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Gastric pain thresholds and mucosal concentrations of sensory neuropeptides correlate in nonulcer dyspepsia
A388 AGA ABSTRACTS
2039 COTRANSMITTER ROLE OF TACHYKININS AND GLUTA· MATE IN THE AFFERENT SIGNALLING OF A GASTRIC ACID INSULT. Peter Holzer, Milana Jocic, Rufina Schuligoi, Univ of Graz, Graz, Austria. Background: Previous work in this laboratory has shown that acid challenge of the rat gastric mucosa is signalled to the brainstern via capsaicinresistant vagal afferents. This study examined whether tachykinins and glutamate participate in the transmission between vagal afferents and neurons in the brainstem as monitored by the expression of c-fos messenger ribonucleic acid (mRNA) in the nucleus of the solitary tract (NTS) and area postrema (AP). Methods: Forty-five min after intragastric administration of hydrochloric acid (HCI, 0.5 M, 10 mlIkg) to conscious rats, the brainstem was removed, cryosectioned and processed for in situ hybridization autoradiography with a c-fos oligo-desoxyribonucleic acid probe. Drugs were given subcutaneously 15 min before the gastric acid challenge. Results: Exposure of the gastric mucosa to HCI (0.5 M). but not saline (0.15 or 0.5 M), caused many neurons in the NTS and some neurons in the AP to express c-fos m RNA. The NMDA-type glutamate receptor channel blocker MK-801 (2 mg/kg), the NK[ tachykinin receptor antagonist GR205, 171 (3 mg/kg) and the NK2 receptor antagonist SR-I44, 190 (0.1 mg/kg) failed to significantly inhibit the gastric acid-evoked transcription of c-fos mRNA in the NTS. While the double combinations of MK-801 plus GR-205, 171, MK-801 plus SR-I44, 190 and GR-205, 171 plus SR-I44, 190 were also without effect, the triple combination of MK-801, GR-205, 171 and SR-144, 190 attenuated the gastric acid-evoked transcription of c-fos mRNA in the NTS by 48 % (P < 0.01). In the AP, MK-801 alone significantly enhanced the gastric acid-induced expression of c-fos mRNA, an effect that was abolished by coadministration of the tachykinin antagonists GR-205, 171 and SR-I44, 190 which per se had no effect. Conclusions: Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK] and NK 2 receptors cooperate in the transmission between vagal afferents and medullary neurons following a gastric mucosal acid insult. These findings may have a bearing on the neuropharmacology of dyspepsia. This study was supported by FWF grant P11834-MED.
2040 ROLE OF NITRIC OXIDE IN GASTRIC RECEPTIVE RELAX· ATION AND GASTRIC ADAPTIVE RELAXATION IN CON· SCIOUS DOGS. Masafumi Kikkawa, Masazumi Okajima, Hajime Haneji, Yosuke Shimizu, Shintaro Nakashima, Shinya Kodama, Satoshi Ikeda, Masahiro Nakahara, Katsufumi Kawahori, Toshimasa Asahara, Dept of Surg II , Hiroshima Univ Faculty of Medici, Hiroshima, Japan; Hiroshima Univ Faculty of Medicine, Hiroshima, Japan. Background Some study showed that gastric receptive relaxation and gastric adaptive relaxation are mediated by non-adrenergic, non-cholinergic nerves via nitric oxide (NO). In order to clarify the physiological role of NO in gastric receptive relaxation and chemically induced gastric adaptive relaxation, we examined in conscious dogs. Materials and methods Experiments were performed on adult dogs with chronic gastric fistula (N=5). A polyethylene bag inserted into the proximal stomach through the fistula was connected to a barostat with a double lumen tube. The procedure as followed. 1) Maintained at 4 mmHg intragastric pressure, water or lipid (20% intralipos) were administrated orally (2 mlIkg). Moreover, lipid was infused (2 mlIkg) to the stomach through the gastric fistula to avoid pharyngeal and esophageal effects. The volume change of the proximal stomach were measured by means of the barostat. 2) Ten minutes after administration ofNG-monomethyl-L-arginine (L-NMMA) an NO synthase inhibitor (5 mg/kg i.v.), lipid was administrated orally (2 ml/kg), and the same procedures were performed. Results I) There was a prompt fall in intragastric pressure after water or lipid ingestion, indicating gastric receptive relaxation. However, intragastric pressure did not promptly decrease after infusion of lipid. Water ingestion induced minimal gastric relaxation (4\.6 :': 24.0 ml; means:': S.D.), and gastric volume returned to the baseline level within 5 min. Lipid ingestion or lipid infusion induced a rapid increase in the capacity of the proximal stomach (150.0 :': 50.2 ml and 153.6:': 25.2 ml, respectively), indicating gastric adaptive relaxation, followed by a plateau phase, and gastric volume gradually returned to the baseline level. 2) Receptive relaxation occurred, and relaxation volume was not affected after administration of L-NMMA (167.6 :': 53.0 ml). Conclusion Our findings indicate that nitrergic input is not necessary for gastric receptive relaxation and chemically induced gastric adaptive relaxation in conscious dogs.
