Therapeutic strategies for targeting excessive central sympathetic activation in human hypertension

Abstract

The pathogenesis of hypertension and its mode of progression are complex, multifactoral and incompletely understood. However, there is accumulating evidence from humans and animal models of hypertension indicating that excessive central sympathetic nerve activity (SNA) plays a pathogenic role in triggering and sustaining the essential hypertensive state (the so-called 'neuroadrenergic hypothesis'). Importantly, augmented central sympathetic outflow has also been implicated in the initiation and progression of a plethora of pathophysiological processes independent of any increase in blood pressure, such as left ventricular hypertrophy and cardiac arrhythmias. Thus, the sympathetic nervous system constitutes an important putative drug target in hypertension. However, traditional pharmacological approaches for the management of essential hypertension appear ineffective in reducing central sympathetic outflow. Recently, several new and promising therapeutic strategies targeting neurogenic hypertension have been developed. The present report will provide a brief update of this topic with a particular emphasis on human studies examining the efficacy of novel pharmacological approaches (central sympatholytics and statins), lifestyle modification (aerobic exercise training, weight loss and stress reduction) and surgical intervention (renal denervation, chronic carotid baroreflex stimulation and deep brain stimulation) in reducing excessive central sympathetic activation in hypertension.

Figure 1. Pharmacological inhibition of nitric oxide synthase (NOS) increases sympathetic nerve activity (SNA) in healthy humans

Panel A: Original records illustrating skin SNA at baseline and 180 minutes after a 60 minute intravenous infusion of the NOS inhibitor N^G-nitro-L-arginine methyl ester (L-NAME; 4mg/kg). Panel B: Individual skin SNA responses from all subjects at the end of the L-NAME infusion (i.e. 60 minutes) and at 180 minutes. These findings clearly indicate that experimental inhibition of NOS increases SNA and supports a role of nitric oxide in central sympathetic control in humans. (Reproduced with permission from Young et al., 2009)

Figure 2. A schematic representation of the current therapeutic strategies and targets for reducing excessive central sympathetic nerve activity in hypertension

The sympathetic nervous system constitutes an important putative drug target in hypertension. As noted in the text of this review, traditional pharmacological approaches for the management of essential hypertension appear ineffective in reducing central sympathetic outflow. This schematic depicts several novel and promising therapeutic strategies for targeting neurogenic hypertension in the future. SNA, sympathetic nerve activity