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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/H553    most recent 00408.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Mochizuki, S. Articles by Kajiya, F. Search for Related Content PubMed PubMed Citation Articles by Mochizuki, S. Articles by Kajiya, F.

Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin

¹Department of Medical Engineering, Kawasaki Medical School, Kurashiki, Japan; ²Laboratory for Physiology, Vrije Universiteit Medical Center, Institute for Cardiovascular Research, Vrije Universiteit, Amsterdam, The Netherlands; and ³Department of Cardiovascular Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Submitted 3 May 2004 ; accepted in final form 5 October 2004

Exogenous nitric oxide (NO) suppresses endothelium-derived NO production. We were interested in determining whether this is also the case in flow-induced endothelium-derived NO production. If so, then is the mechanism because of intracellular depletion of tetrahydrobiopterin [BH₄; a cofactor of NO synthase (NOS)], which results in superoxide production by uncoupled NOS? Isolated canine femoral arteries were perfused with 100 µM S-nitroso-N-acetylpenicillamine (SNAP; an NO donor) and/or 64 µM BH₄. Perfusion of SNAP suppressed flow-induced NO production, which was evaluated as a change in the slope of the linear relationship between perfusion rate and NO production rate (P < 0.02 vs. control; n = 7). Subsequent BH₄ perfusion returned the slope to the control level. Concomitant perfusion of SNAP and BH₄ retained the control-level NO production (n = 7). Concomitant perfusion of SNAP and 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron; 1 mM; a membrane-permeable superoxide scavenger) also retained the control-level NO production (n = 7), whereas perfusion of Tiron after SNAP could not return the NO production to the control level (P < 0.02 vs. control; n = 7). We also found a significant decrease in BH₄ concentration in the endothelial cells after SNAP perfusion. In conclusion, these results indicate that exogenous NO suppresses the flow-induced, endothelium-derived NO production by superoxide released from uncoupled NOS because of intracellular BH₄ depletion.

nitric oxide synthase; shear stress; superoxide; pterin; uncoupling

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