L‐arginine Infusion Reduces Muscle Sympathetic Nerve Activity and Blood Pressure in Patients with Chronic Kidney Disease

Abstract

An overactive sympathetic nervous system is a known cardiovascular risk factor present in chronic kidney disease (CKD) patients. However, limited effort has been directed at identifying the mechanisms contributing to sympathetic overactivity in CKD. Herein, we examined a potential role for accumulation of the endogenous nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) in driving the high sympathetic nerve activity (SNA) present in CKD. ADMA is elevated in CKD and is a strong, independent predictor of future cardiovascular events in these patients. Much of the work with ADMA has been correlational in nature with a focus on the well‐known vascular endothelial properties of nitric oxide. However, increasing functional evidence indicates that NO is also a key signaling molecule involved in the tonic restraint of sympathetic outflow from the brainstem. Thus, it is possible that NO synthase inhibition with elevated endogenous ADMA contributes to sympathetic overactivity in CKD patients. We tested the hypothesis that overcoming accumulation of endogenous ADMA with acute L‐arginine infusion reduces sympathetic overactivity in CKD patients. In 5 hypertensive CKD patients, muscle SNA (peroneal nerve microneurography), blood pressure (BP; finger photoplethysmography), and heart rate (ECG) were measured before, during, and 45 minutes after systemic intravenous infusion of L‐arginine, the natural substrate for NO synthase, at a dose of 250 mg/kg over 20 minutes. Following L‐arginine infusion, mean BP was reduced (111±4 mmHg, baseline vs. 105±4 mmHg, L‐arginine; P=0.009). Likewise, MSNA was significantly decreased with L‐arginine (70±4 bursts per 100 heart beats, baseline vs. 59±6 bursts per 100 heart beats, L‐arginine; P=0.023). The concomitant decrease in MSNA and BP strongly implicates a central sympathetic effect of L‐arginine. If L‐arginine was only restoring peripheral NO production, the endothelial‐mediated reduction in mean BP due to peripheral vasodilation would be accompanied by an arterial baroreflex‐mediated increase in MSNA. These preliminary findings of simultaneous reductions in MSNA and BP suggest that L‐arginine restores central NO production in CKD patients supporting a role for ADMA in mediating sympathetic overactivity and hypertension in CKD patients.Support or Funding InformationNIH R01 HL127071