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Nitric oxide prevents duodenal contractions induced by various potentially noxious agents
A764 AGA ABSTRACTS • G3148
LOWER VAGAL TONE DURING SLEEP IN WOMEN W I T H IRRITABLE BOWEL SYNDROME. M. Heitkemner, RL. Burr, ME. Jarrett, MK. Lustyk, V. Hertlg, EF. Bond University of Washington, Seattle WA. The purpose of this study was to compare the circadian patterns of vagal tone in women with Irritable Bowel Syndrome (IBS) compared to nonsymptomatic controls. Methods: Women with medically diagnosed IBS (n = 42) and healthy controls (n = 21 ) ages 21-45 were interviewed, followed for one menstrual cycle with a symptom diary, and wore a Holter 24-hour heart rate monitor during mid-luteal phase. Summary measures included: low frequency band variance (LF) which was defined to be the integral (area under the curve) of the HRV spectrum between frequencies f = 0.016 and f = 0.04 Hz, medium frequency band (MF, f = 0.04 and f = 0.15 Hz.), and high frequency band (HF, f = 0.15 and f = 0.40 Hz). The mean interval (MI) was calculated as the average of R-R intervals in the context of normal sinus rhythm. The LFHF ratio was computed as LF divided by HF. Analysis of variance/covariance (ANCOVA) by group (IBS vs. Control), incorporating the covariates subject age and mean RR interval, was used to test group differences. The hour-by-hour profile of HF for each woman was estimated and synchronized relative to her selfreported time of awakening. The synchronized pattems were aggregated across subjects to produce representative twenty-four hour profiles for each group. ANCOVA analysis was used to test the differences between the groups at each hour. Results: Women with IBS demonstrated significantly lower HF and higher LFHF when averaged over a 24 hour period relative to nonsymptomatic women (p < .05). In addition, women with IBS had a flattened 24 hour pattern of HR¥, with significantly lower levels of HF during the reported sleep interval. Using age and Mean Interval as covariates, statistically significant differences (p < .05) between the IBS and Control groups can be demonstrated for each of the eight individual hours immediately prior to wakening. Conclusions: These results suggest that systemic sympathovagal balance may be shifted in women with IBS during the sleep interval. Funded by National Institute of Nursing Research, NR04101. • G3149
NITRIC OXIDE PREVENTS DUODENAL CONTRACTIONS INDUCED BY VARIOUS POTENTIALLY NOXIOUS AGENTS. S. Hellgren, G: Flemstr6m and O. Nylander. Dept. of Physiology and Med. Biophysics, Biomedical Center, Uppsala University, Uppsala, Sweden. Data from our laboratory have shown that luminal HCI perfusion does not induce duodenal contractions in anesthetized rats after abdominal surgery. However, in rats treated with the nitric oxide synthase inhibitor L-NAME HC1 induces or augments duodenal motility. The opposite occurs in rats pretreated with the cyclooxygenase inhibitor indomethacin, where HC1 perfusion decreases the motility. The aim of this study was to examine whether these effects of HC1 on duodenal motility could be mimicked by a brief luminal perfusion with capsaicin, a neurotoxin known to activate sensory neurons, or ethanol (EtOH). Method: Rats were anesthetized with Inactin ® (butabarbital) and the proximal duodenum was perfused with isotonic saline. L-NAME (3 mg/kg) or indomethacin (5 mg/kg) was given i.v. 40 or 60 minutes before perfusing the duodenum for 10 minutes with HC1 (10mM), capsaicin (1.2 mg/ml) or EtOH (15%) respectively. Motility was assessed by measuring intraluminal pressure and quantified by calculating the fraction of time occupied by contractions (FCT). Results: In untreated rats no, or very few, contractions occurred during saline perfusion or in response to HCI, capsaicin or EtOH. In rats pretreated with L-NAME HC1 perfusion increased FCT (p<0.05) from 0.13,+0.05 to 0.30 ,+ 0.04 and decreased to 0.08 -+0.04 after cessation of the HCI perfusion (p<0.05). During capsaicin perfusion FCT increased from 0.26 ,+ 0.07 to 0.40.+0.10 (p<0.05). After cessation of the capsaicin perfusion motility decreased to a mean FCT of 0.09 .+ 0.04 (p<0.05). Perfusion with EtOH, similarly, augmented the motility in L-NAME pretreated rats. The FCT increased from 0.27 -+0.01 to 0.37 -+ 0.04 (p<0.05). The motility decreased to 0.20 .+ 0.05 after cessation of the EtOH perfusion (p<0.05). In indomethacin pretreated rats FCT decreased from 0.35.