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 (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.

Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility

“…Dawson et al 12 demonstrated that nNOS protects against adverse postinfarction remodeling and that infarcted nNOS Ϫ/Ϫ mice responded to dobutamine with a significant decrease in LV systolic function. Of note, and contrary to the findings of Dawson, Bendall et al 13 found an increase in ␤-AR response after preferential nNOS inhibition in infarcted rats. They initially described an upregulation of cardiomyocyte nNOS.…”

“…Several studies demonstrated a protective role of nNOS in myocardial infarction 12,13,32 or in ischemia/reperfusion injury. 21 The reason for these favorable results may not only be overexpression or (more physiologically) upregulation, but the translocation of nNOS to the plasmamembrane.…”

“…In this work, we were not able to demonstrate effects from nNOS on PMCA, at least with regard to short term regulation of contractility or beat to beat Ca 2ϩ -regulation. Clearly however, we found an inhibitory effect of abundant nNOS on I ca,L density and Ca 2ϩ -transient amplitudes.Several studies demonstrated a protective role of nNOS in myocardial infarction 12,13,32 or in ischemia/reperfusion injury. 21 The reason for these favorable results may not only be overexpression or (more physiologically) upregulation, but the translocation of nNOS to the plasmamembrane.…”

Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the β-Adrenergic Signal in the Myocardium

“…7). In light of these and other recent data (1,2,15), it appears likely that nNOS molecules in other subcellular compartments (i.e. sarcoplasmic reticulum and mitochondria) also fulfill highly specialized and spatially restricted functions.…”

“…In myocardial cells, nNOS has been localized to the sarcolemma (13), sarcoplasmic reticulum (2), and mitochondria (14), and translocation between compartments has been demonstrated (15). It has been speculated that these various localizations provide specificity to NO signaling, but the exact mechanisms have yet to be elucidated.…”