Sympathoinhibition by Atorvastatin in Hypertensive Patients

Abstract

Background: Experimental animal data suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) might reduce enhanced sympathetic activity, a hallmark of hypertensive patients. This hypothesis was tested for the first time in patients with primary hypertension. Methods and Results:Using a prospective, randomized, placebo-controlled, double-blind, cross-over design, a proof-of-principle trial was performed in 13 patients with mild to moderate primary hypertension, who were randomly assigned to a regimen of atorvastatin (80 mg/day) for 3 weeks, followed by placebo for 3 weeks or to a regimen of placebo for 3 weeks, followed by atorvastatin (80 mg/day) for 3 weeks. Microneurography was used at the end of each treatment period to measure sympathetic nervous system activity (muscle sympathetic nerve activity: MSNA). Heart rate variability (HRV) and plasma norepinephrine concentrations were also measured. Additionally, effects on blood pressure (BP) and heart rate (HR) were assessed by 24-h ambulatory BP measurement. Atorvastatin reduced postganglionic MSNA (atorvastatin 35.0±2.0 vs placebo: 39.2±1.5 bursts/min, P=0.008) and heart frequency corrected MSNA (atorvastatin: 58.5±2.0 vs placebo: 64.7±3.0 bursts/100 beats, P=0.02). Atorvastatin had no significant effect on plasma norepinephrine levels, HRV, BP or HR. Conclusions:In patients with mild to moderate hypertension, atorvastatin reduces postganglionic MSNA, which supports the hypothesis that HMG-CoA reductase plays a role in sympathetic nervous system activity. (Circ J 2010; 74: 2622 - 2626

Sympathoinhibitory Effects of Atorvastatin in Hypertension

“…5 In fact, we demonstrated that oral administration of atorvastatin has sympathoinhibitory effects in SHRSP via an increase in NO production because of upregulation of eNOS in the brain, 8 as Gomes et al in this issue of the Journal cite our article as a motivation for their study, and importantly, they found the sympthoinhibitory effect in patients with hypertension treated with atorvastatin. 12 Furthermore, in our animal experiments, the oral administration of atorvastatin inhibited the activation of the SNS and improved the impaired baroreflex control in SHRSP via reduction of ROS in the RVLM. 9, 10 These results suggest that the antioxidant effect of atorvastatin in the RVLM might contribute to the sympathoinhibitory effects observed in SHRSP.…”

“…14 In this issue of the Journal, Gomes et al describe how, by measuring the postganglionic muscle sympathetic nerve activity (MSNA) directly, which is a gold standard method of evaluating SNS activity in humans, 15 they were able to reduce MSNA in mild to moderate hypertensive patients. 12 Whereas the lower MSNA levels did not translate into lower venous plasma norepinephrine levels, lower blood pressure levels or a change in heart rate variability, their report is the first randomized, placebo-controlled, double-blind, cross-over designed study to demonstrate the sympathoinhibitory effect of atorvastatin in hypertensive humans. Although it is necessary to confirm the longer term clinical outcomes and mechanisms, their message has significant clinical implications.…”

Low-dose atorvastatin reduces ambulatory blood pressure in patients with mild hypertension and hypercholesterolaemia: a double-blind, randomized, placebo-controlled study

“…22,[24][25][26] Only one recent study with ABPM reported non-significant differences between a statin and placebo; however, that should be rather attributed to the low number of subjects (n ¼ 13) and the short total duration (6 weeks). 27 A meta-analysis of 20 randomized studies of statin therapy, in which background antihypertensive treatment remained unchanged also slightly supported a beneficial effect, showing a significant reduction of 1.9 mm Hg in SBP vs placebo or control hypolipidemic therapy. 14 The findings of our study are in line with that of the University of California/San Diego statin trial, 15 where 973 patients without cardiovascular disease were randomized to simvastatin 20 mg, pravastatin 40 mg daily or placebo for 6 months, and office BP was reduced by 2.2/2.4 mm Hg more in statin groups.…”

Rapid Onset of Renal Sympathetic Nerve Activation in Rabbits Fed a High-Fat Diet

“…26 Moreover, a recent study in overweight humans with primary hypertension found that atorvastatin treatment resulted in a reduction in muscle nerve activity independent of blood pressure, indicating that the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase may activate sympathetic drive. 27 Irrespective of the mechanism underlying the phenomenon, this has implications for cardiovascular health in people who are constantly in a cycle of weight gain and acute dieting to reduce body weight. During the weight gain phase, MAP and RSNA rise rapidly, but even after successfully reducing caloric intake, these individuals may retain elevated RSNA and MAP.…”