Mechanoreceptors of the Proximal Stomach and Perception of Gastric Distension

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1 American Journal of Gastroenterology ISSN C 2005 by Am. Coll. of Gastroenterology doi: /j x Published by Blackwell Publishing Mechanoreceptors of the Proximal Stomach and Perception of Gastric Distension Stefania Carmagnola, M.D., Paolo Cantù, M.D., and Roberto Penagini, M.D. Cattedra di Gastroenterologia, Dipartimento di Scienze Mediche, University of Milan-IRCCS, Ospedale Maggiore, Milan, Italy OBJECTIVES: METHODS: RESULTS: CONCLUSIONS: To assess the role of tension receptors in gastric perception by pharmacologically modifying gastric contractile activity during isovolumetric distensions of the proximal stomach with the hypothesis that relaxation decreased perception and contraction increased it. Fourteen healthy subjects underwent two 30-min isovolumetric (75% of the threshold volume for discomfort) distensions using a barostat. During the second distension, either gastric relaxation was induced by intravenous (i.v.) glucagon 4.8 µg/kg bolus plus 9.6 µg/kg per h or contraction by i.v. erythromycin 3 mg/kg. Hunger and fullness were assessed with a 100-mm analog scale before and at 15 and 30 min during each distension. Glucagon decreased baseline intrabag pressure (8.4 ± 1.0 vs 10.7 ± 1.3 mmhg; p < 0.05) and abolished the pressure waves (0 vs 16.7 ± 2.3) when compared with placebo, whereas erythromycin increased baseline pressure (13.2 ± 1.0 vs 11.9 ± 0.9 mmhg; p < 0.05) and the rate of pressure waves (31.7 ± 5.4 vs 20.5 ± 3.1; p < 0.05). Fullness increased (p < 0.05) during distension, but it was unaffected by either of the drugs: score (i.e., score during distension baseline score) of 38 ± 10 mm (glucagon) versus 22 ± 10 (placebo) and 24 ± 17 mm (erythromycin) versus 36 ± 14 (placebo) at 15 min. Similar observation were made at 30 min. Hunger was influenced neither by distension nor by any of the two drugs consistently. Our data do not support a prominent role of tension receptors of the proximal stomach on perception of fullness, suggesting that stretch, that is, volume, is the more relevant stimulus. (Am J Gastroenterol 2005;100: ) INTRODUCTION Although it is established that distension of the proximal stomach induces the perception of fullness (1, 2), the underlying mechanisms are poorly defined. Two types of mechanoreceptors are present in the gastric wall; tension receptors, arranged in series and sensitive to contraction and elongation, and stretch receptors, arranged in parallel and sensitive to elongation only (3 6). Although there is evidence that gastric sensation is related to changes in wall tension (7, 8), a few reports support the importance of circumferential stretch (9 11). A deeper knowledge would be useful to develop effective drugs for many dyspeptic patients with visceral hypersensitivity (1, 12 14), who have a lower threshold for first perception and discomfort when the stomach is distended: if tension receptors are crucial, drugs inducing relaxation of the proximal stomach should be a valuable option; whereas if stretch receptors are the dominant mechanism, these drugs may be detrimental because the increase in volume would enhance symptom. In attempting to discriminate between the role of tension and stretch receptors in mediating sensations induced by proximal gastric distension, a major limitation of previous studies is that progressive gastric distension activates both tension and stretch mechanoreceptors (15). One way of overcoming this problem is to perform fixed volume inflations of an intragastric balloon (isovolumetric distensions) (16), that is, when the stomach relaxes or contracts isometrically against an intragastric balloon of fixed volume, elongation is unchanged, whereas changes in intraballoon pressure directly reflect changes in wall tension; in this way stretch receptors are unaffected, whereas the stimulation of tension receptors varies. Glucagon and erythromycin are effective in relaxing and contracting, respectively, the stomach at doses devoid of side effects (8, 15, 17, 18) and are, therefore, potentially useful in this experimental setting. The aim of the present study was to assess the role of tension receptors on perception, by modifying gastric contractile activity with administration of glucagon or erythromycin during fixed volume proximal gastric distension in healthy volunteers, with the hypothesis that glucagon decreases perception of distension whereas erythromycin increases it. 1704

