Cross-talk Between Nitrate-Nitrite-NO and NO Synthase Pathways in Control of Vascular NO Homeostasis.
OBJECTIVE
Inorganic nitrate and nitrite from endogenous and dietary sources have emerged as alternative substrates for nitric oxide (NO) formation in addition to the classic L-arginine NO synthase (NOS)-dependent pathway. Here, we investigated a potential cross-talk between these two pathways in the regulation of vascular function.


RESULTS
Long-term dietary supplementation with sodium nitrate (0.1 and 1 mmol kg(-1) day(-1)) in rats caused a reversible dose-dependent reduction in phosphorylated endothelial NOS (eNOS) (Ser1177) in aorta and a concomitant increase in phosphorylation at Thr495. Moreover, eNOS-dependent vascular responses were attenuated in vessels harvested from nitrate-treated mice or when nitrite was acutely added to control vessels. The citrulline-to-arginine ratio in plasma, as a measure of eNOS activity, was reduced in nitrate-treated rodents. Telemetry measurements revealed that a low dietary nitrate dose reduced blood pressure, whereas a higher dose was associated with a paradoxical elevation. Finally, plasma cyclic guanosine monophosphate increased in mice that were treated with a low dietary nitrate dose and decreased with a higher dose.


CONCLUSIONS
These results demonstrate the existence of a cross-talk between the nitrate-nitrite-NO pathway and the NOS-dependent pathway in control of vascular NO homeostasis.
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .|2 Department of Medical Cell Biology, Uppsala University , Uppsala, Sweden .
Mattias
M
Carlström
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Ming
M
Liu
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Ting
T
Yang
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Christa
C
Zollbrecht
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .|2 Department of Medical Cell Biology, Uppsala University , Uppsala, Sweden .
Liyue
L
Huang
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Maria
M
Peleli
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Sara
S
Borniquel
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Hiroaki
H
Kishikawa
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Michael
M
Hezel
2 Department of Medical Cell Biology, Uppsala University , Uppsala, Sweden .
A Erik G
AE
Persson
3 Division of Anesthesiology and Intensive Care, Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Eddie
E
Weitzberg
1 Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden .
Jon O
JO
Lundberg
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001120:Arginine / Q000097:blood; D001794:Blood Pressure; D002319:Cardiovascular System / Q000378:metabolism*; D002956:Citrulline / Q000097:blood; D019587:Dietary Supplements; D006706:Homeostasis; D008297:Male; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009566:Nitrates / Q000737:chemistry / Q000378:metabolism*; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009573:Nitrites / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley
D009566:Nitrates; D009573:Nitrites; D002956:Citrulline; D009569:Nitric Oxide; C031618:sodium nitrate; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse