Neuronal nitric oxide synthase negatively regulates xanthine oxidoreductase inhibition of cardiac excitation-contraction coupling

Although interactions between superoxide (12ptminimal amsmath wasysym amsfonts amssymb amsbsy mathrsfs -69pt document equation*O₂^{-}equation*document) and nitric oxide underlie many physiologic and pathophysiologic processes, regulation of this crosstalk at the enzymatic level is poorly understood. Here, we demonstrate that xanthine oxidoreductase (XOR), a prototypic superoxide 12ptminimal amsmath wasysym amsfonts amssymb amsbsy mathrsfs -69pt document equation*O₂^{-}equation*document -producing enzyme, and neuronal nitric oxide synthase (NOS1) coimmunoprecipitate and colocalize in the sarcoplasmic reticulum of cardiac myocytes. Deficiency of NOS1 (but not endothelial NOS, NOS3) leads to profound increases in XOR-mediated 12ptminimal amsmath wasysym amsfonts amssymb amsbsy mathrsfs -69pt document equation*O₂^{-}equation*document production, which in turn depresses myocardial excitation–contraction coupling in a manner reversible by XOR inhibition with allopurinol. These data demonstrate a unique interaction between a nitric oxide and an 12ptminimal amsmath wasysym amsfonts amssymb amsbsy mathrsfs -69pt document equation*O₂^{-}equation*document -generating enzyme that accounts for crosstalk between these signaling pathways; these findings demonstrate a direct antioxidant mechanism for NOS1 and have pathophysiologic implications for the growing number of disease states in which increased XOR activity plays a role.