Effects of an N-methyl-D-aspartate (NMDA) receptor antagonist on transient lower esophageal sphincter relaxations (TLESRs) in the dog

April 1998 mean LES pressure and the percentage of peristaltic contraction and isolated contraction showed no significant correlation with the number of acid reflux longer than 5 min. Condusion: The abnormal esophageal motility are more strongly and frequently associated in GERD with reflux esophagitis than without reflux esophagitis. • G3239 EFFECTS OF AN N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONIST ON TRANSIENT LOWER ESOPHAGEAL SPHINCTER RELAXATIONS (TLESRs) IN THE DOG. A. Lehmann. GI Pharmacology, Astra H~ssle AB, Mtilndal, Sweden. TLESR is the major cause of gastroesophageal reflux and inhibition of TLESR is thus a rational target for pharmacological intervention in reflux disease. TLESRs are triggered primarily by gastric distension which activates vagal afferents. Glutamate is a strong transmitter candidate in the vagal afferents and acts primarily o n NMDA receptors. Consequently, the effect on TLESRs of an NMDA receptor antagonist, CGS 19755, was studied. Labrador retrievers (n=5, 4 males) equipped with esophagostomies were used. They were intubated with a multilumen water perfused assembly fitted with a Dentsleeve to measure esophageal, lower esophageal sphincter (LES) and gastric pressures. A pH electrode was positioned 3 cm above the LES, and an air-perfused pharyngeal catheter was used to monitor swallows. After 10 min of stable recording, saline or CGS 19755 (0.5 ml/kg, 0.3 and 3 mg/kg) was injected i.v. Ten minutes later, a liquid nutrient (10% peptone, 5% D-glucose, 5% Intralipid, pH 3.0) was infused intragastrically (100 ml/min, 30 ml/kg). Air was then insufflated at a rate of 40 ml/min so that the period of liquid infusion/air insuffiation was 90 min. The results from the drug experiments were compared with 5 control experiments in each dog. CGS 19755 did not induce any behavioral changes. The average number of TLESRs during the first 45 min was not different from control values (102% [0.3 mg/kg] and 91% [3 mg/kg]). However, in 3 dogs, there was a reduction in TLESRs during the first 45 min whereas in 2 dogs, there was an increase after 3 mg/kg CGS 19755. This interindividual difference was verified using the high dose in two separate experiments/dog (p=0.03). The number of TLESRs/90 min increased dose dependently (166% [0.3 mg/kg] and 249% [3 mg/kg] of control). The duration of TLESR was unaffected. There was a tendency towards a slower esophageal peristalsis after CGS 19755. Simultaneous contractions of the esophagus were seen in 87% of the TLESRs in control experiments. This number was reduced by CGS 19755 to 9.7% (0.3 mg/kg) and 7.5% (3 mg/kg). The results suggest that NMDA receptors exert positive or negative control on TLESR depending on the subject studied. NMDA receptors are located at several sites thought to be crucial in the triggering of TLESR and it seems that the individual balance of NMDA receptors govern the outcome of receptor blockade. A. Lehmann, Employee, Astra HAssle AB, MNndal, Sweden • G3240 PROJECTIONS OF NEURONS MEDIATING NONCHOLINERGIC FAST EXCITATORY SYNAPTIC POTENTIALS IN MYENTERIC PLEXUS OF GUINEA PIG ILEUM. K.L LePard and J.J. Galligan. Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA. Noncholinergic neurotransmitters mediate fast excitatory postsynaptic potentials (fEPSPs) in myenteric ganglia. Contributions of short, long or circumferentially projecting enteric neurons to hexamethonium-resistant fast neurotransmission were investigated. Under ketamine/xylazine anesthesia, long or circumferential myenteric nerve pathways were interrupted by myotomy (M): single (S, 14 guinea pigs), double (D, 6 guinea pigs), or longitudinal (L, 6 guinea pigs). For sham animals (n=7), the intestine was manually manipulated, washed with PBS, identified with silk suture and returned to the abdominal cavity. Effectiveness of surgical treatment was confirmed by histochemical methods. After severed axons degenerated (4-5 days), fEPSPs were generated at the operated site by supramaximal focal stimulation of interganglionic fiber tracts. Cholinergic fEPSPs were defined as those reduced >95% by hexamethonium (C6, 100 pM); mixed (cholinergic and noncholinergic) I'EPSPs were defined as those reduced < 95% by C6. The control amplitude of nicotinic fEPSPs recorded between a DM and anal to SM (13 -+ 1 mV, n=34) was smaller compared to those recorded from sham and oral to SM (21 -+3 mV, n=20, p<0.05). In contrast, the control amplitude of mixed fEPSPs was the same when recorded between a DM and anal to SM (21 -+ 2 mV, n=47) and from sham and oral to SM (20 +-. 1 mV, N=69). The proportion of fEPSPs that were cholinergic or mixed was not different from sham when recordings were obtained oral to SM, between a DM or between LM. However, when recordings were obtained anal to SM, the proportion of nicotinic fEPSPs increased 3-fold from 17% to 50% (p<0.05 G test). These data indicate that noncholinergic pathways have an oral to anal projection. Nicotinic fast excitatory pathways also project in an oral to anal direction. Supported by NS01738, NS33289, NS07279. • G3241 ARE FUNDIC RECEPTORS SENSITIVE TO CIRCUMFERENTIAL WALL TENSION I N VIVO? L. Lepionka, C.H. Malbert. Station de Recherches Porcines; INRA, St Gilles, France. Although gastric receptors respond clearly to distension, the essential stimuli for these receptors as not yet been defined. In vitro, gastric "tension"