2 Mechanoreceptors and Gastric Perception 1705 ME THODS Study Group Fourteen healthy subjects (six men; age range, yr, BMI 19 23), with no symptoms or past history of gastrointestinal disease were studied. Exclusion criteria were a history of diabetes mellitus, hypoglycemia, pheochromocytoma, and allergy to erythromycin. All the volunteers gave their written informed consent. The study was approved by the Human Research Review Committee of the Ospedale Maggiore of Milan. Barostat Measurements Motor function of the proximal stomach was measured with an electronic barostat (Synectics Visceral Stimulator, Sweden), as previously described (2). The latter was able to maintain a constant volume in a polyethylene bag that had a capacity of approximately 1,400 ml via a tube of 2.5 mm internal diameter (ID) and 650-mm length. Pressure in the barostat bag was measured via a 0.97-mm ID tube that was incorporated into the barostat inflation assembly. Two further manometric lumina incorporated into the assembly had sideholes positioned 25 and 50 mm proximal to the top of the barostat bag, which allowed reliable positioning of the bag within the stomach by detection of the characteristic patterns of pressure at the level of the diaphragm. These lumina were perfused with degassed distilled water. Data from the barostat were digitized and recorded on computer for online display and subsequent analysis. Measurement of Gastric Perception A validated visual analog scale was used to assess fullness and hunger (2, 19). The visual analog scale consisted of a 100- mm line, with 0 mm representing sensation not present and 100 mm strongest sensation ever felt. Study Design Volunteers fasted for at least 8 h. Each subject was evaluated in a single-day study during two sequential distension periods with administration of placebo and glucagon (7 subjects) or placebo and erythromycin (7 subjects) according to a randomized order (Fig. 1). The experimental model used in this study has been previously validated and found to be free of sequence effect between distensions on gastric motility and perception (20, 21). All subjects were blinded to the intravenous (i.v.) infusions. An intravenous line was first established to administer the drugs. The barostat assembly, with the bag folded around it, was introduced orally and positioned into the stomach on the basis of the manometric recording. The bag was then unfolded by inflation with 500 ml of air whilst ensuring that the pressure in the bag did not exceed 20 mmhg. The bag was then deflated and adjusted to its final position so that the point of respiratory reversal laid between the manometric sideholes, thereby positioning the proximal portion of the bag just below the diaphragm. The assembly was then fixed in this position by taping it to the nose. Subjects sat upright on a comfortable stool in a standardized position so as not to compress the abdomen. After a 5-min adaptation period, the intragastric bag was inflated by stepwise 100 ml increments every 2 min until the discomfort threshold was reached. The bag was then deflated completely and reinflated at a volume corresponding to 75% of the previously determined discomfort threshold volume; this volume was then maintained for two 30-min distension periods (i.e., placebo and glucagon or placebo and erythromycin), which were separated by a 45-min washout period with the bag deflated. In the glucagon experiment, 10 min before the second distension, an i.v. bolus of glucagon (Glucagen, Novo Nordisk Farmaceutici, Roma, Italy), 9.6 µg/kg over 1 min followed by continued infusion at 4.8 µg/kg/h in saline until the end of distension (total of 40 min) was administered; a saline bolus and an identical volume of saline were infused during the first distension period. Capillary blood glucose concentrations were determined before and at the end of the infusion of placebo and glucagon. In the erythromycin experiment, an i.v. infusion of erythromycin (Eritromicina lattobionato, Fisiopharma, Palomonte, Italy) 3 mg/kg in saline was administered over 10 min, starting 10 min before the second distension, whereas a corresponding volume of saline was infused during the first distension period. Sensations of fullness and hunger were evaluated immediately before and at 15 and 30 min during each distension of both glucagon and erythromycin studies. Intragastric Bag Imaging In order to be certain that the intragastric bag remained in the fundus during all experimental conditions, upper abdominal x-rays at end expiration were taken in two subjects during placebo, glucagon, and erythromycin distensions. Data Analysis BASELINE INTRABAG PRESSURE AND PRESSURE WAVES. Baseline intrabag pressure, as a measure of proximal gastric tone, was calculated as the mean value of each 5-min interval, excluding time periods when pressure waves occurred, and expressed as the mean value of every 15 min. A pressure wave, that is, phasic contraction, was defined as a change in pressure of 3 mmhg above baseline pressure that was not associated with an abdominal strain. The rate of pressure waves was expressed as number/30 min. GASTRIC WALL TENSION. Wall tension was estimated using the simplified Laplace law, T = P c, as previously described (15), where T is wall tension, P is intrabag pressure (in grams per square centimeters), and c is bag circumference (in centimeters). PERCEPTION OF FULLNESS AND HUNGER. Subjective ratings of fullness and hunger during distension were expressed as difference ( score) from the values obtained immediately before distension. Furthermore, in order to compare glucagon with erythromycin directly, the

