Relationship between hypotensive effects and plasma concentrations of clonidine in spontaneously hypertensive rats: continuous treatment and sudden termination of clonidine infusion.

1. Clonidine was administered subcutaneously (62.5, 125 and 250 micrograms/kg/day) for 8 days using an osmotic infusion pump in spontaneously hypertensive rats (SHR). Clonidine, administered at 125 and 250 micrograms/kg/day at 48 hr after infusion, respectively, and thereafter were maintained at this level throughout the infusion period. 3. After terminating clonidine infusion, a rapid drug elimination from the plasma was manifested in both groups (125 and 250 micrograms/kg/day) with plasma clonidine levels, resulting in a decrease below 0.5 ng/ml at 4 and 6 hr, respectively. Four hours after terminating clonidine infusion at 125 and 250 micrograms/kg/day, transient but not remarkable increases in blood pressure and heart rate were observed only in the latter group compared with the values before termination. 4. These findings reveal that marked hypotensive effects were induced by relatively high doses (125 and 250 micrograms/kg/day) of clonidine in SHR, but no remarkable withdrawal symptoms after termination of clonidine infusion were observed. Therefore, unwanted withdrawal symptoms probably occur when an extremely high dose (250 micrograms/kg/day or more) of clonidine was infused for a long period (8 days or more) in SHR.