A multi-parameter approach to measurement of spontaneous myogenic contractions in human stomach: Utilization to assess potential modulators of myogenic contractions

Straface, Marilisa; Koussai, Marie-Ange; Makwana, Raj; Crawley, Ellie; Palmer, Alexandra; Cai, Weigang; Gharibans, Armen A.; Adebibe, Miriam; Loy, John Dustin; O’Grady, Greg; Andrews, Paul; Sanger, Gareth J.

doi:10.1016/j.phrs.2022.106247

Cited by 5 publications

(4 citation statements)

References 54 publications

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“…Methods have been described elsewhere (Makwana et al, 2021 ; Straface et al, 2022 ). Briefly, mucosa‐free muscle strips (5 × 20 mm) were cut (perpendicular to greater curvature, parallel to circular muscle fibres) and either used immediately or after overnight storage (4°C in the Krebs–Henseleit solution).…”

Section: Methodsmentioning

confidence: 99%

Synergistic augmentation of rhythmic myogenic contractions of human stomach by arginine vasopressin and adrenaline: Implications for the induction of nausea

Makwana

Crawley

Straface

et al. 2022

British J Pharmacology

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Background and Purpose Nausea is associated with the hormonal secretion of vasopressin and adrenaline, although their actions in inducing nausea is poorly understood. Here, we have investigated their actions on human stomach muscle. Experimental Approach Muscle strips were suspended in tissue baths and neuronal‐/non‐neuronally‐mediated contractions were measured. Custom software analysed eight motility parameters defining spontaneous phasic non‐neuronally mediated contractions. Receptor distributions were assessed by qPCR and immunofluorescence. Key Results V1A receptors and α1‐adrenoceptors were located on muscle as well as interstitial cells of Cajal (ICCs). Myogenic contractions of human proximal and distal stomach (respectively, 2.6 ± 0.1 and 2.7 ± 0.0 per minute; n = 44) were larger in the distal area (1.1 ± 0.1 and 5.0 ± 0.1 mN), developing relatively slowly (proximal) or rapidly (distal). Vasopressin caused tonic (proximal) or short‐lived (distal) increases in muscle tone and increased myogenic contraction amplitude, frequency and rate (acting at V1A receptors; thresholds 10−11–10−10 M); by contrast, cholinergically mediated contractions were unaffected. Oxytocin acted similarly to vasopressin but less potently, at OT receptors). Adrenaline increased (10−10–10−5 M; α1‐adrenoceptors) and decreased (≥10−6 M; β‐adrenoceptors) muscle tone and enhanced/reduced myogenic contractions. Cholinergically mediated contractions were reduced (α2‐adrenoceptors). Combined, vasopressin (10−9 M) and adrenaline (10−8 M) increased muscle tone and phasic myogenic activity in a synergistic manner. Conclusions and Implications Vasopressin and adrenaline increased human gastric tone and myogenic contraction amplitude, rate of contraction and frequency. In combination, their actions were further increased in a synergistic manner. Such activity may promote nausea.

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Section: Methodsmentioning

confidence: 99%

Synergistic augmentation of rhythmic myogenic contractions of human stomach by arginine vasopressin and adrenaline: Implications for the induction of nausea

Makwana

Crawley

Straface

et al. 2022

British J Pharmacology

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“…New approaches to novel drug design are also needed. Gastric electrical activity (regulated by ICCs) is dysrhythmic during nausea (including patients with gastroparesis), 18 providing incentive to find ways of restoring ICC function, perhaps by modulating key ion channels affecting slow wave electrical activity 111 . It is worth noting that gastric electrical pacing has some ability to regulate gastric dysrhythmia, 18 potentially providing a model whereby novel drug targets can be identified to improve on the effects of electrical stimulation.…”

Section: Futurementioning

confidence: 99%

Review article: An analysis of the pharmacological rationale for selecting drugs to inhibit vomiting or increase gastric emptying during treatment of gastroparesis

