Development of genetically engineered mice lacking all three nitric oxide synthase isoform

Masato Tsutsui, Hiroaki Shimokawa, Tsuyoshi Morishita, Sei Nakata, Ken Sabanai, Yasuhide Nakashima, Nobuyuki Yanagihara

Research output: Contribution to journalReview articlepeer-review

3 Citations (Scopus)


The nitric oxide (NO) synthases (NOSs) system consists of three different isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). The roles of NO in vivo have been extensively investigated in pharmacological studies with NOS inhibitors and in studies with mice lacking each NOS isoform. However, in the pharmacological studies, the specificity of NOS inhibitors continues to be an issue of debate, while in the studies with mice lacking each NOS isoform, compensatory mechanism by other NOSs appears to be involved. Thus, the ultimate roles of endogenous NO in our body still remain to be fully elucidated. To address this important issue, we have successfully developed mice in which all three NOS genes are completely disrupted. NOS expression and activities were totally absent in the triply n/i/eNOS -/- mice before and after treatment with lipopolysaccharide. While the triply n/i/eNOS-/- mice were viable, their survival and fertility rates were markedly reduced as compared with wild-type mice. The first noticeable phenotypes were polyuria, polydipsia, and renal unresponsiveness to vasopressin, characteristics consistent with nephrogenic diabetes insipidus. We subsequently observed that in those mice, arteriosclerosis is spontaneously developed with a clustering of cardiovascular risk factors. These results provide the first evidence that genetic disruption of all three NOSs causes a variety of cardiovascular diseases in mice in vivo, demonstrating the critical role of the endogenous NOSs system in maintaining cardiovascular homeostasis.

Original languageEnglish
Pages (from-to)1347-1355
Number of pages9
JournalYakugaku Zasshi
Issue number9
Publication statusPublished - 2007 Sep


  • Cardiovascular disease
  • Knockout mouse
  • Metabolic syndrom
  • Nephrogenic diabetes insipidus
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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