April 1995 Motility and Nerve-Gut Interactions A685

I M M U N O M O D U L A T I O N OF C a 2 + C H A N N E L S BY SMALL INTESTINAL INFLAMMATION, K. Scheer, S.K. Sarna, C.P. Johnson, and M.B. Adams. Dept. of Surg, Med Coil of WI, Milwaukee, Wl 53226.

The two major abnormal motor patterns in small intestinal inflammation are: 1) suppression of phasic contractions, and, 2) stimulation of giant migrating contractions (GMCs). These abnormalities contribute to the symptoms of diarrhea, urgency of defecation and abdominal cramping. The enteric neural and cellular mechanisms that produce abnormal motility during inflammation are not known. Our hypothesis is that the inflammatory response mediators and their chemical messengers may alter Ca 2+ channels to suppress phasic contractions during inflammation. We tested this hypothesis in four dogs, each instrumented surgically with 12 strain gauge transducers on the small intestine to record circular muscle contractions. Three close-intraarterial (i.a.) catheters were implanted in the mesenteric arteries to infuse 4 to 6 cm intestinal segments, each containing three strain gauge transducers. An intraluminal catheter was implanted in the proximal ileum to infuse ethanol and acetic acid. Control recordings were made for 5 to 7 days after recovery from surgery. Ileal inflammation was then induced by mucosal exposure to a series of three ethanol (75 ml, 95%) and acetic acid (20 ml, 50%) infusions on days 1, 2 and 5. Close i.a. infusion of test substances was repeated on days 3, 4, 6, 7, and 8. Area under contraction was used to quantitate the motor response. Results: Close i.a. infusion of 2 nmol methacholine over 1 min sdmulated a series of phasic contractions, lasting 1 to 3 min; this response was taken as 100%. Verapamil (L-type channel blocker) infusion (50 to 400 nmol/min for 5 rain) dose dependently decreased the response to methacholine. EC50 value was significandy lower during inflammation than during the normal state. Dantrolene (100 to 800 nmol/min for 5 min), a blocker of intracellular Ca 2+ release, also reduced the response to methacholine. Inflammation reduced the response to Bay K 8644 (S-), an agonist of Ca 2+ channels. The contractile response to Bay K 8644 was not affected by prior t reatment with tetrodotoxin (63 nmols) or hexamethenium (70 lxmols). The response to close i,a. infusion of motilin

(0.20 nmoles over 1 rain) was blocked by 8.0 nmol infusion of (o- conotoxin. We conclude that intestinal inflammation may down regulate L-type Ca 2+ channel activity. The down regulation may be due to a decrease in the number of channels or their open probability or it may be due to changes in affinity and binding sites. The down regulation of Ca 2÷ channel activity may contribute to suppression of phasic contractions during inflammation.

• IS SMALL BOWEL MOTILITY ABNORMAL IN THE IRRITABLE BOWEL SYNDROME ? TSehmi&, N.Hackelsberger, G.Leitel, R.Widmer, C.Meisel, A.Pfeiffer, HKaeas. Department of Gastroenterology, Hospital Miinchen-Bogen- hausen, Munich, Germany.

Background: Whether small bowel motility is abnormal in the irritable bowel syndrome (IBS), is a controversy at present (Dig Dis Sci 1993;38:1773-82). The aim of the study was to compare ambulatory long-term jejunal motility in 35 IBS patients [12 males, 23 females, aged 40 (24-63) years] with predominant diarrhea to normal values obtained in 50 healthy controls [28 males, 22 females, aged 26 (19-46) years]. Methods: Jejunal 24 h motility was recorded beyond the ligament of Treita under fully ambulatory conditions and standardized caloric intake with a portable dataloggar and tube-monnted miniature pressure sensors. A catheter with 2 sensors at 15 cm intervals was used in 20 patients and 30 controls. To analyse the spatial and temporal relationship of individual contractions, a catheter with 6 sensors spaced at 3 cm intervals was used in 15 patients end 20 controls, respectively. Fasting motility in the waking (W) end sleeparg (S) state, end the motor response to a standardized evening meal of 600 kcal underwent indopendant visual analysis by two observers and computer-aided evaluation (Gut 1994;35:27-33). Results: Fasting motility was characterized by MMC (W end S) cycles of normal length and composition in patients. Uninterrupted runs of discrete clustered contractions during phase II (W) occurred in 57 % of patients and 52 % of controls, respectively, but had a significantly longer duration in patients (33 + 5 vs 19 + 7 rain; p<0.005). During phase II (W), IBS patients exhibited an increase in aborally propagated contractions (41 + 2 % vs 35 + 2 %; p<0.01) and higher contraction amplitudes (26.3 + 0.8 vs 23.0 + 0.5 nun Hg; p<0.01). Similar differences were obtained during postprandial motility (47 + 3 % vs 39 + 3 %; p<0.01 and 25.9 + 0.9 vs 23.7 + 0.5 mm Hg; p<0.02). In three patients (8.6 %), disturbed aboral migration of phase III (either retrograde or simultaneous) end irregular burst activity, manometric features of chronic idiopathic intestinal pseudoobstruction (Gut 1987;28:5-12), were identified. While 57 % of patients had an entirely normal 24 h manometry, 43 % demonstrated at least one finding not present in any healthy control. Conclusion: Small intestinal motility is frequently but not universally abnormal in diarrhea-predominant IBS. The abnormal manometric findings are heterogenons and range from subtle quantitative changes to more severe qualitative abnormalities resembling chronic idiopathic intestinal pseudoobstruetion in a small subset of patients.

