Acute vasodilator effects of HMG-CoA reductase inhibitors: Involvement of PI3-kinase/Akt pathway and Kv channels

Yasushi Mukai, Hiroaki Shimokawa, Tetsuya Matoba, Junko Hiroki, Ikuko Kunihiro, Takako Fujiki, Akira Takeshita

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) have several non-lipid-lowering actions; however, characteristics of their acute vasodilator effects remain to be elucidated. In this study, acute vasodilator effects of statins were examined in isolated rat blood vessels. After incubation with cerivastatin (1 μM) for 2 hours, acetylcholine-induced endothelium-dependent relaxations were enhanced in the rat aorta. This effect was abolished by a nitric oxide synthase (NOS) inhibitor, L-NNA, and by a PI3 kinase inhibitor, LY294002. Western blot analysis showed that the extent of phosphorylation of Akt, an active form of Akt, was increased by cerivastatin while it was reduced by LY294002, suggesting an involvement of PI3 kinase/Akt-dependent activation of endothelial NOS. At higher concentrations (1-300 μM), both cerivastatin and fluvastatin, but not pravastatin, directly relaxed the blood vessels, regardless of the presence or absence of the endothelium. These relaxations were abolished by KCI and were significantly inhibited by an inhibitor of Kv channel, 4-aminopyridine. These results indicate that multiple mechanisms are involved in the acute vasodilator effects of statins, including augmentation of nitric oxide-mediated endothelium-dependent relaxations through the PI3 kinase/Akt pathway and endothelium-independent relaxations via Kv channel-mediated smooth muscle hyperpolarizations. These acute vasodilator effects of statins may account, at least in part, for their beneficial effects on cardiovascular diseases associated with impaired organ blood flow.

Original languageEnglish
Pages (from-to)118-124
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume42
Issue number1
DOIs
Publication statusPublished - Jul 1 2003

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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