No development of tolerance to the hypotensive effect of KRN2391, a novel vasodilator containing a nitrate moiety.

The present studies were performed to examine whether tolerance develops to the hypotensive effects of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide monomethanesulfonate. Rats were administered KRN2391 (0.3 or 1 mg/kg, s.c.) or nitroglycerin (10 mg/kg, s.c.) three times a day for 1 to 8 days and blood pressure was then measured under anesthesia. Chronic pretreatment with nitroglycerin attenuated the decrease in blood pressure induced by i.v. nitroglycerin but not that by i.v. KRN2391. Chronic pretreatment with KRN2391 (0.3 or 1 mg/kg, s.c.) had no effect on the decreases in blood pressure induced by i.v. nitroglycerin or i.v. KRN2391. It can be concluded that, in this rat model, no tolerance develops to the hypotensive effects of KRN2391.