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Wang X, Alkaabi F, Cornett A, Choi M, Scheven UM, Di Natale MR, Furness JB, Liu Z. Magnetic Resonance Imaging of Gastric Motility in Conscious Rats. Neurogastroenterol Motil 2024:e14982. [PMID: 39737873 DOI: 10.1111/nmo.14982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/01/2025]
Abstract
INTRODUCTION Gastrointestinal (GI) magnetic resonance imaging (MRI) enables simultaneous assessment of gastric peristalsis, emptying, and intestinal filling and transit. However, GI MRI in animals typically requires anesthesia, which complicates physiology and confounds interpretation and translation to humans. This study aimed to establish GI MRI in conscious rats, and for the first time, characterize GI motor functions in awake versus anesthetized conditions. METHODS Fourteen Sprague-Dawley rats were acclimated to remain awake, still, and minimally stressed during MRI. GI MRI was performed under both awake and anesthetized conditions following voluntary consumption of a contrast-enhanced test meal. RESULTS Awake rats remained physiologically stable during MRI, giving rise to gastric emptying of 23.7% ± 1.4% at 48 min and robust peristaltic contractions propagating through the antrum at 0.72 ± 0.04 mm/s, with a relative amplitude of 40.7% ± 2.3% and a frequency of 5.1 ± 0.1 cycles per minute. Under anesthesia, gastric emptying was approximately halved, mainly due to a significant reduction in peristaltic contraction amplitude, rather than the change in propagation speed, whereas the contraction frequency remained unchanged. Additionally, the small intestine showed faster filling and stronger motility in awake rats. CONCLUSION This study demonstrates the feasibility of GI MRI in awake rats and highlights notable differences in gastric and intestinal motility between awake and anesthetized states. Our protocol provides a novel and valuable framework for preclinical studies of GI physiology and pathophysiology.
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Affiliation(s)
- Xiaokai Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Fatimah Alkaabi
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Ashley Cornett
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Minkyu Choi
- Division of Electrical and Computer Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Ulrich M Scheven
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA
| | - Madeleine R Di Natale
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - John B Furness
- Department of Anatomy and Physiology, University of Melbourne, Parkville, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
| | - Zhongming Liu
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
- Division of Electrical and Computer Engineering, University of Michigan, Ann Arbor, Michigan, USA
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Wang X, Alkaabi F, Cornett A, Choi M, Scheven UM, Di Natale MR, Furness JB, Liu Z. Magnetic Resonance Imaging of Gastric Motility in Conscious Rats. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.09.612090. [PMID: 39314428 PMCID: PMC11419018 DOI: 10.1101/2024.09.09.612090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
Introduction Gastrointestinal (GI) magnetic resonance imaging (MRI) can simultaneously capture gastric peristalsis, emptying, and intestinal filling and transit. Performing GI MRI with animals requires anesthesia, which complicates physiology and confounds interpretation and translation from animals to humans. This study aims to enable MRI in conscious rats, and for the first time, characterize GI motor functions in awake versus anesthetized conditions. Methods We acclimated rats to remain awake, still, and minimally stressed during MRI. We scanned 14 Sprague-Dawley rats in both awake and anesthetized conditions after voluntarily consuming a contrast-enhanced test meal. Results Awake rats remained physiologically stable during MRI, showed gastric emptying of 23.7±1.4% after 48 minutes, and exhibited strong peristaltic contractions propagating through the antrum with a velocity of 0.72±0.04 mm/s, a relative amplitude of 40.7±2.3%, and a frequency of 5.1±0.1 cycles per minute. In the anesthetized condition, gastric emptying was about half of that in the awake condition, likely due to the effect of anesthesia in halving the amplitudes of peristaltic contractions rather than their frequency (not significantly changed) or velocity. In awake rats, the intestine filled more quickly and propulsive contractions were more occlusive. Conclusion We demonstrated the effective acquisition and analysis of GI MRI in awake rats. Awake rats show faster gastric emptying, stronger gastric contraction with a faster propagation speed, and more effective intestinal filling and transit, compared to anesthetized rats. Our protocol is expected to benefit future preclinical studies of GI physiology and pathophysiology.
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Ren H, Yuan F, Tan W, Ding Y, An P, Luo H. Effect of Evodiamine on Rat Colonic Hypermotility Induced by Water Avoidance Stress and the Underlying Mechanism. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:441-452. [PMID: 33603336 PMCID: PMC7882800 DOI: 10.2147/dddt.s298954] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 01/28/2021] [Indexed: 11/23/2022]
Abstract
Background and Aim EVO is a natural alkaloid that reportedly has potential value in regulating gastrointestinal motility, but this conclusion remains controversial, and the molecular mechanism is unclear. In this study, we aimed to explore the effect of short-chain fatty acids on rat colonic hypermotility induced by water avoidance stress and the underlying mechanism. Methods We constructed a hypermotile rat model by chronic water avoidance stress, and Western blot was used to detect the protein level of nNOS in colon tissue. The organ bath and multichannel physiological signal acquisition systems were used to examine the spontaneous contractions of smooth muscle strips. The whole-cell patch-clamp technique was used to investigate L-type voltage-dependent calcium and BKCa channel currents in colonic smooth muscle cells. Results EVO inhibited the spontaneous contractions of colonic smooth muscle strips in a dose-dependent manner. Moreover, EVO decreased the fecal output induced by chronic water avoidance stress. TTX did not block the inhibitory effect of EVO on spontaneous colon contractions, while L-NNA, a selective nNOS synthase inhibitor, did partially abolish this inhibitory effect. The protein expression of nNOS in the colon tissues of rats administered EVO was significantly increased compared to that in control rats. EVO reversibly inhibited the L-type calcium channel current without changing the steady-state activation or inactivation in colonic smooth muscle cells. EVO significantly inhibited the BKCa current but did not change the shape of the I-V curves. Conclusion EVO inhibits gastrointestinal motility by inhibiting L-type calcium and BKCa channels in colonic smooth muscle cells and indirectly interacting with nNOS.
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Affiliation(s)
- HaiXia Ren
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - FangTing Yuan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.,Key Laboratory of Hubei Province for Digestive System Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - Wei Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - YiJuan Ding
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - Ping An
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
| | - HeSheng Luo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China
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Jin M, Son M. DA-9701 (Motilitone): A Multi-Targeting Botanical Drug for the Treatment of Functional Dyspepsia. Int J Mol Sci 2018; 19:ijms19124035. [PMID: 30551633 PMCID: PMC6321359 DOI: 10.3390/ijms19124035] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 12/07/2018] [Accepted: 12/07/2018] [Indexed: 12/12/2022] Open
Abstract
Functional dyspepsia (FD) is the most common functional gastrointestinal disorder (FGID). FD is characterized by bothersome symptoms such as postprandial fullness, early satiety, and epigastric pain or burning sensations in the upper abdomen. The complexity and heterogeneity of FD pathophysiology, which involves multiple mechanisms, make both treatment and new drug development for FD difficult. Current medicines for FD targeting a single pathway have failed to show satisfactory efficacy and safety. On the other hand, multicomponent herbal medicines that act on multiple targets may be a promising alternative treatment for FD. DA-9701 (Motilitone), a botanical drug consisting of Corydalis Tuber and Pharbitidis Semen, has been prescribed for FD since it was launched in Korea in 2011. It has multiple mechanisms of action such as prokinetic effects, fundus relaxation, and visceral analgesia, which are mediated by dopamine D2 and several serotonin receptors involved in gastrointestinal (GI) functions. In clinical studies, DA-9701 has been found to be beneficial for improvement of FD symptoms and GI functions in FD patients, while showing better safety compared to that associated with conventional medicines. In this review, we provide updated information on the pharmacological effects, safety, and clinical results of DA-9701 for the treatment of FGIDs.
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Affiliation(s)
- Mirim Jin
- Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Korea.
- Department of Health Science and Technology, GAIHST, Gachon University, Incheon 21936, Korea.
| | - Miwon Son
- Research Center & Phytotherapeutics Group, Viromed, Co. Ltd., Seoul 08826, Korea.
