The
antihypertensive action of
KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ), a newly synthesized 3-pyridine derivative was examined in conscious spontaneously hypertensive rats (SHRs). A single administration of
KRN4884 (0.5, 1.5 mg/kg, p.o.) produced a dose-dependent and long-lasting
antihypertensive effect. The 7-day repeated administration of
KRN4884 (0.5, 1.5 mg/kg, p.o.) did not diminish
antihypertensive activity during the treatment period or induce rebound
hypertension after the discontinuation of treatment. To examine the mechanism of the
antihypertensive effect of
KRN4884, we studied its vasorelaxing effects in rat isolated aortae precontracted with 25 mM KCl. Single application of
KRN4884 showed a slower onset of inhibitory action than that of
levcromakalim.
KRN4884 was approximately 26-fold more potent than
levcromakalim and 10-fold less potent than
nilvadipine. KRN4884- and
levcromakalim-induced vasorelaxation were antagonized by
glibenclamide. Furthermore, we observed the recovery of the contraction inhibited by these drugs after repeated washing. The inhibitory effect of
KRN4884 was restored only after four washes, whereas that of
levcromakalim was completely restored after one wash. The
nilvadipine-induced inhibitory effect was the most resistant to washing among these drugs. These results suggest that
KRN4884 shows a long-lasting
antihypertensive effect based on its potent
potassium channel-opening action. The long-lasting action may be due to a slow association/dissociation with/from the binding sites on vascular smooth muscle.