‐NAME or ODQ. However, these inhibitors had no significant effect on relaxations and re‐polarizations induced by NS1619 and pinacidil in arteries from controls.
This study provides the electrophysiological and functional evidence showing an abnormal activation of K+ channels in vascular smooth muscle in animals with endotoxic shock. Our observations suggest that overproduction of nitric oxide causes an activation of large conductance Ca2+‐activated K+ channels and ATP‐sensitive K+ channels which contributes to endotoxin‐mediated vascular hyporeactivity.

British Journal of Pharmacology (2000) 131, 213–222; doi:10.1038/sj.bjp.0703564
Low doses of 8‐OH‐DPAT prevent the impairment of spatial learning caused by intrahippocampal scopolamine through 5‐HT1A receptors in the dorsal raphe
Authors: Carli Mirjana , Balducci Claudia , Samanin Rosario 
Published: January 2005

We studied the effects of low doses of 8‐OH‐DPAT, a 5‐HT1A receptor agonist, on the impairment of spatial learning caused by scopolamine injected into the CA1 region of the dorsal hippocampus of rats performing a two‐platform spatial discrimination task.
Bilateral injections of 4 μg (in 1 μl) of scopolamine into the CA1 region of the dorsal hippocampus 10 min before each training session impaired choice accuracy with no effect on choice latency and errors of omission.
Administered subcutaneously 20 min before each training session, 8‐OH‐DPAT 10 and 30 (but not 3) μg kg−1 did not modify choice accuracy but prevented the impairment by intrahippocampal scopolamine
Injection of 1.0 μg (in 0.5 μl) of WAY 100635, a 5‐HT1A receptor antagonist, into the dorsal raphe 5 min before scopolamine had no effect on choice accuracy and latency or errors of omission and did not modify the effect of scopolamine, but completely antagonized the effect of 10 and 30 μg kg−1 8‐OH‐DPAT on scopolamine‐induced impairment of choice accuracy
The results confirm previous findings that stimulation of presynaptic 5‐HT1A receptors in the dorsal raphe attenuates the deficit of spatial learning caused by blockade of cholinergic excitatory input on hippocampal pyramidal cells.
Drugs that stimulate presynaptic 5‐HT1A receptors such as 5‐HT1A receptor partial agonists may be useful in the symptomatic treatment of human memory disturbances associated with loss of cholinergic innervation to the hippocampus.

British Journal of Pharmacology (2000) 131, 375–381; doi:10.1038/sj.bjp.0703567
Vascular bed heterogeneity in age‐related endothelial dysfunction with respect to NO and eicosanoids
Authors: Matz Rachel L , De Sotomayor Maria Alvarez , Schott Christa , Stoclet Jean‐Claude , Andriantsitohaina Ramaroson 
Published: January 2005

Endothelial dysfunction has been described with ageing but the mechanisms responsible have not been clearly elucidated and might be different from one vessel to the other. This study assesses the relative contribution of endothelial nitric oxide (NO) and cyclo‐oxygenase (COX) metabolites in relaxation to acetylcholine with ageing in the aorta and the small mesenteric artery of the rat.
In the aorta and branch II or III of superior mesenteric artery (SMA), endothelium‐dependent relaxation to acetylcholine was not different between 12–14 (adult) and 32‐week‐old rats whereas it was reduced at 70–100 (old) weeks of age.
Despite an increased endothelial NO‐synthase protein expression, the NO‐synthase inhibitor, NG‐nitro‐L‐arginine‐sensitive component of relaxation decreased with ageing.
In old rats, exposure to the COX inhibitor, indomethacin, but not the selective COX‐2 inhibitor, NS‐398, potentiated response to acetylcholine. The thromboxane A2/prostaglandin H2 receptor antagonist, GR 32191B enhanced relaxation to acetylcholine in aorta but it had no effect in SMA. Furthermore, acetylcholine increased thromboxane B2 production (enzymeimmunoassay) in aorta but not in SMA. Finally, Western blot analysis showed enhanced expression of COX‐1 and 2 in the two arteries with ageing.
These results suggest that the decrease in acetylcholine‐induced relaxation with ageing involves reduced NO‐mediated dilatation and increased generation of vasoconstrictor prostanoids most likely from COX‐1. They also point out vascular bed heterogeneity related to the nature of prostanoids involved between the aorta (i.e., thromboxane A2) and the SMA (unidentified) arteries even though increased expression of COX occurs in both vessels.

