Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 110 , Issue 1
Showing 1-15 articles out of 15 articles from the selected issue
Critical Reviews
  • Md. Shenuarin Bhuiyan, Kohji Fukunaga
    2009 Volume 110 Issue 1 Pages 1-13
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: May 08, 2009
    JOURNALS FREE ACCESS
    Treatment with inorganic and organic compounds of vanadium has been shown to exert a wide range of cardioprotective effects in myocardial ischemia/reperfusion-induced injury, myocardial hypertrophy, hypertension, and vascular diseases. Furthermore, administration of vanadium compounds improves cardiac performance and smooth muscle cell contractility and modulates blood pressure in various models of hypertension. Like other vanadium compounds, we documented bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) [VO(OPT)] as a potent cardioprotective agent to elicit cardiac functional recovery in myocardial infarction and pressure overload–induced hypertrophy. Vanadium compounds activate Akt signaling through inhibition of protein tyrosine phosphatases, thereby eliciting cardioprotection in myocardial ischemia/reperfusion-induced injury and myocardial hypertrophy. Vanadium compounds also promote cardiac functional recovery by stimulation of glucose transport in diabetic heart. We here discuss the current understanding of mechanisms underlying vanadium compound–induced cardioprotection and propose a novel therapeutic strategy targeting for Akt signaling to rescue cardiomyocytes from heart failure.
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  • Akihiko Wada
    2009 Volume 110 Issue 1 Pages 14-28
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: May 08, 2009
    JOURNALS FREE ACCESS
    Mood disorders are not merely attributed to the functional defect of neurotransmission, but also are due to the structural impairment of neuroplasticity. Chronic stress decreases neurotrophin levels, precipitating or exacerbating depression; conversely, antidepressants increase expression of various neurotrophins (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor), thereby blocking or reversing structural and functional pathologies via promoting neurogenesis. Since the worldwide approval of lithium therapy in 1970, lithium has been used for its anti-manic, antidepressant, and anti-suicidal effects, yet the therapeutic mechanisms at the cellular level remain not-fully defined. During the last five years, multiple lines of evidence have shown that the mood stabilization and neurogenesis by lithium are due to the lithium-induced inhibition of glycogen synthase kinase-3β (GSK-3β), allowing accumulation of β-catenin and β-catenin–dependent gene transcriptional events. Altered levels of GSK-3β and β-catenin are associated with various neuropsychiatric and neurodegenerative diseases, while various classical neuropsychiatric drugs inhibit GSK-3β and up-regulate β-catenin expression. In addition, evidence has emerged that insulin-like growth factor-I enhances antidepression, anti-anxiety, memory, neurogenesis, and angiogenesis; antidepressants up-regulate expression of insulin-like growth factor-I, while insulin-like growth factor-I up-regulates brain-derived neurotrophic factor expression and its receptor TrkB level, as well as brain-derived neurotrophic factor-induced synaptic protein levels. More importantly, physical exercise and healthy diet raise transport of peripheral circulating insulin-like growth factor I into the brain, reinforcing the expression of neurotrophins (e.g., brain-derived neurotrophic factor) and the strength of cell survival signalings (e.g., phosphoinositide 3-kinase / Akt / GSK-3β pathway). This review will focus on the rapidly advancing new trends in the last five years about lithium, GSK-3β/β-catenin, and neurotrophin cascades.
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Full Papers
  • Karla Veruska Marques Cavalcante, Nádja de Azevedo Correia, Kat ...
