Activation of the sympathetic nervous system has been described in the development and progression of systemic hypertension. Recently, catheter-based renal nerve ablation for treatment of drug-resistant hypertension has been 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 (DA) to NE in sympathetic nerves.
Renal denervation was assessed in the rat by transient (90 sec) ischemia of renal tissues. Bilateral renal artery occlusion (RAO) was assessed in spontaneously hypertensive rats (SHR) to evaluate the effect of renal denervation on NE levels and blood pressure throughout a 28-day period. Oral treatment with the selective peripheral DβH inhibitor etamicastat (30 mg/Kg body weight) was performed in a second cohort of SHR and NE levels and blood pressure was assessed.
Renal denervation resulted in marked depletion of NE levels, selective for the renal sympathetic innervations, 5 days after RAO in renal cortex (16.5±7.7% of control values, P<0.0001). Decreased NE levels persisted up to 28 days after RAO (40.8±19.4% of control values, P<0.0001). No differences in left ventricle NE levels were observed. Renal denervation significantly decreased systolic blood pressure (SBP) 5 days (165±6 vs. 187±2 mmHg, P<0.05) and 14 days post-surgery (194±3 vs. 204±2 mmHg, P<0.05), but had no effect on heart rate. Systolic blood pressure recovered to basal values 28 days post-surgery. Likewise, etamicastat treatment resulted in a depletion of NE levels in both renal cortex (70.9±9.1% of control values, P<0.05) and left ventricle (55.8±3.9% of control values, P<0.01). Etamicastat treatment decreased SBP (228±7 vs. 174±9 mmHg, P<0.001) without effects on heart rate.
In conclusion, these results suggest that renal denervation and DβH inhibition similarly decreases sympathetic hyperactivity and high blood pressure in the SHR. Downregulation of sympathetic drive with DβH inhibitors may be useful in the treatment of hypertension.