2001 Fiscal Year Final Research Report Summary
Development of Novel Therapeutic Agents for Treatment of Congestive Heart Failure by Means of Model Animals
| Project/Area Number |
11557203
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | Yamagata University |
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Principal Investigator |
ENDOH Masao Pharmacology, Yamagata University, Professor, 医学部, 教授 (40004668)
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| Co-Investigator(Kenkyū-buntansha) |
YOMOGIDA Shinichi Pharmacology, Yamagata University, Instructor, 医学部, 助手 (90250802)
TOMOIKE Hitonobu Internal Medicine, Yamagata University, Professor, 病院長 (90112333)
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| Project Period (FY) |
1999 – 2001
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| Keywords | Ca^<2+> sensitizers / Pimobendan / Levosimendan / OR-1896 / UD-CG 212 Cl / Upstream mechanism / Central mechanis / Downstream mechanism |
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| Research Abstract |
Regulation of myocardial contractility by cardiotonic agents is achieved by an increase in intracellular Ca^<2+> mobilization (upstream mechanism), an increase in Ca^<2+> binding affinity to troponin C (TnC; central mechanism) and facilitation of the process subsequent to the Ca^<2+> binding to TnC (downstream mechanism). cAMP mediates the regulation induced by Ca^<2+> mobilizers such as _-adrenoceptor agonists and selective PDE III inhibitors acting through the upstream mechanism. These agents act likewise on the central mechanism to decrease Ca^<2+> sensitivity of TnC in association with the cAMP-mediated phosphorylation of Tnl. In addition to such a well-known action of cAMP, we revealed that Ca^<2+> sensitizers, such as levosimendan, OR-1896 and UD-CG 212 Cl, require cAMP-mediated signaling to induce the Ca^<2+> sensitizing effect. These agents shift the [Ca^<2+>]_i-force relationship to the left, but their positive inotropic effect (PIE) is inhibited by carbachol. These findings imply that cAMP may have a dual action on the Ca^<2+> sensitivity depending on the concentration, i.e., at higher concentrations it decreases the Ca^<2+> sensitivity, but at lower concentrations it may increase the Ca^<2+> sensitivity by cross talk with the action of individual cardiotonic agents on contractile proteins. No currently available agents act primarily via Ca^<2+> sensitization, but the PIE of pimobendan and levosimendan is partly mediated by an increase in Ca^<2+> sensitivity. Pieces of evidence are accumulating that cardiotonic agents with Ca^<2+> sensitizing effects are clinically more effective than the agents that act purely via the upstream mechanism. Further clinical trials are required to establish the effectiveness of Ca^<2+> sensitizers in long-term therapy of congestive heart failure patients.
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