2005 Fiscal Year Final Research Report Summary
Cardiomyocyte apoptosis related with mitochondrial PTP in ischemia-reperfusion injury and the development of new cardiac drug.
| Project/Area Number |
16590443
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied pharmacology
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| Research Institution | Aichi Medical University |
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Principal Investigator |
HOTTA Yoshihiro Aichi Medical University, School of Medicine, Professor, 医学部, 教授 (40109757)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Naohisa Aichi Medical University, School of Medicine, Professor, 医学部, 教授 (80109321)
YAJIMA Michio Aichi Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (50065596)
MURAKAMI Hidetsugu Aichi Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (80131225)
KAWAI Norio Aichi Medical University, School of Medicine, Associate Professor, 医学部, 助教授 (50095535)
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| Project Period (FY) |
2004 – 2005
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| Keywords | Ischemia-reperfusion injury. / ^<31>P-NMR / Fluorometry. / ESR. / apoptosis / eNOS. / MPTP / NO-releasing drug. |
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| Research Abstract |
1.The protective effects of Na^+-H^+ exchange (NHE) inhibitors SM-198110 (Cl in structure) and SM-197378 (F in structure) had beneficial effects of LVDP (about 100% vs. drug free heart 39%) from ischemia/ reperfusion injury in Langendorff hearts. In perfused fura-2 loaded mitochondria preparation, mitochondrial Ca^<2+> uptake by acidification and Ca^<2+> content changes similar to reperfusion after global ischemia were suppressed with both NHE inhibitors. SM-197378 was found to quench directly the active oxygen radical, though SM-198110 had no effect. Number of apoptotic cells after long ischemia by reperfusion was significantly smaller in SM-197378-treated than SM-198110-treated hearts, consist with the level of activity of caspase-3 (Eur.J.Pharmacol.2004).
2.5HT_<2A>(Mol.Cell.Biochem.2005), 5HT_<1A> (Eur.J.Pharmacol.2006) antagonist or SSRI (Life Sciense, in preparation) was beneficial effect against ischemia/reperfusion injury with ATP contents, quenching the active oxygen radical an
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d inhibition of mitochondrial Ca^<2+> upteke by acidification or Ca^<2+> content of perfusate. These compounds also depressed apoptotic cell and the level of activity of caspase-3 in related with 5HT.
3.Atractyroside (10^<-3> M), which opens mitochondrial permeability transition pore (MPTP) also caused similar increases in mitochondrial Na^+, Ca^<2+> uptake by acidification or Ca^<2+> content change. Cyclosporine A (10^<-4> M), which inhibits MPTP or many drugs (Na-Ca exchange or Na-H inhibitor) that promote good recovery of the LVDP in the Langendorff ischemia/reperfusion injury model were also suppressed, but not FK506 (10^<-4> M), which does not inhibit MPTP (Eur.J.Pharmacol.in preparation). This result may be relate with mitochondrial Na^+ or Ca^<2+> and MPTP against ischemia-reperfusion injury.
4.Nicorandil, a K_<ATP>-channel opener (Ther.Res.2005), a green tea cathechin (Eur.J.Pharmacol.In press, Life Science, in preparation), or cyclic dipeptides (in beer or the distilled residue of millet brandy) like the NO donor, was beneficial effect with inhibit MPTP
5.Ex-vivo ESR spectrometry could measure directly the generation of reactive oxygen species (ROS) in ischemia-reperfusion injury model of guinea-pig Langendorff heart preparation (J.Pharmacol.Sci.2005)
These results suggested that ROS and NO are closely involved to the role of the induction of myocardial cell apoptosis through MPTP in post-ischemic myocardial dysfunction. Less
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[Journal Article] Differences in the effects of Na^+-H^+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.2004
Author(s)
Hotta Y, Nishimaki H, Takeo T, Itoh G, Yajima M, Otsuka-Murakami H, Ishikawa N, Kawai N, Huang L, Yamada K, Yamamoto S, Matsui K, Ohashi N.
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Journal Title
Eur J Pharmacol 503
Pages: 109-122
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A role of anti-verotoxin antibody immunoreactive peptide, Virp5, from rat spinal coad.2004
Author(s)
ISHIKAWA Naohisa, FENG Gua-Gang, ITO Yoshitake, HOTTA Yoshihiro, WAKIDA Yasushi, MURAKAMI Hidetsugu, YAJIMA Michio, ISHIKAWA Atuko, YOKOCHI Takashi.
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Journal Title
Peptide 251
Pages: 909-1916
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Positive inotropic effect of purified green tea catechin derivative in guinea pig hearts : the measurements of cellular Ca^<2+> and NO release.
Author(s)
Yoshihiro Hotta, Lei Huang, Tatsuya Muto, Michio Yajima, Kunihiro Miyazeki, Naohisa Ishikawa, Yoshitaka Fukuzawa, Yasushi Wakida, Hiromi Tushima, Hiroaki Ando, Tunemasa Nonogaki.
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Journal Title
Eur J Phannacol. (In press)
Description
「研究成果報告書概要(欧文)」より
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