A number of studies indicate a contribution of red blood cells (RBCs) to nitrite induced vasodilation. These processes are thought to involve nitrite reduction to nitric oxide (NO) by deoxygenated hemoglobin chains. NO generated in the RBC should, however, immediately be scavenged by hemoglobin, apparently negating any possible contribution of this reaction to vasodilation. We have been able to resolve this paradox by showing that nitrite reacted hemoglobin has an unexpectedly high affinity for the red cell membrane. This high affinity contributes to RBC induced vasodilation by two different pathways. (1) The increased membrane binding activates glycolysis and the synthesis of ATP. This newly synthesized ATP is released from the RBC under hypoxic conditions. The released ATP interacts with purinergic receptors on the endothelium that stimulate the synthesis of NO by endothelial NO synthase. This reaction will induce vasodilation without requiring that NO be released from the RBC. (2) The interaction with the membrane, of intermediates formed during the reaction of nitrite with deoxygenated hemoglobin, stimulates the release of NO from these intermediates. NO released on the membrane can escape the large pool of intracellular hemoglobin and be released into the vasculature resulting in vasodilation. Both of these processes linked to membrane associated nitrite reacted hemoglobin explain a role for RBCs in nitrite induced vasodilation.
Argon Nitrite Palladium Ghost NaH2PO4
This is a preview of subscription content, log in to check access
This research was supported by the Intramural Research Program of the NIH, National Institute on Aging.
Ignore LJ, Cirino G, Casini A et al (1999) Nitric oxide as a signaling molecule in the vascular system: an overview. J Cardiovasc Pharmacol 34:879–886CrossRefGoogle Scholar
Gautier C, Van FE, Mikula I et al (2006) Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia. Biochem Biophys Res Commun 341:816–821PubMedCrossRefGoogle Scholar
Liu X, Miller MJ, Joshi MS et al (1998) Diffusion-limited reaction of free nitric oxide with erythrocytes. J Biol Chem 273:18709–18713PubMedCrossRefGoogle Scholar
Nagababu E, Ramasamy S, Abernethy DR et al (2003) Active nitric oxide produced in the red cell under hypoxic conditions by deoxyhemoglobin-mediated nitrite reduction. J Biol Chem 278:46349–46356PubMedCrossRefGoogle Scholar
Cosby K, Partovi KS, Crawford JH et al (2003) Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation. Nat Med 9:1498–1505PubMedCrossRefGoogle Scholar
Cao Z, Bell JB, Mohanty JG et al (2009) Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation. Am J Physiol Heart Circ Physiol 297:H1494–H1503PubMedCrossRefGoogle Scholar
Demehin AA, Abugo OO, Jayakumar R et al (2002) Binding of hemoglobin to red cell membranes with eosin-5-maleimide-labeled band 3: analysis of centrifugation and fluorescence data. Biochemistry 41:8630–8637PubMedCrossRefGoogle Scholar
Tsai IH, Murthy SN, Steck TL (1982) Effect of red cell membrane binding on the catalytic activity of glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem 257:1438–1442PubMedGoogle Scholar
Salgado MT, Nagababu E, Rifkind JM (2009) Quantification of intermediates formed during the reduction of nitrite by deoxyhemoglobin. J Biol Chem 284:12710–12718PubMedCrossRefGoogle Scholar
Jagger JE, Bateman RM, Ellsworth ML et al (2001) Role of erythrocyte in regulating local O2 delivery mediated by hemoglobin oxygenation. Am J Physiol Heart Circ Physiol 280:H2833–H2839PubMedGoogle Scholar
Boland B, Himpens B, Vincent MF et al (1992) ATP activates P2x-contracting and P2y-relaxing purinoceptors in the smooth muscle of mouse vas deferens. Br J Pharmacol 107:1152–1158PubMedCrossRefGoogle Scholar
Wolf CB (2007) Normal cardiac output, oxygen delivery and oxygen extraction. Adv Exp Med Biol 599:169–182CrossRefGoogle Scholar