    2009 Volume 110 Issue 1 Pages 29-35
    Published: 2009
    Released: May 15, 2009
    JOURNALS FREE ACCESS
    This study was performed to investigate the mechanisms involved in the vasorelaxation induced by mesoionic 2-(4-chlorophenyl)-3-methyl-4-(4-methoxyphenyl)-1;3-thiazolium-5-thyolate (CMMTT), a newly synthesized mesoionic compound, in rat superior mesenteric arteries. In phenylephrine (10 μM)–pre-contracted mesenteric rings, CMMTT (1014 – 106 M) induced a concentration-dependent relaxation [pD2 = 10.26 ± 0.05, Emax = 80.8 ± 5.8%], and this effect was almost abolished after either removal of the vascular endothelium [Emax = 17.7 ± 4.2%, P<0.001], removal of the vascular endothelium plus100 μM Nω-nitro-L-arginine methyl esther (L-NAME) [Emax = 21.0 ± 2.0 %, P<0.001], or after pre-treatment of the rings with 100 μM L-NAME [Emax = 13.3 ± 2.4%, P<0.001] or 10 μM 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) [Emax = 13.6 ± 4.8%, P<0.001]. However, endothelium-dependent relaxation induced by CMMTT was not significantly modified after 1 μM indomethacin plus 1 nM atropine [pD2 = 11.12 ± 0.08, Emax = 73.8 ± 5.15%] or 100 nM charybdotoxin (ChTX) plus 100 nM apamin [pD2 = 10.89 ± 0.08, Emax = 58.91 ± 9.8%]. In mesenteric rings, CMMTT (106 M) was able to increase nitric oxide (NO)x levels, and this effect was abolished after removal of the vascular endothelium. In conclusion, the present study, using combined functional and biochemical approaches, demonstrated that CMMTT induced a significant vasorelaxant effect, almost completely mediated by the endothelium, likely via NO release and activation of the NO–cGMP pathway.
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  • Géraldine Poisnel, Martine Dhilly, Reynald Le Boisselier, Louis ...
    2009 Volume 110 Issue 1 Pages 36-46
    Published: 2009
    Released: May 15, 2009
    JOURNALS FREE ACCESS
    In this study, we compared the effects of five short-, medium-, or long-acting benzodiazepine-receptor agonists (BZDs) [alprazolam (APZ), clonazepam (CLZ), flunitrazepam (FLZ), loprazolam (LPZ), zolpidem (ZLP)], at two distinct doses, 0.2 and 2 mg/kg, on the cell surface regulation of μ-opioid receptor induced by 0.15 mg/kg buprenorphine (BPN) in specific regions of the rat brain. Using 0.312 – 5 nM [3H]-DAMGO concentrations and Scatchard plot analysis, Bmax (maximal receptor density) and Kd (dissociation constant) were determined at different brain regions of interest (amygdala, cortex, hippocampus, hypothalamus, thalamus). Acute BPN induced an expected down-regulation and addition of each of the BZDs to BPN induced less down-regulation than did BPN alone, sometimes while altering affinity. Some significant differences in the intensity of these effects were observed between BZDs. FLZ that is widely abused and enlarges BPN toxicity appeared the most potent to increase μ-cell surface receptor density at the lowest dose of 0.2 mg/kg. Besides, LPZ for which the effect on μ-opioid–receptor regulation appeared lower is considered to have a low risk of dependence in the epidemiological data banks. CLZ and ZLP (2 mg/kg) induced the strongest modification on μ-opioid–receptor density, but a substantial decrease in affinity could minimize the functional consequences. The reported changes were maximal in the amygdala, hippocampus, and thalamus. Among people using BPN and BZDs, the effects described here are likely to influence addictive behaviors and induce toxic effects that could be quantitatively different due to the quality of the BZD.
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  • Satoru Sharyo, Kazuyoshi Kumagai, Naoko Yokota-Ikeda, Katsuaki Ito, Ma ...
