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Cardiovascular effects of E4080, a novel bradycardiac agent with coronary vasodilating properties, in anesthetized
T Kawamura1, H Adachi, T Ogawa
1Department of Pharmacology, Eisai Tsukuba Research Laboratories, Ibaraki, Japan.
Insights
E4080, a new bradycardiac agent, effectively lowers heart rate and blood pressure while increasing coronary blood flow in dogs. Its vasodilating action involves ATP-sensitive K+ channels, but the bradycardiac effect does not.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Novel bradycardiac agents are sought for cardiovascular conditions.
- Understanding drug mechanisms is crucial for therapeutic development.
Purpose of the Study:
- To investigate the cardiohemodynamic effects of E4080.
- To elucidate the mechanism underlying E4080's actions, particularly its vasodilating properties.
Main Methods:
- Anesthetized open-chest dogs were used to assess hemodynamic parameters.
- E4080 was administered intravenously and directly into the sinus node artery.
- Glibenclamide, an ATP-sensitive K+ channel blocker, was used to probe the mechanism.
Main Results:
- E4080 decreased heart rate, mean aortic pressure, and total peripheral resistance, while increasing coronary blood flow.
- Cardiac output and electrocardiogram remained unaffected; myocardial oxygen consumption decreased.
- Selective administration into the sinus node artery decreased heart rate.
- Glibenclamide blocked E4080-induced coronary vasodilation and hypotension but not bradycardia.
Conclusions:
- E4080 exhibits both bradycardiac and coronary vasodilating effects.
- ATP-sensitive K+ channel activation contributes to E4080's vasodilating action.
- The bradycardiac effect of E4080 is independent of ATP-sensitive K+ channel activation.
Abstract:
The cardiohemodynamic effects of E4080, a novel bradycardiac agent with a coronary vasodilating feature, were studied in anesthetized open-chest dogs. E4080 (0.3 and 1 mg/kg i.v.) decreased heart rate (HR), mean aortic pressure (MAP) and total peripheral resistance, and increased coronary blood flow (CBF) without affecting cardiac output and the electrocardiogram. The maximum rate of rise in left ventricular pressure decreased at 1 mg/kg. In addition, E4080 (0.3 and 1 mg/kg i.v.) decreased myocardial oxygen consumption. On administration in sinus node artery, E4080 (10 and 30 micrograms) selectively decreased HR. Glibenclamide, an ATP-sensitive K+ channel blocker (5 mg/kg i.v.), inhibited both the increase in CBF and the decrease in MAP caused by E4080 (1 mg/kg i.v.) but did not inhibit the bradycardia. These results suggested that E4080 has both bradycardiac and coronary vasodilating effects, and that activation of ATP-sensitive K+ channel contributes to the vasodilating action of E4080 but not to the bradycardiac action.