(Hypertension. 1998;32:958-964.)
© 1998 American Heart Association, Inc.
Review |
Chronic Nitric Oxide Inhibition Model Six Years On
From the Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil (R.Z.); and the Department of Physiology, West Virginia University, Morgantown, WVa (C.B.).
Correspondence to Dr Roberto Zatz, Laboratório de Fisiopatologia Renal, Av. Dr. Arnaldo, 455, 3-s/67, 01246-903 São Paulo SP, Brazil.
Key Words: models • cardiovascular diseases • nitric oxide synthase • nitric oxide • blood pressure • renin-angiotensin system • vasodilation
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Introduction |
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The discovery in 1987 that endothelium-derived nitric oxide (NO) mediates the vasodilatory effect of certain endothelium-dependent agonists1 2 inaugurated the current huge field of NO biology. It is now recognized that NO plays essential roles in many diverse physiological processes and in some pathophysiologic events. Development of these concepts has been based largely on evidence obtained by limiting NO biosynthesis. This review is centered on the cardiovascular and particularly the renal functional and structural consequences of chronic pharmacologic NO inhibition by L-arginine analogues. We devoted special attention to the mechanisms of hypertension and organ injury that occur under these circumstances, while appreciating the inherent limitations surrounding interpretation of this data.
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Ubiquity and Heterogeneity of NO Biosynthesis |
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NO is made by the enzymatic action of several widely distributed NO synthases (NOS). In the presence of the substrates L-arginine and oxygen, as well as a number of essential cofactors, NO is produced in response to appropriate stimuli. The constitutively expressed NOS play a major role in the physiological control of vascular tone and kidney function.3 4 Vascular endothelial NOS (eNOS) and brain-type NOS (bNOS) are widely distributed throughout the kidney5 as well as the cardiovascular system and in strategic locations in the peripheral and central nervous system (CNS).6 7
Both eNOS and particularly bNOS are abundant in the kidney,
glomeruli, and vasculature as well as in most segments of the
tubule,3 5 and NOS activity in medulla is
considerably greater than in cortex.8 NO
generated within the kidney controls the glomerular
filtration rate (GFR), total renal and medullary blood flow,
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|
|
|
|
|
|
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|
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|
|
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|
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|
|
|
|
|
|
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|
|
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