Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 1st communication: studies on isolated guinea pig cardiac muscles.
Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 1st communication: studies on isolated guinea pig cardiac muscles.
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新型强心剂1,2-二氢-6-甲基-2-氧代-5-(咪唑并[1,2-a]吡啶-6-基)-3-吡啶甲腈盐酸盐一水合物的心血管作用。
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发表时间：
1989
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通讯作者：
T. Shoji
中科院分区：
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作者：
T. Ogawa;H. Ohhara;H. Tsunoda;J. Kuroki;T. Shoji
本文研究了新型强心药1，2-二氢-6-甲基-2-氧代-5-（咪唑并[1，2-a]吡啶-6-基）-3-吡啶腈盐酸盐一水合物（E-1020）的体外强心作用及其作用机制。E-1020（10（-7）-10（-4）mol/l）对乳头肌产生浓度依赖性正性肌力作用。E-1020还引起右心房收缩力增加，伴随自发搏动率小幅增加。E-1020对乳头肌的正性肌力作用不受β-肾上腺素受体或组胺H2受体阻滞剂治疗的影响，但被毒蕈碱激动剂卡巴胆碱减弱。E-1020与异丙肾上腺素（isoproterenol，Iso）一样，恢复了在高钾溶液中停止的乳头肌收缩。用最小有效正性肌力浓度（3 × 10 - 7 mol/l）的E-1020预处理可增强乳头肌对Iso的正性肌力反应。E-1020对犬肾Na+，K+-ATP酶活性无明显影响。另一方面，该化合物特异性抑制磷酸二酯酶的环AMP特异性同工酶（组分III），并引起豚鼠心脏中环AMP含量升高。这些结果表明，E-1020是一种强效强心剂，具有轻微的变时作用，其变力作用主要是通过抑制环AMP特异性磷酸二酯酶引起的心脏环AMP含量升高介导的。
Cardiotonic effects and the mechanism of action of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new cardiotonic agent, were investigated in vitro. E-1020 (10(-7)-10(-4) mol/l) produced a concentration-dependent positive inotropic effect in papillary muscles. E-1020 also caused an increase in contractile force in the right atria which was accompanied by small increases in spontaneous beating rate. The inotropic effect of E-1020 on papillary muscles was not altered by treatment with beta-adrenoceptor or histamine H2-receptor blockade, but was attenuated by the muscarinic agonist, carbachol. E-1020, like isoprenaline (isoproterenol, Iso), restored the contraction of papillary muscles which had been arrested in a high-potassium solution. The inotropic response of papillary muscles to Iso was potentiated by pretreatment with E-1020 at a minimally-effective inotropic concentration (3 x 10(-7) mol/l). E-1020 did not affect the activity of dog kidney Na+, K+-ATPase. On the other hand, the compound specifically inhibited the cyclic AMP-specific isoenzyme (fraction III) of phosphodiesterase and caused an elevation of cyclic AMP content in guinea pig hearts. These results indicate that E-1020 is a potent cardiotonic agent with a minor chronotropic effect and that its inotropic action is mainly mediated by the rise in cardiac cyclic AMP content due to the inhibition of cyclic AMP-specific phosphodiesterase.