Renal nerve ablation has been shown to elicit a chronic, anti-hypertensive effect in drug-resistant hypertensive patients. Precise understanding of the mechanisms underlying the clinical success of renal denervation is currently unknown, and as a consequence, it is predicted the technology will be under-utilized until such information is uncovered. Retrospective multivariate analyses of responders suggest treatment with a central sympatholytic may correlate with a successful response to renal denervation. However, this hypothesis remains untested. This study tested the hypothesis that pretreatment with a central sympatholytic would augment the response to renal denervation (RDX) in the spontaneously hypertensive rat. In rats pre-treated for 1 week with clonidine (125ug/kg/day), MAP was significantly reduced from baseline but there was no difference in response to clonidine between groups (Sham(n=7): -21.3±0.8 vs RDX(n=7): -22.8±1.3mmHg, p>0.05). During clonidine treatment RDX significantly reduced MAP within 48hrs in RDX animals compared to shams (Sham: 145.9±2.5 vs. RDX: 135.0±1.7mmHg, p<0.05). However, this reduction was abolished by day 5 after RDX (Sham: 145.1±2.5 vs RDX: 140.4±3.0 mmHg, p>0.05). Discontinuation of clonidine caused blood pressure to rise, but once pressures stabilized, the average MAP was significantly lower in RDX treated rats (Sham:157.4 ± 0.8 vs. RDX: 146.4 ± 0.8mmHg, p<0.05). Administration of hydralazine, which reflexively increases sympathetic activity, lowered MAP similar to the magnitude observed in clonidine treatment (Sham: -19.6±1.0 vs RDX: -18.2±0.9mmHg). The anti-hypertensive effect of RDX was not augmented by hydralaizine however, it was also not abolished. These findings do not support the idea that patients taking effective doses of centrally acting sympatholytics will enhance the response to renal denervation.