Nitric oxide regulation of myocardial contractility and calcium cycling: Independent impact of neuronal and endothelial nitric oxide synthases

Khan, Shakil A.; Skaf, Michel; Lee, Kwang-Ho; Harrison, Robert W.; Fradley, Micheal; Shoukas, Artin A.; Berkowitz, Dan E.; Hare, Joshua M.

doi:10.1016/s0735-1097(03)81767-9

Cited by 66 publications

(135 citation statements)

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“…The impaired β-adrenergic signaling previously observed in ob/ob mice [18] can be related not only to the decreased protein kinase A (PKA) activity [18] but also to our observation of reduced NOS1 expression and consequent increased XOR activity. Isolated myocytes from NOS1 deficient animals present impaired β-adrenergic response [32], while XOR inhibition restores it [33].…”

Section: Discussionmentioning

confidence: 98%

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

et al. 2007

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Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (ob/ob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease NOS1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2-6 month old ob/ob (n=26) and C57Bl/6 controls (n=27). Cardiac NOS1 protein abundance (P<0.01) and mRNA expression (P=0.03) were reduced in ob/ob (n=10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in ob/ob mice after leptin treatment (n=3; P<0.05 vs leptin untreated ob/ob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in ob/ob mice (n=5; P=0.02). Furthermore, oxidative stress was increased in ob/ob mice as GSH/ GSSG ratio was decreased (n=4; P=0.02). Whereas XOR activity measured by Amplex Red fluorescence assay kit was increased (n=8; P=0.04), XOR and NADPH oxidase subunits protein abundance were not changed in ob/ob mice (n=6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. In conclusion, leptin deficiency is linked to decreased cardiac expression of NOS1 and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity.

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Section: Discussionmentioning

confidence: 98%

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

et al. 2007

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“…Thus, it appears that low SIN-1 may potentially mimic the peroxynitrite production of NOS1, which is hypothesized to produce low concentrations of peroxynitrite due to a co-localization with xanthine oxidase [4]. NOS1 is considered a physiological regulator of cardiac function and is also thought to increase myocardial contractility [41]. Conversely, high SIN-1 may be mimicking the peroxynitrite production of NOS2, which is considered to be a pathophysiological regulator of cardiac function by reducing β-adrenergic responsiveness [3,36].…”

Section: Sin-1 and Plb −/− Myocyte Functionmentioning

confidence: 99%

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

Kohr¹,

Wang²,

Wheeler³

et al. 2008

Free Radical Biology and Medicine

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Many studies have demonstrated a biphasic effect of peroxynitrite in the myocardium, but few studies have investigated this biphasic effect on β-adrenergic responsiveness and its dependence on contractile state. We have previously shown that high SIN-1 (source of peroxynitrite, 200 μmol/L) produced significant anti-adrenergic effects during maximal β-adrenergic stimulation in cardiomyocytes. In the current study, we hypothesize that the negative effects of high SIN-1 will be greatest during high contractile states, while the positive effects of low SIN-1 (10 μmol/L) will predominate during low contractility. Isolated murine cardiomyocytes were field stimulated at 1 Hz and [Ca 2+ ] i transients and shortening were recorded. Following submaximal ISO (β-adrenergic agonist, 0.01 μmol/L) stimulation, 200 μmol/L SIN-1 induced two distinct phenomena. Cardiomyocytes undergoing a large response to ISO showed a significant reduction in contractility, while cardiomyocytes exhibiting a modest response to ISO showed a further increase in contractility. Additionally, 10 μmol/L SIN-1 always increased contractility during low ISO stimulation, but had no effect during maximal ISO (1 μmol/L) stimulation. 10 μmol/L SIN-1 also increased basal contractility. Interestingly, SIN-1 only produced a contractile effect under one condition in phospholamban knockout cardiomyocytes, providing a potential mechanism for the biphasic effect of peroxynitrite. These results provide clear evidence for a biphasic effect of peroxynitrite, with high peroxynitrite modulating high levels of β-adrenergic responsiveness and low peroxynitrite regulating basal function and low levels of β-adrenergic stimulation.

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“…6 Assays for specific NOS1 activity were performed in the presence of the preferential NOS1 inhibitor vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO; 0.1 mol/L). Western blots, immunolocalization, and coimmunoprecipitation were performed with specific antibodies to the following, as described in the online Data Supplement: NOS1, NOS3, caveolin-3 (Cav-3), cardiac ryanodine receptor (a generous gift from Dr I. Marty), vinculin, and ␣-actinin.…”

Section: Animal Modelmentioning

confidence: 99%

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

et al. 2004

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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.

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Nitric oxide regulation of myocardial contractility and calcium cycling: Independent impact of neuronal and endothelial nitric oxide synthases

Cited by 66 publications

References 0 publications

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Biphasic effect of SIN-1 is reliant upon cardiomyocyte contractile state

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

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