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The effect of evocalcet on vagus nerve activity of the gastrointestinal tract in miniature pigs.

ABSTRACT: Evocalcet is a novel calcimimetic agent with fewer gastrointestinal (GI) adverse effects compared to cinacalcet. Although it is thought that cinacalcet induces GI side effects through the direct stimulation of the calcium receptor (CaR) expressed in the GI tract, the differences in the direct stimulatory effects of these two drugs on the GI tract have not been reported. In this study, we analyzed the difference in the GI effects of these two calcimimetic agents using miniature pigs by detecting vagus nerve stimulation after oral administration of the agents. Although cinacalcet induced vomiting in miniature pigs, evocalcet never induced emetic symptoms. A significant increase in the vagus nerve action potentials was observed after the administration of cinacalcet. Although the increase of that after the administration of evocalcet was mild and not significant in comparison to that in the vehicle group, it was not significantly different from the vagus nerve action potentials after cinacalcet treatment.

SUBMITTER: Tokunaga S

PROVIDER: S-EPMC7822337 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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The effect of evocalcet on vagus nerve activity of the gastrointestinal tract in miniature pigs.

Tokunaga Shin S Kawata Takehisa T

PloS one 20210122 1

Evocalcet is a novel calcimimetic agent with fewer gastrointestinal (GI) adverse effects compared to cinacalcet. Although it is thought that cinacalcet induces GI side effects through the direct stimulation of the calcium receptor (CaR) expressed in the GI tract, the differences in the direct stimulatory effects of these two drugs on the GI tract have not been reported. In this study, we analyzed the difference in the GI effects of these two calcimimetic agents using miniature pigs by detecting ...[more]

PMID: 33481922

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Project description:Objective: Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig—an animal model with vagus anatomy similar to human—using the bipolar helical lead deployed clinically.Approach: Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses.Main results: Contraction of the cricoarytenoid muscle occurred at low amplitudes (~0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (~1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting A?-, B-, and C-fibers.Significance: Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 ?A). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with A?- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.

Project description:Background/objectiveChanges in brain metabolism has been investigated thoroughly during unilateral cervical chronic vagal stimulation in epileptic or depressive patients. Bilateral stimulation of the abdominal vagus (aVNS) has received less attention despite the reduction in body weight and an altered feeding behavior in obese animals that could be clinically relevant in obese individuals. Our study aims to examine the changes in brain glucose metabolism (CMRglu) induced by aVNS in obese adult miniature pigs. Dopamine (DAT) and serotonin transporters (SERT) were also quantified to further understand the molecular origins of the alterations in brain metabolism.Subjects/methodsPairs of stimulating electrodes were implanted during laparoscopy on both abdominal vagal trunks in 20 obese adult's miniature pigs. Half of the animals were permanently stimulated while the remaining were sham stimulated. Two months after the onset of stimulation, dynamic 18FDG PET and 123I-ioflupane SPECT were performed. Food intake, resting energy expenditure and fat deposition were also assessed longitudinally.ResultsFood intake was halved and resting energy expenditure was increased by 60% in aVNS group compared to sham. The gain in body weight was also 38% less in aVNS group compared to sham. Brain metabolic connectivity increased between numerous structures including striatum, mid-brain, amygdala and hippocampus. On the contrary, increased CMRglu were restricted to the thalamus, the periaqueducal grey and the amygdala. DAT binding potential was decreased by about one third in the striatum while SERT was about doubled in the midbrain.ConclusionsOur findings demonstrated that aVNS reduced weight gain as a consequence of diminished daily food intake and increased resting energy expenditure. These changes were associated with enhanced connectivity between several brain areas. A lower striatal DAT together with a doubled mid-brain SERT were likely causative for these changes.

Dataset Information

The effect of evocalcet on vagus nerve activity of the gastrointestinal tract in miniature pigs.

Publications

The effect of evocalcet on vagus nerve activity of the gastrointestinal tract in miniature pigs.

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