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Mussa BM, Sood S, Verberne AJM. Implication of neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function in diabetic gastroparesis. World J Gastroenterol 2018; 24:3821-3833. [PMID: 30228777 PMCID: PMC6141338 DOI: 10.3748/wjg.v24.i34.3821] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Recently, diabetic gastroparesis (DGP) has received much attention as its prevalence is increasing in a dramatic fashion and management of patients with DGP represents a challenge in the clinical practice due to the limited therapeutic options. DGP highlights an interrelationship between the gastric emptying and pancreatic secretory function that regulate a wide range of digestive and metabolic functions, respectively. It well documented that both gastric emptying and pancreatic secretion are under delicate control by multiple neurohormonal mechanisms including extrinsic parasympathetic pathways and gastrointestinal (GI) hormones. Interestingly, the latter released in response to various determinants that related to the rate and quality of gastric emptying. Others and we have provided strong evidence that the central autonomic nuclei send a dual output (excitatory and inhibitory) to the stomach and the pancreas in response to a variety of hormonal signals from the abdominal viscera. Most of these hormones released upon gastric emptying to provide feedback, and control this process and simultaneously regulate pancreatic secretion and postprandial glycemia. These findings emphasize an important link between gastric emptying and pancreatic secretion and its role in maintaining homeostatic processes within the GI tract. The present review deals with the neurohormonal-coupled mechanisms of gastric emptying and pancreatic secretory function that implicated in DGP and this provides new insights in our understanding of the pathophysiology of DGP. This also enhances the process of identifying potential therapeutic targets to treat DGP and limit the complications of current management practices.
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Affiliation(s)
- Bashair M Mussa
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Sanjay Sood
- Department of Basic Medical Science, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Anthony JM Verberne
- Department of Medicine, Austin Health, University of Melbourne, Melbourne 3084, Australia
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Change in the Interstitial Cells of Cajal and nNOS Positive Neuronal Cells with Aging in the Stomach of F344 Rats. PLoS One 2017; 12:e0169113. [PMID: 28045993 PMCID: PMC5207530 DOI: 10.1371/journal.pone.0169113] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 12/11/2016] [Indexed: 12/22/2022] Open
Abstract
The gastric accommodation reflex is an important mechanism in gastric physiology. However, the aging-associated structural and functional changes in gastric relaxation have not yet been established. Thus, we evaluated the molecular changes of interstitial cell of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) and the function changes in the corpus of F344 rats at different ages (6-, 31-, 74-wk and 2-yr). The proportion of the c-Kit-positive area in the submucosal border (SMB) and myenteric plexus (MP) layer was significantly lower in the older rats, as indicated by immunohistochemistry. The density of the nNOS-positive immunoreactive area also decreased with age in the SMB, circular muscle (CM), and MP. Similarly, the percent of nNOS-positive neuronal cells per total neuronal cells and the proportion of nNOS immunoreactive area of MP also decreased in aged rats. In addition, the mRNA and protein expression of c-Kit and nNOS significantly decreased with age. Expression of stem cell factor (SCF) and the pan-neuronal marker PGP 9.5 mRNA was significantly lower in the older rats than in the younger rats. Barostat studies showed no difference depending on age. Instead, the change of volume was significantly decreased by L-NG63-nitroarginine methyl ester in the 2-yr-old rats compared with the 6-wk-old rats (P = 0.003). Taken together, the quantitative and molecular nNOS changes in the stomach might play a role in the decrease of gastric accommodation with age.
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Lentle RG, Reynolds GW, Hulls CM, Chambers JP. Advanced spatiotemporal mapping methods give new insights into the coordination of contractile activity in the stomach of the rat. Am J Physiol Gastrointest Liver Physiol 2016; 311:G1064-G1075. [PMID: 27765760 DOI: 10.1152/ajpgi.00308.2016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 10/12/2016] [Indexed: 01/31/2023]
Abstract
We used spatiotemporal mapping of strain rate to determine the direction of propagation and amplitudes of the longitudinal and circumferential components of antrocorporal (AC) contractions and fundal contractions in the rat stomach maintained ex vivo and containing a volume of fluid that was within its normal functional capacity. In the region of the greater curvature the longitudinal and circular components of AC contractions propagated synchronously at right angles to the arciform geometric axis of the stomach. However, the configuration of AC contractions was U shaped, neither the circular nor the longitudinal component of contractions being evident in the upper proximal corpus. Similarly, in the distal upper antrum of some preparations, circumferential components propagated more rapidly than longitudinal components. Ongoing "high-frequency, low-amplitude myogenic contractions" were identified in the upper proximal gastric corpus and on the anterior and posterior wall of the fundus. The amplitudes of these contractions were modulated in the occluded stomach by low-frequency pressure waves that occurred spontaneously. Hence the characteristics of phasic contractions vary regionally in the antrum and corpus and a previously undescribed high-frequency contractile component was identified in the proximal corpus and fundus, the latter being modulated in synchrony with cyclic variation in intrafundal pressure in the occluded fundus.
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Affiliation(s)
- R G Lentle
- Institute of Food, Nutrition and Human Health, Massey University, Palmerston North, New Zealand; and
| | - G W Reynolds
- Institute of Food, Nutrition and Human Health, Massey University, Palmerston North, New Zealand; and
| | - C M Hulls
- Institute of Food, Nutrition and Human Health, Massey University, Palmerston North, New Zealand; and
| | - J P Chambers
- Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand
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Miwa H, Koseki J, Oshima T, Hattori T, Kase Y, Kondo T, Fukui H, Tomita T, Ohda Y, Watari J. Impairment of gastric accommodation induced by water-avoidance stress is mediated by 5-HT2B receptors. Neurogastroenterol Motil 2016; 28:765-78. [PMID: 26833428 DOI: 10.1111/nmo.12775] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 12/21/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Psychological stress has been shown to impair gastric accommodation (GA), but its mechanism has not been elucidated. This study was conducted to clarify the role of 5-HT2B receptors in a guinea pig model of stress-induced impairment of GA. METHODS Gastric accommodation was evaluated by measuring the intrabag pressure in the proximal stomach after administration of a liquid meal. The guinea pigs were subjected to water-avoidance stress. The role of 5-HT2B receptors in impairment of GA was investigated by administering a 5-HT2B receptor agonist (BW723C86) or antagonist (SB215505), the traditional Japanese medicine rikkunshito (RKT), a muscarinic M3 receptor antagonist (1,1-dimethyl-4-diphenylacetoxypiperidium iodide [4-DAMP]), or a nitric oxide synthase inhibitor (Nω -nitro-L-arginine [L-NNA]). KEY RESULTS In normal animals, liquid meal-induced GA was inhibited by BW723C86, but was not affected by SB215505. The inhibition of GA by BW723C86 was reversed by co-administration of 4-DAMP. Compared to normal animals, GA in stressed animals was significantly inhibited. SB215505 and RKT significantly suppressed stress-induced impairment of GA. After meal administration, the level of cyclic guanosine monophosphate in gastric fundus tissue increased by approximately twofold in normal animals, but did not change in stressed animals. The inhibition of GA by L-NNA was suppressed by SB215505 or RKT. At a dose that did not affect GA in normal animals, BW723C86 exacerbated the impairment of GA in stressed animals. CONCLUSIONS AND INFERENCES Stress-induced impairment of GA may be mediated by an increased responsiveness of 5-HT2B receptors, and activation of the 5-HT2B receptor signaling pathway may have an inhibitory effect on nitric oxide function.