2041 GASTRIC PAIN THRESHOLDS AND MUCOSAL CONCENTRATIONS OF SENSORY NEUROPEPTIDES CORRELATE IN NONULCER DYSPEPSIA. Hubert Monnikes, Birgit Wollenberg, Johannes 1. Tebbe, Britta Dickhaus, Rudolf Arnold, P. G. McGregor, Philipps Univ, Marburg, Germany. Visceral hypersensitivity has been shown in patients with non-ulcer dyspepsia (NUD). It has been suggested that this phenomenon is due to alterations in the gastric sensory innervation. CGRP and substance P (SP) are important transmitters in the afferent sensory innervation of the GItract; both peptides are peripherally released from sensory nerve endings.
GASTROENTEROLOGY Vol. 118, No.4
Thus, aim of this study was to assess, if gastric visceral hypersensitivity in NUD patients is associated with altered mucosal concentrations of CGRP and SP. Methods: In biopsies from NUD patients and healthy controls (HC) concentrations of SP and CGRP were determined by radioimmunoassays. In both groups gastric visceral perception thresholds at balloon distension were determined. Also, H. pylori (Hp) infection was verified by urease test. Results: In Hp-positive NUD patients the pain threshold at gastric balloon distension (377 :': 107 ml, N=6) was significantly lower (ANOVA and post-hoc tests, p<0.05) than in Hp-negative NUP patients (625 :': 91 ml, N=7), Hp-negative HC (716 :': 67 ml, N=II), and Hp-positive controls (725 :': 68 ml, N=7). In NUD patients a significant negative correlation (Pearson product-moment correlation) between pain thresholds and antral mucosal concentrations of CGRP (r:-0.73, p
2042 ROLE OF NITRIC OXIDE IN THE ACCOMMODATION REFLEX, IN MEAL-INDUCED SATmTY AND IN THE TREATMENT OF IMPAIRED ACCOMMODATION IN MAN. Jan F. Tack, Ingrid Demedts, Rita Vos, Ann L. Meulemans, Jan A. Schuurkes, Jozef Janssens, Ctr for GI Research KU Leuven, Leuven, Belgium; Janssen Research Fdn, Beerse, Belgium. Accommodation of the stomach to a meal consists of a relaxation of the proximal stomach, providing the meal with a reservoir. In man, impaired accommodation is associated with early satiety, and sumatriptan (Sum) is able to restore accommodation and meal-induced satiety. Animal studies have shown that the accommodation reflex involves activation of nitrergic neurons in the gastric wall. Our aim was to study in man the involvement of nitric oxide (NO) in the accommodation reflex, in the control of meal-induced satiety and in the treatment of impaired accommodation. Methods: A) Five healthy subjects (5 men, age 21-29) underwent in randomized order 3 gastric barostat studies. Isobaric tone measurements (at MDP+2 mm Hg) were performed 30 min before and 60 min after a liquid meal (200 rnl, 300 kcal). Twenty min prior to the meal, placebo or the NO synthase inhibitor L-NMMA 3 or 6 mg/kg were administered i.v, over 45 min. Accommodation was quantified as the difference in mean volume after and before the meal. B) Eight healthy subjects underwent 2 satiety tests. They were asked to ingest Nutridrink at a rate of 15 ml/min until maximum satiety. Twenty min prior to the meal, placebo or L-NMMA 6 mg/kg were administered i.v. over 45 min. C) Five healthy subjects (5 men, age 21-29) underwent in randomized order 3 gastric barostat studies. Isobaric tone measurements were performed 30 min before and 60 min after Sum 6 mg s.c. Twenty minutes prior to Sum, placebo or L-NMMA 3 or 6 mg/kg were administered i.v, over 45 minutes. Results: Ingestion of the meal induced a relaxation of 244:':16 ml which was significantly smaller after L-NMMA 3 mg/kg (l22:':52ml, p
