Antihypertensive and vasorelaxant effects on KRN2391 in spontaneously hypertensive rats

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. 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. In anaesthetized SHR, KRN2391 (3-100 micrograms/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. In isolated aorta obtained from SHR, KRN2391 (0.01-100 microM) produced a concentration-dependent relaxation. Its concentration-relaxation curve was shifted to the right by glibenclamide (1 microM) and methylene blue (3 microM). 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.