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Affiliation(s)
- H Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - J Koseki
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - T Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - T Hattori
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - Y Kase
- Tsumura Research Laboratories, Tsumura & Co., Ibaraki, Japan
| | - T Kondo
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - H Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - T Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Y Ohda
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - J Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
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Kwon YS, Son M. DA-9701: A New Multi-Acting Drug for the Treatment of Functional Dyspepsia. Biomol Ther (Seoul) 2013; 21:181-9. [PMID: 24265862 PMCID: PMC3830115 DOI: 10.4062/biomolther.2012.096] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 03/12/2013] [Accepted: 03/14/2013] [Indexed: 12/17/2022] Open
Abstract
Motilitone® (DA-9701) is a new herbal drug that was launched for the treatment of functional dyspepsia in December 2011 in Korea. The heterogeneous symptom pattern and multiple causes of functional dyspepsia have resulted in multiple drug target strategies for its treatment. DA-9701, a compound consisting of a combination of Corydalis Tuber and Pharbitidis Semen, has being developed for treatment of functional dyspepsia. It has multiple mechanisms of action such as fundus relaxation, visceral analgesia, and prokinetic effects. Furthermore, it was found to significantly enhance meal-induced gastric accommodation and increase gastric compliance in dogs. DA-9701 also showed an analgesic effect in rats with colorectal distension induced visceral hypersensitivity and an antinociceptive effect in beagle dogs with gastric distension-induced nociception. The pharmacological effects of DA-9701 also include conventional effects, such as enhanced gastric emptying and gastrointestinal transit. The safety profi le of DA-9701 is also preferable to that of other treatments.
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Affiliation(s)
- Yong Sam Kwon
- Dong-A ST Research Institute, Yongin 446-905, Republic of Korea
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Koseki J, Oshima T, Kondo T, Tomita T, Fukui H, Watari J, Hattori T, Kase Y, Miwa H. Role of transient receptor potential ankyrin 1 in gastric accommodation in conscious guinea pigs. J Pharmacol Exp Ther 2012; 341:205-12. [PMID: 22262922 DOI: 10.1124/jpet.111.189027] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2025] Open
Abstract
We report the establishment of a new model for measuring gastric tone and liquid meal-induced accommodation in conscious guinea pigs and the role played by transient receptor potential ankyrin 1 (TRPA1). An indwelling polyethylene bag was placed in proximal stomachs of 5-week-old male Hartley guinea pigs. Gastric tone was measured by distending the bag and recording changes in intrabag pressure at various volumes. Gastric accommodation was measured by administering liquid meals and recording intrabag pressure over time. N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME) (a nitric-oxide synthase inhibitor), atropine sulfate (atropine) (a muscarinic receptor antagonist), allyl isothiocyanate (AITC) (a TRPA1 agonist), or theophylline-7-(N-4-isopropylphenyl) acetamide (HC-030031) (a selective TRPA1 antagonist) was administered 15 to 60 min before measurement. Gastric tone was increased by stepwise distension of the bag and was further significantly increased by L-NAME and significantly decreased by atropine. A liquid meal (15% w/v; 1.7 kcal) significantly decreased intrabag pressure 5 to 20 min after administration, indicating gastric accommodation; this was completely suppressed by L-NAME and further enhanced by atropine. AITC significantly increased gastric tone; this increase was decreased by HC-030031 and atropine. A combination of AITC and L-NAME significantly increased gastric tone compared with L-NAME alone. HC-030031 alone significantly decreased gastric tone. Liquid meal-induced gastric accommodation was significantly suppressed by pretreatment with AITC. We established a new model for measuring gastric tone and accommodation in conscious guinea pigs. TRPA1 activation suppresses gastric accommodation by increasing gastric tone through cholinergic neuronal pathways.
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Affiliation(s)
- Junichi Koseki
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
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Vanden Berghe P, Janssen P, Kindt S, Vos R, Tack J. Contribution of different triggers to the gastric accommodation reflex in humans. Am J Physiol Gastrointest Liver Physiol 2009; 297:G902-6. [PMID: 19846891 DOI: 10.1152/ajpgi.00046.2009] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Accommodation of the stomach consists of a vagally mediated relaxation of the proximal stomach, providing the meal with a reservoir. Our aim was to study whether, similar to other vagally mediated processes, the accommodation reflex is also determined by cephalic, oropharyngeal, gastric, and intestinal phases. Eleven healthy subjects underwent in randomized order five gastric barostat studies and two satiety drinking tests. In all studies, isobaric tone measurements (at minimal distending pressure + 2 mmHg) were performed 20 min before and 20 min after a nutrient stimulus. The stimuli included only visual and olfactory exposure to a meal (cephalic stimulation), taking liquid nutrient in the mouth without swallowing (sham feeding), ingestion of a 200-ml 300-kcal nutrient meal with blocked outflow to the pylorus (gastric retention), and meal infusion through a nasointestinal tube (duodenal instillation), or normal ingestion (control). During satiety testing, subjects ingested liquid nutrient at a fixed rate of 15 ml/min until maximum satiety, with an inflated or deflated intrapyloric balloon assembly. Progressively bigger gastric relaxatory responses were seen with cephalic stimulation (18 +/- 19 ml), sham feeding (54 +/- 21 ml), gastric retention (95 +/- 47), duodenal instillation (144 +/- 33), and control (232 +/- 33 ml). The amount of nutrient ingested at maximum satiety was significantly lower with an inflated intrapyloric balloon (1,223 +/- 103 vs. 1,392 +/- 124 ml, P < 0.05). The accommodation reflex in humans lacks a cephalic phase, but it can be activated from the oropharynx, the stomach, and the duodenum. Blocking passage to the duodenum significantly decreases the amplitude of the accommodation reflex and induces early satiety.
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Affiliation(s)
- Pieter Vanden Berghe
- Center for Gastroenterological research K. U. Leuven, 49 Herestraat, 3000 Leuven, Belgium
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Chen J, Xing J, Chen JDZ. Effects of muscarinic receptor stimulation and nitric oxide synthase inhibition on gastric tone and gastric myoelectrical activity in canines. J Gastroenterol Hepatol 2009; 24:1130-5. [PMID: 19638091 DOI: 10.1111/j.1440-1746.2009.05843.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
AIMS This study was designed to assess whether the muscarinic receptor stimulation and nitric oxide synthase inhibition were equally effective on gastric fundic tone or gastric myoelectrical activity (GMA) in canines, and the correlation between gastric fundic tone and GMA. METHODS Gastric fundic tone and GMA were recorded on seven dogs implanted with serosal electrodes and a gastric cannula. RESULTS Bethanechol and L-nitro-N-arginine (L-NNA) significantly increased gastric fundic tone; gastric volume was decreased with bethanechol or L-NNA (P < 0.05). Increased spike activities were observed after both bethanechol and L-NNA. The percentage of slow waves superimposed with spikes was increased with bethanechol (P < 0.001) and L-NNA (P < 0.05). There was a significant reduction in dominant frequency (DF) (P < 0.05), dominant power (DP) (P < 0.05) and percentage of normal slow waves (%N) (P < 0.05) with bethanechol, while no significant change was observed with L-NNA. The variation of gastric tone was not correlated with parameters of GMA. CONCLUSIONS Muscarinic receptor stimulation and nitric oxide synthase inhibition have similar effects on gastric tone and gastric spike activities, but different effects on gastric slow waves. Gastric fundic tone does not correlate with gastric slow waves.