    2009 Volume 110 Issue 1 Pages 47-54
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: April 29, 2009
    JOURNALS FREE ACCESS
    It is largely unknown whether hyperlipidemia is involved in the pathobiology of renal ischemia–reperfusion (I/R) injury that is an important cause of acute kidney injury. Here we studied the effect of experimental dyslipidemia on renal I/R injury. Renal I/R injury was less severe in hyperlipidemic mice treated with poloxamer 407 than in the control mice. Cytokine analyses revealed decreased levels of renal and serum IL-6 in the hyperlipidemic mice after renal I/R. Protection from renal I/R injury in the hyperlipidemic mice was diminished by administration of recombinant IL-6. Concanavalin A–induced IL-6 release from cultured splenocytes derived from the hyperlipidemic mice was lower than that from splenocytes of normal mice. In hypercholesterolemic apolipoprotein E–knockout mice, in which renal I/R injury is less severe than in control mice, renal I/R–induced IL-6 production was also less than that in controls. In angiopoietin-like 3–deficient mice, which were hypolipidemic, renal dysfunction and renal IL-6 level after I/R were similar to those of control mice. Our data indicate that the presence of experimental hyperlipidemia may be associated with a decreased risk of renal I/R injury, possibly mediated by reduced renal IL-6 production after the insult and extend the notion that an anti-IL6 agent would be useful for the treatment of acute kidney injury.
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  • Daisuke Kondo, Hironao Saegusa, Ritsuko Yabe, Ichiro Takasaki, Takashi ...
    2009 Volume 110 Issue 1 Pages 55-63
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: April 29, 2009
    JOURNALS FREE ACCESS
    cDNA microarray analysis showed the expression of peripheral-type benzodiazepine receptor (PBR) mRNA is slightly enhanced in the spinal cord of mice with spinal nerve injury (SNL) as compared with sham-operated mice. PBR transports cholesterol to the mitochondria, where cholesterol is converted to pregnenolone. Pregnenolone is then metabolized to progesterone, an activator of progesterone receptor, and further metabolized to produce allopregnanolone and 3α,21-dihydroxy-5α-pregnan-20-one (3α,5α-THDOC), positive allosteric modulators and activators of the GABAA receptor. In the present study, we first tested whether the enhanced PBR expression is causally related to neuropathic pain, and we found that the PBR antagonist PK11195 is effective in reducing SNL-induced mechanical allodynia and thermal hyperalgesia. Next we tested whether the PK11195-induced antinociception is attributable to reduced neurosteroid synthesis, which may possibly lead to reduced activation of the progesterone receptor and/or GABAA receptor. We found that allopregnanolone and 3α,5α-THDOC are effective in reducing the anti-hyperalgesic effect of PK11195, suggesting a partial contribution of reduced GABAA-receptor activation to PK11195-induced antinociception.
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  • Hayato Yabe, Mohammed Emamussalehin Choudhury, Madoka Kubo, Noriko Nis ...
    2009 Volume 110 Issue 1 Pages 64-68
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: April 29, 2009
    JOURNALS FREE ACCESS
    The effect of zonisamide, an antiepileptic agent with anti-parkinsonian effects, was studied on dopamine neurons of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57 mice and common marmosets. Groups of mice (n = 8 – 9) were treated with: MPTP (15 mg/kg every 2 h ×4); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); zonisamide (40 mg/kg ×4); and saline controls. Groups of common marmosets (n = 4 – 6) were treated with: MPTP (2.5 mg/kg every 24 h ×3); MPTP plus zonisamide (40 mg/kg administered 1 h before each MPTP dose); MPTP plus selegiline (2 mg/kg administered 1 h before the first MPTP dose); and saline controls. Brain dopamine and its metabolites were determined by HPLC. Dopamine content decreased in the striatum of MPTP-treated mice and monkeys. Co-administration of selegiline inhibited the effect of MPTP and dopamine contents were similar to those of the controls. Co-administration of zonisamide did not inhibit the effect of MPTP on dopamine content, but increased striatal dopamine turnover of animals treated with MPTP plus zonisamide more than in those treated with MPTP alone. MPTP treatment caused a compensatory increase of dopamine turnover in the striatum by remaining neurons. Zonisamide may help dopaminergic neurons by increasing striatal dopamine turnover following MPTP treatment.
