Aorta and Skeletal Muscle NO Synthase Expression in Experimental Heart Failure

Comini, Laura; Bachetti, Tiziana; Gaia, Giuseppina; Pasini, Evasio; Agnoletti, Laura; Pepi, Patrizia; Ceconi, Claudio; Curello, Salvatore; Ferrari, Roberto

doi:10.1006/jmcc.1996.0216

Cited by 80 publications

(48 citation statements)

References 4 publications

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“…46 Down-regulation of eNOS expression has also been described in the peripheral vessels of monocrotaline-treated rats with severe CHF. 47 These findings are in accord with findings of decreased NOS activity in heart failure patients, as measured by diminished urinary excretion of nitrates. 48 However, other work has suggested that basal production of NO .…”

Section: Regulation Of Enossupporting

confidence: 84%

The Nitric Oxide Pathway and Oxidative Stress in Heart Failure

Searles

2002

Congestive Heart Failure

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). The neurohormonal changes that accompany and exacerbate CHF have been the subject of much recent study, and, as a result, we have a greater understanding of heart failure and potential targets for therapeutic intervention. Angiotensin-converting enzyme (ACE) inhibition and β-adrenergic receptor blockade are examples of therapeutic interventions that target specific neurohormonal abnormalities and have significant impact on morbidity and mortality in heart failure patients. As we comprehend more about the hormonal pathophysiology of heart failure, we will progress in our ability to treat and/or prevent this disease. This review will focus on the current perception of the NO . pathway in heart failure. It will discuss regulation of the enzyme that synthesizes NO . , nitric oxide synthase (NOS), as well as modulation of NO . bioavailability. Finally, the review will address the effect of oxidative stress on the NO . pathway.Oxidative Stress and the NO . PathwayOxidative stress is a term used to describe a condition in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen

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Section: Regulation Of Enossupporting

confidence: 84%

The Nitric Oxide Pathway and Oxidative Stress in Heart Failure

Searles

2002

Congestive Heart Failure

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“…For example, although eNOS expression was decreased in the endothelium of aortas from rats with CHF, eNOS expression in aortic smooth muscle was increased, with no change in total aortic eNOS expression. 22 Such a change in localization might decrease endothelium-dependent NO-mediated responses.…”

Section: No In Chfmentioning

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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“…7 Mouse monoclonal anti-human ecNOS (Affiniti) and peroxidase-conjugated rabbit anti-mouse IgG (Dako) were used as primary and secondary antibodies, respectively. The specific signal was detected with an enhanced chemiluminescence system (ECL, Amersham) and quantified by densitometry.…”

Section: Ecnos Immunoblottingmentioning

confidence: 99%

High-Dose Heparin Impairs Nitric Oxide Pathway and Vasomotion in Rats

et al. 1999

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Background-Platelet-activating effects have been reported with high-dose heparin in acute thrombotic disorders. Recent studies have shown that increased platelet aggregation is due to reduced nitric oxide (NO) production in endothelial cells cultured in the presence of high-dose heparin. The aim of this study was to determine whether heparin can affect the NO pathway and the regulation of the vascular tone in vivo. Methods and Results-Anesthetized and mechanically ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4 hours, the endothelial constitutive NO synthase (ecNOS) protein content in the aorta decreased (36% reduction, PϽ0.05), as detected by immunoblotting, and NO-dependent vascular reactivity was impaired. In fact, the increase in mean arterial blood pressure after inhibition of ecNOS with N G -nitro-L-arginine methyl ester (30 mg/kg) was smaller in heparin-treated animals than in controls (ϩ26.9Ϯ4.8 versus ϩ48.3Ϯ9.1 mm Hg, PϽ0.05), and further infusion of the biological ecNOS substrate L-arginine (0.5 g/kg) was ineffective in reversing systemic vasoconstriction (Ϫ1% versus 28% vasodilatation, PϽ0.001 eparin is the most widely used anticoagulant in current clinical practice. However, there is growing evidence that heparin can induce platelet activation. Recent studies report that therapeutic doses of heparin increase spontaneous and stimulated platelet aggregation when administered during acute coronary syndromes or unstable angina, but also in healthy subjects. [1][2][3] This effect is associated with impaired endothelial nitric oxide (NO) synthesis in bovine aortic endothelial cells exposed to high-dose heparin. 4 Endothelial synthesis of NO plays a fundamental role both in the regulation of platelet reactivity and in the control of vascular tone. 5 However, the effects of high-dose heparin on NO-mediated vasoreactivity in vivo have never been addressed. This effect would be clinically relevant in procedures such as PTCA and cardiopulmonary bypass, in which an activated partial thromboplastin time Ͼ100 seconds is currently used.The present study investigated the effects of heparin on systemic vascular tone of anesthetized rats after either inhibition or activation of the NO pathway by N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine, respectively. Endothelial constitutive NO synthase (ecNOS) protein expression after heparin administration was also measured. Methods Animal PreparationThe investigation was conducted according to the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health). Twenty-one Sprague-Dawley rats, maintained on a standard diet (mean body weight, 250Ϯ50 g), were anesthetized with sodium pentobarbital (30 mg/kg IP). A tracheostomy was performed, and the animals were mechanically ventilated to ensure physiological levels of arterial blood gases (PO 2 , 70 to 80 mm Hg; PCO 2 , 27 to 35 mm Hg). A single-lumen catheter was placed in the right carotid artery for blood pressure recording, and a second catheter was placed in the ri...

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Aorta and Skeletal Muscle NO Synthase Expression in Experimental Heart Failure

Cited by 80 publications

References 4 publications

The Nitric Oxide Pathway and Oxidative Stress in Heart Failure

The Nitric Oxide Pathway and Oxidative Stress in Heart Failure

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

High-Dose Heparin Impairs Nitric Oxide Pathway and Vasomotion in Rats

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