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Affiliation(s)
- Jihong Chen
- Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas 77555-0632, USA
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Chen J, Koothan T, Chen JDZ. Synchronized gastric electrical stimulation improves vagotomy-induced impairment in gastric accommodation via the nitrergic pathway in dogs. Am J Physiol Gastrointest Liver Physiol 2009; 296:G310-8. [PMID: 19023028 PMCID: PMC2643919 DOI: 10.1152/ajpgi.90525.2008] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Impaired gastric accommodation and gastric dysrhythmia are common in gastroparesis and functional dyspepsia. Recent studies have shown that synchronized gastric electrical stimulation (SGES) accelerates gastric emptying and enhances antral contractions in dogs. The aim of this study was to investigate the effects and mechanism of SGES on gastric accommodation and slow waves impaired by vagotomy in dogs. Gastric tone, compliance, and accommodation as well as slow waves with and without SGES were assessed in seven female regular dogs and seven dogs with bilateral truncal vagotomy, chronically implanted with gastric serosal electrodes and a gastric cannula. We found that 1) vagotomy impaired gastric accommodation that was normalized by SGES. The postprandial increase in gastric volume was 283.5 +/- 50.6 ml in the controlled dogs, 155.2 +/- 49.2 ml in the vagotomized dogs, and 304.0 +/- 57.8 ml in the vagotomized dogs with SGES. The ameliorating effect of SGES was no longer observed after application of N(omega)-nitro-L-arginine (L-NNA); 2) vagotomy did not alter gastric compliance whereas SGES improved gastric compliance in the vagotomized dogs, and the improvement was also blocked by L-NNA; and 3) vagotomy impaired antral slow wave rhythmicity in both fasting and fed states. SGES at the proximal stomach enhanced the postprandial rhythmicity and amplitude (dominant power) of the gastric slow waves in the antrum. In conclusion, SGES with appropriate parameters restores gastric accommodation and improves gastric slow waves impaired by vagotomy. The improvement in gastric accommodation with SGES is mediated via the nitrergic pathway. Combined with previously reported findings (enhanced antral contractions and accelerated gastric emptying) and findings in this study (improved gastric accommodation and slow waves), SGES may be a viable therapy for gastroparesis.
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Affiliation(s)
- Jie Chen
- Division of Gastroenterology and Animal Resources Center, University of Texas Medical Branch, Galveston, Texas; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Transtimulation Research Incorporated, Oklahoma City, Oklahoma
| | - Thillai Koothan
- Division of Gastroenterology and Animal Resources Center, University of Texas Medical Branch, Galveston, Texas; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Transtimulation Research Incorporated, Oklahoma City, Oklahoma
| | - Jiande D. Z. Chen
- Division of Gastroenterology and Animal Resources Center, University of Texas Medical Branch, Galveston, Texas; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; and Transtimulation Research Incorporated, Oklahoma City, Oklahoma
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14
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Waseem S, Moshiree B, Draganov PV. Gastroparesis: Current diagnostic challenges and management considerations. World J Gastroenterol 2009; 15:25-37. [PMID: 19115465 PMCID: PMC2653292 DOI: 10.3748/wjg.15.25] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastroparesis refers to abnormal gastric motility characterized by delayed gastric emptying in the absence of mechanical obstruction. The most common etiologies include diabetes, post-surgical and idiopathic. The most common symptoms are nausea, vomiting and epigastric pain. Gastroparesis is estimated to affect 4% of the population and symptomatology may range from little effect on daily activity to severe disability and frequent hospitalizations. The gold standard of diagnosis is solid meal gastric scintigraphy. Treatment is multimodal and includes dietary modification, prokinetic and anti-emetic medications, and surgical interventions. New advances in drug therapy, and gastric electrical stimulation techniques have been introduced and might provide new hope to patients with refractory gastroparesis. In this comprehensive review, we discuss gastroparesis with emphasis on the latest developments; from the perspective of the practicing clinician.
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15
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Garvin B, Wiley JW. The role of serotonin in irritable bowel syndrome: implications for management. Curr Gastroenterol Rep 2008; 10:363-8. [PMID: 18627647 DOI: 10.1007/s11894-008-0070-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Irritable bowel syndrome (IBS) is a poorly understood, common, chronic condition characterized by -abdominal discomfort associated with altered bowel habits in the absence of structural or biochemical abnormalities. Despite the significant economic and personal burden associated with IBS, treatment options remain limited. Serotonin is recognized as a key neurotransmitter in intestinal secretory, sensory, and motor function. Although the pathophysiology of IBS is incompletely understood, there is evidence that abnormalities in brain-gut signaling and serotonin metabolism play a role. This article reviews the evidence that serotonin, one of the better-understood neurotransmitters with respect to its role in human central and intestinal physiology, plays a role in IBS. Serotonin signaling is discussed, with a focus on receptor subtypes and the therapeutic agents that target these receptors. Evidence that IBS is associated with perturbations in serotonin metabolism at various steps in the signaling pathway is also addressed, along with the limitations on alteration in serotonin metabolism as the sole explanation for the constellation of symptoms observed in patients with IBS.
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Affiliation(s)
- Brian Garvin
- Department of Internal Medicine, University of Michigan Health System, A7007 UH, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
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16
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Chen J, Song GQ, Yin J, Koothan T, Chen JDZ. Electroacupuncture improves impaired gastric motility and slow waves induced by rectal distension in dogs. Am J Physiol Gastrointest Liver Physiol 2008; 295:G614-20. [PMID: 18653722 DOI: 10.1152/ajpgi.90322.2008] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Rectal distension (RD) is known to induce upper gastrointestinal (GI) symptoms. The aim of this study was to investigate the effects and underlying mechanisms of RD on gastric slow waves (GSW) and motor activity and furthermore to investigate the effects and mechanisms of electroacupuncture (EA) on GSW and motor activity. Eight female hound dogs chronically implanted with gastric serosal electrodes and a gastric fistula were studied in six separate sessions. Antral motility, GSW, heart rate variability, and rectal pressure were evaluated for the above purposes. 1) RD at a volume of 120 ml suppressed antral motility significantly. Guanethidine blocked the inhibitory effect of RD. EA at ST36 was able to restore the suppressed antral contractions induced by RD (16.6+/-1.7 vs. 8.0+/-1.4, P<0.001). Naloxone partially blocked the effect of EA on antral contractions. 2) RD reduced the percentage of normal GSW from 98.8+/-0.8% at baseline to 76.1+/-8.6% (P<0.05) that was increased to 91.8+/-3.0% with EA. The effects of EA on the GSW were nullified by the presence of naloxone. 3) EA did not show any significant effect on rectal pressure, suggesting that the ameliorating effects of EA on RD-induced impaired gastric motility were not due to a decrease in rectal pressure. 4) EA increased the vagal activity suppressed by RD. In conclusion, RD inhibits postprandial gastric motility and impairs GSW in dogs, and the inhibitory effects are mediated via the adrenergic pathways. EA at ST36 is able to restore the RD-induced impaired GSW and motor activities, possibly by enhancing vagal activity, and is partially mediated via the opioid pathway. EA may have therapeutic potential for functional gastrointestinal disorders.
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Affiliation(s)
- Jie Chen
- Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX 77555-0632, USA.
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17
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Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedebergs Arch Pharmacol 2008; 377:181-203. [PMID: 18398601 DOI: 10.1007/s00210-008-0276-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2007] [Accepted: 02/15/2008] [Indexed: 12/17/2022]
Abstract
Serotonin (5-hydroxytryptamine or 5-HT) plays a critical physiological role in the regulation of gastrointestinal (GI) function. 5-HT dysfunction may also be involved in the pathophysiology of a number of functional GI disorders, such as chronic constipation, irritable bowel syndrome and functional dyspepsia. This article describes the role of 5-HT in the enteric nervous system (ENS) of the mammalian GI tract and the receptors with which it interacts. Existing serotonergic therapies that have proven effective in the treatment of GI functional disorders and the potential of drugs currently in development are also highlighted. Advances in our understanding of the physiological and pathophysiological roles of 5-HT in the ENS and the identification of selective receptor ligands bodes well for the future development of more efficacious therapies for patients with functional GI disorders.
