Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice

Tetsuya Matoba, H. Shimokawa, M. Nakashima, Y. Hirakawa, Yasushi Mukai, K. Hirano, H. Kanaide, A. Takeshita

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Abstract

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several endothelium-derived relaxing factors, such as prostacyclin, nitric oxide (NO), and the previously unidentified endothelium-derived hyperpolarizing factor (EDHF). In this study, we examined our hypothesis that hydrogen peroxide (H2O2) derived from endothelial NO synthase (eNOS) is an EDHF. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine (ACh) were markedly attenuated in small mesenteric arteries from eNOS knockout (eNOS-KO) mice. In the eNOS-KO mice, vasodilating and hyperpolarizing responses of vascular smooth muscle per se were fairly well preserved, as was the increase in intracellular calcium in endothelial cells in response to ACh. Antihypertensive treatment with hydralazine failed to improve the EDHF-mediated relaxation. Catalase, which dismutates H2O2 to form water and oxygen, inhibited EDHF-mediated relaxation and hyperpolarization, but it did not affect endothelium-independent relaxation following treatment with the K+ channel opener levcromakalim. Exogenous H2O2 elicited similar relaxation and hyperpolarization in endothelium-stripped arteries. Finally, laser confocal microscopic examination with peroxide-sensitive fluorescence dye demonstrated that the endothelium produced H2O2 upon stimulation by ACh and that the H2O2 production was markedly reduced in eNOS-KO mice. These results indicate that H2O2 is an EDHF in mouse small mesenteric arteries and that eNOS is a major source of the reactive oxygen species.

Original languageEnglish
Pages (from-to)1521-1530
Number of pages10
JournalJournal of Clinical Investigation
Volume106
Issue number12
DOIs
Publication statusPublished - Jan 1 2000

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Hydrogen Peroxide
Endothelium
Nitric Oxide Synthase
Acetylcholine
Mesenteric Arteries
Cromakalim
Endothelium-Dependent Relaxing Factors
Hydralazine
Nitric Oxide Synthase Type III
Peroxides
Epoprostenol
Vascular Smooth Muscle
Knockout Mice
Catalase
Antihypertensive Agents
Blood Vessels
Reactive Oxygen Species
Nitric Oxide
Lasers
Homeostasis

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Matoba, T., Shimokawa, H., Nakashima, M., Hirakawa, Y., Mukai, Y., Hirano, K., ... Takeshita, A. (2000). Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. Journal of Clinical Investigation, 106(12), 1521-1530. https://doi.org/10.1172/JCI10506

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. / Matoba, Tetsuya; Shimokawa, H.; Nakashima, M.; Hirakawa, Y.; Mukai, Yasushi; Hirano, K.; Kanaide, H.; Takeshita, A.

In: Journal of Clinical Investigation, Vol. 106, No. 12, 01.01.2000, p. 1521-1530.

Research output: Contribution to journalArticle

Matoba, T, Shimokawa, H, Nakashima, M, Hirakawa, Y, Mukai, Y, Hirano, K, Kanaide, H & Takeshita, A 2000, 'Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice', Journal of Clinical Investigation, vol. 106, no. 12, pp. 1521-1530. https://doi.org/10.1172/JCI10506
Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K et al. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. Journal of Clinical Investigation. 2000 Jan 1;106(12):1521-1530. https://doi.org/10.1172/JCI10506
Matoba, Tetsuya ; Shimokawa, H. ; Nakashima, M. ; Hirakawa, Y. ; Mukai, Yasushi ; Hirano, K. ; Kanaide, H. ; Takeshita, A. / Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. In: Journal of Clinical Investigation. 2000 ; Vol. 106, No. 12. pp. 1521-1530.
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