Sodium nitrite therapy fails to improve tissue perfusion in a mouse model of hind limb ischemia: Slight differences in methodology may be responsible casting suspicion on the reliability and predictive value of this model

Background: The nude mouse model of hind limb ischemia is used to evaluate human-derived, cell-based therapeutics intended to promote tissue perfusion. The criticism of the mouse model of hind limb ischemia is the absence of a well-characterized positive control. The suitability of sodium nitrite (NaNO 2 ) was evaluated. The rationale for doing so was based on a report that NaNO 2 induced unprecedented tissue perfusion in wild-type mice using a similar model. The objective was to evaluate NaNO 2 to improve tissue perfusion in nude mice as well as their wild-type counterparts. Materials and Methods: The mice underwent surgically induced, unilateral hind limb ischemia, and received either NaNO 2 or a vehicle intraperitoneally, twice daily, for seven days. Hind limb tissue perfusion was evaluated on days one, four, seven, and fourteen post-surgery. Results: No increase in tissue perfusion was observed in the nude or wild-type mice treated with NaNO 2 when compared with the vehicle. Nude mice exhibited significantly lower tissue perfusion compared to wild-type mice, irrespective of the treatment. Conclusions: NaNO 2 failed to increase tissue perfusion and, therefore, did not appear suitable for use as a positive control in this model. This is in stark contrast to a previous report indicating that NaNO 2 significantly increased tissue perfusion in wild-type mice using a similar model. The exact cause is not known, but is probably due to differences in methodology employed between laboratories. The lower tissue perfusion in nude mice is a novel finding, suggesting this strain may have less pre-existing collateral vessels and/or a reduced capacity to form new vessels as compared to wild-type mice.