Biomedical Engineering Reference
In-Depth Information
Role of NO in Physiology of the Cardiovascular System
Endothelial production of NO has become a major research area in vascular biology.
NO mediates multiple physiological and pathophysiological processes in the cardio-
vascular system. NO may trigger short- and long-term effects, which are either benefi-
cial or deleterious, depending on the molecular targets with which it interacts. These
interactions are governed by local factors (like the redox state). In the cardiovascular
system, the major targets involve not only guanylyl cyclase, but also other heme
proteins, protein thiols, iron-nonheme complexes, and superoxide anion (forming
peroxynitrite). The latter has several intracellular targets and may be cytotoxic, despite
the existence of endogenous defense mechanisms. These interactions may either trig-
ger NO effects or represent releasable NO stores, able to buffer NO and prolong its
effects in blood vessels and in the heart. Some of the most important effects that NO
exerts in the vascular wall are potentially vasoprotective, because these effects main-
tain important physiological functions such as vasodilation, anticoagulation, leukocyte
adhesion, smooth muscle proliferation, and the antioxidative capacity.
The redox siblings nitroxyl (HNO) and NO have often been assumed to undergo
casual redox reactions in biological systems. However, several studies have demon-
strated distinct pharmacological effects for donors of these two species. In one
study, infusion of the HNO donor Angeli's salt into normal dogs resulted in ele-
vated plasma levels of calcitonin gene-related peptide, whereas neither the NO
donor diethylamine/NONOate nor the nitrovasodilator nitroglycerin had an appre-
ciable effect on basal levels (Miranda et al.
2003
). Conversely, plasma cGMP was
increased by infusion of diethylamine/NONOate or nitroglycerin but was unaf-
fected by Angeli's salt. These results suggest the existence of two mutually exclu-
sive response pathways that involve stimulated release of discrete signaling agents
from HNO and NO. Calcitonin gene-related peptide release is suggested to occur
via altered calcium channel function through binding of HNO to a ferric or thiol
site. The orthogonality of HNO and NO may be due to differential reactivity toward
metals and thiols, and in the cardiovascular system may ultimately be driven by
respective alteration of cAMP and cGMP levels.
NO and Atrial Natriuretic Peptide
Atrial natriuretic peptide (ANP) is part of an endocrine system that maintains fluid
and pressure homeostasis by modulating cardiac and renal function. The physio-
logic functions of the ANP in healthy humans and in patients with cardiovascular
disease are not fully understood. From a physiological standpoint, the most impor-
tant factor governing ANP secretion is mechanical stretching of the atria, which
normally occurs when extracellular fluid volume or blood volume is elevated. In
addition, the ability of several vasoconstrictors to increase ANP secretion can be
traced to their indirect effects on atrial stretch via increases in cardiac preload or
afterload. Whether vasoconstrictors such as angiotensin II and vasopressin have a
direct positive or negative effect on ANP secretion has not been determined with
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