Sympathetic nervous activation in essential hypertension: commonly neglected as a therapeutic target, usually ignored as a drug side effect.

Inappropriate and excessive activation of the sympathetic nervous system has been invoked as a cause of coronary heart disease. This pathophysiological linkage can take 2 forms. The most direct and explicit is when acute sympathetic nervous activation triggers adverse cardiac events (myocardial infarction, atrial fibrillation, ventricular arrhythmias, and Takotsubo cardiomyopathy have all been documented) during acute severe mental stress.1 Systematic evidence has been gathered at times of disasters, including war, missile attacks on civilians, and earthquakes, that strongly supports this proposition. The recently published and already celebrated analysis of coronary heart disease clinical presentations in German nationals in Munich during the 2006 Fédération Internationale de Football Association World Cup provides a telling example in demonstrating a dose-response relationship of the level of acute mental stress (judged from the closeness of the contest and the particular relevance of the result to Germany), and presumably sympathetic nervous activation, to cardiac events.2 The case is no less strong that chronic sympathetic activation is similarly adverse. In patients with heart failure, the cardiac sympathetic outflow is preferentially and often very highly activated. The level of this stimulation of the cardiac sympathetic outflow is directly related to reduced survival.3 -Adrenergic blocking drugs break this link. Similarly, in patients with end-stage renal disease, the very high level of sympathetic activity, which is equal to that present in heart failure, almost certainly contributes directly to cardiovascular mortality.4 A similar claim has been made for depressive illness that the sympathetic activation present in the heart5 underlies the increased cardiovascular mortality that exists, but here the case is less certain. In patients with essential hypertension, sympathetic activation is also common, present in perhaps 50% of patients.6 Recent evidence with endovascular radiofrequency ablation of the renal sympathetic nerves in patients with drug-resistant hypertension suggests that this activation of the sympathetic nervous system sustains the blood pressure elevation.6 Perhaps this sympathetic nervous activation in essential hypertension, much as for cardiac failure, contributes directly to mortality, having a detrimental influence in addition to the blood pressure elevation?7 If this is true, the sympathetic nervous system stimulation produced by some antihypertensive drugs (diuretics and dihydropyridine calcium channel blockers being examples8,9) might be harmful. These considerations provide the backdrop to the interesting article by Wray and Supiano,10 who studied the effect of chronic oral dosing with hydrochlorothiazide on sympathetic nervous system activity in patient with hypertension and compared this with the effect of aldosterone antagonism with spironolactone. The patients with hypertension studied were elderly, the authors reasoning that, in the elderly, any druginduced sympathetic activation would be doubly pertinent, superimposed as it would be on the sympathetic activation, which accompanies aging. Very emphatically, the sympathetic nervous activation anticipated with spironolactone was not seen, with clear cut sympathetic inhibition being documented. This was surprising given the contrary effect on sympathetic tone seen with sodium depletion produced by either a diuretic8 or dietary sodium restriction.11 Brain mineralocorticoid receptors mediating excitation of central nervous system sympathetic outflow have been described12; the effect of antagonizing these (lowered sympathetic tone) must have overridden any sympathetic stimulation from sodium depletion. Perhaps this sympathetic inhibition contributed to the blood pressure reduction being greater with spironolactone than hydrochlorothiazide in the study by Wray and Supiano.10 The sympathetic activation from sodium depletion, which preferentially involves the renal sympathetic outflow,11 is adaptive, promoting a counterbalancing renal retention of sodium.6 Of the differing methods used for investigating the sympathetic nervous system in clinical research, each have strengths and weaknesses.8 The method used by Wray and Supiano,10 a 2-compartment radiotracer kinetic method, has definite strengths, but perhaps one weakness. The principal strength is that the appearance rate of the sympathetic transmitter, norepinephrine, in the extravascular space, “NE2” in the authors’ notation, can be measured. This provides very specific information on whole body norepinephrine flux into the sympathetic synapse and beyond into the interstitial space. The measured value is larger, and the measurement has somewhat greater analytic power than the commonly used whole body norepinephrine “spillover” measurement,8,11 which represents the appearance rate of norepinephrine in the plasma (vascular) compartment. Wray and Supiano10 found that spironolactone lowered the appearance rate of norepinephrine in the extravascular space but did not materially The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. Correspondence to Murray Esler, PO Box 6492, St Kilda Road, Central Melbourne, Vic 8008, Australia. E-mail murray.esler@bakeridi. edu.au (Hypertension. 2010;55:1090-1091.) © 2010 American Heart Association, Inc.