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

Abstract

Background: The nude mouse model of hind limb ischemia is used to evaluate humanderived, 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 (NaNO2
) was evaluated. The rationale for
doing so was based on a report that NaNO2
induced unprecedented tissue perfusion in
wild-type mice using a similar model. The objective was to evaluate NaNO2
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 NaNO2
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 NaNO2
when compared with the vehicle. Nude mice exhibited significantly
lower tissue perfusion compared to wild-type mice, irrespective of the treatment.
Conclusions: NaNO2
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 NaNO2
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.