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.