Blockade of Nitric Oxide Synthesis Reduces Myocardial Oxygen Consumption In Vivo

Sherman, Andrew J.; Davis, Cornelius A.; Klocke, Francis J.; Harris, Kathleen R.; Srinivasan, Gopalakrishnan; Yaacoub, Adel S.; Quinn, Debra A.; Ahlin, KaLee A.; Jang, James J.

doi:10.1161/01.cir.95.5.1328

Cited by 46 publications

(27 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the normal as well as the failing human heart, endogenous and exogenous NO decreased myocardial tissue oxygen consumption (337,588). Suppression of NO production had previously been shown to increase myocardial oxygen consumption in awake dogs (38, 531), although this was not confirmed in other models (130,489,490,532). Inhibition of oxygen consumption by NO was documented also in noncontracting cardiac muscle slices (632).…”

Section: Autocrine and Paracrine Signaling From Cardiac Endothelial Cmentioning

confidence: 98%

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Brutsaert

2003

Physiological Reviews

603

544

View full text Add to dashboard Cite

Experimental work during the past 15 years has demonstrated that endothelial cells in the heart play an obligatory role in regulating and maintaining cardiac function, in particular, at the endocardium and in the myocardial capillaries where endothelial cells directly interact with adjacent cardiomyocytes. The emerging field of targeted gene manipulation has led to the contention that cardiac endothelial-cardiomyocytal interaction is a prerequisite for normal cardiac development and growth. Some of the molecular mechanisms and cellular signals governing this interaction, such as neuregulin, vascular endothelial growth factor, and angiopoietin, continue to maintain phenotype and survival of cardiomyocytes in the adult heart. Cardiac endothelial cells, like vascular endothelial cells, also express and release a variety of auto- and paracrine agents, such as nitric oxide, endothelin, prostaglandin I2, and angiotensin II, which directly influence cardiac metabolism, growth, contractile performance, and rhythmicity of the adult heart. The synthesis, secretion, and, most importantly, the activities of these endothelium-derived substances in the heart are closely linked, interrelated, and interactive. It may therefore be simplistic to try and define their properties independently from one another. Moreover, in relation specifically to the endocardial endothelium, an active transendothelial physicochemical gradient for various ions, or blood-heart barrier, has been demonstrated. Linkage of this blood-heart barrier to the various other endothelium-mediated signaling pathways or to the putative vascular endothelium-derived hyperpolarizing factors remains to be determined. At the early stages of cardiac failure, all major cardiovascular risk factors may cause cardiac endothelial activation as an adaptive response often followed by cardiac endothelial dysfunction. Because of the interdependency of all endothelial signaling pathways, activation or disturbance of any will necessarily affect the others leading to a disturbance of their normal balance, leading to further progression of cardiac failure.

show abstract

Section: Autocrine and Paracrine Signaling From Cardiac Endothelial Cmentioning

confidence: 98%

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Brutsaert

2003

Physiological Reviews

603

544

View full text Add to dashboard Cite

show abstract

“…These effects persist even when the effects of NO on blood flow are taken into account. However, NOS inhibitors do not always seem to increase myocardial oxygen consumption (42,49,68,76); the reasons for this discrepancy are not clear, although in some cases they are likely to relate to differences in the intracellular location, local concentration, permeability and K i of different inhibitors. Interestingly, no effect has been seen of NOS inhibitors on either oxygen consumption (44,69) or the redox state of cytochrome oxidase (30) in the anesthetized brain, even in the absence of potentially NO scavenging red blood cells (90).…”

Section: The Reality Of Inhibition?mentioning

confidence: 98%

Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology

Cooper¹,

Giulivi

2007

American Journal of Physiology-Cell Physiology

144

View full text Add to dashboard Cite

Cooper CE, Giulivi C. Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology. Am J Physiol Cell Physiol 292: C1993-C2003, 2007. First published February 28, 2007 doi:10.1152/ajpcell.00310.2006 is an intercellular signaling molecule; among its many and varied roles are the control of blood flow and blood pressure via activation of the heme enzyme, soluble guanylate cyclase. A growing body of evidence suggests that an additional target for NO is the mitochondrial oxygen-consuming heme/copper enzyme, cytochrome c oxidase. This review describes the molecular mechanism of this interaction and the consequences for its likely physiological role. The oxygen reactive site in cytochrome oxidase contains both heme iron (a3) and copper (CuB) centers. NO inhibits cytochrome oxidase in both an oxygen-competitive (at heme a3) and oxygen-independent (at CuB) manner. Before inhibition of oxygen consumption, changes can be observed in enzyme and substrate (cytochrome c) redox state. Physiological consequences can be mediated either by direct "metabolic" effects on oxygen consumption or via indirect "signaling" effects via mitochondrial redox state changes and free radical production. The detailed kinetics suggest, but do not prove, that cytochrome oxidase can be a target for NO even under circumstances when guanylate cyclase, its primary high affinity target, is not fully activated. In vivo organ and whole body measures of NO synthase inhibition suggest a possible role for NO inhibition of cytochrome oxidase. However, a detailed mapping of NO and oxygen levels, combined with direct measures of cytochrome oxidase/NO binding, in physiology is still awaited. mitochondria; cytochrome oxidase NITRIC OXIDE (NO) is known as an intercellular messenger, synthesized in mammalian systems from arginine, NADPH, and oxygen by the NO synthase (NOS) class of enzymes (1). It has a wide range of physiological functions, most notably the control of blood pressure and blood flow (46, 63) mediated by the production of cGMP via its activation of the heme enzyme, soluble guanylate cyclase (45).Just over a decade ago, several groups demonstrated that the primary target for NO interactions with mammalian mitochondria is at the level of the oxygen-consuming enzyme, cytochrome c oxidase (15,20,73). These, and numerous subsequent studies, have demonstrated that in vitro cytochrome c oxidase is reversibly inhibited by nanomolar levels of NO. The possible cellular consequences of this effect are described in our previous paper (38). This review will instead focus on the importance of NO interactions with cytochrome oxidase at levels of organization above that of the individual cell.Two major questions arise when contemplating the possible consequences of this interaction at the tissue/organ level. First, does it occur in vivo? Second, if so, what are the physiological consequences? Whereas the detailed molecular mechanism of inhibition might appear to be of more interest to biochemists than physiologists, un...

show abstract

“…1 Several investigators have reported that blockade of NO production with nonselective NO synthase (NOS) inhibitors leads to significant increases of myocardial oxygen consumption (MV O 2 ) 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.…”

mentioning

confidence: 99%

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Chen

Traverse

et al. 2002

Circulation

View full text Add to dashboard Cite

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...

show abstract

Blockade of Nitric Oxide Synthesis Reduces Myocardial Oxygen Consumption In Vivo

Cited by 46 publications

References 29 publications

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity

Nitric oxide regulation of mitochondrial oxygen consumption II: molecular mechanism and tissue physiology

Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart

Contact Info

Product

Resources

About