Role of Myocardial Neuronal Nitric Oxide Synthase–Derived Nitric Oxide in β-Adrenergic Hyporesponsiveness After Myocardial Infarction–Induced Heart Failure in Rat

Abstract

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 ( P <0.05 and P <0.001 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 ( P <0.05), and τ, the time constant of left ventricular relaxation, was prolonged (both P <0.05). Acute NOS1 inhibition significantly increased E es by 33±3% and τ by 17±2% ( P <0.05) in shams, although these effects were significantly attenuated in HF hearts. β-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 163±42% ( P <0.01) in sham hearts and 56±9% in HF hearts, and LV +dP/dt increased by 97±9% ( P <0.01) in shams and 37±7% ( P <0.05) in the HF group. Interestingly, preferential NOS1 inhibition enhanced the blunted responses of LV +dP/dt and E es to β-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.