KRN4884, A NOVEL K-CHANNEL OPENER - ANTIHYPERTENSIVE EFFECTS IN CONSCIOUS RENAL HYPERTENSIVE DOGS

We examined the antihypertensive effects of KRN4884, lorophenyl)ethyl] -N-cyano-3-pyridinecarbocamidine, in normotensive dogs, a high-renin m odel acute renal hypertensive dog (RHD), and a low-renin model chronic RHD in the conscious state, compared with levcromakalim and nilvadipi ne. KRN4884 decreased mean blood pressure (MBP) at a dose of 0.1 mg/kg p.o. in normotensive dogs and both RHDs. The decrease in MBP was grea ter in both RHDs than in normotensive dogs, and there were no signific ant differences between the two RHDs. A transient increase in heart ra te (HR) accompanied the increase in MBP in all three types of dogs. In the chronic RHD, KRN4884 at doses of 0.05, 0.1, and 0.2 mg/kg produce d a dose-dependent decrease in MBP. The antihypertensive effect of KRN 4884 (0.1 mg/kg) was similar to those of levcromakalim (0.05 mg/kg) an d nilvadipine (1.0 mg/kg) in magnitude and more prolonged than those o f the compounds. The tachycardia induced by KRN4884 was similar to tha t induced by levcromakalim and was stronger than that induced by nilva dipine. In the 15-day repeated oral-administration study, KRN4884 (0.1 mg/kg) induced sustained hypotensive effects and transient increases in HR and plasma renin activity. No tolerance to the antihypertensive effect of KRN4884 was observed during a IS-day repeated dosing period. After withdrawal of KRN3884, no rebound phenomena in MBP and KR were observed. Neither the maximal concentration nor area under the curve ( AUC) of KRN4884 in plasma were changed at days 1, 8, and 15. These dat a indicate that KRN4884 produces a strong and persistent antihypertens ive response in both low-renin and high-renin models of RHD in a consc ious state, which suggests that KRN4884 may be useful as an antihypert ensive agent.