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| 번호 | 제목 | 등록일 | 조회수 |
|---|---|---|---|
| 60 | Role of Nitric Oxide in the Colon of Patients With Slow-Transit Constipation [2002년 5월 DCR] | 2011-11-17 | 3738 |
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Ryouichi Tomita, M.D., Shigeru Fujisaki, M.D., Tarou Ikeda, M.D., Masahiro Fukuzawa, M.D.
From Department of Surgery, Nippon Dental University Hospital, and First Department of Surgery, Nihon
University School of Medicine, Tokyo, Japan PURPOSE: The cause of dysmotility in patients with slowtransit constipation is unknown. Nitric oxide has recently been shown to be a neurotransmitter in the nonadrenergic, noncholinergic inhibitory nerves of the human gut. To clarify the physiologic significance of nitric oxide in the colon of patients with slow-transit constipation, we investigated the enteric nerve responses in lesional and normal bowel segments derived from patients with slow-transit constipation and patients who underwent colon resection for colonic cancers.
METHODS: Twenty-six preparations were taken from colonic lesions in eight patients with slow-transit constipation (2 men; age, 23 to 69 (mean, 44.8) years). Forty-two preparations were taken from the normal colons of 14 patients with colonic cancer (8 men; age, 40 to 66 (mean, 52.4) years). A mechanographic technique was used to evaluate in vitro muscle responses to electric field stimulation before and after treatment with various autonomic nerve blockers, NG-nitro-L-arginine, and L-arginine.
RESULTS: The colons of patients with slow-transit constipation were more strongly innervated by nonadrenergic, noncholinergic inhibitory nerves than were normal colons (P<0.05). Nitric oxide was found to act on both normal and slow-transit constipation colons. The colons of patients with slow-transit constipation were more strongly innervated by nitric oxide nerves than were normal colons (P< 0.01). Responses to electric field stimulation were the same in each case among the normal colons and were also the same in each case among the slow-transit constipation colons. CONCLUSION: These findings suggest that an increase of nitric oxide mediates nonadrenergic, noncholinergic inhibitory nerves and plays an important role in the dysmotility observed in the colons of patients with slow-transit constipation. Clinically, constipation has been considered a mixture of four pathogenetic phenomena: slowtransit
type, outlet obstruction type, slow transit with outlet obstruction, and irritable bowel syndrome. The most common type is slow transit constipation (STC). There has long been interest in a possible association between abnormal colonic motility and STC. STC is characterized by impaired motility within the total colon. In histologic studies, the colon with STC is associated with changes not only in the structure of the enteric nervous system, such as adrenergic and cholinergic nerves, but also in neurotransmitter content and receptors. Some authors have reported that a decrease of cholinergic nerve activity and an increase of nonadrenergic, noncholinergic (NANC) inhibitory nerve activity play important roles in the dysmotility observed in the colons of patients with STC. During the last decade, with advancements in pharmacology, electrophysiology, and immunohistochemistry, it has been suggested that the NANC nervous system, in addition to the two classic adrenergic and cholinergic components, may play an important role in the regulation of intestinal motility. It is well known that NANC inhibitory nerves act more dominantly than NANC excitatory nerves in the regulation of enteric nerves in the normal colon. There are some reports that the colon with STC is more strongly innervated by inhibitory nerves, especially NANC inhibitory nerves, than the normal colon.
Recently, nitric oxide (NO) has been reported to be a neurotransmitter of NANC inhibitory nerves in the human gastrointestinal tract. Bult et al. reported that excessive production of NO may cause persistent inhibition of colonic motility in the colons of patients with STC. Therefore, the increase of NO might be related to the impaired motility observed in the STC colon. The function of the enteric nervous system in the colons of patients with STC, however, remains unclear. It appears reasonable to infer, therefore, that
investigations of NO reactions to the enteric nervous system in the colon of patients with STC may help to clarify the pathophysiology of colonic dysmotility in patients with STC. In the present study, we investigated the responses of NO in lesional and normal bowel segments
derived from patients with STC and patients who underwent colon resection for colonic cancers. Mechanographic techniques were used to study the specimens in vitro. DISCUSSION
STC is a poorly understood disorder of colonic function that occurs predominantly in women. In
clinic, defecation disorders such as a lifelong history of infrequent bowel motions, absence of the call to stool, and abdominal bloating and pain are a major symptom in STC, because the decrease in colonic
contractions can accentuate the constipation. Studies of motility patterns in STC have described a marked reduction in contractile activity in the total colon. It has been suspected for many years that pathologic changes in the enteric nervous system could be involved in the pathophysiology of STC. Bassotti et al. reported that mass movements occur less frequently in patients with STC. However, their propulsive waves were of normal amplitude, which suggests an abnormality of neural initiation rather than of the colonic muscle itself. Some authors have indicated that reduced activity of cholinergic
nerves was detected within the bowel wall of the colon with STC. In other words, in STC, there is an important alteration of colonic cholinergic activity. On the other hand, Williams and Palmer reported that catecholamine excess was found in STC. In Experiment 1, the responses to EFS before blockade of the adrenergic and cholinergic nerves indicated that a significantly decreased contraction reaction to EFS could be detected in the colons of patients with STC. An increased relaxation reaction to EFS also could be found in the colons of patients with STC. The former may occur via excitatory neurons such as cholinergic nerves and the latter via inhibitory nerves such as adrenergic neurons. Recently, it has been suggested that NANC excitatory and inhibitory nerves, in addition to the two
classic adrenergic and cholinergic nerves, may play an important role in the regulation of intestinal motility. The intestinal peristaltic reflex is mediated via the enteric nervous system, and NANC excitatory nerves have been found to bring about proximal side contraction, whereas NANC inhibitory nerves cause distal side relaxation of the bowel. Previous reports suggest that the innervation contains both NANC inhibitory and excitatory nerves and that the former are dominant. Mitolo- Chieppa et al. reported that excessive NANC inhibitory nerve drive may be involved in the pathophysiologic mechanism in STC. In Experiment 2, the colons of patients with STC were more strongly innervated by inhibitory nerves, especially NANC inhibitory nerves, than were normal colons. These findings suggest that an increase of NANC inhibitory nerves may play an important role in the decreased motility observed in patients with STC. It has been widely reported that NO plays a major role in relaxation of the enteric smooth muscle of
many different animal species, including humans. In 1990, Bult et al. provided evidence that NO is released by stimulation of the NANC inhibitory nerves in the gastrointestinal tract. Recent studies have shown that NO meets most criteria for neurotransmitters, which supports the role of NO as a neurotransmitter in the gastrointestinal tract. On the other hand, histochemical studies have shown that NO is identical to nicotinamide adenine dinucleotide phosphate diaphorase (NADPH diaphorase). Cortesini et al. suggested that NO synthase was abundant in the STC colon. To the best of our knowledge, there have been few in vitro studies of NO in the colon muscle obtained from patients with STC; such investigations may help to clarify the pathophysiology of impaired motility of this muscle in STC. In the present study, when the muscle strips of normal colon were exposed to L-NNA, an inhibitor of NO biosynthesis, the relaxation response to EFS after blockade of both the adrenergic and cholinergic nerves was attenuated or replaced by a contractile response. The effect of L-NNA was reversed in a concentration-dependent manner by L-arginine, a precursor of NO biosynthesis. In contrast to the normal colon, the colon with STC showed a stronger response to L-NNA and L-arginine. The present data confirm that the increase of NO as a neurotransmitter in NANC inhibitory nerves is most likely responsible for the dysmotility in the colons of patients with STC. |
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