Motility and Nerve-Gut Interactions A787

receptors respond to longitudinal wall tension that is only a fraction of tension and other forces induced by distension. The aim of this study was to quantify, in vivo, "tension" receptors characteristics during isovolumic, isobaric and isotension distensions. In anaesthetised, curarised pigs (n=30), three levels of distension (2.1; 4.1 and 6.2 kg.m-l), and three distension modalities (isovolumic, isobaric and isotension) were performed at random using a computer controlled air injection/retrieval system coupled with a high sensitive air pressure transducer connected to a polyurethane balloon inserted in the fundus. During isotension distension, circumferential gastric wall tension was calculated on line using Laplace law applied to a sphere. 0.01 mmHg and 0.1 mmHg hysteresis were incorporated at random in the software for isobaric and isotension distensions. Afferent electrical activity of right vagus nerve was recorded at the cervical level using classical single fibre method. Receptors sensitive to light mucosal stimulation were removed from the study. Conduction speed of neurones was also measured. Initial inflation and final deflation periods during which tension, volume or pressure were not maintained constant were not included in the analysis 25 slow adapting "tension" receptors were studied; about 60 % were C-fibres and the remaining AS-fibres. There was no obvious difference in distension effects on either C-or AS-fibres and they were thus grouped together. With 0.1 mmHg hysteresis, all neurones showed changes in discharge phase-locked with lung motions for isobaric and isotension distensions. With 0.01 mmHg hysteresis, these changes disappeared for isotension and were significantly reduced for isobaric distensions respectively. Irrespective of distension level, isovolumic distension was the most effective stimuli increasing discharge rate (p < 0.05). For 2.1 and 4.1 kg.m"1 distensions, no significant difference was noticed between isobaric versus isotension distensions. Furthermore, three receptors clearly sensitive to isovolumic distension were virtually quiescent during isobaric and isotension distensions (2.1 and 4.1 kg.mq). On the contrary, for the highest distension level and for 21/25 receptors, isobaric distension was significantly more effective than isotension distension. In conclusion, in vivo, circumferential wall tension is not the essential stimuli for fundic "tension" receptors. The absence of response to distension of some receptors while pressure or tension was constant suggests that, similar to "baro" receptors in the cardiovascular system, circumferential strain and not tension might be essential to activate these receptors. G3242

HEALTH CARE UTILIZATION BY ABUSE HISTORY AND GI DISEASE TYPE. Jane Leserman Zhiming Li, Yuming J.B. Hu, Douglas A. Drossman. Depts. of Psychiatry and Medicine, Division of Digestive Diseases, University of North Carolina School of Medicine, Chapel Hill, NC. Recent research has demonstrated that sexual and physical abuse history are common experiences among women with gastrointestinal disorders. The current study examined the relationships of sexual and physical abuse history and disease type (functional versus organic) with utilization of health services, at study baseline and during a one year follow-up period. The sample included 239 female patients from a referral based Gastroenterology clinic; data were available for 197 women during the follow-up. Utilization variables were assessed for the three months before baseline and the one year period following baseline. We performed analysis of covariance (means shown) and logistic regression (raw percentages shown) for interval and bivariate utilization variables, respectively, controlling for age, race, and education. Those with abuse history had more doctor visits, made more calls to doctors, and were more likely to have seen a mental health professional during the three months before baseline, and during the one-year follow-up. Women with abuse history also had more hospitalizations during the followup compared to those without abuse. Those with functional disorders had more doctor visits and were more likely to have seen a mental health professional during the one year follow-up compared to those with organic disorders. We conclude that the poorer health reported by women with abuse history and functional disorders may translate into greater utilization of health care services. No

Baseline

# Dr. visits # Dr. phone calls Had procedure Seen counselor

Functional 4.7 2.5 9% 35%

Organic 4.3 1.9 14% 27%

p .46 .09 .19 .27

Abuse 5.2 2.6 15% 37%

Abuse 3.8 1.8 8% 22%

p .02 .01 .14 .009

15.2 9.3 .26 .96 12% 53%

11.0 8.4 .39 .81 14% 31%

.007 .49 .22 .61 .56 .006

14.7 10.7 .35 1.2 15% 47%

11.4 6.9 .31 .57 11% 32%

.03 .005 .71 .03 .18 .06

1 Year FoUowuo

# Dr. visits # Dr. phone calls # Procedures # Hospitalizations Had major surgery Seen counselor