Abstract 526: Blood Pressure in the SHR Following Renal Denervation or Etamicastat, a Novel Dopamine-β-Hydroxylase Inhibitor

Abstract

Overactivity of the sympathetic nervous system plays an important role in the development and progression of hypertension. Catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been recently developed. An alternative strategy for modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalysis the conversion of dopamine to NE in sympathetic nerves.

Renal denervation (RDN) was performed in spontaneously hypertensive rats (SHR) to evaluate the effect of RDN on NE levels and blood pressure throughout a 28-day period. Chronic oral treatment with the peripheral selective DβH inhibitor etamicastat (30 mg/kg/day) was performed in another cohort of SHR.

RDN and chronic oral treatment with etamicastat did not affect renal function, as assessed by urinary protein, creatinine and urea levels. RDN significantly decreased mean arterial blood pressure (MAP, in mm Hg) 7 days post-surgery (139±6, P<0.01) versus baseline values (158±6). A gradual MAP return to high baseline levels was observed overtime; 139±7 at day 14, 151±12, at day 21 and 155±12 at day 28 after RDN. Treatment with etamicastat decreased baseline MAP (150±5) in a sustained and significant (P<0.01) manner at all-time points: 141±5 at day 7, 139±5 at day 14, 138±5 at day 21 and 143±5 at day 28. At day 28, NE levels (in pmol/mg tissue) in renal tissue were significantly decreased in both RDN (0.12±0.08, P=0.001) and etamicastat-treated group (0.48±0.04, P=0.01) as compared to vehicle group (0.88±0.13). On the other hand, left ventricle NE levels were decreased only after treatment with etamicastat (1.24±0.12, P=0.04) but not in the RDN group (2.53±0.24, P=0.9) when compared to controls (2.59±0.58).

It is concluded that RDN produces transitory decreases in MAP, whereas prolonged down regulation of sympathetic drive with the DβH inhibitor etamicastat results in sustained decreases in MAP.