Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to β-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy

Shinke, Toshiro; Takaoka, Hideyuki; Takeuchi, Motoshi; Hata, Katsuya; Kawai, Hiroya; Okubo, Hideaki; Kijima, Yasufumi; Murata, Takeomi; Yokoyama, Mitsuhiro

doi:10.1161/01.cir.101.16.1925

Cited by 45 publications

(36 citation statements)

References 38 publications

(33 reference statements)

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“…This may represent a primary endothelial effect; as in nonischemic cardiomyopathy, preserved endothelial function has been associated with improved clinical outcomes, 27 and exacerbation of endothelial dysfunction may underlie the adverse impact of the Asp 298 variant in this subset. Alternatively, given the modulation of adrenergic signaling by NO, 8,9 the impact of the Asp 298 variant in nonischemic outcomes may reflect a primary influence on cardiomyocyte function. This study demonstrates that for patients with heart failure, genetic variation of NOS3 contributes to the observed heterogeneity of clinical outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…6 TNF administration to myocytes induces expression of NOS2, 7 which mediates its cardiodepressant effects. NO diminishes the effect of ␤-agonist stimulation on contractility, 8,9 potentially limiting the impact of sympathetic activation on disease progression. Given the effects on adrenergic response and the peripheral vasculature, an increase in NOS activity and NO production can be postulated to have a cardioprotective effect in heart failure.…”

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confidence: 99%

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Effect of the Asp ²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

et al. 2003

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Background— Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp 298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction. Methods and Results— Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56±12 years) with systolic dysfunction (left ventricular ejection fraction ≤0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp 298 variant. Event-free survival was significantly poorer in patients with the Asp 298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P =0.03). In subset analysis, the adverse impact of the Asp 298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P =0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P =0.71). Conclusions— For patients with heart failure caused by systolic function, the Asp 298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Effect of the Asp ²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

et al. 2003

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“…Nonselective NOS inhibition enhances the inotropic response to ␤-adrenergic stimulation in patients and dogs with CHF. 27,28 If the increased MV O 2 after NOS inhibition were due to an enhanced catecholamine response, however, then the effect would probably have been most prominent during exercise, when catecholamines are further increased, in contrast to the observed parallel upward shift in the relationship between MV O 2 rate-pressure product. Finally, it is likely that the increase of MV O 2 resulted in part from the increased arterial and LV systolic pressure that occurred in response to NOS inhibition in animals with CHF.…”

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confidence: 99%

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Chen

Traverse

et al. 2002

Circulation

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Background-Endogenous nitric oxide (NO) has been reported to inhibit oxygen consumption in the normal heart, so that nonselective inhibition of NO synthase (NOS) caused an increase of myocardial oxygen consumption (MV O 2 ). Although endothelial NOS responses are depressed in congestive heart failure (CHF), inducible NOS (iNOS) may be expressed in failing myocardium. Methods and Results-This study tested the hypothesis that NOS inhibition would increase MV O 2 in the failing heart. CHF was produced in dogs by use of the rapid ventricular pacing model. ) in the normal heart, 2,3 although others found no effect 4 or a decrease in MV O 2 . 5 Three distinct NOS isoforms exist in mammalian cells: neuronal (nNOS), inducible (iNOS), and endothelial (eNOS) isoforms. 6 nNOS and eNOS are constitutively expressed in many cell types, whereas iNOS is expressed in response to infection, inflammation, or cytokine activation. Circulating and tissue levels of cytokines, including tumor necrosis factor-␣, interleukin-2, and interleukin-6, are elevated in patients with chronic heart failure, 7-9 and iNOS expression has been found in cardiac myocytes of patients with dilated cardiomyopathy, myocarditis, and ischemic heart disease, 10,11 suggesting that iNOS could be a source of NO in the failing heart. Consequently, this study was performed to determine whether selective iNOS inhibition with S-methylisothiourea (SMT) influences MV O 2 of the failing heart at rest or during exercise. The effect of SMT was compared with nonselective NOS inhibition with N G -nitro-L-arginine (L-NNA) to determine whether constitutive NOS can also modulate MV O 2 in congestive heart failure (CHF). MethodsStudies were performed in 21 adult mongrel dogs weighing 20 to 26 kg and trained to run on a treadmill. All experiments were performed in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals" as approved by the council of the American Physiological Society and with prior approval of the University of Minnesota Animal Care Committee. Surgical PreparationAnimals were anesthetized with sodium pentobarbital (30 to 35 mg/kg), intubated, and ventilated with oxygen-enriched air. A left thoracotomy was performed, and polyvinyl chloride catheters (3.0-mm OD) were inserted into the ascending aorta and the left ventricle (LV). A solid-state micromanometer (Konigsberg Instruments) was introduced into the LV at the apex. A final catheter was introduced into the right atrial appendage and advanced through the coronary sinus until the tip could be palpated at the anterior interventricular vein to allow selective sampling of blood draining the myocardium perfused by the left anterior descending coronary artery (LAD). 3 A Doppler velocity probe (Craig Hartley) was positioned on the LAD, and a silicone catheter (0.3-mm ID) was introduced into the LAD distal to the velocity probe. Catheters were tunneled to exit at the base of the neck; catheters were flushed daily Effect of SMT and L-NNA in the Normal HeartSelective iNOS inhibition was studi...

