Cardiovascular 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 agent with vasodilatory and antiarrhythmic properties.
The cardiovascular 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 (CAS 170684-14-7, UK-1745), a novel cardiotonic agent, were investigated using in vitro and in vivo preparations. In paced left atria isolated from guinea pigs, both UK-1745 and vesnarinone (CAS 81840-15-5) showed a concentration-dependent positive inotropic effect. In spontaneously beating guinea pig right atria, both agents caused only a minimal chronotropic effect. In isolated, blood-perfused canine papillary muscle preparations, UK-1745 and vesnarinone injected intra-arterially into the anterior septal artery (ASA) increased the developed tension in a dose-dependent manner. In isolated, blood-perfused canine sinoatrial node preparations, both agents injected into the right coronary artery (RCA) did not cause any appreciable changes in the sinus rate. UK-1745 increased the blood flow through the ASA and the RCA in a dose-dependent manner, whereas vesnarinone did not. In anesthetized open-chest dogs, UK-1745 injected intravenously increased cardiac contractility and cardiac output, and decreased left ventricular end-diastolic pressure, systemic vascular resistance and heart rate. In experimentally induced acute heart failure in anesthetized open-chest dogs, intravenously injected UK-1745 effectively improved hemodynamic functions. In conscious instrumented dogs, orally administered UK-1745 increased LV dP/dtmax with insignificant changes in systemic blood pressure and heart rate. In mice, orally administered UK-1745 protected the development of ventricular fibrillation induced by chloroform inhalation, whereas vesnarinone did not. Thus, in respect of inotropic and chronotropic effects, UK-1745 closely resembled vesnarinone, but differed from vesnarinone in respect of coronary vasodilating and antiarrhythmic effects. The results suggest that UK-1745 is a novel positive inotropic agent with vasodilatory and antiarrhythmic properties, without significant chronotropic action, and may be beneficial for the treatment of congestive heart failure.
Uchida
Y
Y
Clinical Physiology and Cardiovascular Center, Toho University Hospital at Sakura, Chiba, Japan.
Kawada
M
M
Sawanobori
K
K
Sonoki
H
H
Inoue
K
K
Mizuno
K
K
Itou
T
T
Tabunoki
Y
Y
Tsukamoto
M
M
Ohashi
Y
Y
Kyotani
Y
Y
Shimizu
N
N
Fujii
M
M
Nakamura
M
M
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D012849:Sinoatrial Node / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D007211:Indoles; D014665:Vasodilator Agents; C112026:UK 1745