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Different Influences of Extracellular and Intracellular Superoxide on Relaxation Through the NO/sGC/cGMP Pathway in Isolated Rat Iliac Arteries

Tawa, Masashi MS; Shimosato, Takashi BS; Iwasaki, Hirotaka MD; Imamura, Takeshi MD, PhD; Okamura, Tomio MD, PhD

Journal of Cardiovascular Pharmacology: February 2015 - Volume 65 - Issue 2 - p 160–167
doi: 10.1097/FJC.0000000000000173
Original Article

Abstract: Superoxide production is increased in diseased blood vessels, which is considered to lead to impairment of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cGMP pathway. To investigate the respective influence of extracellular and intracellular superoxide on vascular function through the NO/sGC/cGMP pathway, mechanical responses of rat external iliac arteries without endothelium were studied under exposure to a superoxide-generating agent, pyrogallol, or menadione. Exposure to pyrogallol impaired the relaxation induced by acidified NaNO2 (exogenous NO) but not that by nitroglycerin (organic nitrate), BAY 41-2272 (sGC stimulator), BAY 60-2770 (sGC activator), or 8-Br-cGMP (cGMP analog). Superoxide dismutase (SOD) and tempol restored the impaired relaxation by acidified NaNO2. Superoxide production in the bathing solution, but not in artery segments, was significantly increased by exposure to pyrogallol, which was abolished in the presence of SOD or tempol. However, exposure to menadione impaired the relaxant response to acidified NaNO2, nitroglycerin, or BAY 41-2272, whereas it augmented that to BAY 60-2770. Also, this exposure had no effect on the 8-Br-cGMP-induced vasorelxation. Superoxide production in artery segments was dramatically enhanced by exposure to menadione, whereas that in the bathing solution was not affected. This increase in vascular superoxide production was normalized by tempol but not by SOD. These findings suggest that extracellular superoxide reacts with NO only outside the cell, whereas intracellular superoxide not only scavenges NO inside the cell but also shifts the sGC redox equilibrium.

Department of Pharmacology, Shiga University of Medical Science, Otsu, Japan.

Reprints: Masashi Tawa, MS, Department of Pharmacology, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan (e-mail:

Supported in part by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant number 23390055).

The authors report no conflicts of interest.

Received February 24, 2014

Accepted September 22, 2014

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