Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 102 , Issue 4
Showing 1-8 articles out of 8 articles from the selected issue
Full Papers
  • Guray Soydan, Ender Tekes, Meral Tuncer
    2006 Volume 102 Issue 4 Pages 359-367
    Published: 2006
    Released: December 15, 2006
    [Advance publication] Released: November 28, 2006
    JOURNALS FREE ACCESS
    The aims of this study were to investigate the role of endothelin-1 in FK506-induced hypertension and vascular dysfunction of rats treated with the drug for 8 (short-term) or 30 (long-term) days and to measure malondialdehyde levels in the kidneys. Kidney and mesentery of rats were perfused. In the short-term treated groups, there was no significant change in systolic blood pressure. The response to noradrenaline only in renal vascular beds was significantly increased by FK506 and this increase was prevented by Bosentan. FK506 had no significant effect on sodium nitroprusside-induced vasodilation in comparison with solvent in both vascular beds. Bosentan failed to prevent these responses. In the long-term treated groups, at the end of the treatment with FK506, there was a significant increase in blood pressure, but no change in the response to noradrenaline in either kidneys or mesentery. The increase in blood pressure was prevented by bosentan treatment. FK506 increased malondialdehyde levels in the kidneys of the rats from only the long-term treated groups. Bosentan did not change this increase. Our results indicated that endothelin-1 plays a key role in the FK506-induced change in vascular reactivity to noradrenaline in renal vascular beds and drug-induced hypertension in the rats. There was no relationship between oxidative stress and FK506-induced hypertension.
    Download PDF (497K)
  • Daisaku Kobayashi, Satoko Ohkubo, Norimichi Nakahata
    2006 Volume 102 Issue 4 Pages 368-376
    Published: 2006
    Released: December 15, 2006
    [Advance publication] Released: November 28, 2006
    JOURNALS FREE ACCESS
    UTP causes interleukin (IL)-6 production via mRNA expression through P2Y2/P2Y4 receptors in human HaCaT keratinocytes. In the present study, we analyzed the mechanism of UTP-induced IL-6 production in these cells. UTP, an agonist of P2Y2/P2Y4 receptors, induced phosphorylation of extracellular signal-regulated kinase (ERK) in a concentration- and time-dependent manner. PD98059, a MEK (mitogen-activated protein kinase kinase) inhibitor, and BAPTA-AM [O,O'-bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester], an intracellular Ca2+ chelator, reduced UTP-induced ERK phosphorylation and IL-6 mRNA expression. 2-APB [(2-aminoethoxy)diphenylborane], an inositol 1,4,5-trisphosphate (IP3)-receptor antagonist, inhibited UTP-induced IL-6 mRNA expression; and the action of A23187, a Ca2+ ionophore, resembled the action of UTP. In contrast, protein kinase C (PKC) downregulation and pertussis toxin did not affect UTP-induced IL-6 mRNA expression, suggesting that PKC and Gi are not involved in the UTP-induced IL-6 production. However, AG1478, an epidermal growth factor (EGF)-receptor inhibitor, partially decreased UTP-induced ERK phosphorylation and IL-6 expression. These results suggest that UTP-induced IL-6 production is in part mediated via phosphorylation of ERK through Gq/11/IP3/[Ca2+]i and transactivation of the EGF receptor.
    Download PDF (585K)
  • Akiyoshi Saitoh, Noritaka Hirose, Mitsuhiko Yamada, Misa Yamada, Chihi ...
    2006 Volume 102 Issue 4 Pages 377-386
    Published: 2006
    Released: December 15, 2006
    [Advance publication] Released: November 28, 2006
    JOURNALS FREE ACCESS
    The most consistent behavioral change caused by olfactory bulbectomy (OBX) is a hyperemotional response to novel environmental stimuli. The aim of this study was to characterize the emotional behavior of OBX mice using the hole-board test. After the olfactory bulbs were lesioned, sham and OBX mice were housed in single cages for 14 days. The number of head-dips in the hole-board test in single-housed OBX mice was significantly greater than that in single-housed sham mice. The head-dipping behaviors in single-housed sham and OBX mice were reversed by treatment with diazepam, a typical benzodiazepine anxiolytic. (±)-8-Hydroxy-2-(di-n-propylamino) tetraline hydrobromide (8-OH-DPAT), a selective 5-HT1A-receptor agonist that has a non-benzodiazepine anxiolytic-like effect, and (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethyl benzamide (SNC80), a δ-opioid-receptor agonist, also significantly reversed the number of head-dips in single-housed sham and OBX mice. In conclusion, we suggest that the single-housed OBX mice showed heightened emotional behavior (e.g., increase in head-dipping behavior) in the hole-board test. In addition, we suggest that the hyperemotional behavior characterized by head-dipping behavior in OBX mice was selectively reversed by benzodiazepine and non-benzodiazepine anxiolytics.
    Download PDF (289K)
  • Bei Zhou, Li-Jun Wu, Lin-Hao Li, Shin-ichi Tashiro, Satoshi Onodera, F ...
