Exogenous NO suppresses flow-induced endothelium-derived NO production because of depletion of tetrahydrobiopterin.
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 microM S-nitroso-N-acetylpenicillamine (SNAP; an NO donor) and/or 64 microM 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.
Mochizuki
Seiichi
S
Department of Medical Engineering, Kawasaki Medical School, Kurashiki, Okayama, Japan. mochi@me.kawasaki-m.ac.jp
Sipkema
Pieter
P
Goto
Masami
M
Hiramatsu
Osamu
O
Nakamoto
Hiroshi
H
Toyota
Eiji
E
Kajita
Tatsuya
T
Shigeto
Fumiyuki
F
Yada
Toyotaka
T
Ogasawara
Yasuo
Y
Kajiya
Fumihiko
F
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012039:Regional Blood Flow; D013314:Stress, Mechanical
D000975:Antioxidants; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D001708:Biopterins; D009569:Nitric Oxide; C003402:sapropterin; D010396:Penicillamine