SummaryNitric oxide(NO) is asignaling molecule of major importance modulating not onlyt he functiono ft he vascular wall but also that of blood cells,such as platelets and leukocytes.Thesynthesis of NO in thecirculationhas been attributed mainlytothe vascular endothelium.Red blood cells (RBC)h aveb een demonstrated to carry anon-functional NOS and -due to their huge haemoglobincontent-havebeen assumedtometabolizelarge quantities of NO.Morerecently, however, RBChavebeen ident-
KeywordsRed blood cells,nitric oxide, cell function ifiedtoreversiblybind,transport,and releaseNOwithin the cardiovascular system.We provideevidence that RBCfromhumans expressa na ctivea nd functional endothelialt ype NOS. RBC NOS activitymay regulate deformabilityofRBC,and inhibitsactivation of platelets.This reviewa ims to discuss thep otential role of RBCNOS in the circulationand newconcepts of NO research in the microcirculation.
Role of nitric oxide(NO)inmacro-and microcirculationEndothelium-derivedNOisone of the most potent endogenous vasodilators (1)and has beenviewedboth as an autocrine (2) and aparacrine effector molecule(3). It plays an important role in the localcontrol of vascularhomeostasis by regulating vesseltone and by inhibiting smooth muscle cellproliferation, blood cell adhesion, and lipidperoxidation (1). NO bindstothe heme moiety in guanylyl cyclaseand activatesthe enzyme to producecGMP whichcauses the muscle to relax by decreasing intracellular concentration of free Ca 2+ .I nt he endothelium NO is synthesized from the amino acidL-arginine by the constitutive,Ca 2+ /calmodulin-dependent endothelial NO synthase (eNOS) (4).The biological function of NO is widelyassessedbythe endothelium-dependent dilation of conduit or coronarya rteries. Most convenient is the non-invasive measurement of flow-mediated dilation of the brachial artery (5) whichi sm ainlym ediated by shear stress induced releaseo fe ndothelium-derived NO (6). Pronounced differences in vesselwallstructureare observed between micro-and macrovasculature sinces mooth muscle cells are diminished with decreasing arteriolar diameter, whereas capillaries are only composedofone singleendothelial cell layerapposed onto the capillarybasement membrane (7,8). This is accompaniedbyadaptive changes in biochemical mechanisms. As an examplei th as been suggested thatv asodilation becomes less dependent on NO butm ore on endothelium-derivedhyperpolarizing factor with decreasing arteriolar diameter (9). On the otherhand,physiological permeability is strictlylimitedtothe venular end of capillaries. Furthermore,the impact of the compartment "blood"i nt he microcirculation on blood flowand cell-cell interactions is considerablymore relevant than within the macrocirculation.
The circulating NO poolEndothelial dysfunction as aprecursor of atherosclerosisismediated by alack of bioactiveNO. The NO metabolismmay act as common denominator fort he variousv ascular risk factorso f atherosclerosis. Several biochemical reaction of NO in blood include oxidation to nitrite and further to n...