Effects of ONO-1101, a novel beta-antagonist, on action potential and membrane currents in cardiac muscle.
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.
Muraki
K
K
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Nakagawa
H
H
Nagano
N
N
Henmi
S
S
Kawasumi
H
H
Nakanishi
T
T
Imaizumi
K
K
Tokuno
T
T
Atsuki
K
K
Imaizumi
Y
Y
Watanabe
M
M
D000200:Action Potentials / Q000187:drug effects*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects*; D009025:Morpholines / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D009025:Morpholines; D011412:Propanolamines; C077049:landiolol; D014508:Urea; C036604:esmolol