Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin, which is used to treat diabetes mellitus in humans, inhibited vagal activity and activated nitrergic pathways. In rats, GLP-1 also increased sympathetic activity, heart rate, and blood pressure (BP). However, the effects of GLP-1 on sympathetic activity in humans are unknown. Our aims were to assess the effects of a GLP-1 agonist with or without alpha(2)-adrenergic or -nitrergic blockade on autonomic nervous functions in humans. In this double-blind study, 48 healthy volunteers were randomized to GLP-1-(7-36) amide, the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-l-arginine acetate (l-NMMA), the alpha(2)-adrenergic antagonist yohimbine, or placebo (i.e., saline), alone or in combination. Hemodynamic parameters, plasma catecholamines, and cardiac sympathetic and parasympathetic modulation were measured by spectral analysis of heart rate. Thereafter, the effects of GLP-1-(7-36) amide on muscle sympathetic nerve activity (MSNA) were assessed by microneurography in seven subjects. GLP-1 increased (P = 0.02) MSNA but did not affect cardiac sympathetic or parasympathetic indices, as assessed by spectral analysis. Yohimbine increased plasma catecholamines and the low-frequency (LF) component of heart rate power spectrum, suggesting increased cardiac sympathetic activity. l-NMMA increased the BP and reduced the heart rate but did not affect the balance between sympathetic and parasympathetic activity. GLP-1 increases skeletal muscle sympathetic nerve activity but does not appear to affect cardiac sympathetic or parasympathetic activity in humans.

Fig. 1.

Design for experiments 1 and 2. Hemodynamic parameters, spectral analysis of heart rate and blood pressure, and plasma catecholamines were assessed as shown.

Fig. 2.

Effect of drugs on heart rate variability [i.e., normalized low-frequency power of heart rate variability (HRV_LF, top), HRV_LF/HRV_HF (middle)], and normalized high-frequency power of heart rate variability (HRV_HF, bottom), during fasting and postprandial periods. All values are actual means ± SE. l-NMMA, N^G-monomethyl-l-arginine acetate; GLP-1, glucagon-like peptide-1. *P ≤ 0.05 vs. placebo. †P ≤ 0.05 vs. GLP-1 alone.

Fig. 3.

Effect of drugs on plasma norepinephrine. During the fasting and both postprandial phases, plasma norepinephrine levels were higher among subjects who received yohimbine alone or in combination with GLP-1. *P = 0.06 yohimbine vs. placebo. †P = 0.01 GLP-1 and yohimbine vs. GLP-1 alone. ‡P < 0.05 yohimbine vs. placebo.

Fig. 4.

Effect of drugs on plasma dihydroxyphenylglycol (DHPG). During the postprandial period, plasma DHPG levels were higher among subjects who received yohimbine alone or in combination with GLP-1. *P < 0.03 vs. placebo. †P < 0.03 vs. GLP-1 alone.

Fig. 5.

Effect of GLP-1 on muscle sympathetic nerve activity. GLP-1 increased MSNA recorded under fasting conditions. *0.02 < P ≤ 0.05 vs. baseline (signed rank test).