3 1706 Carmagnola et al. Figure 1. Design of the glucagon and erythromycin experiment. indicates timing of blood glucose determination. Each experiment comprised two 30-min distensions separated by a 45-min washout period. effect of each drug was calculated by subtracting the scores of placebo distension from the corresponding scores of drug distension during each experiment. Finally, the means between the latter values at 15 and 30 min were used to examine the relationship between changes in motor function and changes in perceptions induced by the two drugs. Statistical Analysis Data are expressed as mean values ± SEM. The statistical significance of differences in motility and perception measurements between the two distensions of each experiment and in blood glucose levels during the glucagon experiments was tested with paired Student s t-test, whereas perception changes induced by glucagon and erythromycin were compared by unpaired Student s t-test, and 95% confidence interval (CI) of the difference was calculated. The statistical significance of differences among fullness and hunger scores before and at 15 and 30 min during each distension was tested by repeated-measure analysis of covariance with time as within-subject factor and the value before distension as the covariate. The relationship between changes in motor function and changes in perceptions was assessed by linear regression analysis with the former as independent and the latter as dependent variable, and the coefficient of determination (R 2 ) was calculated. RESULTS No adverse effects occurred in any of the subjects. The intrabag volumes during the glucagon and erythromycin experiments were 570 ± 25 and 490 ± 22 ml, respectively (p = NS). Effects of Glucagon and Erythromycin on Motor Function of the Proximal Stomach BASELINE INTRABAG PRESSURE. In all subjects, glucagon decreased baseline pressure when compared with placebo (8.4 ± 1.0 vs 10.7 ± 1.3 mmhg; p < 0.05), whereas erythromycin increased the values (13.2 ± 1.0 vs 11.9 ± 0.9 mmhg; p < 0.05). GASTRIC WALL TENSION. Glucagon lowered wall tension when compared with placebo (360 ± 50 vs 464 ± 61 g/cm; p < 0.05), erythromycin, on the contrary, increased wall tension (526 ± 32 vs 479 ± 32 g/cm; p < 0.05). INTRABAG PRESSURE WAVES. Glucagon abolished the pressure waves (0 vs 16.7 ± 2.3) compared with placebo, whereas erythromycin markedly increased their rate (31.7 ± 5.4 vs 20.5 ± 3.1; p < 0.05). Effect of Glucagon and Erythromycin on Perception of Fullness and Hunger Within each experiment, fullness and hunger scores were similar immediately before the first and the second distensions (Table 1). In both experimental settings, the perception of fullness increased (p < 0.05) during distension independently of the baseline values; in particular, during placebo distension, the score was +21 ± 10 and +13 ± 7 mm, respectively, at 15 and 30 min in the glucagon experiment and +36 ± 14 and +39 ± 15 mm, respectively at 15 and 30 min in the erythromycin experiment. No differences in score during placebo distension were found between the two experiments. When comparing the two distensions within each experiment, neither glucagon nor erythromycin affected fullness

4 Mechanoreceptors and Gastric Perception 1707 Table 1. Fullness and Hunger Scores before All Distensions Glucagon Experiment Erythromycin Experiment Baseline I Baseline II Baseline I Baseline II Fullness (mm) 27 ± 6 21 ± 6 23 ± 6 25± 7 Hunger (mm) 41 ± 5 40 ± 9 38 ± 7 39± 8 Score before placebo distension. Score before drug distension. compared with placebo (Fig. 2), and this result was confirmed by the between-subject comparison of glucagon versus erythromycin that resulted in a mean difference of +29 mm (95% CI: from 13 to +73; p = NS) at 15 min and of +34 mm (from 7 to+76; p = NS) at 30 min. Distension of the proximal stomach did not modify hunger perception significantly in both experimental settings. When comparing the two distensions within each experiment, hunger was less (p < 0.05) at 15 min, but not at 30 min after glucagon compared with placebo, whereas it was not affected by erythromycin (Fig 3). In line with these results, the between-subject comparison of glucagon versus erythromycin suggested that glucagon induced less hunger than erythromycin with a mean difference of 36 mm (from 59 to 12; p < 0.01) at 15 min and of 26 mm (from 51 to +0.1; p = NS) at 30 min. No relationship was found between changes in motor function of the proximal stomach and changes in either fullness or hunger induced by glucagon and erythromycin, the coefficient of determination being <0.2 in all regressions. Blood Glucose Level in the Glucagon Experiment Blood glucose