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 ((+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxy-propoxy]-2(1H)-qu inolinone CAS 128667-95-8, OPC-18790) in the isolated right atrial and papillary muscles of rabbit and guinea-pig were examined and compared with those of milrinone (CAS 78415-72-2), a pure cyclic GMP-inhibited phosphodiesterase inhibitor. OPC-18790 (10(-7)-10(-4) mol/l) and milrinone (10(-3)-10(-4) mol/l) exerted concentration-dependent increases of contraction in both atrial and papillary muscles isolated from rabbits and guinea-pigs. In the isolated right atrium of rabbits and guinea-pigs, OPC-18790 showed limited increase in heart rate, while milrinone increased heart rate concentration-dependently. 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 isolated papillary muscles, while milrinone exerted no such change. In whole-cell voltage clamp experiments using isolated cardiac myocytes of guinea-pigs, OPC-18790(10(-5) mol/l) increased the L-type calcium current and inhibited outward potassium currents such as inward rectifying currents and delayed rectifier currents. OPC-18790 and milrinone (10(-6), 3 x 10(-5) mol/l) increased intracellular cyclic AMP levels with an increase in developed tension in isolated right ventricular muscles of guinea-pigs. From the above results, OPC-18790 was shown to be a positive inotropic agent with limited chronotropic effect and electrophysiologically properties different from those of milrinone. It was suggested that the prolongation of action potential duration, which is due to the inhibition of potassium currents, may be involved in OPC-18790's mechanism of positive inotropic action with limited chronotropic effect in addition to the inhibition of cyclic GMP-inhibited phosphodiesterase.
Takase
H
H
2nd Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Orito
K
K
Mori
T
T
Fujiki
H
H
Sekiguchi
K
K
Tominaga
M
M
Iijima
T
T
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D018408:Patch-Clamp Techniques; D015363:Quinolones / Q000494:pharmacology*; D011817:Rabbits
D002316:Cardiotonic Agents; D015363:Quinolones; C077543:toborinone; D000242:Cyclic AMP