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18
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Gaggiotti G, Tack J, Garrido AB, Palau M, Cappelluti G, Di Matteo F. Adjustable totally implantable intragastric prosthesis (ATIIP)-Endogast for treatment of morbid obesity: one-year follow-up of a multicenter prospective clinical survey. Obes Surg 2007; 17:949-56. [PMID: 17894156 DOI: 10.1007/s11695-007-9174-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The Adjustable Totally Implantable Intragastric Prosthesis (ATIIP)-Endogas is a new mini-invasive technique for the treatment of morbid obesity. The ATIIP is conducted using a surgical and endoscopic procedure. The permanent presence of an air-inflated prosthesis inside the gastric corpus-fundus area and the fixation of the stomach to the abdominal wall are the two main principles in the technique. The prosthesis is connected to a subcutaneous totally implantable system. The aim of the ATIIP is to induce early satiety and reduction of meal intake. This study presents the preliminary results of 1-year follow-up of a multicenter prospective clinical survey. METHODS From November 2004 to March 2007, 57 patients underwent ATIIP: 28 males (49%) and 29 females (51%), with mean age 43.6 years (18-69) and mean BMI 48.9 (33.7-81.2). Follow-up was 1-28 months. RESULTS Feasibility was 100%, reproducibility 100%, and acceptability found no vomitting. Mean volume of the prosthesis was 210 ml of air (first 3 months, 40 patients). Mean %EWL was 22.3% (3 mos, 40 pts), 28.7% (6 mos, 38 pts), and 39.2% (12 mos, 20 pts). Early postoperative complication was local subcutaneous infection in 7 pts (12.2%). In 16 pts who had a subcutaneous drain and empirical antibiotic therapy until the 4th postoperative day, local infection occurred in 1 patient (6.2%). Late postoperative complications occurred in 3 pts (5.2%) who developed port erosion. CONCLUSIONS Preliminary results indicate that the ATIIP is feasible, reproducible, safe with low risk of complications and has encouraging results in weight loss. Morbidly obese patients >60 years old and the super-obese (BMI>50) are specific indications.
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Affiliation(s)
- Giorgio Gaggiotti
- Centro di Riferimento Regionale Chirurgia Obesita, Clinica Chirurgica FI, Universiti Politecnica delle Marche, INRCA, IRCCS Ancona, Italy.
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19
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Abstract
Functional dyspepsia (FD) is a highly prevalent gastrointestinal disorder and has a complex pathophysiology. Impaired fundic relaxation in response to a meal is present in 40% of patients with FD. This review focuses on impaired gastric accommodation of the stomach as a pathophysiological mechanism and the possible therapeutic targets that can be derived from the current knowledge of the neuroregulation of the accommodation reflex. First the different means of gastric accommodation assessment are described and the relationship between symptoms and impaired gastric accommodation. The different therapeutic options are subsequently discussed in view of their molecular target, based on the different receptor subtypes involved in the accommodation reflex. Although impaired gastric accommodation is highly prevalent in dyspeptic patients and basic knowledge about the accommodation reflex enables to develop pathophysiologically targeted therapies, it is unlikely that therapies aimed at dysaccommodation of the stomach will lead to symptom relief in all dyspeptic patients. A major challenge is the development of methods that readily identify impaired accommodation in clinical practice.
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Affiliation(s)
- R Bisschops
- Center for Gastroenterological Research, K.U. Leuven, Leuven, Belgium
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20
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Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007; 132:397-414. [PMID: 17241888 DOI: 10.1053/j.gastro.2006.11.002] [Citation(s) in RCA: 1094] [Impact Index Per Article: 60.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2006] [Accepted: 11/06/2006] [Indexed: 12/11/2022]
Abstract
Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT(4) partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT(3) antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT(1) agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.
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Affiliation(s)
- Michael D Gershon
- Department of Pathology & Cell Biology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
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21
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Xue L, Camilleri M, Locke GR, Schuurkes JAJ, Meulemans A, Coulie BJ, Szurszewski JH, Farrugia G. Serotonergic modulation of murine fundic tone. Am J Physiol Gastrointest Liver Physiol 2006; 291:G1180-6. [PMID: 16873894 DOI: 10.1152/ajpgi.00224.2006] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fundic tone is maintained through a balance of excitatory and inhibitory input to fundic smooth muscle. The aim of this study was to determine the role of serotonin (5-HT) and 5-HT receptors in modulating murine fundic tone. Muscle strips were prepared from the murine fundus. Intracellular recordings were made from circular smooth muscle cells, and the effects of 5-HT on tone and excitatory and inhibitory junction potentials evoked by electrical field stimulation (EFS) were determined. 5-HT induced a concentration-dependent contraction and smooth muscle depolarization that was tetrodotoxin resistant. The 5-HT(1B/D) receptor antagonists GR-127935 and BRL-155172 significantly inhibited 5-HT-induced contractions. The 5-HT(1B/D) agonist sumatriptan contracted murine fundic muscle. The 5-HT(1A) receptor agonist buspirone relaxed fundic smooth muscle, and the relaxation was inhibited by WAY-100135 but not by N(omega)-nitro-l-arginine or tetrodotoxin. 5-HT enhanced both the excitatory and inhibitory responses to EFS. The 5-HT(3) receptor antagonist MDL-72222 partly inhibited both the excitatory and inhibitory response elicited by EFS, whereas the 5-HT(4) receptor antagonist GR-113808 partly inhibited the EFS-evoked inhibitory response. The 5-HT reuptake inhibitor fluoxetine contracted smooth muscle strips, a contraction that was partially inhibited by GR-127935 and abolished by tetrodotoxin. In conclusion, the data suggest that 5-HT modulates murine fundic contractile activity through several different receptor subtypes. Sustained release of 5-HT maintains fundic tone through postjunctional 5-HT(1B/D) receptors. 5-HT(3) receptors modulate excitatory neural input to murine fundic smooth muscle, and both 5-HT(3) and 5-HT(4) receptors modulate inhibitory neural input to murine fundic smooth muscle.
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Affiliation(s)
- Lin Xue
- Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
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22
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van den Elzen BDJ, Boeckxstaens GEE. Review article: a critical view on impaired accommodation as therapeutic target for functional dyspepsia. Aliment Pharmacol Ther 2006; 23:1499-510. [PMID: 16696798 DOI: 10.1111/j.1365-2036.2006.02930.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Several important pathophysiological mechanisms have been identified in functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accommodation. Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been rather disappointing in general. These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involving other regions of the proximal gut or by the increasing insight that central mechanisms may play an important role. Future studies of impaired accommodation should take these considerations into account.
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Affiliation(s)
- B D J van den Elzen
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
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23
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Abstract
Gastrointestinal (GI) sensory-motor abnormalities are common in patients with diabetes mellitus and may involve any part of the GI tract. Abnormalities are frequently sub-clinical, and fortunately only rarely do severe and life-threatening problems occur. The pathogenesis of abnormal upper GI sensory-motor function in diabetes is incompletely understood and is most likely multi-factorial of origin. Diabetic autonomic neuropathy as well as acute suboptimal control of diabetes has been shown to impair GI motor and sensory function. Morphological and biomechanical remodeling of the GI wall develops during the duration of diabetes, and may contribute to motor and sensory dysfunction. In this review sensory and motility disorders of the upper GI tract in diabetes is discussed; and the morphological changes and biomechanical remodeling related to the sensory-motor dysfunction is also addressed.
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Affiliation(s)
- Jingbo Zhao
- Center of Excellence in Visceral Biomechanics and Pain, the Research Building room 404, Aalborg Hospital, Sdr. Skovvej 15, DK-9000 Aalborg, Denmark.
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24
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Xue L, Locke GR, Camilleri M, Schuurkes JAJ, Meulemans A, Coulie BJ, Szurszewski JH, Farrugia G. Effect of modulation of serotonergic, cholinergic, and nitrergic pathways on murine fundic size and compliance measured by ultrasonomicrometry. Am J Physiol Gastrointest Liver Physiol 2006; 290:G74-82. [PMID: 16166345 PMCID: PMC1434468 DOI: 10.1152/ajpgi.00244.2005] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Reduced fasting or postprandial gastric volumes have been implicated in the pathophysiology of functional dyspepsia. The mechanisms that underlie the control of gastric fundic volume are incompletely understood, partly because of an inability to accurately measure fundic volume in vivo in small animals. Small animals are useful models to evaluate mechanisms, e.g., in knockout animals. The aim of this study was to determine whether an ultrasonometric technique accurately monitors fundic contraction and relaxation in mice in vivo and to determine the effect of modulation of cholinergic, nitrergic, and serotonergic pathways on fundic size and compliance in the intact mouse innervated stomach. Two to four piezoelectric crystals (diameter 1 mm, 24-microm resolution) were glued to the serosal side of fundus and used to measure distance. Validation studies showed excellent correlation between measured changes and actual changes in distances between crystals and excellent reproducibility. The expected responses to pharmacological modulation with bethanechol and nitroglycerin were demonstrated. Atropine increased the distance between the crystals, suggesting a baseline cholinergic regulation of fundic volume. Bethanechol, Nomega-nitro-L-arginine, and the 5-HT1B/D agonist sumatriptan decreased the distance between the crystals, suggesting fundic contraction. Atropine, nitroglycerin, and buspirone caused an increase in intercrystal distance consistent with fundic relaxation. Fundic compliance was investigated by changing intragastric pressure via an implanted catheter. Sumatriptan increased compliance, whereas buspirone increased the distance between crystals but did not change compliance. The data suggest that ultrasonomicrometry is a useful tool that can reproducibly and accurately measure changes in fundic size and the response to pharmacological agents.
