Antihypertensive properties of KRN4884, a novel long-lasting potassium channel opener.
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.
Pharmaceutical Development Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
J
J
Kawahara
T
T
Kashiwabara
N
N
Ogawa
Y
Y
Okada
T
T
Izawa
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006973:Hypertension / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; C096484:KRN 4884; D011725:Pyridines; C035100:nilvadipine; D019806:Cromakalim; D009543:Nifedipine