Carbon monoxide contributes to the constipating effects of granisetron in rat colon

Figure 10 Potential relationship between granisetron, ZnPPIX (HO-1/2 inhibitor), and CORM-3 (CO-releasing agent) on colon neurogenic and myogenic contractile responses. Acting on 5-HT₃ receptors, granisetron may increase calcium influx, thus facilitating the release of acetylcholine (ACh) (neurogenic response), which in turn elicits a myogenic contractile response. By inhibiting the heme oxygenase (HO)-mediated carbon monoxide (CO) production, ZnPPIX may reduce the nerve terminal release of ACh, thereby counteracting granisetron effects. By releasing carbon monoxide (CO), CORM-3 may enhance the ACh-mediated myogenic contraction via a nitric oxide (NO)-dependent mechanism resulting in increased intracellular cAMP and calcium levels, with subsequent activation of L-type calcium channels and potentiation of the granisetron-mediated myogenic response.