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  • Masayuki Fukui, Yukitoshi Nagahara, Yoshiaki Nishio, Tsutomu Honjoh, T ...
    2009 Volume 110 Issue 1 Pages 69-77
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: April 29, 2009
    JOURNALS FREE ACCESS
    Macrolides are a well-known family of oral antibiotics whose antibacterial spectrum of activity covers most relevant bacterial species responsible for respiratory infectious disease. In recent years, it has been reported that macrolides have not only bactericidal activity but also direct immunomodulating activity in mammals. In this study, we observed new physiological activity of macrolides and examined whether various macrolides induce apoptosis in human leukemia cell lines. We investigated the effects of 13 different macrolides on the viability of Jurkat and HL-60 cells. Among all the macrolides used in this study, rokitamycin, a semisynthetic macrolide with a 16-member ring, effectively induced cell death. Rokitamycin induced DNA fragmentation and caspase activation, resembling the progression of apoptosis. Moreover, rokitamycin reduced the mitochondrial transmembrane potential and released cytochrome c from mitochondria to the cytosol, suggesting that mitochondrial perturbation is involved in rokitamycin-induced apoptosis. These results suggest that rokitamycin possesses not only bactericidal activity but also pro-apoptotic activity in human leukemia cells.
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  • Akitoshi Ohno, Susumu Ohya, Hisao Yamamura, Yuji Imaizumi
    2009 Volume 110 Issue 1 Pages 78-86
    Published: 2009
    Released: May 15, 2009
    JOURNALS FREE ACCESS
    Ca2+ release from intracellular store sites via the ryanodine receptor (RyR) and hormonal regulation by flutamide, an androgen-receptor (AR) antagonist, on it were examined in vas deferens (VD) smooth muscle cells (SMCs). VD and VDSMCs were obtained from two groups of male rats that were treated p.o. with 100 mg/kg flutamide (Flu) or vehicle (Vehicle). Both spontaneous and caffeine-induced Ca2+ releases were markedly smaller in single VDSMCs from Flu than in those from Vehicle. Interestingly, [Ca2+]i rise by 100 μM norepinephrine in VDSMCs from Flu was larger than that in those from Vehicle. The contractions induced by direct electrical stimulation in tissue preparations from Flu showed lower susceptibility to 30 μM ryanodine than those from Vehicle. Real-time PCR analyses revealed that the transcripts of ryanodine receptor (RyR) type 2 and type 3 (RyR2 and RyR3) were expressed in VD and markedly reduced in Flu. The protein expression of total RyR was significantly reduced by flutamide treatment, but that of inositol 1,4,5-trisphosphate receptor (IP3R) was not affected. It can be strongly suggested that long term block of AR by flutamide reduced the expression of RyR and its contribution to the contraction, but not those of IP3R in VDSMCs.
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  • Naoko Miyano-Kurosaki, Kou Ikegami, Kunihiko Kurosaki, Takahiko Endo, ...