levels remained stable during the placebo distension (4.4 ± 0.2 vs 4.4 ± 0.1 mmol/l) and increased to values in the postprandial range at the end of glucagon infu- sion (6.8 ± 0.5 vs 4.3 ± 0.1 mmol/l before glucagon infusion; p < 0.01). Intragastric Bag Imaging Distension of the bag increased the cross-section of the proximal stomach. During distension with placebo, glucagon, and erythromycin, the bag always remained in the proximal stomach and kept a similar shape in both subjects (Fig. 4). DISCUSSION The present study has confirmed that distension of the proximal stomach induces fullness (1, 2) and has disproved our hypothesis, showing that its perception is neither decreased by wall relaxation (glucagon) nor increased by contraction (erythromycin), using an experimental design of sustained distension with volume clamping. The lower limit of the 95% confidence interval of the difference in fullness between glucagon and erythromycin, which varied between 13 and 7 mm during the 30-min distension, excluded a relevant clinical effect that could undermine our conclusions. Our findings thus provide evidence that changes in stimulation of tension mechanoreceptors are not an important determinant of gastric sensation, when the proximal stomach is distended. Figure 2. Fullness. score (difference from value before distension) during the glucagon and erythromycin experiments at 15 and 30 min during each distension. Open bars indicate placebo and filled bars glucagon or erythromycin. Values are in mean ± SE. Figure 3. Hunger. score (difference from value before distension) during the glucagon and erythromycin experiments at 15 and 30 min during each distension. Open bars indicate placebo and filled bars glucagon or erythromycin. Values are in mean ± SE. ( ) p < 0.05 versus placebo.

5 1708 Carmagnola et al. Figure 4. Plain upper abdominal x-ray from left to right: in a subject during placebo, glucagon, and erythromycin distension (note the similar shape and location of the bag with placebo and both drugs). Although we were not blinded, due to the obvious changes in motility induced by the two drugs, we are confident that our study was not biased because visual analog scales of perceptions, which were the main outcome of interest, were filled in by the volunteers who were blinded to the i.v. infusions, without any verbal interaction with the investigators. Which are the possible implications of our findings? Patients with functional dyspepsia represent a heterogeneous group, and hypersensitivity to gastric distension is an important determinant of symptoms in a subset of them (1, 12 14); our data suggest that drugs relaxing the proximal stomach, which have been proposed primarily in patients with impaired fundic accommodation (22), are not indicated in patients with visceral hypersensitivity because relaxation of the gastric wall does not decrease sensation, whereas the concomitant increase in proximal gastric volume should actually increase it. These patients may best be treated with drugs that inhibit visceral perception. As expected (8, 15, 17, 18), the doses of glucagon and erythromycin used modified tone and phasic contractions of the proximal stomach. Furthermore, glucagon induced increases in glycemia within the physiological postprandial range (<9 mmol/l), which, based on current knowledge (23), should not have affected the sensory response to distension unlike higher pathological glycemia levels (14 16 mmol/l) (24, 25). It has been suggested that the level of perception during gut distension may be affected by the area that is actually distended, the so-called sensory receptive field (11). This is whywechecked with x-ray whether any changes in position or shape of the bag had occurred after drug administration and found no change. In line with previous results (24), distension of the proximal stomach triggered sensation of fullness but did not decrease hunger, suggesting that the mechanism of satiation is not simply the opposite of fullness but requires concurrent stimulation of small intestine nutrient receptors (26). Furthermore, distension of the antrum may be a more important regulatory mechanism of hunger than distension of the proximal stomach (27, 28). The role of tension and stretch receptors in the perception of upper gut distension is controversial and it has been investigated in different experimental settings. Notivol et al. performed short stepwise isobaric and isovolumetric distensions using glucagon to relax the gastric wall and showed that after glucagon volume and perception increased during isobaric experiments, whereas pressure and perception decreased during isovolumetric experiments (15). These results suggested a possible role of both tension and stretch in perception of gastric distension but were not conclusive. Further, work by Distrutti et al. using a similar experimental design and a tensostat in order to perform distensions at a fixed tension level, suggested