In anesthetized, open-chest dogs 8-tert.-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine (CS-611), in doses of 0.1--1 mg/kg i.v. decreased systemic blood pressure, coronary resistance and arterio-venous O2 difference and increased coronary sinus outflow in a dose-related manner, but myocardial oxygen consumption was virtually unchanged. At 0.3 mg/kg i.v. of the drug, coronary sinus outflow was doubled, but heart rate and AV conduction time were not changed. In canine isolated, blood-perfused heart preparations, CS-611 only in large intra-arterial doses produced the following responses; a decrease in sinus rate followed by a slight increase in the SA node preparation, a transient prolongation of AV conduction time followed by a slight shortening in the AV node preparation and a transient decrease followed by a sizable increase in developed tension in the papillary muscle preparation. The drug in large intra-arterial doses decreased the rate of automaticity of the papillary muscle preparation. From these results CS-611 can be characterized as a coronary dilator virtually devoid of cardiac actions in doses sufficiently increasing coronary blood flow. By comparison of the present results with those of previous results on other coronary dilators it was revealed that CS-611 may have a novel mechanism of action.

01 Jan 1981·Arzneimittel-Forschung

Cardiovascular pharmacology of bumepidil, a new synthetic vasoactive compound for coronary circulation.

Article

Author: Miyake, S ; Nishino, H ; Shimada, Y ; Mizuno, H ; Kumakura, S ; Koike, H ; Oshima, T

Intravenously administered 8-tert.-butyl-7,8-dihydro-5-methyl-6H-pyrrolo[3,2-e]triazolo[1,5-alpyrimidine (bumepidil, CS-611) increased the coronary sinus outflow as well as intramyocardial flows in both subendocardial and subepicardial layers in the anesthetized dog and also the increase in the coronary arterial inflow was observed with short onset time, within 10 min when given orally to the conscious dog, and time for maximum effect is also short, i.e., 20 min after the oral administration. In the anesthetized rabbit flow-increase in the brain by CS-611 was next to the coronary, followed by the stomach and small intestines while there was no organ which showed a decreased flow. In the anesthetized open-chest dog cardiac output was increased by CS-611 while myocardial oxygen consumption was little affected. In addition, CS-611 exerted antiarrhythmic action on ventricular ectopics induced by coronary ligation of the conscious dog. A correlation between the increase in myocardial flow by CS-611 in the intact heart and the antiarrhythmic action in the coronary-lighted heart still remains to be studied further.

01 Mar 1980·Archives internationales de pharmacodynamie et de therapie

Effects of CS-611 on the electrophysiological properties of canine cardiac tissues.

Article

Author: Ito, K ; Koike, H ; Kumakura, S

Effects of CS-611, a new coronary vasodilator, on the electrophysiological properties of Purkinje fibers, auricular and ventricular muscles isolated from dogs were examined with a microelectrodfe technique. CS-611 between 3 X 10(-6) and 3 X 10(-5) g/ml shortened the action potential duration (APD) of each tissue, especially of Purkinje fibers, without any significant alterations in the resting membrane potential, action potential amplitude and maximum rate of rise (V max). CS-611 also shortened the effective refractory period (ERP) of Purkinje fibers and ventricular muscles, but to a lesser extent than APD, resulting in an increase of ERP/ADP. The level of membrane potential needed to elicit premature excitation in Purkinje fibers and Vmax of the earliest response tended to increase in the presence of CS-611. CS-611 partially restored the reduced Vmax of Purkinje fibers exposed to hypoxia. The spontaneous firings in Purkinje fibers were decreased or abolished by CS-611. The possible role of these effects of CS-611 in its antiarrhythmic action was discussed.

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