Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.
Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.
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ONO-1101（一种新型 β 拮抗剂）对心肌动作电位和膜电流的影响。
DOI：
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
Minoru Watanabe
中科院分区：
文献类型：
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作者：
K. Muraki;H. Nakagawa;N. Nagano;S. Henmi;H. Kawasumi;T. Nakanishi;K. Imaizumi;T. Tokuno;K. Atsuki;Yuji Imaizumi;Minoru Watanabe
在心肌中检查了ONO-1101 <$（-）-[（S）-2，2-二甲基-1，3-二氧戊环-4-基]甲基-3-[4-[（S）-2-羟基-3-（2-吗啉代羰基氨基）乙氨基]丙氧基]苯基丙酸酯单盐酸盐（一种新型β-拮抗剂）对动作电位参数和膜电流的直接作用及其β肾上腺素受体拮抗作用。利血平化动物乳头肌的动作电位参数和从豚鼠和兔心脏获得的单个肌细胞记录的膜电流不受1至100 μ M ONO-1101的影响。另一方面，ONO-1101显著抑制豚鼠单个心肌细胞中异丙肾上腺素对Ca电流的增强作用。异丙肾上腺素使钙电流的浓度-反应关系右移。这种作用与艾司洛尔相似，艾司洛尔也是一种β肾上腺素受体拮抗剂。Schild图分析显示了每种拮抗剂的斜率和pA2值（ONO-1101，分别为0.94、8.0;艾司洛尔，分别为0.98、7.3），并证明ONO-1101作为β-拮抗剂的效力约为艾司洛尔的5倍。异丙肾上腺素的另外两种作用：1）延迟整流钾电流的增强作用和2）氯电流的激活作用也被ONO-1101抑制。在去极化乳头肌中，洗脱后ONO-1101和艾司洛尔的β-拮抗作用消除50%所需的时间估计分别为4和6 min。这些结果表明，ONO-1101是一种有效的β-拮抗剂，其作用通过洗脱迅速消除。当以被认为是临床剂量的剂量施用时，ONO-1101对心肌中的动作电位参数和膜电流没有直接影响。ONO-1101的这些特性表明，这种药物在临床应用中可能是有效的。
Direct effects of ONO-1101 ¿(-)-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-3-[4-[(S) -2-hydroxy-3-(2-morpholino carbonylamino)ethylamino] propoxy]phenylpropionate monohydrochloride), a novel beta-antagonist, on action potential parameters and membrane currents, and its beta adrenoceptor antagonism were examined in cardiac muscle. Action potential-parameters in papillary muscle of reserpinized animals and membrane currents recorded from single myocytes obtained from guinea pig and rabbit hearts were not affected by 1 to 100 microM ONO-1101. On the other hand, ONO-1101 markedly inhibited the potentiation of Ca current by isoproterenol in single cardiac myocytes of the guinea pig. The concentration-response relationship of Ca current for isoproterenol was shifted to the right. This effect resembled that of esmolol, which is also a beta adrenoceptor antagonist. A Schild plot analysis revealed the slope and pA2 value of each antagonist (ONO-1101, 0.94, 8.0; and esmolol, 0.98, 7.3, respectively) and demonstrated that ONO-1101 is about 5 times more potent than esmolol as a beta-antagonist. Two other effects of isoproterenol: 1) potentiation of delayed rectifier K current and 2) activation of chloride current, were also inhibited by ONO-1101. The time required for 50% removal of beta-antagonism of ONO-1101 and esmolol after the washout was estimated as 4 and 6 min, respectively, in depolarized papillary muscle. These results suggest that ONO-1101 is a potent beta-antagonist whose effects were removed quickly by washout. When applied at what is thought to be a clinical dosage, ONO-1101 had no direct effects on action potential-parameters and membrane currents in cardiac muscle. These characteristics of ONO-1101 suggest that this agent may be effective in clinical use.