2043 MEASUREMENT OF GASTRIC ACCOMMODATION AND EMp· TYING OF A SOLID MEAL BY MAGNETIC RESONANCE IMAGING. Myung-Gyu Choi, Byung Wook Kim, Kyo Young Choo, Soo Heon Park, Seung Eun Jung, Jae Moon Lee, Sok Won Han, In Sik Chung, Kyu Won Chung, Hee Sik Sun, The Catholic Univ of Korea, Seoul, South Korea. Magnetic resonance imaging(MRI) provides an accurate measurement of the volume change of the stomach after meals. Therefore, we hypothesized that MRI could evaluate both gastric accommodation and emptying of solids. Our aim was to develop a noninvasive test using MRI to measure gastric accommodation and the emptying of solids. Methods: 18 healthy volunteers(l5 males, 3 females; mean age, 28) underwent simultaneous scintigraphy and MRI in order to validate MRI measurement of gastric emptying of solids. After ingestion of a radiolabelled sandwich test meal(325 kcal), MRI and scintigraphic scans were obtained for 2 hours. The volume of the stomach was determined by multiplying areas of interest for each slice of MRI scan by the slice thickness. Proximal and distal gastric regions were divided at the angle from 3 dimensional(3D) reconstructions of the stomach. Half gastric emptying time was derived from k and (3 in a power exponential model;prop(t) =exp{ -(k*t)I3}. All subjects underwent electronic barostat study on the following day in order to compare MRI measurement of gastric accommodation to electronic barostat. Gastric tone was assessed 30 min before and 60 min after ingestion of a 250 kcal liquid test meal. Results: Rapid MRI technique allowed accurate measurement of the volume of the stomach. The proximal stomach was markedly dilated in contrast to the minimally distended distal
2039 COTRANSMITTER ROLE OF TACHYKININS AND GLUTA· MATE IN THE AFFERENT SIGNALLING OF A GASTRIC ACID INSULT. Peter Holzer, Milana Jocic, Rufina Schuligoi, Univ of Graz, Graz, Austria. Background: Previous work in this laboratory has shown that acid challenge of the rat gastric mucosa is signalled to the brainstern via capsaicinresistant vagal afferents. This study examined whether tachykinins and glutamate participate in the transmission between vagal afferents and neurons in the brainstem as monitored by the expression of c-fos messenger ribonucleic acid (mRNA) in the nucleus of the solitary tract (NTS) and area postrema (AP). Methods: Forty-five min after intragastric administration of hydrochloric acid (HCI, 0.5 M, 10 mlIkg) to conscious rats, the brainstem was removed, cryosectioned and processed for in situ hybridization autoradiography with a c-fos oligo-desoxyribonucleic acid probe. Drugs were given subcutaneously 15 min before the gastric acid challenge. Results: Exposure of the gastric mucosa to HCI (0.5 M). but not saline (0.15 or 0.5 M), caused many neurons in the NTS and some neurons in the AP to express c-fos m RNA. The NMDA-type glutamate receptor channel blocker MK-801 (2 mg/kg), the NK[ tachykinin receptor antagonist GR205, 171 (3 mg/kg) and the NK2 receptor antagonist SR-I44, 190 (0.1 mg/kg) failed to significantly inhibit the gastric acid-evoked transcription of c-fos mRNA in the NTS. While the double combinations of MK-801 plus GR-205, 171, MK-801 plus SR-I44, 190 and GR-205, 171 plus SR-I44, 190 were also without effect, the triple combination of MK-801, GR-205, 171 and SR-144, 190 attenuated the gastric acid-evoked transcription of c-fos mRNA in the NTS by 48 % (P < 0.01). In the AP, MK-801 alone significantly enhanced the gastric acid-induced expression of c-fos mRNA, an effect that was abolished by coadministration of the tachykinin antagonists GR-205, 171 and SR-I44, 190 which per se had no effect. Conclusions: Our data show that glutamate acting via NMDA receptors and tachykinins acting via NK] and NK 2 receptors cooperate in the transmission between vagal afferents and medullary neurons following a gastric mucosal acid insult. These findings may have a bearing on the neuropharmacology of dyspepsia. This study was supported by FWF grant P11834-MED.