+0.05 to 0.18,+0.03 and from 0.46-+0.04 to 0.18.+0.04 in response to HCI and capsaicin perfusion respectively (p<0.05). Conclusion~: The reason why HC1, capsaicin or EtOH do not affect motility in untreated rats may be that the tissue level of NO is high enough to block the response, or that these noxious agents increase the release of nitric oxide.Nitric oxide (NO) may exert its inhibitory effect on motility either by blocking the capsaicin sensitive sensory neurons or by a direct action on duodenal smooth muscles. High levels of NO may compromise the ability of the duodenum to contract when exposed to potentially noxious agents. • G3150 SPATIO-TEMPORAL MAPS OF INTESTINAL MOTOR PATTERNS. G. Henni~. M. Costa, G. D'Antona, S. Brnokes. Department of Physiology and Centre for Neurnscience, Flinders University, South Australia. The contraction or relaxation of the smooth muscle layers in the gastrointestinal tract give rise to a variety of motor patterns. The analysis of
GASTROENTEROLOGY Vol. 114, No. 4
these motor patterns has been difficult due to the limited spatial resolution of traditional recording techniques. We have developed a new way to analyse gastrointestinal motor activity using spatio-temporal maps of wall motion from video recordings. Segments of ileum or colon were taken from guinea-pigs killed by cervical dislocation and bleed from the carotid arteries. The segments were mounted in a heated organ bath containing oxygenated Krebs solution and the profile of the isolated segments was recorded onto S-VHS video tape. Frames of motion were digitized into the NIH Image program and thresholding routines were applied. Spatio°temporal maps of gastrointestinal motor activity were constructed by converting the diameters along the length of the segment into a row of greyscale pixels. Parallel recording of intraluminal pressure at the oral and anal ends was performed using a MacLab data acquisition system. This method enabled a direct comparison of the patterns and intraluminal pressures generated by motor activity. Spatio-temporal maps of intestinal segments revealed irregular and variable spontaneous circular muscle activity with a mixture of standing, segmenting, and propagated contractions. Slow liquid infusion into the lumen of the intestinal segments decreased these irregular spontaneous patterns of activity of the circular muscle, but increased rhythmic activity in the longitudinal muscle preceding peristalsis. A peristaltic contraction of the circular muscle started at a threshold volume and propagated rapidly from oral to anal. The threshold diameter at which peristalsis was initiated and the speed of propagation of the peristaltic contraction could be readily measured from the maps. Spatio-temporal maps of wall motion in the proximal and distal colon showed large peristaltic contractions that swept from the ileocaecal valve to the colonic flexure at regular intervals of 1-5 minutes during spontaneous emptying. Shallow contractions in the circular muscle that propagated both anally and orally were also evident in the proximal colon. The spatio-temporal maps of the transit of pellets from the colonic flexure to the rectum, portrayed their anal progression and revealed anal propagation of spontaneous contractions. This method has revealed previously undetected patterns of motility and provides a simple, but powerful way to analyse and quantify patterns of motor activity in the gastrointestinal tract. • G3151 EVALUATION OF A MULTI-COMPONENT BEHAVIORAL TREATMENT FOR THE IRRITABLE BOWEL SYNDROME. I. HeymannM6nnikes. R. Arnold. 1. Florin*, and H. M~nnikes. Departments of Internal Medicine and Psychology*. Philipps-University Marburg. Germany. BACKGROUND: Although the standard treatments for the irritable bowel syndrome (IBS) are medical, growing evidence indicates the substantial therapeutic value of psychological treatment. However, it has not been investigated, if the combination of standardized multicomponent behavioral treatment (SMBT) plus standard medical treatment (SMT) is more effective than standard medical treatment alone. AIM of this study was to investigate this question in patients consulting a tertiary GI referral center. METHODS: IBS-outpatients were randomly assigned to SMT plus SMBT (N= 12) (referred to as SMBT-group) or SMT alone (N=12) (referred to as SMT-group). SMBT included IBS information and education, progressive muscle relaxation, training in illness related cognitive coping strategies, problem solving, and assertiveness