1995 Fiscal Year Final Research Report Summary
Basic and applied studies on cardiotonic
| Project/Area Number |
05557103
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | TOHOKU UNIVERSITY |
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Principal Investigator |
OHIZUMI Yasushi Tohoku University, Department of Pharmaceutical Sciences, Professer, 薬学部, 教授 (00006355)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIKAWA Kiyofumi Banyu Pharmaceutical Co., Ltd., Laboratory of Pharmacology, Vice chief, 創薬研究所, 次長
IKEMOTO Fumihiko Banyu Pharmaceutical Co., Ltd., Laboratory of Pharmacology, Sub chief, 創薬研究所, 副所長
MATSUNAGE Kimihiro Tohoku University, Department of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (90222306)
FURUKAWA Ken-ichi Tohoku University, Department of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (20165468)
NAKAHATA Norimichi Tohoku University, Department of Pharmaceutical Sciences, Assistant professer, 薬学部, 助教授 (60045804)
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| Project Period (FY) |
1993 – 1995
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| Keywords | Gingerol / Xestquinone / Myosin / Ca / Ca pump / Evodiamine |
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| Research Abstract |
During recent years there have been numerous effeors to find and develop novel cardiotonic agensts that are more effeorive and more selective than the cardiac glycosides or catecholamines. [8]-Gingerol produced a concentration-dependent positive inotropic effect on guinea pig isolated left atria. The inotropic effect of gingerol was abolished by ryanodine. Furthermore, our pharmacological studies suggest that the enhancement of the Ca^<2+>-pumping activity of sarcoplasmic reticulum (SR) plays an important role in the cardiotonic action of gingerol. We synthesized gingerol related compounds (AP-004, AP-005 and AP-015) and investigated the effects of these compounds on the Ca^<2+>-ATPase activity of SR.The Ca^<2+>-ATPase activity and the Ca^<2+>-pumping activity increased by these compounds in a concentration-dependent manner. It is probable that both o-methoxy phenol and hydeocarbon chain in the molecule of gingerol analogues are a request for activation of the Ca^<2+>-pumping ATPase.
In
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the course of our survey of cardiotonic substances from natural sources having unique mechanism of action, xestoquinone (XQN) was isolated and purified as a powerfully cardiotonic principle of an Okinawa sea sponge Xestospongia sapra. Our pharmacological data suggest that an enhancement of intracellular cyclic AMP content and Ca^<2+> influx across the cell membrane contribute to the late phase of XQN-caused cardiotonic responses, wheres the early phase may largely be elicited through direct activation of contractile elements. XQN may provide an novel leading compound for valuable cardiotonic agents. Unlike N-ethylmaleimide, modification of 2 mol of SH groups per myosin by xestoxinone caused a marked increase in the actomyosin ATPase activity. XQN modifies the specific SH groups in myosin distinct from SH_1 and SH_2, resulting in activation of actocyosin ATPase.
The crude acetone extract of the fruits of Evodia retaecarpa Bentham (Rutaceae) exhibited a positive inotropic effect with a novel mechanism on the guinea pig isolated left atria. Less
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