Role of Myocyte Nitric Oxide in β-Adrenergic Hyporesponsiveness in Heart Failure

Yamamoto, Shimako; Tsutsui, Hiroyuki; Tagawa, Hirofumi; Saito, Keiko; Takahashi, Masaru; Tada, Hideo; Yamamoto, Miyuki; Katoh, Makoto; Egashira, Kensuke; Takeshita, Akira

doi:10.1161/01.cir.95.5.1111

Cited by 77 publications

(46 citation statements)

References 8 publications

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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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“…It has been demonstrated (3,8,11,33) that NO has a negative inotropic effect in isolated myocytes and in the heart. In the current study, a NO substrate, NO donor, NOS inhibitor, and guanylate cyclase inhibitor were utilized to determine the functional role of NOS and its distal pathway in isolated cardiac myocytes during the SWOP.…”

Section: Discussionmentioning

confidence: 99%

Enhanced iNOS function in myocytes one day after brief ischemic episode

Kim¹,

Kim²,

Takagi³

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Vatner. Enhanced iNOS function in myocytes one day after brief ischemic episode. Am J Physiol Heart Circ Physiol 282: H423-H428, 2002; 10.1152/ajpheart.00609.2001.-There is increasing evidence that nitric oxide (NO) produced by inducible NO synthase (iNOS) plays a key role in cadioprotection during the "second window of protection" (SWOP). The goals of this study were to determine 1) whether a transient ischemic episode [10-min coronary artery occlusion (CAO), followed by full reperfusion] enhances NOS function in cardiac myocytes, 2) which specific NOS isoform is responsible for the enhanced NOS function in myocytes, and 3) to localize iNOS expression during SWOP. To address these questions, 10 dogs were instrumented to measure aortic and left ventricular pressures and wall thickness. At 1-2 wk after recovery, myocardial ischemia was induced regionally by a 10-min left circumflex CAO. After 24-h reperfusion, cardiac myocytes were isolated from the previously ischemic and nonischemic regions (n ϭ 6). Myocyte contractile function was assessed using a video motion detector at 1 Hz (35 Ϯ 2°C). At baseline, myocyte contractile function (% contraction) was similar in the two regions (ischemic 7.8 Ϯ 0.5% vs. nonischemic 7.8 Ϯ 0.2%). L-Arginine (1 mM) significantly reduced (P Ͻ 0.05) myocyte contraction in the ischemic (Ϫ34 Ϯ 3%, P Ͻ 0.05) but not (Ϫ7 Ϯ 4%) nonischemic regions; these responses were abolished by N G -nitro-L-arginine (1 mM), a nonspecific NOS inhibitor, as well as 2-amino-5,6-dihydro-6-methy-4H-1,3,thiazine (1 mM), a specific iNOS inhibitor. Immunohistochemistry also revealed enhanced iNOS expression in the myocardium and in particular the interstitial spaces in the ischemic zone. These results indicate that a brief ischemic episode upregulates iNOS function in myocytes as well as in the interstitial space between blood vessels and myocytes, strategically where it can regulate both vascular and myocyte function during the SWOP. preconditioning; nitric oxide; contraction; second window of protection ISCHEMIC PRECONDITIONING INVOLVES a brief ischemic episode, which increases the tolerance of the heart to subsequent myocardial ischemia (14,21,24). In addition, the late or delayed phase of preconditioning also referred to as the "second window of protection" (SWOP) induces cardioprotection 12-24 h after the initial ischemic stimulus. The protection conferred by the SWOP is sustained longer (3-4 days) than the early phase of preconditioning (2-3 h) in both myocytes and coronary vessels (17,20,22,27,28) and is modified by several pathways including nitric oxide (NO) (2,6,7,13,29,34). However, it remains unclear whether upregulation of NO synthase (NOS) during the SWOP alters myocyte contractile function and which specific isoform is responsible for the enhanced NOS function in cardiac myocytes. In the present study, we induced a brief episode (10 min) of regional myocardial ischemia in the canine model, where the heart is large enough that NO regulation of myocyte contractile function and localization of NOS ...

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“…Thus, whereas some authors reported iNOS expression only in septic hearts but not in other types of HF, 7,8 others demonstrated iNOS expression and activity in HF of various origins. 9,10 Furthermore, some reports support the notion that excessive NO production contributes to ␤-adrenergic hyporesponsiveness in HF patients, 11,12 whereas others disagree. 13 We have previously used rats with aortocaval fistula (ACF) as a rapidly developing volume-overload cardiomyopathy model characterized by cardiac hypertrophy and neurohormonal and renal consequences that resemble those of HF patients.…”

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Role of Myocardial Inducible Nitric Oxide Synthase in Contractile Dysfunction and β-Adrenergic Hyporesponsiveness in Rats With Experimental Volume-Overload Heart Failure

et al. 2002

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Background-Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload-induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS in depressed cardiac contractile properties, intracellular Ca 2ϩ ([Ca 2ϩ ] i ) transients, and ␤-adrenergic hyporesponsiveness. Methods and Results-HF was induced by aortocaval fistula (ACF). Compensated and decompensated subgroups of HFwere selected on the basis of daily sodium excretion. ACF induced cardiac hypertrophy in rats with compensated (36%) and decompensated (76%) HF. Whereas in HF rats, cardiac eNOS expression and activity were unchanged, iNOS expression and activity increased Ϸ2-fold. iNOS immunostaining was observed in ventricular myocytes of compensated and decompensated HF rats but not in controls. Isoproterenol-positive inotropic and lusitropic effects were markedly attenuated in papillary muscle of HF rats, more pronouncedly in decompensated than in compensated rats. Isoproterenol-induced increases in the rates of [Ca 2ϩ ] i activation and relaxation were also depressed in ACF rats. Selective iNOS blockade by N- (3-(aminomethyl)benzylacetamidine improved the attenuated ␤-adrenergic responsiveness in HF rats. Conclusions-Our findings indicate that myocardial iNOS is activated in rats with volume-overload HF and suggest that increased iNOS activity contributes to depressed myocardial contractility and ␤-adrenergic hyporesponsiveness.

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Role of Myocyte Nitric Oxide in β-Adrenergic Hyporesponsiveness in Heart Failure

Cited by 77 publications

References 8 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

Enhanced iNOS function in myocytes one day after brief ischemic episode

Role of Myocardial Inducible Nitric Oxide Synthase in Contractile Dysfunction and β-Adrenergic Hyporesponsiveness in Rats With Experimental Volume-Overload Heart Failure

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Role of Myocyte Nitric Oxide in β-Adrenergic Hyporesponsiveness in Heart Failure

Cited by 77 publications

References 8 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

Enhanced iNOS function in myocytes one day after brief ischemic episode

Role of Myocardial Inducible Nitric Oxide Synthase in Contractile Dysfunction and β-Adrenergic Hyporesponsiveness in Rats With Experimental Volume-Overload Heart Failure

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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