British Journal of Pharmacology (2000) 131, 303–311; doi:10.1038/sj.bjp.0703568
Differences in the pharmacological properties of rat and chicken brain fatty acid amidohydrolase
Authors: Fowler Christopher J , Börjesson Magnus , Tiger Gunnar 
Published: January 2005

The pharmacological properties of fatty acid amidohydrolase (FAAH) were investigated in brains of 35‐day‐old chickens, since nothing is known about the enzyme in avian species.
FAAH activity towards both [3H]‐palmitoylethanolamide (PEA) [KM=1.5 μM] and [3H]‐anandamide (AEA) [KM=5.4 μM] was demonstrated in the chicken brains. The chicken FAAH was inhibited by the substrate analogues oleyl trifluoromethylketone (OTMK) and diazomethylarachidonyl ketone (DAK) with similar potencies to the rat FAAH. However, in contrast to the rat brain, phenylmethylsulphonyl fluoride (PMSF) and the enantiomers of ibuprofen had very weak effects on chicken brain FAAH.
Indomethacin and niflumic acid were found to inhibit rat brain AEA hydrolysis. The inhibition by indomethacin was reversible and competitive, with a Ki value of 120 μM. Chicken FAAH was less sensitive to indomethacin than its rodent counterpart, but the inhibition was also competitive (Ki).
It is concluded that chicken FAAH activity has different pharmacological properties to its rodent counterpart.

British Journal of Pharmacology (2000) 131, 498–504; doi:10.1038/sj.bjp.0703569
Mechanisms underlying the chronic pravastatin treatment‐induced improvement in the impaired endothelium‐dependent aortic relaxation seen in streptozotocin‐induced diabetic rats
Authors: Kobayashi Tsuneo , Matsumoto Takayuki , Kamata Katsuo 
Published: January 2005

We investigated the effects of chronic pravastatin treatment on the impaired endothelium‐dependent relaxation seen in aortae from established streptozotocin (STZ)‐induced diabetic rats. Starting at 6 weeks of diabetes, pravastatin (10 mg kg−1) was administered to STZ‐induced diabetic rats for 4 weeks.
The increased total cholesterol and low‐density lipoprotein (LDL) cholesterol levels seen in STZ‐induced diabetic rats were not restored to normal by pravastatin. Aortae from pravastatin‐treated diabetic rats did not show an impaired endothelium‐dependent relaxation to acetylcholine. The expression of the mRNA for endothelial nitric oxide synthase was unaffected by diabetes or pravastatin.
The enhanced level of malondialdehyde (MDA)‐modified LDL seen in STZ‐induced diabetic rats was normalized by pravastatin treatment. The resistance of LDL to oxidation was assessed by measuring the amount of MDA or conjugated dienes generated by incubation with copper ions. LDL isolated from diabetic rats, but not those from pravastatin‐treated diabetics, showed enhanced the susceptibility to oxidation, but incubation in vitro with pravastatin had no effect on LDL oxidation.
Following incubation of control aortae for 6 h with LDL (0.1 mg protein ml−1) isolated from diabetic rats, the endothelium‐dependent relaxation to acetylcholine or A23187 was impaired, but LDL isolated from control or pravastatin‐treated rats had no such effect. This inhibitory effect of diabetic LDL was prevented by superoxide dismutase (SOD), a superoxide scavenger.
These results suggest that pravastatin preserves endothelial function in aortae from STZ‐induced diabetic rats without lowering plasma cholesterol, and its effect may be due to decreased LDL oxidation.

British Journal of Pharmacology (2000) 131, 231–238; doi:10.1038/sj.bjp.0703572
Investigation into the involvement of phospholipases A2 and MAP kinases in modulation of AA release and cell growth in A549 cells
Authors: Choudhury Qamrul G , Mckay Diane T , Flower Roderick J , Croxtall Jamie D 
Published: January 2005

We have investigated the contribution of specific PLA2s to eicosanoid release from A549 cells by using specific inhibitors of secretory PLA2 (ONO‐RS‐82 and oleyloxyethylphosphocholine), cytosolic PLA2 (AACOCF3 and MAFP) and calcium‐independent PLA2 (HELSS, MAFP and PACOCF3). Similarly, by using specific inhibitors of p38 MAPK (SB 203580), ERK1/2 MAPK (Apigenin) and MEK1/2 (PD 98059) we have further evaluated potential pathways of AA release in this cell line.
ONO‐RS‐82 and oleyloxyethylphosphocholine had no significant effect on EGF or IL‐1β stimulated 3H‐AA or PGE2 release or cell proliferation. AACOCF3, HELSS, MAFP and PACOCF3 significantly inhibited both EGF and IL‐1β stimulated 3H‐AA and PGE2 release as well as cell proliferation. Apigenin and PD 98509 significantly inhibited both EGF and IL‐1β stimulated 3H‐AA and PGE2 release and cell proliferation whereas, SB 203580 had no significant effect on EGF or IL‐1β stimulated 3H‐AA release, or cell proliferation but significantly suppressed EGF or IL‐1β stimulated PGE2 release.
These results confirm that the liberation of AA release, generation of PGE2 and cell proliferation is mediated largely through the actions of cPLA2 whereas, sPLA2 plays no significant role. We now also report a hitherto unsuspected contribution of iPLA2 to this process and demonstrate that the stimulating action of EGF and IL‐1β in AA release and cell proliferation is mediated in part via a MEK and ERK‐dependent pathway (but not through p38MAPK). We therefore propose that selective inhibitors of MEK and MAPK pathways may be useful in controlling AA release, eicosanoid production and cell proliferation.

