OBJECTIVE:The aim of the present study was to compare the effects of the combination of lercanidipine/enalapril versus amlodipine/enalapril and hydrochlorothiazide/enalapril on blood pressure, target organ damage and sympathetic activation in patients with grade 2 essential hypertension. RESEARCH DESIGN AND METHODS:This was a 3 month, randomized, blinded-endpoint study in essential hypertensive patients. MAIN OUTCOME MEASURES:Office and ambulatory blood pressure, arterial stiffness, urinary albumin to creatinine ratio, renal arterial resistive index, and muscle sympathetic nerve activity were evaluated at baseline, after a 2 week run-in placebo period, at 1 month and at 3 months. RESULTS:In total, 56 patients were assigned to lercanidipine/enalapril (n = 19), enalapril/amlodipine (n = 18) and hydrochlorothiazide/enalapril (n = 19). Each pharmacological combination tested was effective in reducing office blood pressure at 1 month and 3 months, and 24 h ambulatory blood pressure at 3 months. Renal arterial resistive index (RI) significantly improved at 1 month and 3 months compared with baseline in all groups. However in the lercanidipine/enalapril and hydrochlorothiazide/enalapril groups, RI was favorably reduced (0.53 ± 0.03 and 0.54 ± 0.04 respectively, p < 0.05) in comparison with the enalapril/amlodipine RI value (0.57 ± 0.03) at 3 months. Moreover, after 3 months of treatment, a significant decrease (by -5.47 bursts/min) (p < 0.05) in muscle sympathetic nerve activity was observed in the lercanidipine/enalapril group (50.79 ± 6.49) compared with baseline (56.26 ± 6.05), while no differences were detected in the amlodipine/enalapril and hydrochlorothiazide/enalapril groups. CONCLUSIONS:Our study provides evidence of the efficacy of the lercanidipine/enalapril combination in ameliorating hypertension-related target organ damage and in reducing sympathetic overdrive.