Muraki K, Nakagawa H, Nagano N, Henmi S, Kawasumi H, Nakanishi T, Imaizumi K, Tokuno T, Atsuki K, Imaizumi Y, Watanabe M
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
J Pharmacol Exp Ther. 1996 Aug;278(2):555-63.
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.
新型β受体拮抗剂盐酸奥诺-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-吗啉羰基氨基)乙氨基]丙氧基]苯丙酸酯）对心肌动作电位参数和膜电流的直接作用及其β肾上腺素能受体拮抗作用进行了研究。利血平化动物乳头肌的动作电位参数以及从豚鼠和兔心脏获得的单个心肌细胞记录的膜电流不受1至100微摩尔奥诺-1101的影响。另一方面，奥诺-1101显著抑制异丙肾上腺素对豚鼠单个心肌细胞钙电流的增强作用。异丙肾上腺素钙电流的浓度-反应关系向右移动。这种作用类似于艾司洛尔，艾司洛尔也是一种β肾上腺素能受体拮抗剂。Schild图分析显示了每种拮抗剂（奥诺-1101的斜率和pA2值分别为0.94和8.0；艾司洛尔分别为0.98和7.3），并证明奥诺-1101作为β受体拮抗剂的效力比艾司洛尔强约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和2）氯电流的激活，也被奥诺-1101抑制。在去极化的乳头肌中，洗脱后奥诺-1101和艾司洛尔β受体拮抗作用50%消除所需的时间分别估计为4分钟和6分钟。这些结果表明奥诺-1101是一种强效β受体拮抗剂，其作用通过洗脱可迅速消除。当以被认为是临床剂量应用时，奥诺-1101对心肌动作电位参数和膜电流没有直接影响。奥诺-1101的这些特性表明该药物在临床应用中可能有效。