Sanger

Andrews

2023

Aliment Pharmacol Ther

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Background: Drugs which can inhibit nausea/vomiting and/or increase gastric emptying are used to treat gastroparesis, mostly 'off-label'. Within each category, they act at different targets and modulate different physiological mechanisms.Aims: Address the questions: In gastroparesis, why should blocking one pathway causing vomiting, be more appropriate than another? Why might increasing gastric emptying via one mechanism be more appropriate than another? Methods: Drugs used clinically were identified via consensus opinions and reviews, excluding the poorly characterised. Their pharmacology was defined, mapped to mechanisms influencing vomiting and gastric emptying, and rationale developed for therapeutic use. Results:Vomiting: Rationale for 5-HT 3 , D 2 , H 1 or muscarinic antagonists, and mirtazapine, amitriptyline, nortriptyline, are poor. Arguments for inhibiting central consequences of vagal afferent transmission by NK 1 antagonism are complicated by doubts over effects on nausea. Gastric emptying: Confusion emerges because of side-effects of drugs increasing gastric emptying: Metoclopramide (5-HT 4 agonist, D 2 and 5-HT 3 antagonist; also blocks some emetic stimuli and causes tardive dyskinesia) and Erythromycin (high-efficacy motilin agonist, requiring low doses to minimise side-effects). Limited trials with selective 5-HT 4 agonists indicate variable efficacy.Conclusions: Several drug classes inhibiting vomiting have no scientific rationale. NK 1 antagonism has rationale but complicated by limited efficacy against nausea. Studies must resolve variable efficacy of selective 5-HT 4 agonists and apparent superiority over motilin agonists. Overall, lack of robust activity indicates a need for novel approaches targeting nausea (e.g., modulating gastric pacemaker or vagal activity, use of receptor agonists or new targets such as GDF15) and objective assessments of nausea.

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“…For the colonic spontaneous contractions, in comparison, the administration of MAF increased all three parameters (i.e., AUC, amplitude, and frequency) significantly in a dose-dependent manner, suggesting that the MAF-induced increase in the total contractility in the sigmoid colon was due to increases in both the amplitude and frequency of the spontaneous contractions. Spontaneous contractions are caused by slow waves generated by the pacemaker interstitial cells of the Cajal (ICC) in the GI tract [35]. Because the spontaneous contractions occur without neural input in the smooth muscle layer, they are referred to as myogenic contractions [36].…”

Section: Effects Of Maf On Spontaneous Contractions Of Smooth Muscle ...mentioning

confidence: 99%

“…Spontaneous contractions are caused by slow waves generated by the pacemaker interstitial cells of the Cajal (ICC) in the GI tract [35]. Because the spontaneous contractions occur without neural input in the smooth muscle layer, they are referred to as myogenic contractions [36].…”

Section: Effects Of Maf On Efs-induced Contractions In Human Intestin...mentioning

confidence: 99%

Prokinetic Activity of Mulberry Fruit, Morus alba L.

et al. 2023

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The fruit of Morus alba L. (MAF) has been consumed as a food worldwide. MAF has also been widely used in traditional medicine for thousands of years in East Asia, and its diverse bioactivities have been reported in numerous publications. However, no prokinetic activity has been reported for MAF or its components. In the present study, therefore, we investigated the effects of MAF on gastrointestinal motor function by measuring the intestinal transit rate (ITR) of Evans blue in mice in vivo. The ITR values accelerated by MAF were significantly higher than those accelerated by cisapride or metoclopramide, suggesting that MAF has potential as a new prokinetic agent to replace cisapride and metoclopramide. We also investigated the effects of MAF on myogenic and neurogenic contractions in human intestinal smooth muscles by measuring spontaneous contractions of smooth muscle strips, smooth muscle contractions induced by neural stimulation, and migrating motor complexes from intestinal segments in the human ileum and sigmoid colon in situ. MAF increased both myogenic and neurogenic contractions to enhance ileal and colonic motility in the human intestine. Taken together, these results indicate that MAF enhanced intestinal motility by increasing both myogenic and neurogenic contractions, thereby accelerating the ITR.

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A multi-parameter approach to measurement of spontaneous myogenic contractions in human stomach: Utilization to assess potential modulators of myogenic contractions

Cited by 5 publications

References 54 publications

Synergistic augmentation of rhythmic myogenic contractions of human stomach by arginine vasopressin and adrenaline: Implications for the induction of nausea

Synergistic augmentation of rhythmic myogenic contractions of human stomach by arginine vasopressin and adrenaline: Implications for the induction of nausea

Review article: An analysis of the pharmacological rationale for selecting drugs to inhibit vomiting or increase gastric emptying during treatment of gastroparesis

Prokinetic Activity of Mulberry Fruit, Morus alba L.

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