Autonomic regulation of pacemaker activity: role of heart nitric oxide synthases

Fellet, Andrea L.; Balaszczuk, Ana M.; Arranz, Cristina; López‐Costa, Juan José; Boveris, Alberto; Bustamante, Juanita

doi:10.1152/ajpheart.00711.2005

Cited by 24 publications

(25 citation statements)

References 42 publications

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“…In the heart, however, the most convincing data implicate nNOS as the primary candidate for the cytoplasmic NOS izosyme targeted into mitochondria (40,72,142). Evidence in favor of eNOS (10,66,140) and iNOS (45,60,79,129) (Fig. 2B) presence in heart mitochondria has also been published.…”

Section: Heart Nossmentioning

confidence: 95%

“…There is a general consensus that iNOS is transiently expressed in the heart during immune responses under stress (8) and, therefore, during pathophysiological conditions of the myocardium such as in ischemia-reperfusion injury (133), septicemia (125), heart failure (146), as well as during aging (138). During the last fifteen years, different groups have used various experimental approaches and reported the presence of mtNOS in the heart (1,10,16,40,45,60,66,72,79,91,115,129,130,140,141,143,147). Regarding the localization of mtNOS, one interesting study provided evidence about the docking of eNOS to the outer mitochondrial membrane in endothelial cells (52).…”

Section: Heart Nossmentioning

confidence: 99%

“…2C). Studies of cardiac mtNOS have used various methods including immunohistochemistry (10,66), spectrophotometry (16,30,45,79,115,141,142), radiometry (139,143), fluorometry (40,139,143,147), chemiluminescence (143), and electrochemistry (72). On the other hand, one study reported that the ubiquinone/cyt bc 1 is a site where nitrite is reduced to form NO congeners within mitochondria in a NOS-independent manner (100).…”

Section: Heart Nossmentioning

confidence: 99%

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Strategic localization of heart mitochondrial NOS: a review of the evidence

Zaobornyj

Ghafourifar²

2012

American Journal of Physiology-Heart and Circulatory Physiology

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chondria play a central role in cell energy provision and in signaling. Nitric oxide (NO) is a free radical with primary regulatory functions in the heart and involved in a broad array of key processes in cardiac metabolism. Specific NO synthase (NOS) isoforms are confined to distinct locations in cardiomyocytes. The present article reviews the chemical reactions through which NO interacts with biomolecules and exerts some of its crucial roles. Specifically, the article discusses the reactions of NO with mitochondrial targets and the subcellular localization of NOS within the myocardium and analyzes the available data about heart mitochondrial NOS activity and identity. The article also describes the regulation of heart mtNOS by the distinctive mitochondrial environment by showing the effects of Ca 2ϩ , O2, L-arginine, mitochondrial transmembrane potential, and the metabolic states on heart mitochondrial NO production. The article depicts the effects of NO on heart function and highlights the relevance of NO production within mitochondria. Finally, the evidence on the functional implications of heart mitochondrial NOS is delineated with emphasis on chronic hypoxia and ischemia-reperfusion studies. mitochondrial nitric oxide synthase; calcium; transmembrane potential; hypoxia; ischemia-reperfusion SINCE THE RECOGNITION OF MITOCHONDRIA as the powerhouses of the cells, numerous studies have shown that these organelles play a central role in various biological processes. Under physiological conditions, mitochondria provide the cell with both the energy and the signals involved in the genetic expression and metabolic regulation (35). About two decades ago, the discovery that nitric oxide (NO) is the endothelium-derived relaxing factor caused a paradigm shift in the understanding of cardiovascular physiology and pathophysiology (68,102). NO is a gaseous uncharged 30-Da molecule. It is highly diffusible in aqueous and lipid phases and possesses a biochemistry that supports its role as one of the most versatile molecules in various biological regulatory and signaling processes (76,86,134).In the cardiovascular system, NO plays integral roles not only in the regulation of vascular smooth muscle tone but also in the function of ion channels, myocyte contraction, O 2 consumption, apoptosis, and hypertrophic myocardial remodeling (36, 92). In cardiac endothelial cells and myocytes, NO is generated by NO synthase (NOS) isozymes: neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3) (71, 75). Initially, eNOS was considered to be the only isoform constitutively expressed in myocytes and thus the source of NO involved in the autocrine regulation of myocardial contraction and Ca 2ϩ homeostasis (7, 37). However, subsequent studies showed that NOS is targeted to the cardiac sarcoplasmic reticulum (SR) (137) and localized in cardiac mitochondria (72). Additionally, iNOS has been shown to be expressed in the myocardium upon induction by cytokines (8) during inflammatory responses implicated in...

