Coumarin Inhibits the Contractile Activity of the Duodenal Visceral Smooth Muscle by NO Mediated–cGMP Signalling Pathway

Coumarin, a naturally occurring aromatic compound found in many plants, has been widely studied for its pharmacological properties. However, its effects on the contractions of the visceral smooth muscles located in the wall structure of the small intestine remain underexplored. Therefore, this study aimed to examine the effects of coumarin on the contractions of the duodenal visceral smooth muscle (dVSM) in rats. through ex vivo recordings of the movement of duodenum, a representative and initial part of the small intestine, using an isotonic transducer (IT-2245) connected to RMS Polyrite D. Coumarin induced a significant, concentration-dependent suppression of duodenal contractions, as evidenced by decrease in amplitude and frequency of spontaneous contractions. From this result, it could be hypothesised that the Coumarin induced inhibition of the contractions of the dVSM might be due to suppression of the activity of intrinsic cholinergic myenteric neurons and/or facilitation of the activity of intrinsic adrenergic/ nitrergic myenteric neurons. Further, to understand the probable pharmacodynamic mechanisms involved in the Coumarin induced inhibition of the contractions of the dVSM, we focused on the involvement of nitrergic nitric oxide (NO)-cGMP signalling pathway, a key regulatory mechanism involved in smooth muscle relaxation. From the single dose experiments, it has been observed that pre-treatment with L-NAME and methylene blue (MB) further significantly counteracted the inhibitory effect of coumarin on the dVSM contraction, suggesting that coumarin may stimulate endogenous NO production or interfere with upstream cGMP signalling. In contrast, administration of sodium nitroprusside significantly suppressed both spontaneous and coumarin-induced contractions, confirming the functional integrity of the nitrergic relaxation pathway and its agonism by coumarin. The findings indicate that coumarin decreases the duodenal visceral smooth muscle contraction by facilitating the nitrergic NO–cGMP signalling pathway. These results provide novel insights into the action of coumarin on SiVSM upon dietary exposure. Keywords: Coumarin, duodenal visceral smooth muscle, intrinsic myenteric neurons, nitrergic signalling pathway, Nitric Oxide (NO)-cGMP signalling pathway