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Affiliation(s)
- Lin Xue
- Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - G. Richard Locke
- Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Michael Camilleri
- Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | | | - Ann Meulemans
- Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
| | - Bernard J. Coulie
- Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium
| | - Joseph H. Szurszewski
- Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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25
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Sun Y, Chen JDZ. Gastric electrical stimulation inhibits postprandial antral tone partially via nitrergic pathway in conscious dogs. Am J Physiol Regul Integr Comp Physiol 2005; 290:R904-8. [PMID: 16284081 DOI: 10.1152/ajpregu.00842.2004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Gastric electrical stimulation (GES) has recently been explored as a therapeutic option for gastrointestinal motility disorders or obesity. The mechanism behind it is not fully elucidated. The aims of this study were to assess the effects of GES with different parameters on antral tone and to explore the involvement of the nitrergic pathway. Eight dogs equipped with a gastric cannula and one pair of serosal electrodes in the greater curvature 4 cm above the pylorus were studied on separate days. The study was composed of seven randomized sessions in the fed state [control, GES with different parameters, and GES plus neuronal nitric oxide synthase (nNOS) inhibitor]. Each session included three consecutive 30-min periods (baseline, GES, and recovery). GES was performed with long pulses or pulse trains. The antral volume was measured using an intragastric balloon connected with a barostat device. Behaviors of the dogs during each stimulation period were also noted. We found that 1) postprandial antral tone was reduced with GES with all tested parameter settings, reflected as a significant and substantial increase in antral volume ranging from 179 to 309%; 2) the inhibitory effect of GES on antral tone was partially blocked (decreased by 39.5%) with an nNOS inhibitor; and 3) mild symptoms were induced with GES and found to be correlated with the GES-induced increase in antral volume. We conclude that retrograde GES with long pulses or pulse trains inhibits antral tone, and this inhibitory effect is partially mediated via the nitrergic pathway. These results suggest that retrograde GES may have a therapeutic potential for obesity.
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Affiliation(s)
- Ying Sun
- Veterans Research and Education Foundation and Transneuronix Research Laboratory, Veterans Affairs Medical Center, Oklahoma City, Oklahoma, USA
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26
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Janssen P, Prins NH, Moreaux B, Meulemans AL, Lefebvre RA. Characterization of 5-HT7-receptor-mediated gastric relaxation in conscious dogs. Am J Physiol Gastrointest Liver Physiol 2005; 289:G108-15. [PMID: 15746214 DOI: 10.1152/ajpgi.00012.2005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We aimed to evaluate the gastric relaxant capacity of the 5-HT(1/7)-receptor agonist 5-carboxamidotryptamine (5-CT) in conscious dogs and to clarify the mechanism of action by use of selective antagonists, vagotomy, and in vitro experiments. A barostat enabled us to monitor the intragastric volume in response to different treatments (intravenously administered) before and after supradiaphragmatic vagotomy [results presented as the maximum volume change after treatment (mean; n = 5-11)]. In vitro experiments were performed with isolated muscle strips cut from four different stomach regions of the vagotomized dogs [results were fitted to the operational model of agonism to determine the efficacy parameter tau (n = 5)]. 5-CT (0.5-10 microg/kg) caused a dose-dependent gastric relaxation (29-267 ml) that was completely blocked by the selective 5-HT(7)-receptor antagonist SB-269970 (50 microg/kg). After vagotomy, the relaxation to 10 microg/kg 5-CT was significantly less pronounced (73 vs. 267 ml; P < 0.05) but still blocked by SB-269970, whereas the response to the nitric oxide donor nitroprusside was similar to that before vagotomy (178 vs. 218 ml). In vitro, 5-CT concentration dependently inhibited the PGF(2alpha)-contracted muscle strips before and after vagotomy. Although before and after vagotomy the response in every region was mediated by 5-HT(7) receptors (apparent affinity dissociation constant: SB-269970, 8.2-8.6 vs. 8.3-8.6, respectively), the response after vagotomy was less efficacious (log tau: 1.9 to 0.5 vs. 1.4 to -0.1). The results indicate that the 5-CT-induced proximal stomach relaxation in conscious dogs before and after vagotomy is mediated via 5-HT(7) receptors. The decreased efficacy of 5-CT in vitro after vagotomy is probably related to vagotomy-induced changes in receptor density or coupling efficiency and provides a possible explanation for the decreased in vivo response to 5-CT after vagotomy.
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Affiliation(s)
- Pieter Janssen
- Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
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27
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Sarnelli G, Sifrim D, Janssens J, Tack J. Influence of sildenafil on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2004; 287:G988-92. [PMID: 15475488 DOI: 10.1152/ajpgi.00419.2003] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
After a meal, the proximal stomach relaxes probably through the activation of nitrergic neurons in the gastric wall. Nitric oxide-induced smooth muscle relaxation involves activation of soluble guanylate cyclase, with cGMP production, which is then degradated by phosphodiesterase-5 (PDE-5). The aim of this study was to investigate the effect of sildenafil, a selective PDE-5 inhibitor, on fasting and postprandial proximal gastric volume and on gastric emptying rates in humans. A gastric barostat was used to study gastric compliance and perception to isobaric distension in healthy subjects before and after placebo (n = 13) or sildenafil, 50 mg (n = 15). In 10 healthy subjects, two gastric barostat studies were performed in randomized order to study the effect of placebo or sildenafil on postprandial gastric relaxation. Similarly, solid and liquid gastric emptying rates were studied in 12 healthy subjects. Sildenafil significantly increased fasting intragastric volume (141 +/- 15 vs. 163 +/- 15 ml, P < 0.05) and volumes of first perception. Sildenafil induced a higher and prolonged gastric relaxation either at 30 min (357 +/- 38 vs. 253 +/- 42 ml, P < 0.05) or 60 min (348 +/- 49 vs. 247 +/- 38 ml, P < 0.05) after the meal. Sildenafil did not alter solid half-emptying time but significantly delayed liquid emptying (43 +/- 4 vs. 56 +/- 4 min, P < 0.01). In conclusion, sildenafil significantly increases postprandial gastric volume and slows liquid emptying rate, confirming that meal-induced accommodation in humans involves the activation of a nitrergic pathway. The effect of sildenafil on gastric fundus suggests a therapeutic potential for phosphodiesterase inhibitors in patients with impaired gastric accommodation.
