Granisetron is a 5-HT3 receptors antagonist used in the management of emesis associated with anticancer chemotherapy. It affects intestinal motility with constipating effect. Since the pathway heme oxygenase/carbon monoxide (HO/CO) is involved in gastrointestinal motility, we evaluated the possible interplay between granisetron and agents affecting HO/CO pathways such as zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, or hemin, an HO-1 inducer. ZnPPIX (10？μM) or hemin (10？μM), but not granisetron (0.1, 0.3, 1？μM), affected spontaneous basal activity recorded in rat duodenal strips, in noncholinergic nonadrenergic conditions. Granisetron restored spontaneous basal activity after ZnPPIX, but not after hemin. ZnPPIX decreased and hemin increased the inhibition of activity after electrical field stimulation (EFS), but they did not affect the contraction that follows the relaxation induced by EFS called off contraction. Granisetron did not alter the response to EFS per se but abolished both ZnPPIX and hemin effect when coadministered. In vivo study showed constipating effect of granisetron (25, 50, 75？μg/kg/sc) but no effect of either ZnPPIX (50？μg/kg/i.p.) or hemin (50？μM/kg/i.p.). When coadministered, granisetron effect was abolished by ZnPPIX and increased by hemin. Specimens from rats treated in vivo with hemin (50？μM/kg/i.p.) showed increased HO-1 protein levels. In conclusion, granisetron seems to interact with agents affecting HO/CO pathway both in vitro and in vivo. 1. Introduction It is well known that, in mammals, a very high amount of 5-hydroxytryptamine (5-HT or serotonin) is synthesized within the gastrointestinal tract. In particular, 5-HT is mainly present in enterochromaffin cells of the mucosa and less represented in the neurons of the enteric nervous system, exerting its physiological effects acting on several 5-HT receptors. Therefore, a growing number of studies have been undertaken both in humans and using animal models to investigate the involvement of 5-HT in gastrointestinal disorders. Those studies have led to drugs acting at enteric 5-HT receptor subtypes, namely, 5-HT3 receptors, that have significantly improved the management of emesis associated with anticancer chemotherapy [1]. In fact, both first (dolasetron, granisetron, ondansetron, and tropisetron) and second (palonosetron) generation of 5-HT3 receptor antagonists are indicated by current guidelines as one of the pharmacologic interventions for acute and delayed nausea and vomiting associated with moderately and highly emetogenic chemotherapy, the other being dexamethasone
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