Effects of NO Modulation on Cardiac Arrhythmias in the Rat Isolated Heart

Pabla, Ravinder; Curtis, Michael J.

doi:10.1161/01.res.77.5.984

Cited by 108 publications

(81 citation statements)

References 46 publications

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“…This increase in coronary vascular resistance can be directly attributed to the inhibition of NOS activity and the subsequent impairment of ⅐ NO-induced vasorelaxation, as was described previously in a similar model (Pabla and Curtis, 1995). During L-NAME administration, the progressive decrease in RPP might be related to the impairment of oxygen and substrate supplies due to vasoconstriction.…”

Section: Tablesupporting

confidence: 72%

Postischemic Recovery and Oxidative Stress Are Independent of Nitric-Oxide Synthases Modulation in Isolated Rat Heart

Vergely¹,

Perrin-Sarrado²,

Clermont³

et al. 2002

J Pharmacol Exp Ther

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During myocardial ischemia and reperfusion, nitric oxide ( ⅐ NO) was shown to exert either beneficial or detrimental effects. Uncoupled ⅐ NO synthases (NOS) can generate superoxide anion under suboptimal concentrations of substrate and cofactors. The aim of our study was to investigate the role of NOS modulation on 1) the evolution of functional parameters and 2) the amount of free radicals released during an ischemia-reperfusion sequence. Isolated perfused rat hearts underwent 30 min of total ischemia, followed by 30 min of reperfusion in the presence of N G -nitro-D-or L-arginine methyl ester (NAME, 100 M) or of D-or L-arginine (3 mM). Functional parameters were recorded and coronary effluents were analyzed with electron spin resonance to identify and quantify the amount of ␣-phenyl-N-tert-butylnitrone spin adducts produced during reperfusion.The antioxidant capacities of the compounds were determined with the oxygen radical absorbance capacity test. L-NAMEtreated hearts showed a reduction of coronary flow and contractile performance, although neither L-NAME nor L-arginine improved the recovery of coronary flow, left end diastolic ventricular pressure, rate pressure product, and duration of reperfusion arrhythmia, compared with their D-specific enantiomers. A large and long-lasting release of alkyl/alkoxyl radicals was detected upon reperfusion, but no differences of free radical release were observed between D-and L-NAME or D-and L-arginine treatment. These results may indicate that, in our experimental conditions, cardiac NOS might not be a major factor implicated in the oxidative burst that follows a global myocardial ischemia.

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Section: Tablesupporting

confidence: 72%

Postischemic Recovery and Oxidative Stress Are Independent of Nitric-Oxide Synthases Modulation in Isolated Rat Heart

Vergely¹,

Perrin-Sarrado²,

Clermont³

et al. 2002

J Pharmacol Exp Ther

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“…We have described premature death in NOS1-and NOS1/NOS3 Ϫ/Ϫ -deficient mice (39) and recently, in a model of myocardial infarction, that the survival is dramatically decreased in NOS1 Ϫ/Ϫ mice (40). Interestingly, it has been described that pharmacological blockade of NOS1 increases ventricular fibrillation in models of ischemia-reperfusion, in a manner that is reversed by NO donors (41)(42)(43).…”