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“…3,4 Previous studies have shown that inhibition of cardiac NO synthase (NOS) augments the positive inotropic response to -adrenergic receptor stimulation in human heart failure, suggesting that increased activity of myocardial NOS and NO attenuates -adrenergic responsiveness. [5][6][7] In patients with severe CHF, the increase in intracellular cyclic AMP and myocardial contractility in response toadrenergic receptor stimulation is reduced, 5 which reflects cardiac desensitization to -receptor agonists, 8 partly modulated by the increased production of NO in the myocardium. 5 Previous studies have shown that forskolin produces beneficial cardiac effects by directly stimulating adenylyl cyclase in the failed human heart, especially in those with a relative insensitivity to -adrenergic receptor stimulation.…”

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confidence: 99%

Inhibition of Endogenous Nitric Oxide Synthase Augments Contractile Response to Adenylyl Cyclase Stimulation Without Altering Mechanical Efficiency in Patients With Idiopathic Dilated Cardiomyopathy

Ohta

Shinke

Hata

et al. 2007

Circ J

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itric oxide (NO) is an important regulator of cardiac function. 1,2 In patients with congestive heart failure (CHF) the concentrations of NO and tumor necrosis factor-increase in proportion to the severity of heart failure. 3,4 Previous studies have shown that inhibition of cardiac NO synthase (NOS) augments the positive inotropic response to -adrenergic receptor stimulation in human heart failure, suggesting that increased activity of myocardial NOS and NO attenuates -adrenergic responsiveness. [5][6][7] In patients with severe CHF, the increase in intracellular cyclic AMP and myocardial contractility in response toadrenergic receptor stimulation is reduced, 5 which reflects cardiac desensitization to -receptor agonists, 8 partly modulated by the increased production of NO in the myocardium. 5 Previous studies have shown that forskolin produces beneficial cardiac effects by directly stimulating adenylyl cyclase in the failed human heart, especially in those with a relative insensitivity to -adrenergic receptor stimulation. 9 Colforsin daropate (NKH477; 6-(3-dimethyl-aminopropionyl) forskolin hydrochloride) is a new water-soluble forskolin derivative, which experimental studies have shown to be able to generate positive inotropic and vasodilatory actions. 10,11 Furthermore, we previously reported that NKH477 might be a superior alternative to dobutamine for mechanical energy transduction in patients with left ventricular (LV) systolic dysfunction. 12 It remains to be clarified how NO modulates -adrenergic post-receptor signaling, such as adenylyl cyclase stimulation in the failing human heart. The objective of this study was to address the role of NO by evaluating the effects of cardiac NOS inhibition on LV hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation with colforsin daropate in patients with idiopathic cardiomyopathy (IDC). Methods Study SubjectsWe examined 13 patients (10 men, 3 women, mean age 56±13 years) who were undergoing diagnostic cardiac catheterization for the evaluation of heart failure on their first admission to hospital. All patients showed normal sinus rhythm and were diagnosed as IDC by the absence of coronary artery disease or other known causes of dilated cardiomyopathy. The patients were in New York Heart Association functional class II (n=8) or class III (n=5) with a LV ejection fraction (LVEF) of less than 40%. None of Background Increased nitric oxide (NO) in the failing heart attenuates the myocardial contractile response to -adrenergic receptor stimulation. However, the physiological effects of NO on the -adrenergic post-receptor signaling system are unknown. The objective of the present study was to examine the effects of cardiac NO synthase (NOS) inhibition on left ventricular (LV) hemodynamics and mechanoenergetics in response to adenylyl cyclase stimulation in human heart failure. Methods and ResultsThe study group comprised 13 patients with heart failure because of idiopathic cardiomyopathy (IDC). Emax was examined as an index of LV contractility, LV...

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Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to β-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy

Cited by 45 publications

References 38 publications

Effect of the Asp ²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Effect of the Asp ²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Inhibition of Endogenous Nitric Oxide Synthase Augments Contractile Response to Adenylyl Cyclase Stimulation Without Altering Mechanical Efficiency in Patients With Idiopathic Dilated Cardiomyopathy

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Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to β-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy

Cited by 45 publications

References 38 publications

Effect of the Asp 298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Effect of the Asp 298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Inhibition of Endogenous Nitric Oxide Synthase Augments Contractile Response to Adenylyl Cyclase Stimulation Without Altering Mechanical Efficiency in Patients With Idiopathic Dilated Cardiomyopathy

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Effect of the Asp ²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Effect of the Asp ²⁹⁸ Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure