KRN4884, a novel K channel opener: antihypertensive effects in conscious renal hypertensive dogs.

Abstract

We examined the antihypertensive effects of KRN4884, 5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarbocamidine+ ++, in normotensive dogs, a high-renin model acute renal hypertensive dog (RHD), and a low-renin model chronic RHD in the conscious state, compared with levcromakalim and nilvadipine. 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 greater in both RHDs than in normotensive dogs, and there were no significant differences between the two RHDs. A transient increase in heart rate (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 produced a dose-dependent decrease in MBP. The antihypertensive effect of KRN4884 (0.1 mg/kg) was similar to those of levcromakalim (0.05 mg/kg) and nilvadipine (1.0 mg/kg) in magnitude and more prolonged than those of the compounds. The tachycardia induced by KRN4884 was similar to that induced by levcromakalim and was stronger than that induced by nilvadipine. 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 15-day repeated dosing period. After withdrawal of KRN4884, no rebound phenomena in MBP and HR 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 data indicate that KRN4884 produces a strong and persistent antihypertensive response in both low-renin and high-renin models of RHD in a conscious state, which suggests that KRN4884 may be useful as an antihypertensive agent.