Inhibition of nitric oxide synthesis induces coronary vascular remodeling and cardiac hypertrophy associated with the activation of p70 S6 kinase in rats

Tetsuo Minamino, Masafumi Kitakaze, Philip J. Papst, Yasunori Ueda, Yasuhiko Sakata, Hiroshi Asanuma, Akiko Ogai, Tsunehiko Kuzuya, Naohiro Terada, Masatsugu Hori

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Chronic inhibition of nitric oxide (NO) synthesis is reported to induce the thickening of coronary artery walls and cardiac hypertrophy in vivo via angiotensin II receptors. Increased protein synthesis is the main feature of these structural changes. Activation of 70 kD S6 kinase (p70(S6K)) phosphorylates the 40S ribosomal protein S6 that regulates protein synthesis. We examined the role of p70(S6K) in the vascular and myocardial structural changes induced by the chronic inhibition of NO synthesis. The following 5 groups were studied: untreated Wister-Kyoto rats, those treated with an inhibitor of NO synthase, N(ω)-nitro-L-arginine methyl ester (L-NAME), those treated with L-NAME and an angiotensin I converting enzyme inhibitor (imidapril), those treated with L-NAME and hydralazine, and those treated with L-NAME and an inhibitor of p70(S6K) (rapamycin). After 8 weeks, wall-to-lumen ratio in myocardium and cardiomyocyte cross-sectional areas were quantified. L-NAME increased systolic blood pressure, wall-to-lumen ratio, and cardiomyocyte cross-sectional area compared with control animals. Imidapril or rapamycin, but not hydralazine, markedly reduced these structural changes. L-NAME increased p70(S6K) activity in myocardium compared with control rats. Imidapril or rapamycin prevented the activation of p70(S6K) activity in myocardium induced by L-NAME. These results suggest that activation of p70(S6K) plays an important role in coronary vascular remodeling and cardiac hypertrophy induced by the chronic inhibition of nitric oxide synthesis in vivo.

Original languageEnglish
Pages (from-to)533-542
Number of pages10
JournalCardiovascular Drugs and Therapy
Volume14
Issue number5
DOIs
Publication statusPublished - 2000 Nov 9
Externally publishedYes

Keywords

  • ACE inhibitor
  • Hydralazine
  • L-NAME
  • Protein synthesis
  • Rapamycin

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine
  • Pharmacology (medical)

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