Background-An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined. Methods and Results-Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats (PϽ0.05 and PϽ0.001 versus shams, respectively). This was associated with translocation of NOS1 from the ryanodine receptor to the sarcolemma through interactions with caveolin-3 in HF hearts. With ex vivo and in vivo pressure-volume analysis, cardiac NOS1-derived NO was found to be negatively inotropic in shams but not HF hearts. Ventricular elastance (E es ) was significantly reduced in HF rats (PϽ0.05), and , the time constant of left ventricular relaxation, was prolonged (both PϽ0.05). Acute NOS1 inhibition significantly increased E es by 33Ϯ3% and by 17Ϯ2% (PϽ0.05) in shams, although these effects were significantly attenuated in HF hearts. ␤-Adrenergic stimulation induced a marked increase in systolic performance in sham hearts, with the responses being significantly blunted in HF hearts. E es increased by 163Ϯ42% (PϽ0.01) in sham hearts and 56Ϯ9% in HF hearts, and LV ϩdP/dt increased by 97Ϯ9% (PϽ0.01) in shams and 37Ϯ7% (PϽ0.05) in the HF group. Interestingly, preferential NOS1 inhibition enhanced the blunted responses of LV ϩdP/dt and E es to ␤-adrenergic stimulation in HF rats but had no effect in shams. Conclusions-These results provide the first evidence that increased NOS1-derived NO production may play a role in the autocrine regulation of myocardial contractility in HF.

Atrial fibrosis caused by chronic CHF is reduced by spironolactone.