Antihypertensive and vasorelaxant effects on KRN2391 in spontaneously hypertensive rats

• 1.1. In conscious spontaneously hypertensive rats (SHR), the oral administration of KRN2391 (0.1–3.0 mg/kg) produced a dose-dependent decrease in blood pressure. The antihypertensive effect of KRN2391 was about 2 and 20 times more potent than those of pinacidil and nifedipine, respectively, but about 2 times less potent than that of cromakalim.
• 2.2. During oral administration of KRN2391 (0.5 and 1.0 mg/kg) once daily for 5 weeks, its antihypertensive effect did not diminish in conscious SHR.
• 3.3. In anaesthetized SHR, KRN2391 (3–100 μg/kg, i.v.) produced a decrease in blood pressure in a dose-dependent manner. Its antihypertensive effect was antagonized by glibenclamide (20 mg/kg, i.v.).
• 4.4. In isolated aorta obtained from SHR, KRN2391 (0.01–100 μM) produced a concentration-dependent relaxation. Its concentration-relaxation curve was shifted to the right by glibenclamide (1 μM) and methylene blue (3 μM).
• 5.5. These results indicate that the antihypertensive effect of KRN2391 in SHR is due to its direct action on vascular smooth muscle based on a K⁺ channel opening action and a nitrate action. In addition, KRN2391 is absorbed from the gastrointestinal tract into blood and does not induce tolerance despite possessing some nitrate action.