Electropharmacological effects of UK-1745, a novel cardiotonic drug, in guinea-pig ventricular myocytes

Abstract

Effects of (2 RS, 3 SR)-2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8,8-pentamethyl-6 H-furo-[2,3-e] indol-7-one hydrochloride (UK-1745), a novel cardiotonic drug with β-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 μM) produced a mild positive inotropic response and depressed the maximum upstroke velocity of the action potential ( V̇ max) at 100 μM. 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 μM and rather decreased I Ca at 100 μM. 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 β-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.