2040 ROLE OF NITRIC OXIDE IN GASTRIC RECEPTIVE RELAX· ATION AND GASTRIC ADAPTIVE RELAXATION IN CON· SCIOUS DOGS. Masafumi Kikkawa, Masazumi Okajima, Hajime Haneji, Yosuke Shimizu, Shintaro Nakashima, Shinya Kodama, Satoshi Ikeda, Masahiro Nakahara, Katsufumi Kawahori, Toshimasa Asahara, Dept of Surg II , Hiroshima Univ Faculty of Medici, Hiroshima, Japan; Hiroshima Univ Faculty of Medicine, Hiroshima, Japan. Background Some study showed that gastric receptive relaxation and gastric adaptive relaxation are mediated by non-adrenergic, non-cholinergic nerves via nitric oxide (NO). In order to clarify the physiological role of NO in gastric receptive relaxation and chemically induced gastric adaptive relaxation, we examined in conscious dogs. Materials and methods Experiments were performed on adult dogs with chronic gastric fistula (N=5). A polyethylene bag inserted into the proximal stomach through the fistula was connected to a barostat with a double lumen tube. The procedure as followed. 1) Maintained at 4 mmHg intragastric pressure, water or lipid (20% intralipos) were administrated orally (2 mlIkg). Moreover, lipid was infused (2 mlIkg) to the stomach through the gastric fistula to avoid pharyngeal and esophageal effects. The volume change of the proximal stomach were measured by means of the barostat. 2) Ten minutes after administration ofNG-monomethyl-L-arginine (L-NMMA) an NO synthase inhibitor (5 mg/kg i.v.), lipid was administrated orally (2 ml/kg), and the same procedures were performed. Results I) There was a prompt fall in intragastric pressure after water or lipid ingestion, indicating gastric receptive relaxation. However, intragastric pressure did not promptly decrease after infusion of lipid. Water ingestion induced minimal gastric relaxation (4\.6 :': 24.0 ml; means:': S.D.), and gastric volume returned to the baseline level within 5 min. Lipid ingestion or lipid infusion induced a rapid increase in the capacity of the proximal stomach (150.0 :': 50.2 ml and 153.6:': 25.2 ml, respectively), indicating gastric adaptive relaxation, followed by a plateau phase, and gastric volume gradually returned to the baseline level. 2) Receptive relaxation occurred, and relaxation volume was not affected after administration of L-NMMA (167.6 :': 53.0 ml). Conclusion Our findings indicate that nitrergic input is not necessary for gastric receptive relaxation and chemically induced gastric adaptive relaxation in conscious dogs.
2041 GASTRIC PAIN THRESHOLDS AND MUCOSAL CONCENTRATIONS OF SENSORY NEUROPEPTIDES CORRELATE IN NONULCER DYSPEPSIA. Hubert Monnikes, Birgit Wollenberg, Johannes 1. Tebbe, Britta Dickhaus, Rudolf Arnold, P. G. McGregor, Philipps Univ, Marburg, Germany. Visceral hypersensitivity has been shown in patients with non-ulcer dyspepsia (NUD). It has been suggested that this phenomenon is due to alterations in the gastric sensory innervation. CGRP and substance P (SP) are important transmitters in the afferent sensory innervation of the GItract; both peptides are peripherally released from sensory nerve endings.