    2009 Volume 110 Issue 1 Pages 87-97
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: April 29, 2009
    JOURNALS FREE ACCESS
    Adult T-cell leukemia (ATL) is a malignant tumor of human CD4+ T cells infected with a human retrovirus, T lymphotropic virus type-1 (HTLV-1). The aim of the present study was to investigate the apoptotic effects of phenoxazines, 2-amino-4,4α-dihydro-4α,7-dimethyl-3H-phenoxazine-3-one (Phx-1), 3-amino-1,4α-dihydro-4α,8-dimethyl-2H-phenoxazine-2-one (Phx-2), and 2-aminophenoxazine-3-one (Phx-3) on a T cell leukemia cell line from ATL patients, MT-1 cells; HTLV-1 transformed T-cell lines, HUT-102 cells and MT-2 cells; and an HTLV-1–negative rat sarcoma cell line, XC cells. Among these phenoxazines, Phx-3 at concentrations of less than 10 μg/ml extensively inhibited growth and cell viability; arrested cell cycles at sub G0/G1 phase; and augmented apoptosis of MT-1, HUT-102, and MT-2 cells. However, these phenoxazines did not affect the cell viability of an HTLV-1–negative rat sarcoma cell line, XC cells, and phytohemaggutinin-activated human peripheral blood mononuclear cells, although they markedly inhibited the growth of these cells. The transmission of HTLV-1 from HTLV-1–positive cells (MT-2 cells) to HTLV-1–negative cells (XC cells) was considered to be prevented by Phx-1, Phx-2, or Phx-3 because the syncytium formation between these cells was inhibited markedly in the presence of these phenoxazines. The present results suggest that Phx-1, Phx-2, and, in particular, Phx-3 may be useful as therapeutic agents against ATL, which is extremely refractory to current therapies.
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  • Sandra Vezmar, Branislava Miljkovic, Katarina Vucicevic, Ivana Timotij ...
    2009 Volume 110 Issue 1 Pages 98-104
    Published: 2009
    Released: May 15, 2009
    JOURNALS FREE ACCESS
    Although often necessary for obtaining remission following major depressive disorder, combined antidepressant treatment is frequently associated with drug interactions and enhanced adverse drug effects. We investigated pharmacokinetic interactions following combined fluvoxamine and amitriptyline treatment and their impact on therapeutic efficacy and tolerability. Twenty-two inpatients with major depression [Hamilton Depression Scale (HAM-D) rating ≥18] were treated with either amitriptyline (75 mg/day), fluvoxamine (100 mg/day) or both. Blood samples, for determination of amitriptyline, its major metabolite nortritpyline, and fluvoxamine, were obtained after single dose administration and in steady-state. Therapeutic efficacy was evaluated using HAM-D and adverse drug effects were evaluated using the clinical global impression scale. Following combined treatment, steady-state plasma levels of nortriptyline were significantly decreased compared to monotherapy. HAM-D scores after two-week treatment showed that there was a better response to combined treatment. There was no significant difference in severity of adverse effects among groups. We observed a pharmacokinetic interaction between fluvoxamine and amitritpyline resulting in impaired metabolism of the later. However, no signifcant impact of the interaction on treatment safety was observed. Moreover, concomitant use of amitriptyline at 75 mg/day and fluvoxamine at 100 mg/day was well tolerated with a more prompt and stronger onset of clinical response compared to monotherapy in patients with major depression.
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  • Byung-Yoon Cha, Wen Lei Shi, Takayuki Yonezawa, Toshiaki Teruya, Kazuo ...
    2009 Volume 110 Issue 1 Pages 105-110
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: May 08, 2009
    JOURNALS FREE ACCESS
    Platelet-derived growth factor (PDGF)-BB is one of the most potent factors in the development and progression of various vascular disorders such as restenosis and atherosclerosis. Chrysoeriol is a flavonoid with antioxidant and anti-inflammatory activities. In this study, we investigated the effect of chrysoeriol on the proliferation of human aortic smooth muscle cells (HASMC). Chrysoeriol significantly inhibited PDGF (20 ng/mL)-induced migration and [3H]-thymidine incorporation into DNA at concentrations of 5 and 10 μM without any cytotoxicity. Chrysoeriol also blocked PDGF-stimulated dissociation of actin filament and inhibited PDGF beta-receptor (Rβ) phosphorylation in a concentration-dependent manner. As a result, the downstream signal transduction pathways of PDGF-Rβ, including ERK1/2, p38, and Akt phosphorylation, were also inhibited by chrysoeriol in the same pattern. These findings suggest that in addition to its antioxidant and anti-inflammatory activities, chrysoeriol may be used for the prevention and treatment of vascular diseases and during restenosis after coronary angioplasty.
