Electropharmacological effects of UK-1745, a novel cardiotonic drug, in guinea-pig ventricular myocytes.
Effects of (2RS, 3SR)-2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8, 8-pentamethyl-6H-furo-[2,3-e] indol-7-one hydrochloride (UK-1745), a novel cardiotonic drug with beta-adrenoceptor blocking property and antiarrhythmic activity, on the action potentials of isolated papillary muscles and the membrane currents of single ventricular myocytes of guinea pigs were examined and compared with those of milrinone using conventional microelectrode and patch-clamp techniques. In papillary muscles, UK-1745 (3-100 microM) produced a mild positive inotropic response and depressed the maximum upstroke velocity of the action potential (V(max)) at 100 microM. Milrinone, a phosphodiesterase III inhibitor, markedly shortened the action potential duration with a significant increase in developed tension. In enzymatically-dissociated ventricular myocytes, UK-1745 failed to increase the L-type Ca(2+) current (I(Ca)) at 10 and 30 microM and rather decreased I(Ca) at 100 microM. The high concentration of UK-1745 slightly inhibited the delayed rectifier K(+) current (I(K)). Although UK-1745 antagonized the isoproterenol-induced increase in I(Ca), it potentiated the histamine-induced increase in I(Ca). On the other hand, milrinone per se significantly increased I(Ca) and markedly enhanced the isoproterenol-induced increase in I(Ca). It can be concluded that UK-1745 is a unique cardiotonic drug possessing beta-adrenoceptor blocking and weak phosphodiesterase-inhibitory actions in addition to direct inhibitory actions on the Na(+), Ca(2+) and K(+) channels with its high concentrations.
Uemura
H
H
Department of Pharmacology, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, Japan.
Sakamoto
N
N
Nakaya
H
H
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D020105:Milrinone / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology
D002316:Cardiotonic Agents; D007211:Indoles; D010726:Phosphodiesterase Inhibitors; C112026:UK 1745; D020105:Milrinone