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- MATERIALS AND METHODS
Patients with ulcerative colitis experience diarrhoea, tenesmus, or urgent defecation. The pathogenesis of these symptoms is incompletely understood. While decreased absorption and/or excessive secretion of fluids and electrolytes may partly explain liquid diarrhoea, there is often a mismatch between severity of symptoms and the degree of inflammation demonstrable endoscopically.1–5 This discrepancy suggests that symptoms may in part be attributable to other mechanisms, including disturbances of colorectal motor or sensory functions. However, the results of previous studies have been inconsistent; for example, different studies have reported either a reduced or an exaggerated postprandial colonic phasic pressure response.6–10
The rectum is poorly compliant in patients with active proctitis;11, 12 however, previous studies have not evaluated colonic tone or compliance in ulcerative colitis. The radiological appearance of ‘lead-piping’ is suggestive of impaired colonic compliance. It is conceivable that reduced colonic capacitance, or accommodation of a load of chyme delivered from the small bowel into the proximal colon may contribute to diarrhoea or urgency. Viscoelastic properties of the colon in ulcerative colitis could be altered either as a result of mucosal and submucosal inflammation, or by reflex changes in the muscularis layer. Indeed, Collins et al. have shown that mucosal inflammation alters nerve and muscle function in in vitro models of colitis.13
The prevalence of ulcerative colitis in lifetime non-smokers is five times greater than in current smokers.14–17 A causal relationship between smoking and ulcerative colitis is supported by the recurrence of colitis after smoking cessation and remission with smoking commencement in non-smokers or resumption among smokers.16, 18, 19 Clinical trials in patients with active ulcerative colitis indicate that transdermal nicotine reduces diarrhoea and urgency, but nicotine does not significantly impact the endoscopic features of inflammation.20–22 These observations suggest that alternative mechanisms, unrelated to anti-inflammatory actions, may be responsible for the beneficial clinical effects of nicotine. Nicotine receptors are abundantly present on colonic intrinsic and extrinsic nerves and in pre- and paravertebral ganglia. It is unknown whether nicotine influences colonic motility, compliance or tone in ulcerative colitis, or whether the beneficial effects of nicotine on symptoms are attributable to alterations in motor function.
We hypothesized that: (i) ulcerative colitis is associated with increased colonic tone, and reduced colonic compliance; and (ii) nicotine relaxes the colon thereby ameliorating symptoms. To test these hypotheses, we conducted a series of studies: first, to assess the effects of ulcerative colitis on colonic compliance, fasting and postprandial motility and tone; and second, to evaluate the acute effects of nicotine on colonic motor activity and tone in healthy subjects and ulcerative colitis patients. To preliminarily assess possible mechanisms of action of nicotine, we also measured plasma levels of catecholamines (dopamine, adrenaline, noradrenaline), and substance P as markers of inhibitory and excitatory innervation of the gut, respectively.
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- MATERIALS AND METHODS
The present data demonstrate that fasting phasic pressure activity (but not tone or compliance) in the upper descending colon is significantly greater in ulcerative colitis patients compared to healthy controls. In contrast, the colonic contractile response to a meal is significantly reduced in patients with ulcerative colitis compared to that of healthy controls.
Intravenous nicotine has dose-dependent effects on colonic motor activity in healthy subjects. Low dose nicotine infusions, at concentrations which mimic a 22 mg nicotine dermal patch, do not affect phasic contractility or tone of the colon, but they do reduce colonic compliance. A high dose of nicotine induces an initial burst of high amplitude propagated contractions while relaxing the descending colon. Colonic transit is accelerated soon after beginning a nicotine infusion. Thereafter, colonic relaxation persists and high amplitude propagated contractions and non-propagated phasic contractile activity subside during a continuous infusion of nicotine.
Our data show that ulcerative colitis, primarily affecting the proctosigmoid region and unassociated with ‘lead piping’, does not alter compliance in the descending colon. In contrast to our data, others have shown decreased rectal compliance in patients with active ulcerative proctitis.11, 12 This discrepancy can be explained by a difference in the colonic region studied and the severity of inflammation of that region. In nine out of 13 patients in our study, the disease was limited to the rectosigmoid, and compliance was assessed in the endoscopically normal descending colon, in contrast to the previous studies of rectal compliance in patients with active proctitis.11, 12
An impaired colonic tone response to a meal was evident in patients with either mild or no inflammation in the descending colon. This raises the possibility that neuromuscular responsiveness to physiological stimuli may be altered at sites distant from the region of active mucosal inflammation. Supporting this concept are observations by Collins et al. in experimental models of mucosal inflammation induced by Trichinella spiralis infection that demonstrate abnormal enteric nerve and muscle functions even in uninflamed tissue.13 However, the pathogenesis of these disturbances in uninflamed tissue is unclear because alterations in ion channels that regulate contractility have only been reported in inflamed segments.36, 37
Given the presence of nicotine receptors on intrinsic and extrinsic neurones innervating colonic smooth muscle, and the discrepancy between therapeutic effects on inflammation and symptoms in ulcerative colitis, we hypothesized that motor effects of nicotine would, at least partly, explain its beneficial effects on symptoms. Previous studies provided some support for this hypothesis, in view of the report of a dose-dependent reduction in colonic transit time with transdermal nicotine in healthy non-smokers, a reduction in colonic tone with intrarectal nicotine, and a biphasic effect of smoking on distal colonic phasic pressure activity in chronic smokers.38–40
Our study expands on these observations by assessing the dose-dependent effects of nicotine on fasting colonic tone and compliance and the postprandial colonic response. While low dose nicotine did not affect fasting phasic pressure activity, colonic tone or transit, high dose nicotine induced a series of alterations in motor activity. The effects of high dose nicotine include an initial surge of high amplitude propagated contractions, followed by a pronounced, persistent inhibition of colonic tone and phasic pressure activity. We suspect that these events, in part, reflect the several known neurohumoral effects of nicotine accompanied by rapid tachyphylaxis at nicotine receptors.41 Thus, high amplitude propagated contractions may be induced by activation of nicotine receptors on cholinergic or neurokinergic (substance P, neurokinins A and B) motor neurones.42, 43 The relatively short burst of high amplitude propagated contractions may be explained either by rapid desensitization and tachyphylaxis at nicotine receptors, or by the pronounced increase in plasma adrenaline levels, reflecting stimulation of nicotine receptors in the adrenal medulla.44, 45 Increased adrenaline levels may inhibit high amplitude propagated contractions and reduce colonic tone and phasic pressure activity. Adrenaline evokes a relaxing effect on longitudinal and circular muscles of the proximal colon from cattle; these effects were mediated by beta and alpha-1 receptors, respectively.46
Low dose nicotine, at concentrations designed to mimic the nicotine patch, did not influence colonic transit in healthy subjects or colonic motility in patients with ulcerative colitis. These observations do not support the hypothesis that the beneficial therapeutic effects of nicotine in ulcerative colitis are consequent to its motor effects. We acknowledge that the pharmacokinetics of intravenous and topical nicotine may differ. While the intravenous route mimics the maximum and the steady state concentrations achieved with the transdermal nicotine patch, other pharmacokinetic parameters (e.g. time to reach maximal plasma concentration) may differ between the two methods of administration.23, 24 Hence, we cannot completely exclude an effect of transdermal nicotine on colonic motor functions. Future studies are necessary to assess the effects of long-term transdermal nicotine on colonic transit and motility in healthy participants and in patients with ulcerative colitis, to dissect the effects of nicotine on inflammation and motility.