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1 NHMRC CCRE in Therapeutics, Monash University, Melbourne, Victoria, Australia
2 Baker Heart Research Institute, Melbourne, Victoria, Australia
3 Department of Medicine, St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia
* To whom correspondence should be addressed. E-mail: henry.krum{at}med.monash.edu.au.
It has long been proposed that the renin-angiotensin system exerts a stimulatory influence on the sympathetic nervous system, including the augmentation of central sympathetic outflow and presynaptic facilitation of norepinephrine release from sympathetic nerves. We tested this proposition in 19 patients with essential hypertension, evaluating whether the angiotensin receptor blockers, eprosartan and losartan, had identifiable antiadrenergic properties. This was done in a prospective, randomised, three-way placebo controlled study of cross-over design. Patients were randomised to eprosartan 600mg daily, losartan 50mg daily or placebo. The treatment period was four weeks, with two week wash-out periods. Multiunit firing rates in efferent sympathetic nerves distributed to skeletal muscle vasculature (MSNA), was measured using microneurography, testing whether angiotensin receptor blockers (ARBs) inhibit central sympathetic outflow. In parallel, isotope dilution methodology was used to measure whole-body norepinephrine spillover to plasma. Mean blood pressure on placebo was 151/98 mmHg, with both ARBs causing reductions of approximately 11 mmHg systolic and 6 mmHg diastolic pressure, placebo-corrected. Both MSNA, 35±12 bursts/min (mean ± SD) on placebo, and whole body norepinephrine spillover, 366±247 ng/min, were unchanged by ARB administration, indicating that the ARBs did not materially inhibit central sympathetic outflow or act presynaptically to reduce norepinephrine release at existing rates of nerve firing. These findings contrast with the easily demonstrable reduction in sympathetic nervous activity produced by antihypertensive drugs of the imidazoline-binding class, which are known to act within the brain to inhibit sympathetic nervous outflow. We conclude that sympathetic nervous inhibition is not a component of the blood pressure lowering action of ARBs in essential hypertension.
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