British Journal of Pharmacology (2000) 131, 255–265; doi:10.1038/sj.bjp.0703573
Endotoxin causes up‐regulation of endothelin receptors in cultured hepatic stellate cellsvianitric oxide‐dependent and ‐independent mechanisms
Authors: Gandhi Chandrashekhar R , Uemura Tadahiro , Kuddus Ruhul 
Published: January 2005

Hepatic stellate cells (HSC) and their transformed phenotype found in the chronically injured liver play important roles in hepatic physiology and pathology. HSC produce and react to a potent contractile peptide endothelin‐1 (ET‐1) and also synthesize a vasorelaxant nitric oxide (NO) upon stimulation with endotoxin. However, whether endotoxin affects ET‐1 system of HSC and if this is a mechanism of endotoxin‐induced hepatic injury is not known.We characterized synthesis of ET‐1 and NO and ET‐1 receptors in cultured quiescent and transformed HSC subjected to endotoxin treatment. Endotoxin (1–1000 ng ml−1) stimulated synthesis of ET‐1 and NO and up‐regulated ET‐1 receptors in both cell types.Inhibition of NO synthesis by NG‐monomethyl‐L‐homoarginine strongly inhibited endotoxin‐induced increase in ET‐1 receptors in transformed HSC but produced small additional increase in quiescent HSC. Inhibition of soluble guanylyl cyclase by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one blocked the effect of endotoxin on ET‐1 receptors in both cell types. Moreover, ET‐1 receptors were increased in both cell types during earlier time points (1–4 h) of endotoxin treatment in the absence of the stimulation of NO synthesis.These results demonstrate that endotoxin up‐regulates ET‐1 receptors in HSC by NO‐dependent and ‐independent mechanisms. Such effects of endotoxin can be of importance in acute endotoxemia and during chronic injury of the liver.British Journal of Pharmacology(2000)131, 319–327; doi:10.1038/sj.bjp.0703577
Contractile responses to sumatriptan and ergotamine in the rabbit saphenous vein: effect of selective 5‐HT1F receptor agonists and PGF2α
Authors: Cohen Marlene L , Schenck Kathryn 
Published: January 2005

Contractile responses to ergotamine, sumatriptan and the novel 5‐HT1F receptor agonists, LY334370 and LY344864 were examined using the rabbit saphenous vein.
Ergotamine (pEC50=8.7±0.06) was 30 fold more potent than 5‐hydroxytryptamine (5‐HT) (pEC50=7.2±0.13) and 300 fold more potent than sumatriptan (pEC50=6.0±0.08) in contracting the rabbit saphenous vein in vitro. The selective 5‐HT1F receptor agonists, LY334370 or LY344864 (up to 10−4 M), did not contract the rabbit saphenous vein.
The contractile response to ergotamine in this tissue resulted from activation of both alpha1 and 5‐HT1B/1D receptors based on the observation that prazosin (10−6 M), an α‐adrenoceptor antagonist, and GR127935 (10−8 M) a 5‐HT1B/1D receptor antagonist, dextrally shifted the contractile response to ergotamine. In contrast, prazosin (10−6 M) did not alter contraction to sumatriptan whereas GR127935 (10−8 M) was a potent antagonist (−log KB=10.0) suggesting that sumatriptan‐induced contraction of the rabbit saphenous vein was mediated only by activation of receptors similar or identical to 5‐HT1B/1D receptors.
PGF2α (3×10−7 M) produced a modest increase (approximately 5.0–10.0% maximum PGF2α contraction) in saphenous vein force. Precontraction with PGF2α (3×10−7 M) dramatically augmented the potency and maximal contractile response to sumatriptan (pEC50=7.1) and modestly enhanced the contractile potency of ergotamine (pEC50=9.0) in the rabbit saphenous vein. However, PGF2α (3×10−7 M) only unmasked a contraction to the 5‐HT1F receptor agonists when concentrations exceeded 10−5 M, concentrations considerably higher than their 5‐HT1F receptor affinities.
LY334370 (10−6 M) pretreatment did not alter contraction to either sumatriptan or ergotamine and a higher concentration (10−5 M) of LY334370 or LY344864 inhibited contraction to sumatriptan.
Thus, activation of 5‐HT1F receptors will not induce vascular contraction (either alone or following modest tone with PGF2α) or augment contraction to other contractile agonists in the rabbit saphenous vein.

British Journal of Pharmacology (2000) 131, 562–568; doi:10.1038/sj.bjp.0703587