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BACKGROUND: Heightened central sympathetic nervous outflow is common in essential hypertension, contributing to hypertension development and perhaps also to complications. Acute sympathetic nervous activation is a proven trigger for adverse cardiovascular events. Accordingly, antihypertensive drugs inhibiting sympathetic outflow represent a theoretically attractive therapeutic option. OBJECTIVES: To study the sympatholytic and blood pressure lowering activity of the imidazoline binding agent rilmenidine at rest and during reflex sympathetic activation. DESIGN AND METHODS: The HERA study (Hyperium Effect on the sympathetic Reflex activation and Adrenaline) is a randomised, double-blind, 6-week cross-over trial, with a 1-week placebo run-in period, two 2-week active treatment intervals (rilmenidine 1 mg bid, placebo) and intervening one week placebo wash-out. In 15 hypertensive patients, noradrenaline and adrenaline plasma kinetics and intra-arterial blood pressure measurements were performed at rest, after mental stress (difficult mental arithmetic) and during head-up tilting, at the end of the 2-week dosing periods. RESULTS: The noradrenaline spillover rate, indicative of whole body sympathetic activity, was reduced 35% by rilmenidine at rest (p<0.01) and remained significantly lower during mental stress and tilting, although the increases in noradrenaline spillover with both stimuli were preserved. The effects on intraarterial blood pressure ran in parallel, a fall in supine resting pressure, but no reduction in BP rise during mental stress and a lack of fall in BP with tilting. On placebo, adrenaline secretion was 162 +/- 27 ng/min (mean, SE) at rest, increased by 77 +/- 42 ng/min with mental stress (p=0.019) and was unchanged with tilting. Rilmenidine left adrenaline secretion untouched under all conditions. CONCLUSIONS: This study confirms a sympatholytic effect of rilmenidine during supine rest but demonstrates that sympathetic responses during mental stress and tilting are preserved, the latter underlying a perhaps surprising absence of postural hypotension on the drug. The absence of suppression of reflexive sympathetic responses contrasts with the effects of rilmenidine in experimental animals, and emphasises the previously demonstrated unique importance in humans of suprabulbar noradrenergic neuronal projections from the brainstem, which are inhibited by imidazoline binding agents, in regulating tonic sympathetic activity in essential hypertension. Sympathetic nervous inhibition with rilmenidine contrasted with an absence of suppression of the secretion of adrenaline affirming that here, as elsewhere, sympathetic nervous and adrenal medullary function can be disconnected.

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