Sub-cellular targeting of constitutive NOS in health and disease

► Different from plasmalemmal eNOS, sarcoplasmic nNOS facilitates basal myocardial relaxation and attenuates contraction. ► nNOS promotes PKA-dependent phospholamban phosphorylation and inhibits L-type Ca2+ channel activity. ► nNOS modulates myocardial oxidases and maintains eNOS 'coupling' to produce NO. ► nNOS is up-regulated and translocates to sarcolemma in diseased heart and attenuates its adverse remodeling. ► eNOS is 'uncoupled' and contributes to oxidative stress in failing myocardium.