Katsuhiko Harada (1), Jun-ichi Kawahara (1), Yuji Okada (2), Hiroya Uzumaki
(1), Masaru Kusaka (1) and Tomonobu Tokiwa (1)
(1) Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., 2-2 Soja-machi 1 Chome, Maebashi, Gunma 371-0853, Japan
(2) Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., 3 Miyahara-cho, Takasaki, Gunma 370-1295, Japan
Abstract: The effects of KRN4884 (5-amino-N-[2-(2-chrolophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine), a novel K+ channel opener, on the electrocardiogram changes caused by the intracoronary administration of endothelin-1 (ET-1) were studied in anesthetized rats and compared with the effects of levcromakalim, a K+ channel opener; nilvadipine, a Ca2+ antagonist; and propranolol, a beta-adrenoceptor antagonist. KRN4884 (50 microg/kg, i.v.) and levcromakalim (300 microg/kg, i.v.) inhibited the ST segment elevation and the development of arrhythmias induced by ET-1 (5 microg, i.c.) and decreased the incidence of death. Nilvadipine (300 microg/kg, i.v.) and propranolol (1000 and 3000 microg/kg, i.v.) each prevented the ST segment elevation, but the suppressions of the occurrence of arrhythmias produced by nilvadipine and propranolol were less than that shown by KRN4884. KRN4884 (30 and 50 microg/kg, i.v.), levcromakalim (100 and 300 microg/kg, i.v.) and nilvadipine (100 and 300 microg/kg, i.v.) significantly decreased the mean blood pressure in a dose-dependent manner, but propranolol did not. The heart rate was decreased by nilvadipine (100 and 300 microg/kg, i.v.) and propranolol (1000 and 3000 microg/kg, i.v.), but was not affected by KRN4884 (30 and 50 microg/kg, i.v.) or levcromakalim (100 and 300 microg/kg, i.v.). These results suggest that pretreatments with KRN4884 and levcromakalim are more effective on ET-1-induced electrocardiogram changes than those with nilvadipine and propranolol.
Keywords: KRN4884, K+ channel opener, Electrocardiogram change, Endothelin, Heart disorder