Abstract
Electrophysiological mechanisms of co‐transmission by serotonin (5‐HT) and acetylcholine (ACh), co‐expression of receptor types 5‐HT type 3 and 4, nicotinic cholinerginc (nACh) and muscarinic cholinergic (μACh), and effects of selective and non‐selective 5‐HT3 and 5‐HT4 receptor agonists/antagonists, on intestinal propulsion of a solid non‐deformable bolus were studied numerically. Results indicated that the propagation of the wave of excitation in the presence of 5‐HT3 receptor antagonists was supported by co‐release of ACh. Co‐stimulation of 5‐HT3, nACh and μACh receptors significantly impairs propulsive activity of the gut. In an ACh‐free environment, Lotronex increased the transit time of the bolus along a segment of the gut. In the presence of ACh, Lotronex produced intensive tonic‐type contractions in the longitudinal and circular smooth muscle layers and eliminated propulsive activity. Zelnorm preserved the reciprocal electromechanical relationships between the longitudinal and circular smooth muscle layers. The drug changed the normal mixing pattern of activity to an expulsive type. Treatment of the gut with selective 5HT4 receptor antagonists increased the transit time by disrupting the migrating myoelectrical complex. Cisapride increased the excitability of the myenteric nervous plexus and increased the frequency of slow waves. In the presence of Cisapride smooth muscle syncytia responded with the generation of tonic contractions, resulting in a “squeezing” type of bolus movement. Comparison of the theoretical results to in vivo and in vitro experimental data indicated satisfactory qualitative and quantitative agreement.
Highlights
Mathematical modeling and computer simulation are universal approximators that accurately simulate complex biological phenomena comprising multiple non-linear interactions
This paper focuses primarily on the analysis of: (i) the concurrent effects of co-activation of muscarinic, nicotinic and 5-HT types 3 and 4 receptors, on the dynamics of signal transduction and electromechanical responses in the gut, and (ii) the role of pharmacological agents with selective, nonselective and mixed 5-HT3 and 5-HT4 receptor agonist/antagonist mechanisms of action on its propulsive activity
The contact forces exerted on the surface of the pellet and the propulsive forces generated by the longitudinal and circle smooth muscle layers are insufficient to propel the bolus along the segment
Summary
Mathematical modeling and computer simulation are universal approximators that accurately simulate complex biological phenomena comprising multiple non-linear interactions. They have become an indispensable supplement to experimental in vivo and in vitro techniques that explore inaccessible biological processes and thereby assist researchers in drug design, development and screening for potential side effects. Significant current issues are: (i) the processes of co-transmission by multiple neurotransmitters and co-activation of different receptor types cannot be studied effectively by any of the existing experimental techniques, and (ii) traditional in vivo and in vitro approaches have failed, so far, to provide required quantitative information about the role of synaptic neurotransmission in the pathogenesis of the syndrome
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