Abstract：
:Nitric oxide (NO) exerts a variety of biological actions under both physiological and pathological conditions. NO is synthesized by three distinct NO synthase (NOS) isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOS (eNOS), all of which are expressed in the human cardiovascular system. The roles of endogenous NO in the cardiovascular system have been investigated in pharmacological studies with NOS inhibitors and in studies with mice that lack each NOS isoform. However, in the pharmacological studies, the specificity of the NOS inhibitors continues to be an issue of debate, while in each of the NOS isoform-deficient mice, a compensatory mechanism by other NOSs that are not genetically deleted is apparently involved. Thus, the authentic roles of endogenous NO are still poorly understood. To address this issue, genetically engineered mice in which all three NOS genes are completely disrupted have been developed. In the triply n/i/eNOS(-/-) mice, but not in singly eNOS(-/-) mice, several cardiovascular phenotypes, including arteriosclerosis/atherosclerosis, myocardial infarction, and dyslipidemia, have been described. Furthermore, by using the triply NOS(-/-) mice, the roles of the NOS system in endothelium-dependent hyperpolarization and stain-induced NO production have been elucidated. These results provide novel insight into the cardiovascular role of the endogenous NO/NOS system at the molecular level. This review, based on the research outcomes obtained from the triply NOS(-/-) genetic model, summarizes the latest knowledge of the pathophysiological relevance of NO signaling in the cardiovascular system.
journal_name
Pharmacol Therjournal_title
Pharmacology & therapeuticsauthors
Tsutsui M,Shimokawa H,Otsuji Y,Yanagihara Ndoi
10.1016/j.pharmthera.2010.08.010subject
Has Abstractpub_date
2010-12-01 00:00:00pages
499-508issue
3eissn
0163-7258issn
1879-016Xpii
S0163-7258(10)00171-3journal_volume
128pub_type
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