POSITIVE INOTROPIC AND CHRONOTROPIC EFFECTS OF TOBORINONE AND ITS ELECTROPHYSIOLOGICAL PROPERTIES IN THE ISOLATED HEARTS OF RABBITS AND GUINEA-PIGS

The inotropic and chronotropic actions of toborinone ybenzylamino)-2-h ydroxy-propoxy]-2(1H)-quinolinone CAS 128667-95-8, OPC-18790) in the i solated right atrial and papillary muscles of rabbit and guinea-pig we re examined and compared with those of milrinone (GAS 78415-72-2), a p ure cyclic GMP-inhibited phosphodiesterase inhibitor. OPC-18790 (10(-7 )-10(-4) mol/l) and milrinone (10(-8)-10(-4) mol/l) exerted concentrat ion-dependent increases of contraction in both atrial and papillary mu scles isolated from rabbits and guinea-pigs. In the isolated right atr ium of rabbits and guinea-pigs, OPC-18790 showed limited increase in h eart rate, while milrinone increased heart rate concentration-dependen tly. OPC-18790 (10(-6) and 10(-5) mol/l in guinea-pigs and 10(-7)-10(- 4) mol/l in rabbits) prolonged the action potential duration in the is olated papillary muscles, while milrinone exerted no such change. In w hole-cell voltage clamp experiments using isolated cardiac myocytes of guinea-pigs, OPC-18790 (10(-5) mol/ 1) increased the L-type calcium c urrent and inhibited outward potassium currents such as inward rectify ing currents and delayed rectifier currents. OPC-18790 and milrinone ( 10(-6), 3x10(-5) mol/l) increased intracellular cyclic AMP levels with an increase in developed tension in isolated right ventricular muscle s of guinea-pigs. From the above results, OPC-18790 was shown to be a positive inotropic agent with limited chronotropic effect and electrop hysiologically properties different from those of milrinone. It was su ggested that the prolongation of action potential duration, which is d ue to the inhibition of potassium currents, may be involved in OPC-187 90's mechanism of positive inotropic action with limited chronotropic tropic effect in addition to the inhibition of cyclic GMP-inhibited ph osphodiesterase.