    2006 Volume 102 Issue 4 Pages 387-395
    Published: 2006
    Released: December 15, 2006
    JOURNALS FREE ACCESS
    Terminally differentiated adult injured cardiac myocytes have been used for various animal models of heart failure. It has recently been shown that isoproterenol induces injury in rat neonatal cardiac myocytes via a β-adrenergic pathway, suggesting that it might be one of the factors involved in myocardial cell injury in heart failure in vivo. In the study, silibinin, a plant flavanoid from milk thistle was first evaluated for its protective effect against β-adrenergic agonist isoproterenol-induced injury in cultured rat neonatal cardiac myocytes. The viability, activation of lactate dehydrogenase (LDH), and content of maleic dialdehyde (MDA) were chosen for measuring the degree of cardiac myocytes injury. As a result, silibinin protected isoproterenol-treated rat cardiac myocytes from death and significantly decreased LDH release and MDA production. Silibinin increased superoxide dismutase activity, decreased [Ca2+]i, and increased mitochondrial membrane potential (ΔΨ). Furthermore, the release of pro-apoptotic cytochrome c from mitochondria was reduced by silibinin. Silibinin increased the expression of anti-apoptotic Bcl-2 family protein Bcl-2, and up-regulation of SIRT1 inhibited the translocation of Bax from cytoplasm to mitochondria, which caused mitochondrial dysfunction and cell injury. These results demonstrate that silibinin protects against isoproterenol-induced cardiac myocytes injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.
    Download PDF (796K)
  • Akira Takahara, Atsushi Sugiyama, Yoshioki Satoh, Keitaro Hashimoto
    2006 Volume 102 Issue 4 Pages 396-404
    Published: 2006
    Released: December 15, 2006
    [Advance publication] Released: November 28, 2006
    JOURNALS FREE ACCESS
    The utility of corrected and uncorrected QT interval changes for assessing net repolarization delay by IKr (a rapid component of delayed rectifier K+ currents) blockers was assessed in halothane-anesthetized dogs using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of dl-sotalol (0.2 – 2 mg/kg) prolonged the MAP duration and RR interval, while terfenadine (3 mg/kg) increased the MAP duration but transiently shortened RR interval. The order of correlation coefficient between the MAP duration at a pacing cycle length of 400 ms and MAP duration itself or that with arithmetical correction was uncorrected > Van de Water = Matsunaga > Fridericia > Bazett. These results suggest that Matsunaga’s and Van de Water’s formulae would better predict the net repolarization delay in the in vivo canine model. Also, the risk of drug candidates that may prolong the QT interval should be judged by change in uncorrected QT interval as well as corrected QT interval.
    Download PDF (516K)
  • Mirjam Kuipers, Ronald Smulders, Walter Krauwinkel, Timothy Hoon
    2006 Volume 102 Issue 4 Pages 405-412
    Published: 2006
    Released: December 15, 2006
    JOURNALS FREE ACCESS
    Determining the pharmacokinetics and safety of solifenacin succinate, a once-daily, oral antimuscarinic agent indicated for treatment of overactive bladder, in subjects with hepatic impairment. In this open-label study, 16 subjects (eight with moderate hepatic impairment [defined as a Child-Pugh score of 7 – 9], eight healthy) received a single oral 10 mg solifenacin dose. Blood and urine were collected for pharmacokinetic assessments. Pharmacokinetic parameters (primary: area under the plasma concentration-time curve from time 0 to infinity [AUC0–∞] and maximum plasma concentration [Cmax]) and safety were evaluated for solifenacin and its metabolites. There were no clinically relevant differences in safety. Moderate hepatic impairment increased AUC0–∞ by 60%, and the mean elimination half-life of solifenacin and several of its metabolites was longer versus healthy subjects. Mean Cmax values were comparable between the groups. A single oral dose of solifenacin was well tolerated in hepatically impaired and healthy subjects; however, moderate hepatic impairment influenced solifenacin pharmacokinetics. In patients with mild hepatic impairment, solifenacin may be used without special caution; however, in patients with moderate hepatic impairment, doses greater than 5 mg are not recommended and the 5 mg dose should be used with caution.
    Download PDF (323K)
Short Communications
  • Zorica Nesic, Zoran Todorovic, Radan Stojanovic, Gordana Basta-Jovanov ...
    2006 Volume 102 Issue 4 Pages 413-417
    Published: 2006
    Released: December 15, 2006
    [Advance publication] Released: November 28, 2006
    JOURNALS FREE ACCESS
    The effect of acute pretreatment with a single dose of simvastatin (1 mg/kg, i.v.; 30 min before ischemia) on renal dysfunction caused by ischemia-reperfusion (I/R) injury in the rat was investigated. I/R injury was induced by clamping both renal vascular pedicles for 45 min, followed by 4 h of reperfusion with saline (2 ml/kg per hour). Simvastatin significantly improved both parameters of glomerular and tubular dysfunction (e.g., creatinine levels and fractional excretion of Na+, respectively) and especially improved the histological score, compared to control I/R-injured rats treated with saline or 10% DMSO only.
    Download PDF (937K)
  • Yukio Ago, Maiko Sato, Shigeo Nakamura, Akemichi Baba, Toshio Matsuda
    2006 Volume 102 Issue 4 Pages 419-422
    Published: 2006
    Released: December 15, 2006
    [Advance publication] Released: November 28, 2006
    JOURNALS FREE ACCESS
    We have shown that coadministration of sulpiride and fluvoxamine preferentially increases the release of dopamine in the prefrontal cortex. To study the possible role of the cortical cholinergic system in this effect, we combined several other antipsychotic drugs with fluvoxamine and examined the effects on acetylcholine release in rat prefrontal cortex. Risperidone and clozapine significantly increased the release of acetylcholine but sulpiride did not, and fluvoxamine did not enhance the effects of the antipsychotics. These results further support the previous suggestion that the cortical dopamine system plays an important role in the effects of antipsychotic drugs administered in combination with fluvoxamine.
    Download PDF (268K)
feedback
Top