• PA'T'HOPHYSIOLOGICAL ASPECTS AND CLINICAL OUTCOME OF INTRA- ANAL APPLICATION OF ISOSORBIDE-DI-NITRATE IN PATIENTS WITH CHRONIC ANAL FISSURE. W.R, Schouten, J.W. Briel, Me. Boerma, J.J.A. Auwerda. Department of General Surgery, University Hospital Dijkzigt, Rotterdam, The Netherlands

Recently we have demonstrated that local ischemia, due to increased activity of the internal anal sphincter (lAB), is a major contri- buting factor in the pathogenesis of anal fissure. Relaxation of the lAB can be achieved by local application of exogenous nitric oxide donors, such as isosorbide-di-nitrate (IBDN). Aim of this study was to evaluate the influence of local application of 1% ISDN-ointment on anal pressure, anodermal bloodflow and fissure healing. Twelve consecutive patients (male/female: 7/5; median age: 36; range: 26-51) with a chronic anal fissure were studied. Prior to treatment, ambulant anal manometry was performed in 6 patients. Because sleep was associated with a reduction of anal pressure to 39% of ambulatory values, we decided to applicate the ISDN ointment only by day (5-6 X daily during 6 weeks). Before, during and after this treatment all patients underwent conventional manometry and laser Doppler flowmetry of the anoderm. All patients experienced mild, transient headache during the first 2 days. Within 10 days the fissure related pain was resolved in all patients. At 6 weeks anal fissure was heeled in 8 patients (67%), whereas in the remaining 4 patients the fissure was nearly healed. Prolonged manometry, started directly after ISDN application, showed that the maximal anal resting pressure (MARP) decreased within 5 minutes (median pressure drop: 41%; median duration: 39 rain). This pressure reduction represents the short-term effect of ISDN itself. At 3 and 6 weeks manometry was performed at least one hour after the last ISDN application. These recordings revealed also a reduction of MARP (mean values; pre: 115 -+41 mm Hg; 3 weeks: 80_+13; 6 weeks: 91-+26, p<0.05, paired t-test). This pressure reduction represents the long-term effect of ISDN, caused by its active metebolite isosorbide-mono-nitrate. At the same time anodermal bloodflow showed a significant increase (0.59 _+0.18 V; 3 weeks: 0.88-+0.09; 6 weeks: 0.80-+ 0.21, p<0.05). Conclusion: local application of ISDN reduces anal pressure and improves anodermal bloodflow. This dual effect results in a healing rate of 67% at 6 weeks.

PSYCHOLOGICAL DISTRESS AMONG PATIENTS WITH DISORDERS OF DEFECATION: CAUSE OR EFFECT? A. Schueneman_, K. Breninga, F, Harford, A. Keshavarzian. Depts. of Medicine and Surgery, Loyola University, Maywood, IL. Baekground. Complaints of depression, diffuse somatic discomfort, anxiety and emotional agitation have been clinically and psychometrically observed in patients with constipation end those exhibiting ftmetional disorders of defecation. The assumption that these emotional disturbances are sequellae of the underlying physical disease is often made on the basis that the defecation disorder interferes with daily living astivites. This assumption, however, has not been systematically examined. An alternative explanation of this phenomenon would be that these emotional disturbances are associated only with specific types of defecation disorders, raising the possibility that they are presdisposing or causal factors. Metheds. To test this possibility, bowel symptom questionnaire and MMPI data were collected prespeetively on 26 non-medicated consecutive patients referred to a university outpatient motility clinic end on a group of 11 control subjects. 17 oftbe patients were constipated and 9 had fecal incontinence. MMPI scale scores for the three groups were eompared statistically and by clinical decision-rule. Results. Both ANOVA and Chi-square indicated significant psychopathology in the group of constipated patients, but not in control or in the majority of incontinent patients (Table; p=0.1 between patient groups=*; vs normal=+).

Constipation Incontinence Normal

abnormal 15/17 2/9 0/11 MMPI 88% *+ 22% ~

Hypochondriasis T-score 71 + 70 + 56

Depression 70 *+ 66 54 T-score

Conclusion. These findings support the assumption that psychological disturbance such as depression nmy play a more specific, possibly causal role in the development of constipation but not in fecal incontinence. However, disorders of defecation can result in anxiety and somatic preoccupation (hypechondriasis).