Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation.
A role for nitric oxide (NO) produced during the reduction of nitrite by deoxygenated red blood cells (RBCs) in regulating vascular dilation has been proposed. It has not, however, been satisfactorily explained how this NO is released from the RBC without first reacting with the large pools of oxyhemoglobin and deoxyhemoglobin in the cell. In this study, we have delineated a mechanism for nitrite-induced RBC vasodilation that does not require that NO be released from the cell. Instead, we show that nitrite enhances the ATP release from RBCs, which is known to produce vasodilation by several different methods including the interaction with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This mechanism was established in vivo by measuring the decrease in blood pressure when injecting nitrite-reacted RBCs into rats. The observed decrease in blood pressure was not observed if endothelial NO synthase was inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME) or when any released ATP was degraded by apyrase. The nitrite-enhanced ATP release was shown to involve an increased binding of nitrite-modified hemoglobin to the RBC membrane that displaces glycolytic enzymes from the membrane, resulting in the formation of a pool of ATP that is released from the RBC. These results thus provide a new mechanism to explain nitrite-induced vasodilation.
Cao
Zeling
Z
Molecular Dynamics Section, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Bell
Jeffrey B
JB
Mohanty
Joy G
JG
Nagababu
Enika
E
Rifkind
Joseph M
JM
D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000097:blood*; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D001794:Blood Pressure; D015687:Cell Hypoxia; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006868:Hydrolysis; D007275:Injections, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000097:blood; D009573:Nitrites / Q000008:administration & dosage / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D006454:Hemoglobins; D009573:Nitrites; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D001081:Apyrase; D019331:NG-Nitroarginine Methyl Ester
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