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Short Communications
  • Iyuki Namekata, Yayoi Tsuneoka, Akira Takahara, Hideaki Shimada, Takah ...
    2009 Volume 110 Issue 1 Pages 111-116
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: May 08, 2009
    JOURNALS FREE ACCESS
    We examined the involvement of the Na+/Ca2+ exchanger in the automaticity of the pulmonary vein myocardium with a specific inhibitor, SEA0400. Action potentials were recorded from the myocardial layer of isolated guinea-pig pulmonary vein preparations, and Ca2+ transients were recorded from the cardiomyocytes. Spontaneous electrical activity was observed in 17.7% of the preparations, which was inhibited by either SEA0400 or ryanodine. In quiescent preparations, ouabain induced electrical activity and spontaneous Ca2+ transients, which were inhibited by SEA0400, as well as ryanodine. These results provide pharmacological evidence that the Na+/Ca2+ exchanger underlies the automaticity of the pulmonary vein myocardium.
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  • Mika Mizunuma, Naoya Takahashi, Atsushi Usami, Norio Matsuki, Yuji Ike ...
    2009 Volume 110 Issue 1 Pages 117-121
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: May 09, 2009
    JOURNALS FREE ACCESS
    We describe the effect of high pressure and high temperature on neuronal activity. Increased intracranial pressure is generally a pathological sign observed in intracerebral hemorrhage, brain edema, and brain tumor, yet little is known about how the hyperbaric pressure per se affects neuronal activity. Using a pressure/temperature-changeable perfusion chamber, we carried out functional multineuron calcium imaging to record spontaneous spiking activity simultaneously from about 100 neurons in hippocampal slice cultures. High-pressure conditions (up to 100 mmHg) did not alter the network excitability, whereas high-temperature conditions (up to 40°C) increased synchronized network activity. Thus, neurons are sensitive to feverish conditions, but the acute hyperbaric circumstance itself is unlikely to exert a detrimental effect on neuronal function.
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  • Shu-ichi Kojima, Masashi Ikeda, Yuichiro Kamikawa
    2009 Volume 110 Issue 1 Pages 122-126
    Published: 2009
    Released: May 15, 2009
    [Advance publication] Released: May 08, 2009
    JOURNALS FREE ACCESS
    The effects of the monoamine oxidase A (MAO-A) inhibitor clorgyline, the L-type calcium-channel blocker nicardipine, the syntaxin inhibitor botulinum toxin type C, and the potent thiol-oxidant phenylarsine oxide (PAO) on the selective tachykinin NK2–receptor agonist [β-Ala8]-neurokinin A4-10 [βAla-NKA-(4-10)]–evoked 5-hydroxytryptamine (5-HT) outflow from colonic enterochromaffin (EC) cells was investigated in vitro using isolated guinea-pig proximal colon. The βAla-NKA-(4-10)–evoked outflow of 5-HT from clorgyline-treated colonic strips was markedly higher than that from clorgyline-untreated colonic strips. The βAla-NKA-(4-10)–evoked 5-HT outflow from the clorgyline-treated colonic strips was sensitive to nicardipine or botulinum toxin type C. Moreover, PAO concentration-dependently suppressed the βAla-NKA-(4-10)–evoked 5-HT outflow from the clorgyline-treated colonic strips. The suppressant action of PAO was reversed by the reducing agent dithiothrietol, but was not blocked by the protein tyrosine kinase inhibitor genistein. These results suggest that the tachykinin NK2 receptor–triggered 5-HT release from guinea-pig colonic EC cells is mediated by syntaxin-related exocytosis mechanisms and that colonic mucosa MAO-A activity has the important function of modulating the tachykinin NK2 receptor–triggered 5-HT release. It also appears that PAO-mediated sulfhydryl oxidation plays a role in modulating the tachykinin NK2 receptor–triggered 5-HT release through a mechanism independent of inhibition of protein tyrosine phosphatase activity.
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