Section: Discussionmentioning

confidence: 98%

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

González

Beigi

Treuer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

201

192

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Altered Ca 2؉ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via Snitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca 2؉ homeostasis. Diastolic Ca 2؉ levels are elevated in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not NOS3 ؊/؊ myocytes compared with wild-type (WT), suggesting diastolic Ca 2؉ leakage. Measured leak was increased in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not in NOS3 ؊/؊ myocytes compared with WT. Importantly, NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in NOS1 ؊/؊ hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca 2؉ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.heart ͉ nitric oxide ͉ excitation-contraction coupling ͉ oxidative stress ͉ heart failure T he cardiac myocyte has emerged as a prototypic example of the manner in which nitric oxide (NO) signaling occurs in a spatially confined manner. Although neuronal (NOS1) and endothelial (NOS3) isoforms of nitric oxide synthase are located extremely close to one another within the cell on opposite sides of the dyad, they exert opposite effects on myocardial contractility (1). The mechanism(s) for this effect remains controversial. One explanation derived from in vitro observations is that NOS3 inhibits the sarcolemmal L-type calcium channel on the sarcolemmal aspect of the dyad, whereas NOS1 modulates ryanodine receptor (RyR) activity on the sarcoplasmic reticulum (SR) (1-3). Although this paradigm explains many facets of NO activity within the heart, other studies suggest that in the myocyte, NOS1 may bind to and/or regulate other ion channels or effectors, including the plasma membrane calcium/calmodulin-dependent calcium ATPase (4), sarcoplamic reticulum Ca 2ϩ -ATPase (SERCA) (5), and possibly phospholamban (PLB). In addition, there is support for the notion that this effect is mediated by a direct protein posttranslational modification; but again, this assertion is controversial (6).Another facet of NO cardiobiology has emerged that further motivates the importance of understanding the direct NOS effector molecules. In heart failure and/or other states of cardiac injury, NOS1 levels within the heart rise, and NOS1 effectively translocates from the SR to the plasma membrane (2,7,8). Because this phenomenon could have either deleterious effects or adaptive consequences, it is imperative to address definitively the physiologic role of NOS1 in the heart.To address these issues, we tested the hypothesis that the cardiac RyR i...

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“…Indeed, Pabla and Curtis (25) showed that endogenous NO does not appear to facilitate early recovery from systolic and diastolic stunning as a result of any direct action on the myocardium. The role of NO in ischemia/reperfusion appears to be dependent on the time of ischemia (26), being more significant with longer periods of coronary occlusion (>35 min). One may argue that L-NAME had no effect because it was washed out from the isolated heart.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-(1-7) improves the post-ischemic function in isolated perfused rat hearts

Ferreira

Santos

Almeida

2002

Braz J Med Biol Res

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We evaluated the effects of angiotensin-(1-7) (Ang-(1-7)) on postischemic function in isolated hearts from adult male Wistar rats perfused according to the Langendorff technique. Local ischemia was induced by coronary ligation for 15 min. After ischemia, hearts were reperfused for 30 min. Addition of angiotensin II (Ang II) (0.20 nM, N = 10) or Ang-(1-7) (0.22 nM, N = 10) to the Krebs-Ringer perfusion solution (KRS) before the occlusion did not modify diastolic or systolic tension, heart rate or coronary flow (basal values for Ang-(1-7)-treated hearts: 0.72 ± 0.08 g, 10.50 ± 0.66 g, 216 ± 9 bpm, 5.78 ± 0.60 ml/min, respectively). During the period of occlusion, the coronary flow, heart rate and systolic tension decreased (values for Ang-(1-7)-treated hearts: 2.83 ± 0.24 ml/min, 186 ± 7 bpm, 6.95 ± 0.45 g, respectively). During reperfusion a further decrease in systolic tension was observed in control (4.95 ± 0.60 g) and Ang II-treated hearts (4.35 ± 0.62 g). However, in isolated hearts perfused with KRS containing Ang-(1-7) the further reduction of systolic tension during the reperfusion period was prevented (7.37 ± 0.68 g). The effect of Ang-(1-7) on the systolic tension was blocked by the selective Ang-(1-7) antagonist A-779 (2 nM, N = 9), by the bradykinin B 2 antagonist HOE 140 (100 nM, N = 10), and by indomethacin pretreatment (5 mg/ kg, ip, N = 8). Pretreatment with L-NAME (30 mg/kg, ip, N = 8) did not change the effect of Ang-(1-7) on systolic tension (6.85 ± 0.61 g). These results show that Ang-(1-7) at low concentration (0.22 nM) improves myocardial function (systolic tension) in ischemia/reperfusion through a receptor-mediated mechanism involving release of bradykinin and prostaglandins.

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Effects of NO Modulation on Cardiac Arrhythmias in the Rat Isolated Heart

Cited by 108 publications

References 46 publications

Postischemic Recovery and Oxidative Stress Are Independent of Nitric-Oxide Synthases Modulation in Isolated Rat Heart

Postischemic Recovery and Oxidative Stress Are Independent of Nitric-Oxide Synthases Modulation in Isolated Rat Heart

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

Angiotensin-(1-7) improves the post-ischemic function in isolated perfused rat hearts

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