training in 10 sessions over 10 weeks. Post-treatment outcome measures consisted of quantification of gi, vegetative and psychological symptoms by means of daily symptom diaries, determination of recto-visceral perception thresholds to balloon distention, as well as in questionnaire measures of psychological distress, overall well-being, illness related coping abilities and quality of life. Follow-ups were conducted at three and six months. RESULTS: Symptom diaries: Pre- to post-treatment evaluations showed a significantly greater IBS-symptom reduction as measured by daily symptom diaries for the SMBT-group than for the SMTogroup. The scale values of all 20 IBS-related diary items were calculated as a composite IBS global symptom-score. In the SMBT-group this score showed a significant decrease from 0.84 -+0.52 at pre-treatment to 0.41 -+ 0.54 at post-treatment (p<0.001), but it remained unchanged in the SMT-group (0.6-+0.4 vs 0.74-+ 0.43 pre/post). Additionally, according to the three symptom subgroups composite gastrointestinal, psychological, and vegetative symptom-scores were calculated. In the SMBTogroup the results yielded significant decreases for the gastrointestinal symptom-score (0.91 -+ 0.59 vs 0.46 ,+ 0.48 pre/pust; p<0.01) and the psychological symptom-score (1.14 -+ 1.33 vs 0.49 ± 1.43 pre/post; p<0.001). The vegetative symptom-score (0.54 ,+ 0.4 vs 0.25 + 0.46 pre/post) showed a similar trend but failed to reach significance. In the SMT-group in contrast, the gastrointestinal symptomscore (0.69-+0.48 vs 0.85 -+0.5 pre/post), psychological symptom-score (0.29-+0.35 vs 0.52-+0.98 pre/post), and the vegetative symptom-score (0.51 -+0.4 vs 0.55-+0.36 pre/post) remained unchanged. Physiological measure~: Recto-visceral perception thresholds remained unchanged by either treatment. Standardized ouestionnaires: Overall well-being as measured by the 'list of complaints' (BL) was significantly improved in the SMBT-group with a decrease from 28.7-+ 8.6 at pre-treatment to 20.25-+ 9.1 at posttreatment (p<0.01) but remained unchanged in the SMT-group (32.8 _+12.1 vs 35.0 .+ 7.5 pre/post). Subjects in the SMBT-group (22.9 .+ 6.4 vs 27.5 .+ 4.7 pre/post; p<0.001) unlike those in the SMT-group (21.1 .+ 4.0 vs 18.7 .+ 6.1 pre/post) felt significantly more in control of their health as assessed by an
LOWER VAGAL TONE DURING SLEEP IN WOMEN W I T H IRRITABLE BOWEL SYNDROME. M. Heitkemner, RL. Burr, ME. Jarrett, MK. Lustyk, V. Hertlg, EF. Bond University of Washington, Seattle WA. The purpose of this study was to compare the circadian patterns of vagal tone in women with Irritable Bowel Syndrome (IBS) compared to nonsymptomatic controls. Methods: Women with medically diagnosed IBS (n = 42) and healthy controls (n = 21 ) ages 21-45 were interviewed, followed for one menstrual cycle with a symptom diary, and wore a Holter 24-hour heart rate monitor during mid-luteal phase. Summary measures included: low frequency band variance (LF) which was defined to be the integral (area under the curve) of the HRV spectrum between frequencies f = 0.016 and f = 0.04 Hz, medium frequency band (MF, f = 0.04 and f = 0.15 Hz.), and high frequency band (HF, f = 0.15 and f = 0.40 Hz). The mean interval (MI) was calculated as the average of R-R intervals in the context of normal sinus rhythm. The LFHF ratio was computed as LF divided by HF. Analysis of variance/covariance (ANCOVA) by group (IBS vs. Control), incorporating the covariates subject age and mean RR interval, was used to test group differences. The hour-by-hour profile of HF for each woman was estimated and synchronized relative to her selfreported time of awakening. The synchronized pattems were aggregated across subjects to produce representative twenty-four hour profiles for each group. ANCOVA analysis was used to test the differences between the groups at each hour. Results: Women with IBS demonstrated significantly lower HF and higher LFHF when averaged over a 24 hour period relative to nonsymptomatic women (p < .05). In addition, women with IBS had a flattened 24 hour pattern of HR¥, with significantly lower levels of HF during the reported sleep interval. Using age and Mean Interval as covariates, statistically significant differences (p < .05) between the IBS and Control groups can be demonstrated for each of the eight individual hours immediately prior to wakening. Conclusions: These results suggest that systemic sympathovagal balance may be shifted in women with IBS during the sleep interval. Funded by National Institute of Nursing Research, NR04101. • G3149
