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

Abstract

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.

Mechanism of Oxytocin-Induced Contraction in Rat Gastric Circular Smooth Muscle

“…The present excitatory effect of oxytocin on rat gastric antrum strips has been previously reported in few investigations [8,16,17]. Oxytocin increased muscle contraction in a dose-dependent manner in strips from rats' gastric bodies, antrum, and pyloric sphincter [8].…”

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

“…In brief, the nucleus tractus solitarius (NTS) in the dorsal brainstem receives inputs from the viscera (primarily vagus), vestibular system and the area postrema (AP). The AP, a circumventricular organ outside the blood–brain barrier, is densely vascularized and exposed to molecules released into the blood during disease, including those implicated in induction of nausea and/or vomiting (e.g., adrenaline, vasopressin, GLP‐1, PYY, GDF15 31,32 ). When appropriately activated the NTS can initiate retching and vomiting via additional neuronal circuitry within the ventral brainstem, whereas induction of nausea requires the NTS to influence pathways in the cerebral hemispheres 33–35 …”

“…If gastric emptying is increased, the mechanism is unclear (e.g., no direct activity of domperidone on gastric functions; no evidence for increased dopamine availability affecting the stomach; Table S2). It may be possible that domperidone can increase gastric movements indirectly, by reducing nausea, early satiety and abdominal bloating 27,31 . Accordingly, the pharmacology of D 2 receptor antagonists has been discussed in more detail above (Section 3).…”

“…It may be possible that domperidone can increase gastric movements indirectly, by reducing nausea, early satiety and abdominal bloating. 27,31 Accordingly, the pharmacology of D 2 receptor antagonists has been discussed in more detail above (Section 3).…”

An assessment of the effects of neurokinin1 receptor antagonism against nausea and vomiting: Relative efficacy, sites of action and lessons for future drug development

“…[142][143][144] However, there is only limited evidence that systemic endogenous agents which can induce vomiting (e.g., adrenaline, cholecystokinin, GDF15, argininevasopressin), act via the AP, with alternative sites of action suggested. 143,145,146 The above discussion suggests that SP, acting via NK 1 receptors in the AP should be added to the list of systemic endogenous emetic agents.…”