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Affiliation(s)
- Giovanni Sarnelli
- Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, University of Leuven, B-3000 Leuven, Belgium
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Janssen P, Prins NH, Peeters PJ, Zuideveld KP, Lefebvre RA. 5-HT7 receptor efficacy distribution throughout the canine stomach. Br J Pharmacol 2004; 143:331-42. [PMID: 15339857 PMCID: PMC1575344 DOI: 10.1038/sj.bjp.0705922] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
This study aimed to determine, quantify and explain regional differences in the relaxant response to the selective 5-HT(1) and 5-HT(7) receptor agonist 5-carboxamidotryptamine (5-CT) throughout the canine stomach. Longitudinal muscle strips from eight gastric corpus regions and six antrum regions were mounted for isotonic measurement. The 5-CT-induced relaxation was examined on a prostaglandin F(2alpha)-induced submaximal response, expressed as percentage of this response and fitted to the operational model of agonism (OMOA). 5-HT(7) receptor messenger RNA (mRNA) expression was compared by means of quantitative PCR. 5-CT inhibited PGF(2alpha)-induced tonic contraction (corpus) and increase of phasic contraction amplitude (antrum). The consistent antagonism produced by the selective 5-HT(7) receptor antagonist SB-269970 (10 nm, pA(2) estimates 8.2-8.9) confirmed that in every region, the inhibition by 5-CT was 5-HT(7) receptor mediated. However, variation in the maximum effect (61-108%) and pEC(50) (6.4-8.6) was observed throughout the different regions. The OMOA explained these differences as differences in the efficacy parameter tau (ratio of receptor density and coupling efficiency; log tau estimates ranging from 0.1 to 2.1). The log tau gradient decreases going from the lesser to the greater curvature. A proportional difference (68%) in the relative expression of 5-HT(7) receptor mRNA between the lesser and the greater curvature indicates that differences in receptor density contribute to the observed functional differences. This study illustrates that 5-HT(7) receptors are present throughout the ventral wall of the canine stomach, but the efficacy (expressed as log tau) is clearly greater close to the lesser curvature. Differences in 5-HT(7) receptor expression at least partially explain the functional differences.
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Affiliation(s)
- Pieter Janssen
- Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
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Janssen P, Prins NH, Moreaux B, Meulemans AL, Lefebvre RA. In vivo characterization of 5-HT1A receptor-mediated gastric relaxation in conscious dogs. Br J Pharmacol 2003; 140:913-20. [PMID: 14517177 PMCID: PMC1574099 DOI: 10.1038/sj.bjp.0705507] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2003] [Revised: 08/08/2003] [Accepted: 08/18/2003] [Indexed: 11/08/2022] Open
Abstract
Accumulating data have been published emphasizing the important role of 5-hydroxytryptamine (5-HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5-HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5-HT1A receptors mediating relaxation of the proximal stomach in conscious dogs. Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean+/-s.e.m.). All drugs were injected intravenously. The 5-HT1A receptor agonist flesinoxan (10, 50, 100 and 150 microg kg-1) induced a dose-dependent relaxation of the canine proximal stomach (50+/-10, 230+/-51, 290+/-38 and 275+/-33 ml, respectively; n=9-11). The selective 5-HT1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation. NG-nitro-l-arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved. After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317+/-50 vs 142+/-28 ml, respectively; n=5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol. It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5-HT1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves.
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Affiliation(s)
- P Janssen
- Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
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De Ponti F, Crema F, Moro E, Nardelli G, Frigo G, Crema A. Role of 5-HT1B/D receptors in canine gastric accommodation: effect of sumatriptan and 5-HT1B/D receptor antagonists. Am J Physiol Gastrointest Liver Physiol 2003; 285:G96-104. [PMID: 12646419 DOI: 10.1152/ajpgi.00280.2002] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The 5-HT1B/D receptor agonist sumatriptan has been proposed to treat dyspeptic symptoms, because it facilitates gastric accommodation. It is unknown whether stimulation of 5-HT1B/D receptors is involved. Thus, in four conscious dogs, we compared the effects of sumatriptan alone or combined with N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1-biphenyl]-4-carboxamide hydrocloride (GR-127935), N-[3-[3 (dimethylamino)-ethoxy]-4-methoxyphenyl]-2'-[methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)]-[1,1-biphenyl]-4-carboxamide hydrocloride (SB-216641 hydrochloride), or 3-[4-(4-chloro-phenyl)piperazin-1-yl]-1,1-diphenyl-2-propanol hydrochloride (BRL-15572 hydrochloride) (respectively, nonselective 5-HT1B/D, selective 5-HT1B, and selective 5-HT1D receptor antagonists) on gastric accommodation to isobaric distensions performed with a barostat. An exponential and a linear model were used to fit the pressure-volume relationship. An exponential equation fitted the data better than a linear equation. Sumatriptan (800 nmol/kg iv) induced an immediate gastric relaxation (Deltavolume: 112 +/- 44 ml, P < 0.05). After sumatriptan, the pressure-volume curve was shifted toward significantly higher volumes. This effect was fully reversed by GR-127935 or SB-216641 but not by BRL-15572. In conclusion, 5-HT1B receptors seem to play an important role in modulating gastric accommodation to a distending stimulus. An exponential model for pressure-volume curves fits well with the concept of gastric adaptive relaxation.
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Affiliation(s)
- Fabrizio De Ponti
- Department of Pharmacology, University of Bologna, Via Irnerio 48, I-40126 Bologna, Italy.
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31
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Stanghellini V, De Ponti F, De Giorgio R, Barbara G, Tosetti C, Corinaldesi R. New developments in the treatment of functional dyspepsia. Drugs 2003; 63:869-92. [PMID: 12678573 DOI: 10.2165/00003495-200363090-00003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Functional dyspepsia is a clinical syndrome defined by chronic or recurrent pain or discomfort in the upper abdomen of unknown origin. Although generally accepted, investigators differently interpret this definition and clinical trials are often biased by inhomogeneous inclusion criteria. The poorly defined multifactorial pathogenesis of dyspeptic symptoms has hampered efforts to develop effective treatments. A general agreement exists on the irrelevant role played by Helicobacter pylori in the pathophysiology of functional dyspepsia. Gastric acid secretion is within normal limits in patients with functional dyspepsia but acid related symptoms may arise in a subgroup of them. Proton pump inhibitors appear to be effective in this subset of patients with dyspepsia. Non-painful dyspeptic symptoms are suggestive of underlying gastrointestinal motor disorders and such abnormalities can be demonstrated in a substantial proportion of patients. Postprandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety and weight loss to postcibal impaired accommodation of the gastric fundus. Prokinetics have been shown to exert beneficial effects, at least in some patients with dyspepsia. In contrast, drugs enhancing gastric fundus relaxation have been reported to improve symptoms, although conflicting results have also been published. An overdistended antrum may also generate symptoms, but its potential pathogenetic role and the effects of drugs on this abnormality have never been investigated formally. Visceral hypersensitivity plays a role in some dyspeptic patients and this abnormality is also a potential target for treatment. Both chemo- and mechanoreceptors can trigger hyperalgesic responses. Psychosocial abnormalities have been consistently found in functional digestive syndromes, including dyspepsia. Although useful in patients with irritable bowel syndromes (IBS), antidepressants have been only marginally explored in functional dyspepsia. Among the new potentially useful agents for the treatment of functional dyspepsia, serotonin 5-HT(4) receptor agonists have been shown to exert a prokinetic effect. Unlike motilides, 5-HT(4) receptor agonists do not appear to increase the gastric fundus tone and this may contribute to improve symptoms. 5-HT(3) receptor antagonists have been investigated mainly in the IBS and the few studies performed in functional dyspepsia have provided conflicting results. Also, kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but available results in functional dyspepsia are scanty and inconclusive. Other receptors that represent potential clinical targets for antagonists include purinoceptors (i. e., P2X2/3 receptors), NMDA receptors (NR2B subtype), protease-activated receptor-2, the vanilloid receptor-1, tachykinin receptors (NK(1)/NK(2)) and cholecystokinin (CCK)(1) receptors.
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Affiliation(s)
- Vincenzo Stanghellini
- Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy.