NITRIC OXIDE PREVENTS DUODENAL CONTRACTIONS INDUCED BY VARIOUS POTENTIALLY NOXIOUS AGENTS. S. Hellgren, G: Flemstr6m and O. Nylander. Dept. of Physiology and Med. Biophysics, Biomedical Center, Uppsala University, Uppsala, Sweden. Data from our laboratory have shown that luminal HCI perfusion does not induce duodenal contractions in anesthetized rats after abdominal surgery. However, in rats treated with the nitric oxide synthase inhibitor L-NAME HC1 induces or augments duodenal motility. The opposite occurs in rats pretreated with the cyclooxygenase inhibitor indomethacin, where HC1 perfusion decreases the motility. The aim of this study was to examine whether these effects of HC1 on duodenal motility could be mimicked by a brief luminal perfusion with capsaicin, a neurotoxin known to activate sensory neurons, or ethanol (EtOH). Method: Rats were anesthetized with Inactin ® (butabarbital) and the proximal duodenum was perfused with isotonic saline. L-NAME (3 mg/kg) or indomethacin (5 mg/kg) was given i.v. 40 or 60 minutes before perfusing the duodenum for 10 minutes with HC1 (10mM), capsaicin (1.2 mg/ml) or EtOH (15%) respectively. Motility was assessed by measuring intraluminal pressure and quantified by calculating the fraction of time occupied by contractions (FCT). Results: In untreated rats no, or very few, contractions occurred during saline perfusion or in response to HCI, capsaicin or EtOH. In rats pretreated with L-NAME HC1 perfusion increased FCT (p<0.05) from 0.13,+0.05 to 0.30 ,+ 0.04 and decreased to 0.08 -+0.04 after cessation of the HCI perfusion (p<0.05). During capsaicin perfusion FCT increased from 0.26 ,+ 0.07 to 0.40.+0.10 (p<0.05). After cessation of the capsaicin perfusion motility decreased to a mean FCT of 0.09 .+ 0.04 (p<0.05). Perfusion with EtOH, similarly, augmented the motility in L-NAME pretreated rats. The FCT increased from 0.27 -+0.01 to 0.37 -+ 0.04 (p<0.05). The motility decreased to 0.20 .+ 0.05 after cessation of the EtOH perfusion (p<0.05). In indomethacin pretreated rats FCT decreased from 0.35.+0.05 to 0.18,+0.03 and from 0.46-+0.04 to 0.18.+0.04 in response to HCI and capsaicin perfusion respectively (p<0.05). Conclusion~: The reason why HC1, capsaicin or EtOH do not affect motility in untreated rats may be that the tissue level of NO is high enough to block the response, or that these noxious agents increase the release of nitric oxide.Nitric oxide (NO) may exert its inhibitory effect on motility either by blocking the capsaicin sensitive sensory neurons or by a direct action on duodenal smooth muscles. High levels of NO may compromise the ability of the duodenum to contract when exposed to potentially noxious agents. • G3150 SPATIO-TEMPORAL MAPS OF INTESTINAL MOTOR PATTERNS. G. Henni~. M. Costa, G. D'Antona, S. Brnokes. Department of Physiology and Centre for Neurnscience, Flinders University, South Australia. The contraction or relaxation of the smooth muscle layers in the gastrointestinal tract give rise to a variety of motor patterns. The analysis of
GASTROENTEROLOGY Vol. 114, No. 4
these motor patterns has been difficult due to the limited spatial resolution of traditional recording techniques. We have developed a new way to analyse gastrointestinal motor activity using spatio-temporal maps of wall motion from video recordings. Segments of ileum or colon were taken from guinea-pigs killed by cervical dislocation and bleed from the carotid arteries. The segments were mounted in a heated organ bath containing oxygenated Krebs solution and the profile of the isolated segments was recorded onto S-VHS video tape. Frames of motion were digitized into the NIH Image program and thresholding routines were applied. Spatio°temporal maps of gastrointestinal motor activity were constructed by converting the diameters along the length of the segment into a row of greyscale pixels. Parallel recording of intraluminal pressure at the oral and anal ends was performed using a MacLab data acquisition system. This method enabled a direct comparison of the patterns and intraluminal pressures generated by motor activity. Spatio-temporal maps of intestinal segments revealed irregular and variable spontaneous circular muscle activity with a mixture of standing, segmenting, and propagated contractions. Slow liquid infusion into the lumen of the intestinal segments decreased these irregular spontaneous patterns of activity of the