Nitric oxide release by deoxymyoglobin nitrite reduction during cardiac ischemia: A mathematical model

- In normoxia, oxygenated Mb is a strong scavenger of NO to maintain homeostasis.
- During ischemia, deoxygenated Mb can significantly generate NO from tissue nitrite.
- NO elevation is highest at the lowest blood PO2 and tissue pH conditions.
- This effect is consistent at different flow rates, but relatively higher at low flow.
- This released NO could be responsible for mitigating deleterious ischemic effects.

Interactions between cardiac myoglobin (Mb), nitrite, and nitric oxide (NO) are vital in regulating O2 storage, transport, and NO homeostasis. Production of NO through the reduction of endogenous myocardial nitrite by deoxygenated myoglobin has been shown to significantly reduce myocardial infarction damage and ischemic injury. We developed a mathematical model for a cardiac arteriole and surrounding myocardium to examine the hypothesis that myoglobin switches functions from being a strong NO scavenger to an NO producer via the deoxymyoglobin nitrite reductase pathway. Our results predict that under ischemic conditions of flow, blood oxygen level, and tissue pH, deoxyMb nitrite reduction significantly elevates tissue and smooth muscle cell NO. The size of the effect is consistent at different flow rates, increases with decreasing blood oxygen and tissue pH and, in extreme pathophysiological conditions, NO can even be elevated above the normoxic levels. Our simulations suggest that cardiac deoxyMb nitrite reduction is a plausible mechanism for preserving or enhancing NO levels using endogenous nitrite despite the rate-limiting O2 levels for endothelial NO production. This NO could then be responsible for mitigating deleterious effects under ischemic conditions.