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Section: Heart Nossmentioning

confidence: 95%

Section: Heart Nossmentioning

confidence: 99%

Section: Heart Nossmentioning

confidence: 99%

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Strategic localization of heart mitochondrial NOS: a review of the evidence

Zaobornyj

Ghafourifar²

2012

American Journal of Physiology-Heart and Circulatory Physiology

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“…Cardiac mitochondria were isolated as described previously (31). The isolated left ventricle (LV) was immediately minced and homogenized by a Teflon Potter-Elvejhem homogenizer in MST solution containing 0.23 M mannitol, 0.07 M sucrose, 1 mM EDTA and 10 mM Tris-HCl (pH 7.4).…”

Section: Animals and Preparationmentioning

confidence: 99%

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Shimizu

Ishibashi

Kumagai

et al. 2013

International Journal of Molecular Medicine

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Abstract. Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.

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“…mtNOS activity has been found to be regulated by important physiological effectors; it is downregulated by ANG II (6) and thyroid hormones (15) and upregulated by insulin (16), the autonomic system (15), and during cold acclimation (37). Environmental O 2 pressure has been recognized as a physiological regulator of heart mtNOS activity.…”

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confidence: 99%

Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments

Zaobornyj¹,

Valdez²,

Iglesias³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Zaobornyj T, Valdez LB, Iglesias DE, Gasco M, Gonzales GF, Boveris A. Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil, L-NAME, and L-arginine treatments. Am J Physiol Heart Circ Physiol 296: H1741-H1747, 2009. First published April 3, 2009 doi:10.1152/ajpheart.00422.2008.-Rats submitted to high altitude (Cerro de Pasco, Perú, 4,340 m, PO2 ϭ 12.2 kPa) for up to 84 days showed a physiological adaptive response with decreased body weight gain (15%), increased right ventricle weight (100%), and increased hematocrit (40%) compared with sea level animals. These classical parameters of adaptation to high altitude were accompanied by an increase in heart mitochondrial enzymes: complexes I-III activity by 34% and mitochondrial nitric oxide synthase (mtNOS) activity and expression by Ͼ75%. The hyperbolic increase for mtNOS activity during adaptation to high altitude was similar to the observed pattern for hematocrit. Hematocrit and mtNOS activity mean values correlated linearly (r 2 ϭ 0.75, P Յ 0.05). Chronic treatment for 28 days with sildenafil (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) decreased the response of mtNOS to high altitude by 25%. Conversely, N Gnitro-L-arginine methyl ester treatment (8.3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) increased such response by 40%, whereas L-arginine treatment (106 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) had no effect. Nitric oxide (NO) production by mtNOS accounts for ϳ49% of total cellular NO production in sea level rats and for ϳ54% in rats exposed to high altitude for 84 days. It is concluded that mtNOS is a substantial source of cardiac NO, a factor in the adaptive response to sustained heart hypoxia that is susceptible to be modified by pharmacological treatments. mitochondrial nitric oxide synthase activity; mitochondrial nitric oxide synthase expression; mitochondrial respiratory complexes; hematocrit; nitro-L-arginine methyl ester HIGH ALTITUDE IS A MULTIFACTORIAL source of stress in which hypobaric hypoxia is the most important component. The O 2 gradient between atmospheric air and cells decreases from 105 mmHg at sea level to 49 mmHg at high altitude (20). There are a number of adaptive responses that are triggered by this situation, such as increased ventilation (28), pulmonary hypertension (40), erythropoiesis (39), and heart work load. The adaptation to high altitude constitutes a situation that has both advantageous and disadvantageous consequences for human health. The main long term effects are decreased physical activity and life span. Among the beneficial effects, there is a recognized cardioprotection with improvement of the myocardial tolerance to ischemic episodes. A number of studies involving exposure to natural (22) or simulated (29) hypobaric hypoxia reported that this adaptation is associated to lower incidence and smaller size of myocardial infarction (30).Although the mechanism by which adaptation to hypoxia has cardioprotective effects remains not elucidated, nitric oxide (NO) has been extensively proposed as one of the molecular messengers inv...

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Autonomic regulation of pacemaker activity: role of heart nitric oxide synthases

Cited by 24 publications

References 42 publications

Strategic localization of heart mitochondrial NOS: a review of the evidence

Strategic localization of heart mitochondrial NOS: a review of the evidence

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Mitochondrial nitric oxide metabolism during rat heart adaptation to high altitude: effect of sildenafil,l-NAME, andl-arginine treatments

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