The renal sympathetic nerves have been identified as a major contributor to the complex pathophysiology of hypertension in both experimental models and in humans.¹ Patients with essential hypertension generally have increased efferent sympathetic drive to the kidneys, as evidenced by elevated rates of renal norepinephrine spillover, defined as the amount of transmitter that escapes neuronal uptake and local metabolism and thus “spills over” into the circulation. Hypertension is also characterized by an increased rate of sympathetic-nerve firing, possibly modulated by afferent signaling from renal sensory nerves.^2-4

There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac ³ [H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.

Background— Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular morbidity and mortality in hypertensive subjects. Sympathetic activation has been suggested to contribute to LV hypertrophy, but this has not yet been conclusively validated in humans. Methods and Results— We comprehensively assessed total systemic and regional sympathetic activity by radiotracer dilution methods and microneurography in 15 untreated hypertensive subjects with echocardiographic evidence of LV hypertrophy (EH+), 11 hypertensive subjects with similar blood pressure but without LV hypertrophy (EH−), and 10 age-matched normotensive control subjects (NT). LV mass index was 87±15 g/m ² in NT, 106±11g/m ² in EH−, and 138±17g/m ² in EH+ ( P <0.001). Total body and renal norepinephrine spillover were higher in both hypertensive groups compared with NT (total norepinephrine spillover, NT 223±145 versus EH− 418±135 versus EH+ 497±303 ng/min; renal norepinephrine spillover, NT 38.8±25.3 versus EH− 88.6±58.0 versus EH+ 103.4±56.2 ng/min; both P <0.05). However, muscle sympathetic nerve activity (NT 25±6 versus EH− 38±20 versus EH+ 57±19 bursts per 100 heartbeats; P <0.01) and cardiac norepinephrine spillover (NT 11.7±6.2 versus EH− 13.1±7.2 versus EH+ 28.6±17.4 ng/min; P <0.01) were only increased in EH+. Cardiac norepinephrine spillover correlated positively with LV mass index in all subjects ( r =0.52; P <0.001). Conclusions— Our findings demonstrate that hypertensive LV hypertrophy is associated with increased sympathetic activity largely confined to the heart, suggesting that increased cardiac norepinephrine release is related to the development of LV hypertrophy.

The potential involvement of sympathetic overactivity has been neglected in this population despite accumulating experimental and clinical evidence suggesting a crucial role of sympathetic activation for both progression of renal failure and the high rate of cardiovascular events in patients with chronic kidney disease. The contribution of sympathetic neural mechanisms to the occurrence of cardiac arrhythmias, the development of hypertension, and the progression of heart failure are well established; however, the exact mechanisms contributing to heightened sympathetic tone in patients with chronic kidney disease are unclear. This review analyses potential mechanisms underlying sympathetic activation in chronic kidney disease, the range of adverse consequences associated with this activation, and potential therapeutic implications resulting from this relationship.

Renal denervation (RDN) has been shown to reduce blood pressure (BP) and muscle sympathetic nerve activity (MSNA) in patients with resistant hypertension. The mechanisms underlying sympathetic neural inhibition are unknown. We examined whether RDN differentially influences the sympathetic discharge pattern of vasoconstrictor neurons in patients with resistant hypertension. Standardized office BP, single-unit MSNA, and multi-unit MSNA were obtained at baseline and at 3-month follow-up in 35 patients with resistant hypertension. Twenty-five patients underwent RDN, and 10 patients underwent repeated measurements without RDN (non-RDN). Baseline BP averaged 164/93 mm Hg (RDN) and 164/87 mm Hg (non-RDN) despite use of an average of 4.8±0.4 and 4.4±0.5 antihypertensive drugs, respectively. Mean office BP decreased significantly by −13/−6 mm Hg for systolic BP ( P <0.001) and diastolic BP ( P <0.05) with RDN but not in non-RDN at 3-month follow-up. RDN moderately decreased multi-unit MSNA (79±3 versus 73±4 bursts/100 heartbeats; P <0.05), whereas all properties of single-unit MSNA including firing rates of individual vasoconstrictor fibers (43±5 versus 27±3 spikes/100 heartbeats; P <0.01), firing probability (30±2 versus 22±2% per heartbeat; P <0.02), and multiple firing incidence of single units within a cardiac cycle (8±1 versus 4±1% per heartbeat; P <0.05) were substantially reduced at follow-up. BP, single-unit MSNA, and multi-unit MSNA remained unaltered in the non-RDN cohort at follow-up. RDN results in the substantial and rapid reduction in firing properties of single sympathetic vasoconstrictor fibers, this being more pronounced than multi-unit MSNA inhibition. Whether the earlier changes in single-unit firing patterns may predict long-term BP response to RDN warrants further exploration.