circular muscle, but increased rhythmic activity in the longitudinal muscle preceding peristalsis. A peristaltic contraction of the circular muscle started at a threshold volume and propagated rapidly from oral to anal. The threshold diameter at which peristalsis was initiated and the speed of propagation of the peristaltic contraction could be readily measured from the maps. Spatio-temporal maps of wall motion in the proximal and distal colon showed large peristaltic contractions that swept from the ileocaecal valve to the colonic flexure at regular intervals of 1-5 minutes during spontaneous emptying. Shallow contractions in the circular muscle that propagated both anally and orally were also evident in the proximal colon. The spatio-temporal maps of the transit of pellets from the colonic flexure to the rectum, portrayed their anal progression and revealed anal propagation of spontaneous contractions. This method has revealed previously undetected patterns of motility and provides a simple, but powerful way to analyse and quantify patterns of motor activity in the gastrointestinal tract. • G3151 EVALUATION OF A MULTI-COMPONENT BEHAVIORAL TREATMENT FOR THE IRRITABLE BOWEL SYNDROME. I. HeymannM6nnikes. R. Arnold. 1. Florin*, and H. M~nnikes. Departments of Internal Medicine and Psychology*. Philipps-University Marburg. Germany. BACKGROUND: Although the standard treatments for the irritable bowel syndrome (IBS) are medical, growing evidence indicates the substantial therapeutic value of psychological treatment. However, it has not been investigated, if the combination of standardized multicomponent behavioral treatment (SMBT) plus standard medical treatment (SMT) is more effective than standard medical treatment alone. AIM of this study was to investigate this question in patients consulting a tertiary GI referral center. METHODS: IBS-outpatients were randomly assigned to SMT plus SMBT (N= 12) (referred to as SMBT-group) or SMT alone (N=12) (referred to as SMT-group). SMBT included IBS information and education, progressive muscle relaxation, training in illness related cognitive coping strategies, problem solving, and assertiveness training in 10 sessions over 10 weeks. Post-treatment outcome measures consisted of quantification of gi, vegetative and psychological symptoms by means of daily symptom diaries, determination of recto-visceral perception thresholds to balloon distention, as well as in questionnaire measures of psychological distress, overall well-being, illness related coping abilities and quality of life. Follow-ups were conducted at three and six months. RESULTS: Symptom diaries: Pre- to post-treatment evaluations showed a significantly greater IBS-symptom reduction as measured by daily symptom diaries for the SMBT-group than for the SMTogroup. The scale values of all 20 IBS-related diary items were calculated as a composite IBS global symptom-score. In the SMBT-group this score showed a significant decrease from 0.84 -+0.52 at pre-treatment to 0.41 -+ 0.54 at post-treatment (p<0.001), but it remained unchanged in the SMT-group (0.6-+0.4 vs 0.74-+ 0.43 pre/post). Additionally, according to the three symptom subgroups composite gastrointestinal, psychological, and vegetative symptom-scores were calculated. In the SMBTogroup the results yielded significant decreases for the gastrointestinal symptom-score (0.91 -+ 0.59 vs 0.46 ,+ 0.48 pre/pust; p<0.01) and the psychological symptom-score (1.14 -+ 1.33 vs 0.49 ± 1.43 pre/post; p<0.001). The vegetative symptom-score (0.54 ,+ 0.4 vs 0.25 + 0.46 pre/post) showed a similar trend but failed to reach significance. In the SMT-group in contrast, the gastrointestinal symptomscore (0.69-+0.48 vs 0.85 -+0.5 pre/post), psychological symptom-score (0.29-+0.35 vs 0.52-+0.98 pre/post), and the vegetative symptom-score (0.51 -+0.4 vs 0.55-+0.36 pre/post) remained unchanged. Physiological measure~: Recto-visceral perception thresholds remained unchanged by either treatment. Standardized ouestionnaires: Overall well-being as measured by the 'list of complaints' (BL) was significantly improved in the SMBT-group with a decrease from 28.7-+ 8.6 at pre-treatment to 20.25-+ 9.1 at posttreatment (p<0.01) but remained unchanged in the SMT-group (32.8 _+12.1 vs 35.0 .+ 7.5 pre/post). Subjects in the SMBT-group (22.9 .+ 6.4 vs 27.5 .+ 4.7 pre/post; p<0.001) unlike those in the SMT-group (21.1 .+ 4.0 vs 18.7 .+ 6.1 pre/post) felt significantly more in control of their health as assessed by an