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Abstract

Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.

K Muraki, H Nakagawa, N Nagano, S Henmi, H Kawasumi, T Nakanishi, K Imaizumi, T Tokuno, K Atsuki, Y Imaizumi and M Watanabe
Journal of Pharmacology and Experimental Therapeutics August 1996, 278 (2) 555-563;
K Muraki
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H Nakagawa
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N Nagano
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S Henmi
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H Kawasumi
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T Nakanishi
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K Imaizumi
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T Tokuno
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K Atsuki
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Y Imaizumi
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M Watanabe
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Abstract

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.

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Journal of Pharmacology and Experimental Therapeutics
Vol. 278, Issue 2
1 Aug 1996
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Abstract

Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.

K Muraki, H Nakagawa, N Nagano, S Henmi, H Kawasumi, T Nakanishi, K Imaizumi, T Tokuno, K Atsuki, Y Imaizumi and M Watanabe
Journal of Pharmacology and Experimental Therapeutics August 1, 1996, 278 (2) 555-563;

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Abstract

Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.

K Muraki, H Nakagawa, N Nagano, S Henmi, H Kawasumi, T Nakanishi, K Imaizumi, T Tokuno, K Atsuki, Y Imaizumi and M Watanabe
Journal of Pharmacology and Experimental Therapeutics August 1, 1996, 278 (2) 555-563;
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