Protective effect of pharmacologic preconditioning with pioglitazone on random-pattern skin flap in rat is mediated by nitric oxide system

Background: Pioglitazone, a thiazolidinedione, is primarily used as an antidiabetic agent. In addition, recent reports have identified anti-ischemic and anti-inflammatory properties of pioglitazone through nitric oxide (NO) pathways. Objective: To determine the protective effects of pioglitazone on random-pattern skin flaps in a rat model. Methods: Forty-eight male Rats were randomly assigned to eight groups. Bipedicled dorsal skin flaps (2 × 8 cm) were elevated at the midline. In pharmacologic preconditioning groups, three different doses of pioglitazone (25, 40, 80, mg/kg; doses were selected according to our pilot study) gavaged 4 h before elevating flaps. Seven days after operation, the survival of skin flap was measured. For investigating the role of NO system, in other groups the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg) was administered alone or with an effective dose of pioglitazone. Finally, in another group, subeffective dose of nitric oxide precursor L-arginine (100 mg/kg) was coadministered with subeffective pioglitazone. Results: Significant increase in flap survival was seen with pioglitazone (40 mg/kg). This protective effect was abolished by systemic administration of L-NAME (10 mg/kg). Coadministration of subeffective doses of pioglitazone with subeffetcive L-arginine significantly improved flap survival. Conclusion: Pharmacologic preconditioning with pioglitazone improves survival of random-pattern skin flaps in rats through NO dependent mechanisms.