(Circulation. 2000;101:2126.)
© 2000 American Heart Association, Inc.
Editorials |
What We Know and Don’t Know About L-Arginine and NO
From Whitaker Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine, Boston, Mass.
Key Words: Editorials • amino acids • nitric oxide • atherosclerosis
In the latter half of the nineteenth century, amyl nitrate, sodium nitrite, and nitroglycerin were each shown to relieve angina pectoris. These early observations, coupled with the rapid growth of the chemical and pharmaceutical industries, led to the development of nitrovasodilator drugs as the cornerstone of therapy for ischemic heart disease throughout most of the next century. Despite a rather thorough understanding of the pharmacology of these agents, only recently have the vascular actions of nitrovasodilators been placed in their proper biological context. The identification of nitric oxide (NO) as a product of the normal endothelium with smooth-muscle relaxing effects1 2 3 led to the recognition that nitrovasodilators work by providing an exogenous source of NO to the diseased blood vessel. As such, nitrovasodilators may be viewed as replacement therapy for the ailing vasculature.
Over the past 10 years, this paradigm has been strengthened by the
observation that the normal endothelium can become
dysfunctional when exposed to risk factors for
atherothrombosis.4 In addition, in the setting of many
vascular disorders, including essential hypertension and
atherothrombosis itself, endothelial dysfunction is
apparent. Dysfunctional endothelium is defined by a
change in its essential phenotype5 : the normal
endothelial cell promotes vascular smooth muscle cell
relaxation, inhibits platelet activation, limits leukocyte
adhesion, and inhibits vascular smooth muscle proliferation; the
dysfunctional endothelial cell, in the extreme, cannot
support smooth muscle relaxation, cannot inhibit platelet
activation, is avid for leukocytes, and cannot inhibit vascular smooth
muscle cell proliferation. There are varying degrees of
endothelial dysfunction, and these may
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