Development of tolerance to guanethidine in three hypertensive rat models

The development of tolerance to the antihypertensive effects of guanethidine was determined in one-kidney one clip and two-kidney one clip renovascular hypertensive rats and spontaneously hypertensive rats (SHR). The effect of gender on the tolerance development was also studied in SHR. Although initial guanethidine administration acutely reduced arterial pressure in all hypertensive models, initial dose responsiveness to the blood pressure lowering effects of guanethidine (50 mg/kg, i.p.) was greatest in male SHR. After two weeks of daily guanethidine dosing (50 mg/kg/day, i.p.) only female SHR demonstrated an acute depressor response to the day 14 guanethidine dose. During the two week dosing interval tolerance development began after day 3 in all models, and systolic pressure (SP) was not significantly different from preguanethidine values in tolerant animals by day 7. In both renovascular hypertensive models a subpopulation of guanethidine responders was identified which maintained a lowered SP (p less than 0.05) after day 3. SHR demonstrated a high degree of tolerance after day 7 regardless of gender. Tolerance did not develop to the guanethidine-induced bradycardia in any model. These data suggest that both renovascular models and SHR are suitable models for studying the mechanism(s) of tolerance development to guanethidine and possibly other sympatholytic drugs.