|Budget Amount *help
¥11,600,000 (Direct Cost : ¥11,600,000)
Fiscal Year 1994 : ¥2,100,000 (Direct Cost : ¥2,100,000)
Fiscal Year 1993 : ¥2,800,000 (Direct Cost : ¥2,800,000)
Fiscal Year 1992 : ¥6,700,000 (Direct Cost : ¥6,700,000)
The purpose of the study was to elucidate the mechanism of action of novel cardiotonic agents to provide basic information about useful for clinical application of these agents. Among new compounds investigated, Org 30029 [N-hydroxy-5,6-dimethoxybenzo [b] thiophene-2-carboximide hydrochloride] was the agent with most efficacious positive inotropic effect (PIE), which was mainly due to an increase in Ca^<2+> sensitivity of myofibrils. Because agents belonging to this class (Ca^<2+> sensitizer) neither require activation energy nor cause Ca^<2+> overload, they may provide beneficial clinical procedures to cure the patients with heart failure. Org 3731 with a slight modification of chemical structure of Org 30029 had much less Ca^<2+> sensitizing action and acted mainly by PDE inhibition, indicating that the site of these actions may possess a closely related characteristic. Another result obtained are concerned with the mechanism of action of PDE III inhibitors in intact cardiac muscle.
These are summarized as follows : 1) PDE isozymes involved in cAMP hydrolysis in mammalian cardiac muscle show a wide range of species dependent variation ; 2) PDE inhibitors have a dual action, i.e., a direct PIE and the action to potentiate the PIE of adrenoceptor activation. The former action requires much higher concentration than the latter, which has a crucial meaning in clinical application of these agents ; 3) some novel compounds such as vesnarinone and pimobendan possess ancillary actions in addition to PDE inhibition. Since both agents have beneficial effects on the prognosis (survival rate) of the patients with severe heart failure, it is important to differentiate which mechanisms contribute most significantly to the clinical usefulness ; 4) while cAMP decreases the Ca^<2+> sensitivity of myofibrils in association with phosphorylation of troponin I,PDE III inhibitors did not produce such an action in contrast to beta- agonists, implying the intracellular compartmentation of cAMP in myocardial cells. Pathophysiological relevance of this difference under clinical setting is unknown for the time being and requires further study. Several novel agents have been developed, but there are no agents so far to replace digitalis in the treatment of heart failure. Further intensive effort will be required including evaluation of the clinical usefulness of these agents by careful investigation and synthesis of new agents with novel mechanism.
(4)cAMPは トロポニンIのリン酸化にともなわれてトロポニンCのCa感受性を減少させる。本研究においてβ受容体刺激は[Ca]o上昇に比してCa感受性減少作用を示したが,PDEIII阻害薬は前者と異なりCa感受性減少作用を惹起せずその薬理学的なプロフィールが異なっており細胞内cAMPコンパートメントの存在を示唆している。新しい強心薬の臨床応用への道のりはまだまだ長く基礎的研究成果に基づくこれらの薬物の的確な臨床的評価と同時にさらなる新しい化合物の合成・開発への努力の積み重ねが必要である。 Less