Sympathetic overactivity in active ulcerative colitis: effects of clonidine

Abstract

Previous reports suggest that inflammatory bowel diseases may be accompanied by abnormalities in the neural autonomic profile. We tested the hypotheses that 1) an exaggerated sympathetic activity characterizes active ulcerative colitis (UC) and 2) a reduction of sympathetic activity by clonidine would be associated with clinical changes of UC. In 23 patients with UC and 20 controls, muscle sympathetic nerve activity (MSNA), ECG, blood pressure, and respiration were continuously recorded, and plasma catecholamine was evaluated both at rest and during a 75 degrees head-up tilt. Autonomic profile was assessed by MSNA, norepinephrine, epinephrine, spectral markers of low-frequency (LF) cardiac sympathetic (LF(RR); normalized units) and high-frequency (HF) parasympathetic (HF(RR); normalized units) modulation and sympathetic vasomotor control (LF systolic arterial pressure; LF(SAP)), obtained by spectrum analysis of the R-R interval and systolic pressure variability. Among UC patients, 16 agreed to be randomly assigned to 8-wk transdermal clonidine (15 mg/wk, 9 subjects), or placebo (7 patients). An autonomic profile, Disease Activity Index (DAI), and endoscopic pattern were compared before and after clonidine/placebo. At rest, MSNA, heart rate (HR), LF(RR), LF/HF, and LF(SAP) were higher and HF(RR) was lower in patients than in controls. Tilt decreased HF(RR) and increased MSNA and LF(RR) less in patients than in controls. Clonidine decreased HR, MSNA, epinephrine, LF(RR), and increased HF(RR), whereas placebo had no effects. Changes of the autonomic profile after clonidine were associated with reduction of DAI score. An overall increase of sympathetic activity characterized active UC. Normalization of the autonomic profile by clonidine was accompanied by an improvement of the disease.

Altered adrenal chromaffin cell function during experimental colitis

“…Crohn's disease and ulcerative colitis are the two most prevalent forms of IBD that collectively place a substantial socioeconomic burden on developed countries around the world (6,7,33). Although the precise etiology of IBD remains elusive, evidence suggests that aberrant sympathetic nervous system (SNS) function may contribute to symptom generation during the course of this disease (25,58). Patients with IBD have been examined to determine whether SNS activity is altered by the disease.…”

“…Patients with IBD have been examined to determine whether SNS activity is altered by the disease. Using direct recordings from postganglionic sympathetic axons within the peroneal nerve (25) and power spectrum analysis of heart rate variability (25,27,46), sympathetic hyperexcitability has been observed in patients with active ulcerative colitis, but not Crohn's disease. However, ulcerative colitis patients exhibit normal plasma epinephrine and norepinephrine levels, which indicates that the release of sympathoadrenal transmitters may be impaired despite elevated sympathetic activity (25).…”

Analysing the effect of I1 imidazoline receptor ligands on DSS-induced acute colitis in mice

“…Although some data suggest that activation of these receptors by clonidine improve the symptoms of patients with IBD (Furlan et al 2006;Lechin et al 1985), more recent evidence indicate that stimulation of alpha2-adrenoceptors may rather exacerbate colitis by inducing directly the release of various pro-inflammatory cytokines and chemokines from immune cells (Bai et al 2009(Bai et al , 2015Zádori et al 2016). Moreover, their activation may inhibit the release of acetylcholine from cholinergic enteric nerves, which otherwise is anti-inflammatory by activating alpha7 nicotinic ACh receptors on macrophages (Wang et al 2003).…”

“…This might contribute to their anti-inflammatory effect in some types of inflammation (see above), and according to earlier studies may improve the symptoms of patients with inflammatory bowel disease (IBD) as well (Furlan et al 2006;Lechin et al 1985).…”

Effects of Inflammation on the Innervation of the Colon

“…There is a large body of evidence suggesting that GI inflammation affects the SNS as there are marked changes in SNS excitability (Dong et al 2008), neurotransmitter release (Blandizzi et al 2003;Swain et al 1991), and structure (Dvorak et al 1980;Dvorak and Silen 1985;Magro et al 2002;Straub et al 2008). Patients with active UC display increased SNS activity at rest (Furlan et al 2006;Ganguli et al 2007;Maule et al 2007), while Crohn's disease patients and animal models typically have decreased SNS activity (Swain et al 1991). Nerve dysfunction may continue after clinical symptoms are no longer observed in the patient as there is often increased SNS activity in IBD patients while in clinical remission (Sharma et al 2009).…”