AJP - Heart Calcium Transients and Cell-Sarcomere
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Am J Physiol Heart Circ Physiol 288: H553-H558, 2005. First published October 7, 2004; doi:10.1152/ajpheart.00408.2004
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Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin

Seiichi Mochizuki,1 Pieter Sipkema,2 Masami Goto,1 Osamu Hiramatsu,1 Hiroshi Nakamoto,1 Eiji Toyota,1 Tatsuya Kajita,1 Fumiyuki Shigeto,1 Toyotaka Yada,1 Yasuo Ogasawara,1 and Fumihiko Kajiya3

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


Address for reprint requests and other correspondence: S. Mochizuki, Dept. of Medical Engineering, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan (E-mail: mochi{at}me.kawasaki-m.ac.jp)






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