Background – Thiazolidinediones (TZDs) including rosiglitazone (ROSI) are insulin sensitizing agents with beneficial gastrointestinal effects. However, no studies are available on TZDs effect in gastrointestinal motility. We evaluated the effects of ROSI on gastrointestinal inhibitory neurotransmission focusing on the modulatory roles of nitric oxide synthase/nitric oxide (NOS/NO) and heme oxygenase/carbon monoxide (HO/CO) pathways. Methods – Spontaneously hypertensive rats (SHR) were used as model of insulin-resistance. Duodenal strips were obtained from vehicle-treated SHR, ROSI-treated SHR (5 mg/kg by gavage daily per 6 weeks), and Wistar Kyoto (WKY). Inhibitory responses to electrical field stimulation (EFS) were evaluated in the presence of HO inhibitor zinc protoporphyrin IX (ZnPPIX, 10 μM) or NOS inhibitor NG-nitro-L-arginine (L-NNA, 100 μM), alone and in combination. Protein levels of HO and NOS isoforms were evaluated by immunohistochemistry and western blot analysis. Key results – Basal responses to EFS were significantly increased in duodenum strips from vehicletreated SHR vs. WKY. This effect was reversed in ROSI-treated SHR. EFS-mediated relaxation was comparably reduced by ZnPPIX in WKY and SHR, but not in ROSI -treated SHR animals. LNNA reduced EFS response to a similar extent in WKY and ROSI -treated SHR, but its effect was significantly higher in vehicle-treated SHR. Expression of HO-1 protein was significantly lower, while HO-2 protein levels were unchanged in ROSI-treated SHR with respect to vehicle-treated SHR. Finally, increased levels of nNOS in vehicle-treated SHR were reduced in ROSI-treated SHR. Conclusions – Chronic ROSI treatment reverses increased SHR duodenal inhibitory response acting on CO and NO components.