摘要
Background: Heightened central sympathetic nervous outflow is common in essent ial hypertension, contributing to hypertension development and possibly also to complications. Acute sympathetic nervous activation is a proven trigger for adve rse cardiovascular events. Accordingly, antihypertensive drugs inhibiting sympat hetic outflow represent a theoretically attractive therapeutic option. Objectiv e s: To study the sympatholytic and blood pressure-lowering activity of the imida zoline binding agent rilmenidine at rest and during reflex sympathetic activatio n. Design and methods: We used a randomized, double-blind, 6-week cross-over study, with a 1-week placebo runin period, two 2-week active treatment interva ls (rilmenidine 1 mg twice daily or placebo) and intervening 1-week placebo was hout. In 15 hypertensive patients, noradrenaline and adrenaline plasma kinetics and intraarterial blood pressure measurements were performed at rest, after ment al stress (difficult mental arithmetic) and during head-up tilting, at the end of the 2-week dosing periods. Results: The noradrenaline spillover rate, indica tive of whole body sympathetic activity, was reduced 35%by rilmenidine at rest (P< 0.01) and remained significantly lower during mental stress and tilting, alt hough the increases in noradrenaline spillover with both stimuli were preserved. The effects on intra-arterial blood pressure ran in parallel, a fall in supine resting pressure, but no reduction in blood pressure rise during mental stress and a lack of fall in blood pressure with tilting. On placebo, adrenaline secret ion was 0.88 ±0.15 nmol/min (mean ±SE) at rest, increased by 0.42 ±0.23 nmol/ min with mental stress (P=0.019) and was unchanged with tilting. Rilmenidine lef t adrenaline secretion untouched under all conditions. Conclusions: The present study confirms a sympatholytic effect of rilmenidine during supine rest but pres ervation of sympathetic responses during mental stress and tilting, with the lat ter underlying a freedom from postural hypotension on the drug. The absence of s uppression of reflexive sympathetic responses contrasts with the described effec ts of rilmenidine in experimental animals, and emphasizes the previously demonst rated unique importance in humans of suprabulbar noradrenergic neuronal projecti ons from the brainstem in regulating tonic sympathetic activity, with these bein g inhibited by imidazoline binding agents. Sympathetic nervous inhibition with r ilmenidine contrasted with an absence of suppression of adrenaline secretion, af firming that sympathetic nervous and adrenal medullary function can be disconnec ted.
Background: Heightened central sympathetic nervous outflow is common in essent ial hypertension, contributing to hypertension development and possibly also to complications. Acute sympathetic nervous activation is a proven trigger for adve rse cardiovascular events. Accordingly, antihypertensive drugs inhibiting sympat hetic outflow represent a theoretically attractive therapeutic option. Objectiv e s: To study the sympatholytic and blood pressure-lowering activity of the imida zoline binding agent rilmenidine at rest and during reflex sympathetic activatio n. Design and methods: We used a randomized, double-blind, 6-week cross-over study, with a 1-week placebo runin period, two 2-week active treatment interva ls (rilmenidine 1 mg twice daily or placebo) and intervening 1-week placebo was hout. In 15 hypertensive patients, noradrenaline and adrenaline plasma kinetics and intraarterial blood pressure measurements were performed at rest, after ment al stress (difficult mental arithmetic) and during head-up tilting, at the end of the 2-week dosing periods. Results: The noradrenaline spillover rate, indica tive of whole body sympathetic activity, was reduced 35%by rilmenidine at rest (P< 0.01) and remained significantly lower during mental stress and tilting, alt hough the increases in noradrenaline spillover with both stimuli were preserved. The effects on intra-arterial blood pressure ran in parallel, a fall in supine resting pressure, but no reduction in blood pressure rise during mental stress and a lack of fall in blood pressure with tilting. On placebo, adrenaline secret ion was 0.88 ±0.15 nmol/min (mean ±SE) at rest, increased by 0.42 ±0.23 nmol/ min with mental stress (P=0.019) and was unchanged with tilting. Rilmenidine lef t adrenaline secretion untouched under all conditions. Conclusions: The present study confirms a sympatholytic effect of rilmenidine during supine rest but pres ervation of sympathetic responses during mental stress and tilting, with the lat ter underlying a freedom from postural hypotension on the drug. The absence of s uppression of reflexive sympathetic responses contrasts with the described effec ts of rilmenidine in experimental animals, and emphasizes the previously demonst rated unique importance in humans of suprabulbar noradrenergic neuronal projecti ons from the brainstem in regulating tonic sympathetic activity, with these bein g inhibited by imidazoline binding agents. Sympathetic nervous inhibition with r ilmenidine contrasted with an absence of suppression of adrenaline secretion, af firming that sympathetic nervous and adrenal medullary function can be disconnec ted.
