Arsenic contaminated groundwater consumption is the main route of human exposure for arsenicosis. We set out to illustrate the as yet poorly understood cellular mechanisms resulting in altered motility of small gut ensuing severe gastrointestinal dysfunctions related to arsenicosis. The current study was designed in two parts- A. Charles foster rats (male, 100 ± 17g, n=7) were exposed orally to 10 mg/kg body wt/day sodium arsenite for 5, 10 and 20 days and B. in vitro organbath studies were conducted on intestine with a combination of different neurotransmitters and arsenite (As+3) applied postmortem. Rats were humanely killed by cervical dislocation following institutional guidelines foregoing anesthesia due to the nature of the experiment. Chronic As+3 treatment resulted in reduced bound calcium deposition (1), consistent with the finding of significantly enhanced contraction of the gut (vide Fig 1), achieved with isotonic transducer (IT-2245) coupled to RMS-Polyrite D. The peak contraction was reached on the 10th day of treatment. Set B results proved, the effect of As+3 on smooth muscle contraction was upstream of calcium release where it acted as a partial antagonist to atropine and exerted synergistic effect with acetylcholine. This was supported by the As+3 induced decrease of acetylcholine esterase activity (2) found under Set A. Set B results further showed that As+3 inhibited the relaxant effect of exogenous nitric oxide and breached the cholinergic blockade completely when coupled with a soluble guanylyl cyclase (sGC) blocker. Evidence under Set A attested to As+3 induced downregulation of nitric oxide synthase leading support to the final conclusion that on the early days of chronic treatment As+3 induced facilitation of intestinal motility by stimulating muscarinic and suppressing sGC receptor. Set A results further showed a decrease in motility increment after 20 days of constant As+3 treatment, supported by histopathological evidence of progressive degeneration and gross architectural damage of the muscle layer of intestine. This was substantiated by studies on oxidative stress indices which showed that As+3 depleted protein thiol levels (3), increased lipid peroxidation (4), and severely depleted reduced glutathione (5) which may explain the decrease of gut motility due to tissue damage after prolonged exposure of 20 days (vide Table 1 for set A results).