GASTROENTEROLOGY Vol. 118, No.4
Thus, aim of this study was to assess, if gastric visceral hypersensitivity in NUD patients is associated with altered mucosal concentrations of CGRP and SP. Methods: In biopsies from NUD patients and healthy controls (HC) concentrations of SP and CGRP were determined by radioimmunoassays. In both groups gastric visceral perception thresholds at balloon distension were determined. Also, H. pylori (Hp) infection was verified by urease test. Results: In Hp-positive NUD patients the pain threshold at gastric balloon distension (377 :': 107 ml, N=6) was significantly lower (ANOVA and post-hoc tests, p<0.05) than in Hp-negative NUP patients (625 :': 91 ml, N=7), Hp-negative HC (716 :': 67 ml, N=II), and Hp-positive controls (725 :': 68 ml, N=7). In NUD patients a significant negative correlation (Pearson product-moment correlation) between pain thresholds and antral mucosal concentrations of CGRP (r:-0.73, p
2042 ROLE OF NITRIC OXIDE IN THE ACCOMMODATION REFLEX, IN MEAL-INDUCED SATmTY AND IN THE TREATMENT OF IMPAIRED ACCOMMODATION IN MAN. Jan F. Tack, Ingrid Demedts, Rita Vos, Ann L. Meulemans, Jan A. Schuurkes, Jozef Janssens, Ctr for GI Research KU Leuven, Leuven, Belgium; Janssen Research Fdn, Beerse, Belgium. Accommodation of the stomach to a meal consists of a relaxation of the proximal stomach, providing the meal with a reservoir. In man, impaired accommodation is associated with early satiety, and sumatriptan (Sum) is able to restore accommodation and meal-induced satiety. Animal studies have shown that the accommodation reflex involves activation of nitrergic neurons in the gastric wall. Our aim was to study in man the involvement of nitric oxide (NO) in the accommodation reflex, in the control of meal-induced satiety and in the treatment of impaired accommodation. Methods: A) Five healthy subjects (5 men, age 21-29) underwent in randomized order 3 gastric barostat studies. Isobaric tone measurements (at MDP+2 mm Hg) were performed 30 min before and 60 min after a liquid meal (200 rnl, 300 kcal). Twenty min prior to the meal, placebo or the NO synthase inhibitor L-NMMA 3 or 6 mg/kg were administered i.v, over 45 min. Accommodation was quantified as the difference in mean volume after and before the meal. B) Eight healthy subjects underwent 2 satiety tests. They were asked to ingest Nutridrink at a rate of 15 ml/min until maximum satiety. Twenty min prior to the meal, placebo or L-NMMA 6 mg/kg were administered i.v. over 45 min. C) Five healthy subjects (5 men, age 21-29) underwent in randomized order 3 gastric barostat studies. Isobaric tone measurements were performed 30 min before and 60 min after Sum 6 mg s.c. Twenty minutes prior to Sum, placebo or L-NMMA 3 or 6 mg/kg were administered i.v, over 45 minutes. Results: Ingestion of the meal induced a relaxation of 244:':16 ml which was significantly smaller after L-NMMA 3 mg/kg (l22:':52ml, p
2043 MEASUREMENT OF GASTRIC ACCOMMODATION AND EMp· TYING OF A SOLID MEAL BY MAGNETIC RESONANCE IMAGING. Myung-Gyu Choi, Byung Wook Kim, Kyo Young Choo, Soo Heon Park, Seung Eun Jung, Jae Moon Lee, Sok Won Han, In Sik Chung, Kyu Won Chung, Hee Sik Sun, The Catholic Univ of Korea, Seoul, South Korea. Magnetic resonance imaging(MRI) provides an accurate measurement of the volume change of the stomach after meals. Therefore, we hypothesized that MRI could evaluate both gastric accommodation and emptying of solids. Our aim was to develop a noninvasive test using MRI to measure gastric accommodation and the emptying of solids. Methods: 18 healthy volunteers(l5 males, 3 females; mean age, 28) underwent simultaneous scintigraphy and MRI in order to validate MRI measurement of gastric emptying of solids. After ingestion of a radiolabelled sandwich test meal(325 kcal), MRI and scintigraphic scans were obtained for 2 hours. The volume of the stomach was determined by multiplying areas of interest for each slice of MRI scan by the slice thickness. Proximal and distal gastric regions were divided at the angle from 3 dimensional(3D) reconstructions of the stomach. Half gastric emptying time was derived from k and (3 in a power exponential model;prop(t) =exp{ -(k*t)I3}. All subjects underwent electronic barostat study on the following day in order to compare MRI measurement of gastric accommodation to electronic barostat. Gastric tone was assessed 30 min before and 60 min after ingestion of a 250 kcal liquid test meal. Results: Rapid MRI technique allowed accurate measurement of the volume of the stomach. The proximal stomach was markedly dilated in contrast to the minimally distended distal