Reversal of inducible nitric oxide synthase uncoupling unmasks tolerance to ischemia/reperfusion injury in the diabetic rat heart

▶iNOS is upregulated in the diabetic heart by oxidative stress. ▶Oxidative stress induces iNOS uncoupling by depleting BH4. ▶iNOS uncoupling produces more superoxide and causes oxidative/nitrosative stress. ▶Replenishment with BH4 promotes recoupling of iNOS and increases bioavailable NO. ▶Increased NO confers tolerance to I/R injury through protein S-nitrosylation.