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Janssen P, Prins NH, Meulemans AL, Lefebvre RA. Smooth muscle 5-HT2A receptors mediating contraction of porcine isolated proximal stomach strips. Br J Pharmacol 2002; 137:1217-24. [PMID: 12466231 PMCID: PMC1573616 DOI: 10.1038/sj.bjp.0704992] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
1. The aim of this study was to characterize the 5-HT receptors involved in the 5-HT-induced contraction of longitudinal muscle (LM) strips of porcine proximal stomach. This was done in a classical organ bath set-up for isotonic measurement. 2. The concentration-contraction curve to 5-HT was not modified by 5-HT(3) and 5-HT(4) receptor antagonism. Methysergide, ketanserin and mesulergine antagonized the curve to 5-HT. Concomitantly, increasing concentrations of ketanserin and mesulergine progressively revealed a biphasic nature of the 5-HT curve. Ketanserin antagonized the low-affinity receptor while it did not modify the high-affinity receptor. 3. Tetrodotoxin did not influence the concentration-contraction curve to 5-HT neither in the absence nor presence of ketanserin, indicating that nerves are not involved. 4. Ketanserin competitively antagonized the monophasic concentration-response curve to alpha-Methyl-5-HT, yielding a Schild slope that was not significantly different from unity. After constraining the Schild slope to unity, a pK(B) estimate of 8.23+/-0.90 was obtained. This affinity estimate of ketanserin closely approximates previously reported affinities at 5-HT(2A) receptors. 5. In the presence of ketanserin (0.1 microM; exposing the high-affinity receptor), a wide range of 5-HT receptor antagonists covering all 5-HT receptors known, was tested. Only methysergide and ritanserin inhibited the response to 5-HT, thus expressing affinity for the high-affinity receptor. This did not reveal the identity of the receptor involved. 6 It can be concluded that 5-HT induces pig proximal stomach (LM) contraction via 5-HT(2A) receptors located on smooth muscle. A ketanserin-insensitive phase of contractions could not be characterized between the actually known classes of 5-HT receptors with the pharmacological tools that were used.
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Affiliation(s)
- P Janssen
- Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
- Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
- Author for correspondence:
| | - N H Prins
- Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
| | - A L Meulemans
- Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
| | - R A Lefebvre
- Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium
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Janssen P, Prins NH, Meulemans AL, Lefebvre RA. Pharmacological characterization of the 5-HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle. Br J Pharmacol 2002; 136:321-9. [PMID: 12010782 PMCID: PMC1573351 DOI: 10.1038/sj.bjp.0704716] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
1. We aimed to characterize 5-HT receptors mediating contraction and relaxation to 5-HT in dog proximal stomach longitudinal muscle (LM) strips. 2. Of the tryptamine analogues tested, 5-HT was the most potent contractile agent at basal length, while 5-CT was the most potent relaxant of PGF(2alpha)-induced contraction. Neither the contractions to 5-HT, nor the relaxations to 5-CT were influenced by tetrodotoxin, illustrating that action potential propagation is not involved. 3. The 5-HT-induced contraction was antagonized by mesulergine (0.03 to 0.3 microM) and ketanserin (2 - 20 nM), but the antagonism was not of a simple competitive nature, indicating multiple receptor involvement. Ketanserin (3 to 30 nM) and mesulergine (30 nM) competitively antagonized the alpha-Me-5-HT-induced contraction (pK(B): 8.83+/-0.09 and pA(2): 8.25+/-0.06 respectively). These affinity values are in line with literature affinities of ketanserin and mesulergine at 5-HT(2A) receptors in various bioassays. 4. The 5-CT-induced inhibition of PGF(2alpha)-induced contraction was competitively antagonized by mesulergine (pK(B) estimate: 8.52+/-0.12) and by the selective 5-HT(7) receptor antagonist SB-269970 (pK(B) estimate: 9.36+/-0.14). Both pK(B) estimates are in line with literature affinities of these compounds for 5-HT(7) receptors. Mesulergine (30 nM) and SB-269970 (10 nM) shifted the relaxant curve to 5-HT parallel to the right in the presence of ketanserin (0.3 microM) (pA(2) estimates of 8.08+/-0.10 and 8.75+/-0.14 respectively), indicative of 5-HT(7) receptor involvement. 5. It is concluded that 5-HT induces dog proximal stomach (LM) contraction via smooth muscle 5-HT(2A) receptors and relaxation via smooth muscle 5-HT(7) receptors.
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Affiliation(s)
- P Janssen
- Heymans Institute of Pharmacology, Ghent University, Gent, Belgium.
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Delgado-Aros S, Kim DY, Burton DD, Thomforde GM, Stephens D, Brinkmann BH, Vella A, Camilleri M. Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol 2002; 282:G424-31. [PMID: 11841992 DOI: 10.1152/ajpgi.2002.282.3.g424] [Citation(s) in RCA: 136] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) relaxes the stomach during fasting but decreases hunger and food consumption and retards gastric emptying. The interrelationships between volume, emptying, and postprandial symptoms in response to GLP-1 are unclear. We performed, in healthy human volunteers, a placebo-controlled study of the effects of intravenous GLP-1 on gastric volume using (99m)Tc-single photon emission computed tomography imaging, gastric emptying of a nutrient liquid meal (Ensure) using scintigraphy, maximum tolerated volume (MTV) of Ensure, and postprandial symptoms 30 min after MTV. The role of vagal cholinergic function in the effects of GLP-1 was assessed by human pancreatic polypeptide (HPP) response to the Ensure meal. GLP-1 increased fasting and postprandial gastric volumes and retarded gastric emptying; MTV and postprandial symptoms were not different compared with controls. Effects on postprandial gastric function were associated with reduced postprandial HPP levels. GLP-1 does not induce postprandial symptoms despite significant inhibition of gastric emptying and vagal function; this may be partly explained by the increase in postprandial gastric volume.
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Affiliation(s)
- Silvia Delgado-Aros
- Enteric Neuroscience Program, Gastroenterology Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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Affiliation(s)
- Doe Young Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
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36
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Abstract
Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity.
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Affiliation(s)
- F De Ponti
- Department of Pharmacology, University of Bologna, Italy.
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Rayner CK, Samsom M, Jones KL, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care 2001; 24:371-81. [PMID: 11213895 DOI: 10.2337/diacare.24.2.371] [Citation(s) in RCA: 302] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Acute changes in the blood glucose concentration have a major reversible effect on esophageal, gastric, intestinal, gallbladder, and anorectal motility in both healthy subjects and diabetic patients. For example, gastric emptying is slower during hyperglycemia than euglycemia and accelerated during hypoglycemia. Acute hyperglycemia also affects perceptions arising from the gastrointestinal tract and may accordingly, be important in the etiology of gastrointestinal symptoms in diabetes. Elevations in blood glucose that are within the normal postprandial range also affect gastrointestinal motor and sensory function. Upper gastrointestinal motor function is a critical determinant of postprandial blood glucose concentrations by influencing the absorption of ingested nutrients. Interventions that reduce postprandial hyperglycemia, by modulating the rate of gastric emptying, have the potential to become mainstream therapies in the treatment of diabetes.
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Affiliation(s)
- C K Rayner
- University of Adelaide Department of Medicine, Royal Adelaide Hospital, South Australia, Australia
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Quigley EM. Gastroduodenal motility. Curr Opin Gastroenterol 1999; 15:481-91. [PMID: 17023994 DOI: 10.1097/00001574-199911000-00005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Several major themes emerged over the past year in the area of gastroduodenal motility. Mostly, these themes represented extensions of research areas discussed in prior reviews in this series rather than the emergence of completely new concepts. Thus, for example, considerable emphasis has again been placed on regional gastric motor function in dyspepsia and on the role of fundic relaxation and accommodation, in particular. Not surprisingly, basic physiologic research has also shown a keen interest in the regulation of fundic relaxation. One new and exciting development is the recognition of the stomach's role in satiety. The spectrum of gastric motor dysfunction in diabetes mellitus continues to be explored, and the important role of hyperglycemia in regulating gastric function has been further emphasized. More data have been provided on noninvasive alternatives to gastric motor function testing, and several studies have looked at factors that may influence variability in these various tests. There have been few innovations over the past year in the therapeutic arena; rather, the indications and limitations of current therapies have been further developed.
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Affiliation(s)
- E M Quigley
- Department of Medicine, National University of Ireland, Cork, Ireland.
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