The antihypertensive property of NIP-121, a novel potassium channel opener in rats.
The antihypertensive effects of NIP-121, a novel potassium channel opener, were examined in comparison with cromakalim and its active enantiomer, lemakalim. In experiments by direct blood pressure measurements, orally administered NIP-121 dose-relatedly decreased arterial blood pressure in conscious spontaneously hypertensive rats (SHRs), and the ED20 values (the doses to produce 20% decrease of the mean blood pressure) of NIP-121 and cromakalim were 0.010 and 0.11 mg/kg, respectively, NIP-121 thus being about ten times more potent than cromakalim. The duration of the hypotensive effect by NIP-121 was longer than that by cromakalim. The hypotensive effect of NIP-121 was stronger in SHRs than in normotensive rats. All three drugs showed tachycardia that was antagonized by a beta-blocker, propranolol. Intravenously administered NIP-121 also showed a more potent hypotensive action with longer duration than cromakalim in conscious SHRs. The ED20 values for hypotension by NIP-121, cromakalim, and lemakalim were 0.017, 0.040, and 0.016 mg/kg, respectively. The intravenous hypotensive potency of NIP-121 but not cromakalim was similar to that of p.o. administration. The repeated treatments with NIP-121 (0.025, 0.05, and 0.1 mg/kg p.o. once a day) for 15 days did not modify the degree of the hypotensive action. In the anesthetized SHRs, pretreatment with glibenclamide but not other antagonists (atropine, propranolol, diphenhydramine + cimetidine, or indomethacin) suppressed the decrease in blood pressure induced by NIP-121.(ABSTRACT TRUNCATED AT 250 WORDS)
Masuda
Y
Y
Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Saitama, Japan.
Arakawa
C
C
Yokoyama
T
T
Shigenobu
K
K
Tanaka
S
S
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D013045:Species Specificity
D000959:Antihypertensive Agents; D001578:Benzopyrans; D010069:Oxadiazoles; D010880:Piperidines; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; C070366:NIP 121