that tension rather than volume is important (7). However, it can be argued that observations during short intermittent distensions have little relevance to the prolonged gastric distension of the postprandial period during which fullness is usually perceived; furthermore, the sensory receptive field varies with distension volume (29), thus introducing a potential bias in interpretation of the results. Another paper has suggested that changes in wall tension may be involved in the genesis of gastric symptoms (8). Piessevaux et al. showed that, during a 10-min fixed volume gastric distension at perception threshold, half of fundic contractions are perceived as a sensation of increasing fullness. Although results of this study may seem in contrast with ours, they are simply noncomparable as they look at different variables. Whereas, Piessevaux et al. investigated perception of single gastric contractions in the setting of a minimally distended stomach, we focused on the average 15-min sensation of fullness while the stomach was in a state of much greater distension, comparable to the postprandial period. Finally, in favor of a role of tension receptors in gastric perception, it has been suggested that pharmacologically induced increase in gastric accommodation to a meal alleviates dyspeptic symptoms. The subject, however, is still debated, as studies have shown conflicting results (22, 30, 31). Three recent studies suggest a prevalent role of stretch in perception of upper gut distension. Ladabaum et al. showed that gastric sensation during intermittent isobaric fundic distensions correlated most robustly with gastric volume than with pressure changes (10). Barlow et al. using a sophisticated model combining impedance planimetry and manometry, demonstrated that circumferential stretch was the main factor influencing sensation in the esophagus and that decrease in wall tension using hyoscine-n-methyl-bromide did not alter the relationship between intensity of sensation and cross-sectional area (11). Similarly, in another study, subjects experienced heartburn and chest pain during isovolumetric esophageal distensions without any change in the degree of sensation after atropine, which modified esophageal pressure but not the circumferential stretch (9). Furthermore,

6 Mechanoreceptors and Gastric Perception 1709 data showing that during nutrient-induced gastric distension, atropine increased both volume of the proximal stomach and fullness (32) and dexloxiglumide decreased both variables (33) support the view that volume is an important determinant of postprandial sensation. Finally, several basic science studies, which have clearly shown afferent fibers either within the vagus nerve of the cat, dog, and ferret (3, 6, 34) or projecting to prevertebral ganglia of the mouse (35) that increase their activity during gut distension and not during contraction, support the existence of mechanoreceptors sensitive to elongation only. Aword of caution should be spent on interpretation of data on wall tension calculated with the Laplace s law because, as pointed out by Gregersen et al. and Camilleri et al. (16, 29, 36), several assumptions the law is based on are actually not satisfied when applied to gut physiology (i.e., the balloon has a spherical shape, the gut wall is infinitely thin, and no active contraction occurs). A final comment on the unexpected trends induced by our two drugs: glucagon tended to increase fullness and decrease hunger, whereas, erythromycin induced opposite trends in both variables and it cannot be excluded that statistical significance was not reached because of a type II error. These trends may be related to variations in distension of the antrum, which has recently been suggested as an important region for perception of upper gastrointestinal symptoms (27, 28, 37 40), hunger, and food intake (27, 28), and the hypothesis could be addressed in a further study also measuring antral volumes. Glucagon is known to dilate the stomach (41) through its muscle relaxing properties, whereas erythromycin induces powerful antral contractions (17); the latter motor effects are quite likely to decrease antral volume, although to our knowledge, there are no formal studies on antral volume or tone during erythromycin. In conclusion, changes in stimulation of tension mechanoreceptors located in the proximal stomach have no major impact on perception of fullness during prolonged distension, suggesting that variation in stretch, that is, volume, is the more relevant stimulus. Our observations contribute to a better understanding of the relationship between gastric motor function and upper gastrointestinal symptoms and satiety and may impact on future therapeutic strategies for functional dyspepsia. ACKNOWLEDGMENTS We thank Prof. P. G. Duca of Unità di Statistica Medica, University of Milan-Ospedale L Sacco, for statistical advice. 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