The Antihypertensive Property of NIP-121, A Novel Potassium Channel Opener in Rats

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Abstract
The antihypertensive effects of NIP-121, a novel potassium channel opener, were examined in comparison with cromakalim and its active enantiomer, le-makalim. 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 β-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, diphenhy-dramine + cimetidine, or indomethacin) suppressed the decrease in blood pressure induced by NIP-121. In anesthetized and ganglion-blocked rats. NIP-121 (0.003–0.3 mg/kg. i.v.) dose-dependently antagonized the pressor responses to i.v. injection of norepinephrine, angiotensin I, angiotensin II, arginine vasopressin, prostaglandin F2a, or Bay K 8644; among these interventions, the pressor response to Bay K 8644 was antagonized most potently. These results indicate that NIP-121 has a potent and long-lasting antihypertensive effect that may largely be produced by its activity as a potassium channel opener.

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